ONC12 • Oncology Special Offer

Table of Contents

ONC12 • Oncology Special Offer

How to Receive Credit

NetCE 15 Hour Course #92342 • Childhood Leukemias and Lymphomas

92342 • Childhood Leukemias and Lymphomas

1. INTRODUCTION

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

3. TYPES OF LEUKEMIA

4. TYPES OF LYMPHOMA

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

6. DIAGNOSIS OF LEUKEMIAS

7. DIAGNOSIS OF LYMPHOMA

8. COMMUNICATION WITH THE PATIENT AND FAMILY

9. TREATMENT APPROACHES

10. SUPPORTIVE CARE

11. PALLIATIVE AND END-OF-LIFE CARE

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

14. CASE STUDIES

15. CONCLUSION

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #30722 • Lung Cancer: Diagnosis and Management

30722 • Lung Cancer: Diagnosis and Management

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PREVENTION AND SCREENING

4. PATHOPHYSIOLOGY OF LUNG CANCER

5. SIGNS AND SYMPTOMS

6. DIAGNOSIS

7. CLASSIFICATION AND STAGING

8. TREATMENT

9. THE CLINICAL COURSE OF LUNG CANCER

10. CONDITIONS CAUSED BY ADVANCED LUNG CANCER AND CANCER TREATMENTS

11. VASCULAR ACCESS DEVICES

12. THE TERMINAL PATIENT

13. CASE MANAGEMENT OF THE PATIENT WITH LUNG CANCER

14. PATIENT TEACHING GOALS

15. CASE STUDY

16. CONCLUSION

17. RESOURCES

18. APPENDIX 1: SAMPLE CASE MANAGEMENT CARE PLANS

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #90772 • Skin Cancers

90772 • Skin Cancers

1. INTRODUCTION

2. OVERVIEW OF SKIN CANCERS

3. NONMELANOMAS

4. MELANOMA

5. SKIN CANCER SCREENING

6. PREVENTION

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

ONC12 • Oncology Special Offer

Lori L. Alexander, MTPW, ELS, MWC

Marilyn Fuller Delong, MA, BSN, RN

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

ONC12 • Oncology Special Offer

Expiration Date: 08/31/2021

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

92342 • Childhood Leukemias and Lymphomas

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Cancer is the leading cause of death among children 14 years of age and younger and leukemia and lymphoma are among the most prevalent cancers in children. Leukemia and lymphoma may have a genetic basis, and primary care practitioners should know which patients may be at risk for the development of one of these diseases. Also essential is an understanding of appropriate diagnostic testing, as well as the cellular classification, staging, and prognostic variables associated with the disease. A diagnosis of cancer in a child creates devastating effects on the child and his or her family. Because of the key relationship between a pediatrician, family medicine physician, nurses, and a child and his or her family, these practitioners are often an important resource for emotional support, guidance, and referrals. Interventions can also help children with cancer through problems with social interactions and school-related issues. Primary pediatric care must continue during treatment for cancer, and primary care practitioners should understand how leukemia and lymphoma and their treatment affect growth and development and routine preventive measures, such as immunizations. The child's primary care practitioner should also be responsible for maintaining documentation of the child's treatment and providing follow-up care. Over the past several years, research has documented the long-term effects of childhood cancer and its treatment. Studies have shown that more than two-thirds of childhood cancer survivors have serious health conditions, and many have more than one health condition. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans.

Table of Contents

92342 • Childhood Leukemias and Lymphomas

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

RISK FACTORS

3. TYPES OF LEUKEMIA

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

ACUTE MYELOID LEUKEMIA (AML)

4. TYPES OF LYMPHOMA

HODGKIN LYMPHOMA

NON-HODGKIN LYMPHOMA

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

6. DIAGNOSIS OF LEUKEMIAS

CLINICAL SIGNS AND SYMPTOMS

DIAGNOSTIC TESTING

CLASSIFICATION

PROGNOSTIC VARIABLES

7. DIAGNOSIS OF LYMPHOMA

HODGKIN LYMPHOMA

NON-HODGKIN LYMPHOMA

8. COMMUNICATION WITH THE PATIENT AND FAMILY

COMMUNICATING EFFECTIVELY

9. TREATMENT APPROACHES

IMPORTANCE OF CLINICAL TRIALS

DISEASE-DIRECTED TREATMENT

TREATMENT OF LEUKEMIAS

TREATMENT OF LYMPHOMA

10. SUPPORTIVE CARE

INFECTION

NEUTROPENIA

ANEMIA OR THROMBOCYTOPENIA

METABOLIC DISTURBANCES

DEEP VEIN THROMBOSIS

11. PALLIATIVE AND END-OF-LIFE CARE

ASSESSING AND MANAGING SYMPTOMS

PSYCHOSOCIAL AND SPIRITUAL ISSUES

PROVIDING END-OF-LIFE CARE

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

PSYCHOSOCIAL ISSUES FOR THE PATIENT

PSYCHOSOCIAL ISSUES FOR THE FAMILY AND FAMILY DYNAMICS

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

LATE EFFECTS AMONG CHILDHOOD CANCER SURVIVORS

HEALTH PROMOTION AND EDUCATION

CHALLENGES IN PROVIDING HEALTH CARE

14. CASE STUDIES

CASE STUDY 1

CASE STUDY 2

15. CONCLUSION

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

GENERAL EDUCATION AND ADVOCACY

SURVIVORSHIP

INSURANCE, LEGAL, AND EDUCATIONAL ISSUES

FREE WEEKLONG AND WEEKEND CAMPS

Works Cited

Evidence-Based Practice Recommendations Citations

92342 • Childhood Leukemias and Lymphomas

Education Category. Pediatrics

Release Date. 09/01/2018

Expiration Date. 08/31/2021

Course Overview

Cancer is the leading cause of death among children 14 years of age and younger and leukemia and lymphoma are among the most prevalent cancers in children. Leukemia and lymphoma may have a genetic basis, and primary care practitioners should know which patients may be at risk for the development of one of these diseases. Also essential is an understanding of appropriate diagnostic testing, as well as the cellular classification, staging, and prognostic variables associated with the disease. A diagnosis of cancer in a child creates devastating effects on the child and his or her family. Because of the key relationship between a pediatrician, family medicine physician, nurses, and a child and his or her family, these practitioners are often an important resource for emotional support, guidance, and referrals. Interventions can also help children with cancer through problems with social interactions and school-related issues. Primary pediatric care must continue during treatment for cancer, and primary care practitioners should understand how leukemia and lymphoma and their treatment affect growth and development and routine preventive measures, such as immunizations. The child's primary care practitioner should also be responsible for maintaining documentation of the child's treatment and providing follow-up care. Over the past several years, research has documented the long-term effects of childhood cancer and its treatment. Studies have shown that more than two-thirds of childhood cancer survivors have serious health conditions, and many have more than one health condition. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans.

Audience

This course is designed primarily for pediatricians, family medicine physicians, nurses, and other healthcare practitioners in the pediatric or family medicine setting. Primary care physicians, other practitioners in primary care, social workers, and marriage and family therapists will also benefit from this course.

Course Objective

All healthcare professionals should understand how pediatric leukemia and lymphoma and their treatment affect growth and development and routine preventive measures and be skilled in discussing emotional well-being and psychosocial issues and in recommending psychosocial interventions. The purpose of this course is to enhance healthcare professionals' understanding of treatment options for childhood leukemias and lymphomas, the effects of treatment on normal growth and development, and the psychosocial effect of cancer on a child and his or her family.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the prevalence and types of childhood leukemia and lymphoma.

2. Identify the clinical signs and symptoms associated with childhood leukemia.

3. Describe the diagnostic testing for and classification of childhood leukemias.

4. Discuss the prognostic variables for childhood leukemias.

5. Describe the clinical presentation, diagnosis, and prognostic variables of Hodgkin lymphoma.

6. Discuss the signs and symptoms, diagnosis, and prognostic variables associated with non-Hodgkin lymphomas.

7. Explain the principles of communicating a diagnosis of childhood cancer.

8. Discuss the importance of clinical trials and the issues unique to trials involving children.

9. Outline the treatment approaches for childhood leukemia and lymphoma.

10. Discuss the various means of supportive care needed for children/adolescents with leukemia or lymphoma.

11. Describe the elements of effective palliation of symptoms in the end of life for children/adolescents with cancer.

12. Recognize the psychosocial and spiritual needs of children/adolescents with cancer and their families.

13. Discuss coping mechanisms of children/adolescents with cancer and their effect on psychosocial adjustment.

14. Explain the psychosocial effect of childhood cancer on family dynamics.

15. Define the most common long-term effects of childhood leukemias and lymphomas and their treatment.

16. Outline recommendations for necessary surveillance and long-term monitoring specific for a child's or adolescent's cancer and treatment.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Alice Yick Flanagan, PhD, MSW

James Trent, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Cancer is the leading cause of death among children 14 years of age and younger, and leukemia and lymphoma are among the most prevalent cancers in children/adolescents [1,2]. Two types of leukemia—acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)—and two types of lymphoma—Hodgkin and non-Hodgkin—occur in this population. Each of these diseases is distinct, with variations in etiology, patient characteristics, signs and symptoms, treatment approaches, and outcomes. Primary care practitioners should be able to identify the clinical signs and symptoms that may be indicative of these diseases and have knowledge of diagnostic testing, staging, and prognostic variables. A discussion of all of these aspects is included here, as well as a broad overview of treatment options.

A diagnosis of cancer in a child/adolescent creates devastating effects on him or her, as well as the family. As a result of the key relationship between primary care practitioners and children/adolescents and their families, these clinicians are often an important resource for emotional support, guidance, and referrals. Clinicians should be skilled in discussing emotional well-being and psychosocial issues and in recommending psychosocial interventions to help the patient and family develop coping mechanisms and deal with the disruption to normal family dynamics. Interventions can also help children/adolescents with cancer through problems with social interactions and school-related issues.

Primary pediatric care should continue during treatment for cancer, and clinicians in this setting should understand the effects of leukemia and lymphoma and their treatments on the child's/adolescent's growth and development and on routine preventive measures. In addition, studies have shown higher rates of morbidity and mortality among childhood cancer survivors compared with healthy siblings and the overall (age-matched) population [3,4,5,6,7]. The specific findings of these studies point to the need for heightened awareness of the health risks for survivors and the value of creating survivorship care plans. A discussion of late effects of childhood cancer and its treatment, the maintenance of health documentation, and appropriate follow-up care offers information to help clinicians provide optimal primary care to their patients with childhood leukemia or lymphoma.

2. OVERVIEW OF CHILDHOOD LEUKEMIAS AND LYMPHOMAS

The term "childhood cancer" is used to describe cancers that affect individuals from birth to 19 years of age. Although this age range is wide, cancers that occur throughout these ages have many similarities; however, the physical and psychosocial needs of infants differ greatly from those of young children as well as those of adolescents (defined as 15 to 19 years of age). The incidence of childhood leukemias and lymphoma vary among age groups, as do outcomes. Treatment varies as well, and some adolescents are treated in pediatric clinical practice, while others are treated in adult practices; this difference makes it difficult to evaluate the efficacy of certain treatment protocols and also creates challenges in improving survival rates [8]. In addition, issues related to dependency, access to care, treatment compliance, and decision making differ between children and adolescents with cancer [8,9]. In sum, adolescents represent a distinct population of individuals with cancer, and their unique needs have been recognized, as evidenced by several recent articles and, especially, the 2011 launch of the peer-reviewed journal The Journal of Adolescent and Young Adult Oncology[10].

In 2017, cancer was diagnosed in an estimated 15,270 children/adolescents 1 to 19 years of age and was the cause of 1,790 deaths [2]. Among children 1 to 9 years of age in the United States, cancer is the second leading cause of death (behind unintentional injuries), and it is the fourth leading cause for older children, representing approximately 5.7% of all deaths among individuals 10 to 24 years of age [11]. Hematologic cancers are among the most common childhood cancers in children 1 to 14 years of age; lymphomas are the most common types of cancer diagnosed in adolescents 15 to 19 years of age [2]. Hematologic cancers are classified as leukemia when they involve primarily blood and bone marrow and as lymphoma when they arise from lymph nodes or other organs. Over the years, several systems have been developed to classify hematologic cancers. The uniform standard now used is the World Health Organization (WHO)/Revised European-American Lymphoma (REAL) system [12]. This system differentiates hematologic cancers into four broad categories: myeloid, lymphoid, mast cell, and histiocytic neoplasms. Specific disease entities are further defined within these categories on the basis of morphologic, immunophenotypic, genetic, biologic, and clinical criteria. The hematologic cancers occurring in childhood are predominantly lymphoid or myeloid.

Lymphoid and myeloid leukemias are further classified as acute or chronic, depending on the maturity of the cells affected and the pace of disease progression; acute leukemia affects immature cells (lymphoblasts) and progresses rapidly, whereas chronic leukemia affects mature cells and progresses more slowly. According to the International Classification of Childhood Cancer (ICCC), leukemia is categorized according to five diagnostic groups. Two of these groups—lymphoid leukemia and acute myeloid leukemia—account for approximately 95% of all leukemias [1].

Acute leukemia is the leading type of childhood cancer and is far more prevalent among children 14 years of age and younger, with 4,339 cases (33% of all cancers in this age group) in 2015, compared with 963 (14% of all cancers) in adolescents [1]. Lymphoid leukemia is more common in both children and adolescents, with acute lymphocytic leukemia (ALL) accounting for 25% of leukemias in children and 8% of leukemias in adolescents, compared with acute myeloid leukemia (AML), which accounts for 8% of leukemias in children and 18% in adolescents [1]. Chronic lymphocytic leukemia and chronic myeloid leukemia occur primarily in individuals who are at least 50 years of age and are rare in children/adolescents [13]. Because of the rarity of the chronic forms of leukemia in children, the focus in this course is on ALL and AML.

According to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, 2,417 children and adolescents were diagnosed with lymphoma between 2011 and 2015, occurring more often among adolescents (1,260) than among children (1,157) [1]. Hodgkin lymphoma is the most prevalent cancer among adolescents, representing approximately 18% of all childhood cancers in this age group; non-Hodgkin lymphoma accounts for 5% [1]. Among children 14 years of age and younger, non-Hodgkin lymphoma is the more prevalent lymphoma, accounting for 6% of cancers, with Hodgkin lymphoma representing less than 3% [1].

The incidence of pediatric ALL and AML increased significantly between 1975 and 2015. The incidence of non-Hodgkin lymphoma increased slightly, while the incidence of Hodgkin lymphoma has decreased [1]. Mortality associated with pediatric leukemia and lymphoma has also decreased, with the greatest decreases in ALL and AML [1].

RISK FACTORS

Unlike other types of cancers in adults, childhood leukemia and lymphoma are not associated with lifestyle risk factors, but the etiology is unclear. The only clear risk factor for childhood hematologic cancer is an inherited genetic syndrome, especially Down syndrome, which is associated with a 10-fold to 20-fold increased risk of leukemia [14,15,16,17]. Increased risk is associated with several other genetic syndromes as well (Table 1) [15,16,17].

Table 1: GENETIC SYNDROMES ASSOCIATED WITH PEDIATRIC LEUKEMIA AND LYMPHOMA

Genetic Syndrome

Type of Pediatric Leukemia or Lymphoma

Inherited Syndromes

Ataxia-telangiectasia

ALL, AML

Bloom syndrome

ALL, AML

Diamond-Blackfan anemia

AML

Down syndrome

ALL, AML

Familial monosomy 7

AML

Fanconi anemia

AML

Klinefelter syndrome

ALL

Kostmann syndrome (severe congenital neutropenia)

AML

Langerhans cell histiocytosis

ALL

Neurofibromatosis type 1

ALL, AML

Severe combined immunodeficiency syndrome

NHL

Shwachman syndrome

ALL, AML

Acquired Syndromes

Acquired monosomy 7

AML

Amegakaryocytic thrombocytopenia

AML

Human immunodeficiency virus (HIV) infection

NHL

Immunocompromise (drug-related)

NHL

Paroxysmal nocturnal hemoglobinuria

AML

ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia; NHL = non-Hodgkin lymphoma.

Source: [15,16,17]

Many factors have been investigated for their role in the development of childhood leukemia and lymphoma, including infection and environmental factors. The combination of genetic susceptibility and an abnormal response to infection is thought to be one cause of leukemia in children 2 to 5 years of age [18,19,20]. In addition, infection with the Epstein-Barr virus (EBV) in the presence of an immunodeficiency condition has been linked to an increased risk of Hodgkin lymphoma, and a history of serologically confirmed infectious mononucleosis significantly increases the risk for EBV-positive Hodgkin lymphoma among young adults [21,22,23,24]. A Children's Oncology Group study found that parental history of autoimmunity and parent or sibling with an allergy is associated with increased risk for EBV-positive Hodgkin lymphoma [25]. Infection in early childhood may reduce the risk of Hodgkin lymphoma, as the incidence is lower for children with many siblings or many playmates [26,27]. With regard to non-Hodgkin lymphoma, the prevalence ranges from 1% to 25% among children/adolescents with primary or acquired immunodeficiency disorders, and a Swedish study demonstrated a significant increase in the risk of non-Hodgkin lymphoma in association with infections in infancy [21,28]

Radiation has emerged as a causal factor of hematologic cancers. Exposure to large doses of radiation, as from such catastrophes as atomic bombs or nuclear reactor accidents, has been associated with higher rates of leukemia and a slightly higher risk for non-Hodgkin lymphoma [29]. Low-dose radiation, from x-rays or radiation therapy, has also been found to be associated with a slight increase in risk for leukemia and lymphoma [29]. However, because of the time needed for disease to develop from such exposure, this cause is not as common in children as it is in adults. Prenatal exposure to radiation has been linked to the development of leukemia, but this cause has been rare since the routine use of preventive measures in performing radiographs on women. In one study, researchers evaluated three types of exposure to radiation: parental exposure before conception, intrauterine exposure, and postnatal exposure. None was found to increase leukemogenesis for children with Down syndrome [30].

Maternal exposure to chemicals and carcinogens during pregnancy has also been evaluated as an etiologic factor for hematologic cancer. Gestational exposure to petroleum products has been associated with an increased risk of infant leukemia, particularly AML and leukemia without mixed lineage leukemia gene rearrangements [31]. In the same study, eight other classes of household chemicals were not found to increase the risk of leukemia. One study explored a possible association between residential proximity to oil and gas development and increased risk for ALL [32]. A meta-analysis found that maternal smoking during pregnancy was associated with a modest increase in risk for non-Hodgkin lymphoma [33].

A family history of Hodgkin lymphoma increases the risk of pediatric Hodgkin lymphoma, with a sevenfold increase in risk for children who have a sibling with the disease [34]. The risk of non-Hodgkin lymphoma is not higher for children who are born to parents who are survivors of non-Hodgkin lymphoma, unless the cancer was associated with a congenital disorder [34].

For reasons that are unclear, the risk of non-Hodgkin lymphoma has been higher among children/adolescents in families with higher parental incomes and educational levels and lower in families with large numbers of children [35]. Other demographic variables may also be risk factors, as the prevalence of childhood leukemia and lymphoma varies according to age, sex, and race/ethnicity, as will be discussed.

The risk factors for childhood hematologic cancers continue to be explored, and it currently appears that a complex set of factors is involved in the development of these diseases.

3. TYPES OF LEUKEMIA

Acute leukemia occurs in approximately 5,302 children and adolescents each year, with most cases occurring in children 1 to 4 years of age [1]. The incidence is higher for male than female children/adolescents (51 vs. 44 per million) [1]. Among racial/ethnic populations of children/adolescents, the incidence of leukemia (all types) is highest for the Hispanic population and lowest for the non-Hispanic black population (Table 2) [1].

Table 2: INCIDENCE OF PEDIATRIC LEUKEMIA AND LYMPHOMA ACCORDING TO RACE/ETHNICITY

Cancer Type

Incidence (per 1 million)

Non-Hispanic White

Non-Hispanic Black

Hispanic

Asian/Pacific Islander

Leukemia (all types)

62.9

37.5

78.8

56.8

Acute lymphoblastic leukemia

48.9

25.5

63.7

40.3

Acute myeloid leukemia

7.1

9.8

10.5

12.1

Lymphoma (all types)

35.5

28.6

27.1

26.3

Hodgkin lymphoma

17.5

12.7

12.8

8.7

Non-Hodgkin lymphoma

18.1

15.9

14.4

17.6

Source: [1]

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

ALL represents a heterogeneous group of biologic subtypes of leukemia and is classified into two principal types depending on the lymphocytes from which it develops. Most cases of B-lymphocyte ALL originate in cells early in the development of B cells and are therefore designated as precursor B-cell type [36]. Research has demonstrated that childhood ALL is initiated in utero, with another event required for full malignant transformation [37,38]. DNA injury leads to the uncontrolled development of leukemic lymphoblasts in the marrow, which causes a deficiency of normally functioning blood cells. As a result, anemia, thrombocytopenia, and neutropenia occur.

ALL accounts for 81% of leukemias in children and 48% of leukemias in adolescents [1]. The incidence of ALL varies according to sex, age, and race/ethnicity. ALL is more common among male children/adolescents (30.9 million) than among female children/adolescents (25.2 per million) [1]. ALL typically develops in children between 1 and 9 years old, with a sharp peak in the incidence for children 2 to 4 years old [1]. The incidence of ALL is highest in the white population, followed by the black and Hispanic populations, with the lowest incidence in the American Indian/Alaska Native population [1].

Advances in treatment since the mid-1970s have improved survival rates for ALL [1]. According to SEER data, the five-year relative survival rate for ALL improved from 41% in 1975–1977 to 72% in 2008–2014 (Table 3) [1]. The observed long-term survival for ALL is 85% at 5 years, with an 82% probability of 10-year survival for children/adolescents who have 5-year survival (Table 4) [1].

Table 3: FIVE-YEAR OBSERVED SURVIVAL RATES FOR PEDIATRIC LEUKEMIA AND LYMPHOMA AMONG CHILDREN/ADOLESCENTS (BIRTH TO 19 YEARS OF AGE)

Cancer Type

1975– 1977

2008– 2014

Acute lymphocytic leukemia

41%

72%

Acute myeloid leukemia

6%

28%

Hodgkin lymphoma

72%

88%

Non-Hodgkin lymphoma

47%

74%

Source: [1]

Table 4: LONG-TERM SURVIVAL IN PEDIATRIC LEUKEMIA AND LYMPHOMA

Cancer Type

Survival

5 Years

10 Years

Acute lymphoblastic leukemia

85%

82%

Acute myeloid leukemia

56%

54%

Hodgkin lymphoma

96%

94%

Non-Hodgkin lymphoma

84%

83%

Source: [1]

ACUTE MYELOID LEUKEMIA (AML)

Pediatric myeloid leukemia refers to a spectrum of hematopoietic malignant diseases, but AML accounts for the majority of cases. Although AML is less prevalent than ALL, AML is more lethal, accounting for approximately 30% of childhood leukemia-related deaths [39]. AML involves the malignant transformation of stem cells or progenitor cells in the bone marrow.

As noted, AML accounts for 8% of leukemias in children and 18% of leukemias in adolescents [1]. As with ALL, the incidence of AML varies according to age, but the pattern differs. The incidence of AML is highest for infants and lowest for children 5 to 9 years of age [1]. After 9 years of age, the rate slowly increases throughout adolescence [1]. Unlike ALL, the incidence of AML is similar for male and female children/adolescents (5.0 vs. 4.6 per million, respectively) [1]. As with ALL, the incidence is highest in the Hispanic population, but the range across race/ethnicities is narrow [1].

The five-year survival rate for AML has consistently been the lowest of all childhood cancers. Although the rate remains low, it has increased substantially, from 19% in 1975 to 67% in 2010 [1]. The observed long-term survival is 56% at five years, with a 54% probability of 10-year survival for children/adolescents who have five-year survival [1]. A review of data from two AML studies conducted by the Children's Cancer Group (now part of the Children's Oncology Group [COG]) showed that overall survival was substantially higher for white children/adolescents than for black or Hispanic children/adolescents [40]. Because treatment was given according to established cooperative group treatment protocols, compliance rates, access to therapy, type of supportive care, or leukemia phenotype were not likely to be factors in the differences.

4. TYPES OF LYMPHOMA

Lymphomas arise from lymphoid cells. The distinction between Hodgkin and non-Hodgkin lymphoma is defined by the presence of Reed-Sternberg cells in Hodgkin lymphoma [22]. The two types of lymphoma differ from each other in several ways, including clinical behavior, biology, and histopathologic features.

Hodgkin and non-Hodgkin lymphoma occur in approximately 2,180 children and adolescents, and the incidence increases with age, with significant peaks in adolescence [1]. Hodgkin lymphoma accounts for 33% of lymphomas in children and 67% of lymphomas in adolescents, while non-Hodgkin lymphoma accounts for 70% of lymphomas in children and 30% of lymphomas in adolescents [1]. The disease is more common among male children/adolescents (30 per million) than among female children/adolescents (20 per million) [1]. Among racial/ethnic groups, the incidence of Hodgkin and non-Hodgkin lymphoma is highest for non-Hispanic white children/adolescents and lowest for Hispanic children/adolescents [1].

As with leukemia, advances in treatment options have improved survival for children/adolescents with lymphoma.

HODGKIN LYMPHOMA

Hodgkin lymphoma was first described in 1832 by Thomas Hodgkin as a "peculiar enlargement" and "affection" of the lymph nodes of the neck and other areas of the body, along with enlargement of the spleen and possibly the liver; there were often deposits of firm tubercle-like nodules in the spleen and liver [22]. The malignant cells, subsequently named Reed-Sternberg cells, arise from B lymphocytes and exist with Hodgkin cells (large, mononuclear cell variants) within an immunoreactive background consisting of lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen [22]. According to the WHO/REAL system, Hodgkin lymphoma may be categorized as nodular lymphocyte-predominant or classical. Classical Hodgkin lymphoma is further categorized into four subtypes: lymphocyte predominant, nodular sclerosis, mixed cellularity, and lymphocyte depleted [12,41]. Two of the four subtypes of classical Hodgkin lymphoma account for most cases in children. Lymphocyte-predominant Hodgkin lymphoma and lymphocyte-depleted Hodgkin lymphoma are both rare in children.

In the United States, the incidence of Hodgkin lymphoma is much lower for children up to 4 years of age than for older children and adolescents. This type of lymphoma is slightly more common among male children/adolescents (13 per million) than female children/adolescents (11 per million) [1]. With regard to race/ethnicity, the incidence of Hodgkin lymphoma is highest in the non-Hispanic white population and lowest in the Asian/Pacific Islander population [1]. Hodgkin lymphoma is the most curable childhood cancer, with a five-year survival rate of nearly 97% in 2008–2014, an increase from 87% in 1975–1983 [1].

NON-HODGKIN LYMPHOMA

Pediatric non-Hodgkin lymphoma is a heterogeneous group of malignant tumors of lymphoreticular cells that arise from both mature and blastic B cells and T cells [42]. Non-Hodgkin lymphomas in children/adolescents differ from those in adults in that adult lymphomas are more clinically aggressive.

As with Hodgkin lymphoma, the incidence of non-Hodgkin lymphoma increases with age and remains relatively constant across all ages for both boys and girls [1,43]. Non-Hodgkin lymphoma develops nearly twice as often in male than female children/adolescents across all age-groups (7.1 vs. 3.6 per million) [1]. The incidence is fairly similar across races/ethnicities, with the highest incidence in the non-Hispanic white population and the lowest incidence in the American Indian/Alaska Native population [1].

The five-year survival rate for non-Hodgkin lymphoma improved from approximately 47% to 74% between 1975–1979 and 1988–2014 [1].

There are nearly 30 different types of non-Hodgkin lymphoma, but only four are predominant in children: small noncleaved cell lymphoma (Burkitt lymphoma and Burkitt-like lymphoma), lymphoblastic lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (systemic or cutaneous). Burkitt lymphoma and diffuse large B cell lymphomas both develop from B lymphocytes; anaplastic large-cell lymphoma and lymphoblastic lymphoma typically arise from T cells.

Burkitt Lymphoma

Burkitt lymphoma is the most prevalent type of non-Hodgkin lymphoma among children/adolescents, accounting for approximately 22% of pediatric non-Hodgkin lymphoma in the United States [1]. It most commonly develops in boys 10 to 14 years of age [43]. It is more common in non-Hispanic whites than in Hispanic whites [43]. This type of lymphoma was first noted by Denis Burkitt, who was studying children in Africa [42]. Burkitt lymphoma is endemic in Africa, where it occurs at a very high rate [44].

There are clinicopathologic differences between the endemic and sporadic forms of the disease [42]. Burkitt lymphoma most commonly affects the jaw and maxilla of African children, whereas the abdomen is the most common site in children in the United States [44].

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is the second most common non-Hodgkin lymphoma, representing 22% of pediatric non-Hodgkin lymphoma. It occurs most frequently in adolescents 15 to 19 years of age [43]. This type of lymphoma differs from other types of non-Hodgkin lymphoma in that it grows more slowly and does not usually spread to the bone marrow, central nervous system (CNS), or skin.

Diffuse large B-cell lymphoma is further categorized as nonmediastinal or primary mediastinal. Nonmediastinal disease is more common; primary mediastinal occurs predominately in adolescents [45]. The gene expression profile of this type of non-Hodgkin lymphoma is distinct and suggests a close association with Hodgkin lymphoma [46,47].

Lymphoblastic Lymphoma

Lymphoblastic lymphoma represents approximately 16% of pediatric non-Hodgkin lymphoma [43]. It develops most often in boys, especially in the 10 to 14 year age group [43]. The malignant lymphoblasts are the same as those involved with childhood ALL. If the lymphoblasts involve more than 25% of the bone marrow, the disease is reclassified as leukemia and is treated accordingly. Lymphoblastic lymphoma can arise from early T cells or B cells; precursor B-cell lymphoblastic lymphoma occurs less frequently, representing 2.5% of all non-Hodgkin lymphoma [48].

Anaplastic Large-Cell Lymphoma

Anaplastic large-cell lymphoma accounts for approximately 20% of pediatric non-Hodgkin lymphoma, occurring most often among male adolescents [1,43]. This type of non-Hodgkin lymphoma varies substantially in its clinical presentation, with possible involvement of lymph nodes and extranodal sites, typically bone and skin.

5. IDENTIFYING LEUKEMIAS AND LYMPHOMAS

Leukemia and lymphoma are often not suspected during the evaluation of children because of the rarity of the diseases. This low level of suspicion can make diagnosis in the primary care setting a challenge. In addition, the symptoms associated with these hematologic cancers are typically vague or nonspecific and are similar to those of common childhood conditions. Clinicians in the pediatric and family medicine settings must recognize early signs and symptoms and make appropriate referrals to ensure timely diagnosis and treatment, which are essential for enhancing survival.

Diagnosis begins with a history and physical examination. The subsequent course of diagnostic testing varies among patients and may include:

- Laboratory testing

- Imaging studies

- Evaluation of bone marrow aspirate

- Analysis of cerebrospinal fluid (CSF)

- Biopsy of lymph nodes

- Immunophenotyping

- Cytogenetic testing

- Molecular genetic testing

Some diagnostic procedures are uncomfortable, and children may be fearful and distressed at the prospect of diagnostic testing. Bone marrow aspiration and lumbar puncture are the most feared procedures, and care should be taken to ensure that the child is not in pain during either procedure [49]. The goal of pain intervention in this setting is unconsciousness, amnesia, and analgesia. The drugs used should be available in oral and/or intravenous form, have a rapid onset of action, and be of short duration [50]. Optimum anesthesia will provide the maximum amount of comfort for the child and help him or her cooperate with the procedure. A review demonstrated that mind-body interventions, such as hypnosis, distraction, and imagery, may be useful, either alone or in combination with pharmacologic interventions, in managing procedure-related pain [51]. Preventing pain in diagnostic procedures also has important implications for future care. Children who have a painful experience will be distressed about further diagnostic or therapeutic procedures and will be reluctant to undergo such procedures. The distress related to a painful experience can also manifest several years later, as a painful diagnostic procedure is often recalled as a traumatic event in childhood cancer survivors who experience post-traumatic stress [50].

Specialized testing, such as immunophenotyping, cytogenetic testing, and molecular genetic testing, is complex and beyond the scope of this course. In brief, immunophenotyping is carried out with use of flow cytometry, immunohistochemical assay, or immunophenotyping panel. The results demonstrate the cell lineage of the leukemia or lymphoma (T or B cell origin). Immunophenotyping also demonstrates associations between specific clusters of differentiation antigens and subtypes of disease and is used to diagnose and classify leukemia and lymphoma [52].

Cytogenetic testing identifies chromosomal abnormalities with respect to either number or structure [53]. In addition to conventional cytogenetic methods, molecular cytogenetic methods, such as fluorescent in situ hybridization (FISH); molecular genetic methods, such as reverse transcriptase polymerase chain reaction (RT-PCR) or Southern blot analysis; or DNA probes are used to identify chromosome abnormalities. Molecular studies are expensive and not necessary in all cases. However, they may help to detect translocations involving parts of chromosomes that are too small to be seen with conventional cytogenetic techniques.

The accurate diagnosis of leukemia and lymphoma requires careful evaluation and interpretation of the results of these studies, which, in turn, necessitates consultation with pediatric oncologists with expertise in hematologic malignancies. For this reason, the American Academy of Pediatrics (AAP) recommends that diagnostic testing be carried out in pediatric cancer centers, where the availability of appropriate technology and subspecialists helps to ensure an accurate diagnosis [54,55].

6. DIAGNOSIS OF LEUKEMIAS

CLINICAL SIGNS AND SYMPTOMS

There is a wide variation in the signs and symptoms of leukemia, and the onset is usually acute. However, in some cases, symptoms are insidious and persistent [36]. On average, symptoms are present for four to six weeks before diagnosis and are associated primarily with leukemia-related pancytopenia [17,36]. The clinical manifestations of ALL and AML are similar, although there are some distinctions (Table 5) [17,36,56]

Table 5: CLINICAL MANIFESTATIONS OF ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AND ACUTE MYELOGENOUS LEUKEMIA (AML)

Clinical Sign/Symptom

ALL

AML

Involvement of central nervous system

Yes (20% to 25%)

Yes (5% to 30%)

History

Low-grade fever; fatigue/weakness

Most common symptom

Yes

Anorexia or weight loss

Yes

Yes

Discomfort in bones and/or joints

Yes

Yes

Easy bruising or increased bleeding

Yes (33%)

Uncommon

Infection

No

Often first presenting symptom

Physical Examination

Pallor

Yes

Yes

Lymphadenopathy

Yes

Yes

Splenomegaly/hepatomegaly

Yes (60%)

Yes (<50%)

Mediastinal mass

Yes (10% to 18%)

Rare

Ecchymoses of skin or mucous membranes

Yes

No

Petechiae

Yes

No

Inflammation/bleeding of gums

No

Yes

Cutaneous rash

No

Yes

Laboratory Values (Median)

Hemoglobin

8 g/dL

8 g/dL

White blood cell count

12 x 10^9/L

20 x 10^9/L

Platelet count

53 x 10^9/L

70 x 10^9/L

Source: [17,36,56]

In taking a history from the child and/or a parent or caregiver, the clinician should determine if any of the following symptoms have been present:

- Fever

- Fatigue or weakness

- General malaise or loss of well-being

- Easy bruising or increased bleeding

- Anorexia or weight loss

- Dyspnea on exertion

- Discomfort in bones and/or joints

- Headache

- Seizures

- Vomiting

A low-grade fever of unknown etiology is the most common symptom associated with ALL [36]. If fever has persisted for more than two weeks, further evaluation for leukemia is warranted. Findings on physical examination that should prompt diagnostic testing for leukemia include pallor, petechiae, ecchymoses of the skin or mucous membranes, or lymphadenopathy (enlargement of more than 2 centimeters). Splenomegaly or hepatomegaly is evident at the time of diagnosis in approximately 60% of children with ALL and in less than half of children with AML [36].

The first sign of AML is often severe infection. Other common signs include swelling, pain, and bleeding of the gums; inflammation of the mucous membranes of the upper airways; and cutaneous rash (reddish papules, plaques, or nodules or maculopapular rash).

A mediastinal mass is rare in children with AML and is found in a small percentage (10% to 18%) of children with ALL [17,36]. With ALL, an enlarged thymus may lead to compression of the trachea or the superior vena cava, which can cause coughing and dyspnea or superior vena cava syndrome, respectively. A chest x-ray should be done if a cough persists for more than two weeks without an identifiable cause [56]. Overt testicular disease is rare (2%) at the time of diagnosis of ALL, but testicular leukemia is identified on evaluation of biopsy specimen in as many as 25% of male children/adolescents [36].

There are some differences between the initial laboratory values for ALL and AML. Although the median hemoglobin is approximately 8 g/dL for both types of leukemia, a higher percentage of children/adolescents with ALL have a hemoglobin of less than 8 g/dL. In addition, AML is associated with higher white blood cell (WBC) and platelet counts [17,36].

Involvement of the CNS is present at the time of the initial diagnosis of leukemia in approximately 20% to 25% of cases of ALL and 5% to 30% of cases of AML [17,36]. Signs of CNS involvement include headache, seizures, vomiting, asthenia, blurred vision, slurred speech, imbalance, cranial nerve palsy, and poor performance in school [17,36].

Many of the symptoms related to leukemia are associated with other diseases and conditions, and care is needed in making a differential diagnosis. Lymphadenopathy may be related to infectious mononucleosis or other infection, but a lack of a response to a routine course of antibiotics should prompt laboratory testing consisting of a complete blood cell count (CBC) with differential and a reticulocyte count. The likelihood of leukemia is high when such testing demonstrates anemia, thrombocytopenia, leukopenia, high mean corpuscular volume, and reticulocytopenia [56]. Light microscopy of stained blood cells can demonstrate leukemic blast cells; blast cells may also be present on the peripheral blood smear. However, blast cells are often present in the bone marrow only.

Children with ALL often have bone and/or joint pain before leukemic blast cells are evident in the peripheral blood, which can prompt evaluation for juvenile rheumatoid arthritis before leukemia. A study showed that for children with bone or joint pain, three factors predicted the diagnosis of ALL: a low WBC count (less than 4,000/mcL), a low-normal platelet count (150,000–250,000/mcL), and a history of nighttime pain [57]. When all three of these factors were present, the sensitivity of a diagnosis of ALL was 100% and the specificity was 85% [57].

DIAGNOSTIC TESTING

Computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) can be helpful in detecting leukemic involvement of organs, bone, joints, soft tissue, or brain. Examination of CSF obtained through lumbar puncture can also help to determine whether leukemia involves the CNS [58]. A trephine biopsy should be performed if the tap is dry to differentiate between AML and myelodysplastic syndrome. Differentiation is important for treatment decision making, as myelodysplastic syndrome can only be cured by hematopoietic stem cell transplantation (HSCT) [58].

When the suspicion of leukemia is high on the basis of laboratory testing and/or imaging studies, the child should be referred to a pediatric hematologist or oncologist. Further diagnostic testing begins with bone marrow aspiration. The presence of leukemic blast cells on examination of a bone marrow sample confirms a diagnosis of leukemia. Cells obtained through bone marrow aspiration are also used for cytogenetic examination, immunophenotyping, and other special studies to determine whether the leukemia is lymphocytic or myeloid and to identify the specific leukemia subgroup. Determining this information is important for planning appropriate treatment and providing prognostic information about response to treatment.

CLASSIFICATION

The French-American-British (FAB) Cooperative Group developed a comprehensive classification system for acute leukemias, with three subtypes of ALL based solely on morphologic features and eight subtypes of AML based on morphology and findings of immunohistochemical analysis [59]. However, the discovery that immunophenotypic, cytogenetic, and molecular features of ALL are better than morphology alone for stratifying risk has led to the abandonment of the FAB classification of ALL [60]. The FAB classification for AML is widely accepted (Table 6), but it has been noted that strict application of the system will not allow for the diagnosis and classification of a considerable number of childhood cases [17].

Table 6: FRENCH-AMERICAN-BRITISH (FAB) COOPERATIVE GROUP CLASSIFICATION SYSTEM FOR ACUTE MYELOGENOUS LEUKEMIA AND PREVALENCE OF SUBTYPES

Subtype

Description

Prevalence

M0

Acute myeloblastic leukemia without differentiation; no expression of myeloperoxidase (MPO) at light microscopy level

–

M1

Acute myeloblastic leukemia with minimal differentiation; expression of MPO detected by immunohistochemistry or flow cytometry

18%

M2

Acute myeloblastic leukemia with differentiation

26%

M3

Acute promyelocytic leukemia (APL) hypergranular type

6%

M3v

APL, microgranular variant; cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded

–

M4

Acute myelomonocytic leukemia (AMML)

17%

M4Eo

AMML with eosinophilia

–

M5a

Acute monocytic leukemia (AMoL) without differentiation (monoblastic)

21%

M5b

AMoL with differentiation

–

M6

Acute erythroid leukemia (AEL)

–

M7

Acute megakaryocytic leukemia (AMKL); flow cytometry is helpful to distinguish blasts from lymphoblasts

7%

Source: [17,59]

Although a comprehensive discussion of the cytogenetic characteristics of leukemia is beyond the scope of the course, an overview of the most common features is helpful in understanding risk, as chromosomal abnormalities are among the most important factors for classifying risk in leukemia [53]. Hyperploidy (more than 50 chromosomes in a tumor cell) is evident in approximately 25% of pediatric ALL but is extremely rare in AML [53]. The most frequent numerical abnormalities in AML are trisomy 8 (three copies of chromosome 8) and acquired trisomy 21 [53].

In infant leukemia (both ALL and AML), abnormality of the mixed-lineage leukemia (MLL) gene at 11q23 is found in nearly 80% of cases [29]. Across all pediatric age groups, the most common structural abnormality in ALL, occurring in approximately 20% to 25% of cases of B-cell ALL, is reciprocal translocation of t(12;21)(p13;q22), which results in fusion of the TEL and AML1 genes. However, TEL-AML1 fusion is rare in T-cell ALL [61]. Several other common abnormalities occur frequently in ALL (Table 7) [53].

Table 7: COMMON CYTOGENETIC FINDINGS IN LEUKEMIA

Type of Leukemia

Cytogenetic Abnormality

Acute lymphoblastic leukemia (ALL)

Hyperploidy

t(12;21)(p13;q22) TEL-AML1 fusion

t(1;19)

t(17;19)(q22;p13.3)

t(9;22)(q34;q11.2) (Philadelphia chromosome)

Aberrations of 12p

Acute myelogenous leukemia (AML)

Trisomy 8

Acquired trisomy 21

t(8;21)

t(15;17)

Aberrations of 11q23

inv(16)

Infant leukemia (ALL and AML)

Abnormality of the MLL gene at 11q23

Source: [53,61,62]

Structural abnormalities are found in approximately 60% of pediatric AML cases and are usually linked to specific subtypes. The most common translocations are t(8;21), which is associated primarily with the M2 subtype, and t(15;17), which is strongly linked to the M3 subtype [53,62]. Other common abnormalities associated with AML are aberrations of 11q23 and inv(16) [53].

PROGNOSTIC VARIABLES

The use of prognostic variables has been of more value in ALL than in AML. Several factors predictive of outcome have enabled the stratification of ALL into high-risk and standard-risk groups, and treatment is planned according to risk [36]. However, studies have been inconsistent in identifying factors present at or shortly after the time of diagnosis of AML that are predictive of outcome [17,63,64,65,66,67,68]. The greatest prognostic factor is the response to treatment [69].

Acute Lymphoblastic Leukemia (ALL)

The following factors have been found to have prognostic significance for children with ALL [69,70]:

- Age at the time of diagnosis

- WBC count at the time of diagnosis

- CNS status at the time of diagnosis

- Subtype of ALL

- Sex

- Race/ethnicity

- Cytogenetic findings

Age at the time of diagnosis is a strong prognostic factor, and the variation in outcome reflects differences in the underlying biology of ALL in different age groups [71,72]. For example, there is a high percentage of favorable cytogenetic features, such as high hyperdiploidy and t(12;21), in children who are 1 to 9 years of age, and the disease-free survival is better for that age group than for infants and older children and adolescents [73,74,75,76]. In addition, the risk of treatment failure is high for infants with ALL, especially infants younger than 3 months of age [77,78,79].

The risk of treatment failure is also high for children with precursor B-cell ALL who have an increased WBC count (more than 50,000/mcL) at the time of diagnosis [76]. In turn, a high WBC count is associated with other high-risk prognostic factors, such as t(4;11) and t(9;22).

The CNS status at the time of diagnosis is described according to results of a nontraumatic diagnostic lumbar puncture, specifically, the number of WBCs and the presence or absence of blasts on cytospin of the CSF sample. CNS3, which is defined as a WBC count of ≥5/mcL and the presence of blasts on cytospin, is associated with a higher risk of treatment failure compared with patients who do not have CNS involvement at the time of diagnosis. CNS2 status (WBC count less than 5/mcL and the presence of blasts) may be associated with a higher risk of relapse, but this risk may depend on treatment [80,81,82]. With respect to the sex of the patient, the prognosis has been slightly better for girls than for boys [83,84,85]. Although testicular relapse is one reason for this difference, relapse in bone marrow and CNS is also more frequent among boys [83,84,85]. Male sex has not been a risk factor in studies in which the event-free survival rate is more than 80% [86,87]. Studies that have examined sex differential for etiologic clues have identified several sex-specific genetic markers for childhood ALL risk [88,89,90,91] .

The role of race/ethnicity as a prognostic variable is unclear. Early studies indicated better survival rates for white children than for black children, and later studies demonstrated lower survival rates for black, Hispanic, and American Indian/Alaska Native children compared with white and Asian/Pacific Islander children/adolescents [92]. However, studies done at St. Jude Children's Research Hospital have indicated no racial/ethnic differences in survival, leading researchers to believe that survival depended instead on access to the same treatment protocols [79,93]. Social, biologic, and pharmacokinetic factors should be explored in an effort to better understand racial/ethnic variations in outcome [94]. Clinical and public health strategies can help improve access to health care, clinical trial enrollment, treatment, and survivorship care for children with ALL [95].

With regard to cytogenetic findings, hyperdiploidy is associated with a highly favorable prognosis and is also associated with other favorable prognostic factors, including an age of 1 to 9 years, a low WBC count, and t(12;21) with the TEL-AML1 fusion gene [73,74,96,97,98,99]. Hypodiploidy has been associated with progressively worse outcomes as the number of chromosomes decreases, with the worst outcome associated with near haploidy (24 to 28 chromosomes) [69,97]. Extreme hypoploidy and presence of the Philadelphia chromosome has been an indicator of very poor prognosis in B-cell ALL [100].

Chromosome translocations may influence prognosis, but other prognostic factors and the type of treatment may determine the effect of a specific translocation. TEL-AML1 fusion has been associated with an excellent outcome [61,74,101]. In contrast, the Philadelphia chromosome is related to an unfavorable prognosis, especially when it occurs in children who have a high WBC count or in whom the response to initial therapy is slow [53,102]. The t(4;11) has also been related to a high risk of treatment failure, and the event-free and overall survival rates are lower for children with Down syndrome and ALL [103,104,105].

Acute Myeloid Leukemia (AML)

The first prognostic factors identified for AML were age, WBC count, and FAB classification at the time of diagnosis, but their ability to predict outcome has been inconsistent [64,65]. A report of 61 children treated between 1976 and 1984 indicated that an age of younger than 2 years at the time of diagnosis, a WBC count of less than 100,000/mcL, and an FAB subtype of M4 or M5 were predictive of an increased risk of relapse and a decreased overall survival [65]. Adolescent patients are at higher risk for treatment-related mortality compared with younger children [106].

In another study of nearly 500 patients treated between 1986 and 1989, univariate and multivariate analyses demonstrated several clinical, morphologic, and cytogenetic factors associated with a lower rate of complete remission, including hepatomegaly, low platelet count (20,000/mcL or less), FAB subtype M5, and trisomy 8 [64]. In addition, a higher platelet count (more than 20,000/mcL) and absence of hepatomegaly were independent prognostic factors of better overall survival [64].

Data for a series of nearly 300 patients treated at St. Jude Children's Research Hospital from 1980 to 1996 indicated that the five-year event-free survival was slightly better for an age of 2 years or younger, an initial WBC count of less than 50,000/mcL, and an FAB subtype of M3 or M5 [17]. Although sex has not been used as a prognostic factor, several studies have suggested that the outcome is more favorable for girls than boys [17,64].

The ability of cytogenetic findings to predict outcome has varied, but they appear to be the best prognostic factors in AML [63,107,108]. In one study, trisomy 8 was the strongest predictor of poor prognosis, and in another, abnormalities of 11q23, q3, or chromosomes 5 or 7 were associated with a high rate of treatment failure [75]. In the series of patients treated at St. Jude, the best outcome was associated with t(9;21), and a favorable outcome has also been associated with t(8;21), t(15;17), and inv(16) [17,63]. Aberrations of chromosome 16q have also been shown to be a prognostic indicator of complete remission and better overall survival [62,64]. For children with monosomy 7, AML progresses rapidly and the response to treatment is poor [53]. In contrast to the situation in ALL, children with Down syndrome and AML have a good response to treatment [64,107]. Advances in technology are allowing researchers to identify other factors associated with outcome, and further studies are needed to confirm the usefulness of these factors as prognostic variables [109].

7. DIAGNOSIS OF LYMPHOMA

The clinical presentation of lymphoma is similar to that of leukemia in several ways, and the course of diagnostic testing is also similar. However, some signs and symptoms of lymphoma are distinct from those of leukemia. Furthermore, there are differences even between the two types of lymphoma, especially with regard to the sites of disease.

Imaging studies are done not only to determine or confirm the presence of lymphoma but also to assess the extent of disease, which assists in staging as well as in establishing a baseline for monitoring response to treatment. As with leukemia, immunophenotyping and cytogenetic analysis are done to determine the cell lineage of disease, evaluate the pattern of CD antigen expression, and identify chromosomal abnormalities. The role of these studies in the diagnosis of lymphoma is not discussed here, as other factors currently play a more significant role in prognosis.

HODGKIN LYMPHOMA

Clinical Signs and Symptoms

Children and adolescents with Hodgkin lymphoma are often asymptomatic, and the disease is frequently an incidental finding during a routine examination or evaluation of an injury. Approximately 25% to 30% of children will have one of three archetypal constitutional symptoms, known as B symptoms: unexplained, intermittent fever of 38 degrees Centigrade; drenching night sweats; or unintentional loss of more than 10% of body weight within the past six months (Table 8) [110]. The suspicion of Hodgkin lymphoma is increased when B symptoms are present with lymphadenopathy or splenomegaly. Patients may also have nonspecific systemic symptoms, such as fatigue and anorexia. In some patients, generalized pruritus may be present for months before lymphadenopathy is found, and excoriations may be evident as a result of excessive scratching [110]. On physical examination, the most common finding is a persistent, painless adenopathy, usually in the supraclavicular or cervical area [56,110]. As noted, reactive lymphadenopathy is common in children/adolescents, making it necessary to carefully evaluate patients to first rule out other infectious or inflammatory conditions. Involvement of the supraclavicular nodes should prompt earlier evaluation for Hodgkin lymphoma, as the cervical nodes are most commonly involved in infection and inflammatory conditions. Infectious mononucleosis can be distinguished from Hodgkin lymphoma by the presence of symmetrical cervical lymphadenopathy with pharyngitis. A tuberculin test may be helpful to rule out tuberculosis, which also may have similar clinical characteristics.

Table 8: CLINICAL MANIFESTATIONS OF HODGKIN AND NON-HODGKIN LYMPHOMA

Clinical Sign/Symptom

Hodgkin Lymphoma

Non-Hodgkin Lymphoma

B-Cell

Lymphoblastic

Anaplastic Large Cell

History

Presence of symptoms

Usually asymptomatic

–

–

Wax and wane for weeks

B symptoms (unexplained fever, night sweats, weight loss)

Occurs in approximately 28%

Occurs in approximately 50%

–

Occurs in approximately 42% to 68%

Other

Pruritus

–

–

–

Physical Examination

Lymphadenopathy

Cervical or supraclavicular, painless

Peripheral

Relatively uncommon

Cervical or axilla, painless

Peripheral (occurs in 88% to 97%)

Most common extranodal site(s)

Lung, liver, bone

Abdomen (Burkitt); neck, mediastinum, throat (DLBCL)

Mediastinum (T cell); head and neck (B cell)

Skin, soft tissue

Splenic involvement

30% to 40%

–

–

11% to 23%

Hepatic involvement

Rare

–

–

15% to 27%

Mediastinal involvement

66%

–

75%

19% to 52%

Other

–

–

Pallor, petechiae, ecchymoses

–

Abnormal laboratory values

Elevated erythrocyte sedimentation rate

Elevated erythrocyte sedimentation rate and lactate dehydrogenase

–

–

DLBCL = Diffuse large B-cell lymphoma.

Source: [110,111,112,113]

Involvement of only lymph nodes and/or the spleen is present in most patients [110]. In general, enlarged lymph nodes are firm and nontender. In advanced disease, enlarged nodes may grow together to form aggregate masses that become attached to underlying tissues [110]. Approximately 15% to 20% of patients will have noncontiguous extranodal involvement, and the lung, liver, bone marrow, and bone are the most common sites of extranodal involvement [114,115]. Extranodal involvement is more commonly associated with the mixed cellularity subtype of Hodgkin lymphoma, whereas involvement of the cervical, supraclavicular, and mediastinal lymph nodes is most often associated with the nodular sclerosis subtype [110].

The mediastinum is involved in about two-thirds of patients [110]. Symptoms accompanying mediastinal involvement may include a persistent, nonproductive cough, dyspnea, or chest pain. Evaluation for Hodgkin lymphoma should be carried out if these symptoms are present, especially if accompanied by B symptoms. It is important to distinguish involvement of the mediastinum from a large, normal thymus or from other mediastinal tumors [22,110]. Morphology, clinical signs, radiographic findings, and immunophenotyping findings must all be evaluated closely to make the distinction.

Non-Hodgkin lymphoma should be considered in the differential diagnosis of Hodgkin lymphoma. One distinguishing feature is the rate of disease progression; involved lymph nodes will grow more rapidly in non-Hodgkin lymphoma than in Hodgkin lymphoma. In addition, abnormal laboratory values are more common with non-Hodgkin lymphoma [110].

Diagnostic Testing

The diagnostic work-up for suspected Hodgkin lymphoma includes laboratory testing and imaging studies to evaluate the site and extent of disease. Laboratory testing should begin with a CBC with differential and an erythrocyte sedimentation rate. The results of the CBC may be nonspecific, demonstrating neutrophilia, eosinophilia, and thrombocytosis [22,110]. Lymphopenia and normochromic normocytic anemia are indicators of extensive disease [116,117]. In the presence of other signs of Hodgkin lymphoma, elevations of the erythrocyte sedimentation rate, lactate dehydrogenase level, and ferritin level may be further indicators of Hodgkin lymphoma [56]. An elevated level of alkaline phosphatase may indicate metastatic bone disease, and further testing should be done to determine if there is skeletal involvement [110].

Evaluation of a bone marrow sample is usually not routinely done. Bone marrow involvement is a characteristic of primarily lymphocyte-depleted Hodgkin lymphoma, which is rare in the pediatric population; approximately 10% to 15% of children/adolescents will have bone marrow involvement at the time of the initial diagnosis [22]. The frequency of bone marrow involvement is higher for older male children who have constitutional symptoms. Bone marrow biopsy should be limited to patients who have B symptoms and in whom advanced disease is suspected [110].

A diagnosis of Hodgkin lymphoma can be confirmed only through evaluation of a specimen from an involved lymph node, and biopsy should be done when there is no response to a course of antibiotics. The biopsy technique depends on the site of the involved node. Excisional biopsy is often the preferred technique, as it allows for better determination of the histologic subtype [110]. However, the least invasive procedure should be used [118,119]. Thus, fine-needle aspiration may be more appropriate if the involved node is in the thoracic or abdominal cavity, and CT can be used to guide biopsy in these situations.

Classification and Staging

As noted, Hodgkin lymphoma is classified histologically according to four subtypes. Nodular sclerosis is the most common subtype, representing approximately 72% of the cases of pediatric Hodgkin lymphoma. This subtype occurs most frequently in adolescents, and the mediastinum is involved in 80% of cases [22]. Mixed cellularity Hodgkin lymphoma accounts for approximately 25% of pediatric Hodgkin lymphoma, most frequently developing in children younger than 10 years of age [22]. It is usually associated with the peripheral lymph nodes of the upper part of the body.

Hodgkin lymphoma is staged according to the Ann Arbor classification system, which categorizes the disease as stage I through IV according to the extent of lymph node involvement (Table 9). The system is based on the premise that Hodgkin lymphoma progresses along contiguous lymph nodes [120]. Within this classification system there are additional designations that are applied to further define symptoms and disease [120].

Table 9: ANN ARBOR CLASSIFICATION FOR STAGING OF HODGKIN LYMPHOMA

Stage

Criteria

I

Involvement of a single lymph node region

II

Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm

III

Involvement of lymph node regions on both sides of the diaphragm

IV

Noncontiguous involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement

Subclassifications

A

Asymptomatic

B

Displaying specific symptoms of unexplained loss of more than 10% of body weight in the six months before diagnosis, unexplained fever with temperatures greater than 38 degrees Centigrade for more than three days, or drenching night sweats

E

Extralymphatic disease resulting from direct extension of an involved lymph node region

S

Involvement of the spleen

Source: [121,122]

Prognostic Variables

Evidence Based Practice Recommendation

According to the American College of Radiology, the stage of disease persists as the most important prognostic variable for Hodgkin lymphoma. Pediatric patients with advanced-stage disease, especially stage IV, have a poorer outcome than patients with early-stage disease.

https://acsearch.acr.org/docs/70602/Narrative

Last Accessed: August 22, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Prognostic variables have less importance in Hodgkin lymphoma because of advances in treatment, but some variables are helpful in predicting outcome. The most significant prognostic indicator is stage of disease. The outcome associated with stage I, II, or III disease is better than that for stage IV disease [114,123,124]. Studies in which prognostic factors were evaluated in multivariate analysis have demonstrated the following factors to be of import [123,125]:

- Presence of B symptoms

- Mediastinal disease bulk

- Results of laboratory studies

The presence of B symptoms (low-grade fever, night sweats, and weight loss) reflects aggressive disease and has been associated with a worse prognosis [123,125,126]. High tumor burden is also predictive of a worse prognosis; a ratio of mediastinal mass-to-thoracic cavity of more than one-third has been associated with a greater risk of recurrence and with a slightly lower survival rate in several studies [123,126,127]. The number of disease sites may also play a role in predicting outcome. Patients who have fewer than four sites of involvement generally have a better outcome [128].

Several laboratory studies, including the WBC count, hemoglobin, erythrocyte sedimentation rate, and serum ferritin level, have also been correlated with a poor prognosis [123,129]. In one study, a WBC of more than 13,500/mcL and a hemoglobin level of less than 11.0 g/dL were significantly associated with shorter disease-free survival [123].

The predictive value of patient-related factors such as sex and age is unclear. One study indicated that disease-free survival was better for girls than for boys [123]. Age has been an important indicator in some studies, with 5-year and 10-year survival rates being higher for children 10 years of age or younger than for older children and adolescents (11 to 16 years of age) or young adults [130].

The rate of response to initial cycles of chemotherapy appears to be prognostically important and is being used in the research setting to tailor subsequent therapy, avoid treatment-associated risks that compromise long-term health, and achieve high cure rates [124,131].

NON-HODGKIN LYMPHOMA

Clinical Signs and Symptoms

The clinical evaluation and diagnostic testing for non-Hodgkin lymphoma is similar to that for Hodgkin lymphoma. Lymphadenopathy should be evaluated, and infectious or inflammatory conditions should be ruled out before a biopsy is performed. The sites of disease and associated symptoms vary according to the histopathologic type of non-Hodgkin lymphoma [111,112,113]. Most children/adolescents will have advanced disease at the time of presentation [43,112].

B-Cell Lymphoma (Burkitt, Burkitt-like, and Diffuse Large B-Cell)

Diffuse large B-cell lymphoma and Burkitt or Burkitt-like lymphoma may appear clinically similar, but the former is more often localized [132,133]. The most common site of B-cell lymphoma is the abdomen, and involvement of peripheral lymph nodes is relatively uncommon [43,111]. When present, peripheral lymph node involvement is more likely to be associated with diffuse large B-cell lymphoma, with sites in the neck, mediastinum, or throat [111]. Symptoms associated with B-cell lymphoma in the abdomen include abdominal pain, nausea, vomiting, and diarrhea. A mass may be palpable on physical examination of the abdomen [56,111]. Persistent abdominal pain with vomiting or diarrhea, especially when accompanied by significant weight loss, should prompt further diagnostic testing. Intussusception of the small bowel is common.

Lymphoblastic Lymphoma

In comparison with B-cell lymphoma, the abdomen is rarely involved with lymphoblastic non-Hodgkin lymphoma. Instead, the mediastinum is involved in nearly 75% of children/adolescents with T-cell lymphoblastic lymphoma, as a result of development of the lymphoma from the thymus [43]. The mass forms in the anterior mediastinum. Dyspnea is often the first symptom [112]. Coughing, wheezing, stridor, dysphagia, and superior vena cava syndrome may also be presenting symptoms. Because mediastinal involvement with non-Hodgkin lymphoma progresses more rapidly than with Hodgkin lymphoma, these symptoms may be more severe. Pleural effusion may also occur [43]. Localized lymphoblastic lymphoma may occur in lymph nodes, bone, and subcutaneous tissue. Other lymph nodes, such as the tonsils or neck nodes, are less commonly the primary site of T-cell lymphoblastic lymphoma. Disease spread can be rapid, with the brain, pleura, pericardium, and bone marrow being the most common sites of metastases. Disease is in an advanced stage (stage III or IV) at the time of diagnosis in most cases [112].

In the case of precursor B-cell lymphoblastic lymphoma, disease is usually more limited and involves skin, soft tissue, bone, tonsil, or a sole peripheral nodal region [112].

Anaplastic Large-Cell Lymphoma

The course of symptoms with anaplastic large-cell lymphoma may be indolent, with fever and a waxing and waning of lymphadenopathy [134,135]. Nearly 50% of patients have B symptoms, and 88% to 97% of patients have lymphadenopathy, with the peripheral nodes being involved most often. CNS and bone marrow involvement occur less frequently with anaplastic large-cell lymphoma than with other types of non-Hodgkin lymphoma [43,113,135].

Soft tissue and skin are the most frequent sites of extranodal involvement [113,135,136,137]. Cutaneous manifestations may be single or multiple nodules, multiple or disseminated red-yellow papillomatous lesions, or large ulcerated lesions [113]. Other extranodal sites include the gastrointestinal tract, lung, pleura, and muscle.

Diagnostic Testing

As with Hodgkin lymphoma, the diagnostic work-up for suspected non-Hodgkin lymphoma includes laboratory testing, diagnostic imaging, and biopsy of suspicious nodes. A CBC can help distinguish non-Hodgkin lymphoma from infectious or inflammatory adenopathy [112]. A high level of serum lactate dehydrogenase level is often indicative of a large mass, but the level is increased less often in patients with anaplastic large-cell lymphoma than in patients with B-cell lymphoma or lymphoblastic lymphoma [113]. A CSF sample should be examined, and evaluation of biopsy specimens should include histopathologic analysis, immunophenotyping, and cytogenetic and molecular analysis [111,112,113,135].

The use of imaging studies is similar for all types of suspected lymphoma. The choice of study is based on the suspected site of involvement. A chest x-ray or CT of the chest is indicated if a mediastinal mass is suspected, which is often associated with T-cell lymphoblastic lymphoma or diffuse large B-cell lymphoma [111]. MRI of the head and neck should be done if signs or symptoms are suggestive of involvement of neck nodes. The abdomen is the most frequent site of involvement for B-cell lymphoma, making CT of the abdomen perhaps the most valuable imaging study in that setting. CT also is useful for staging the lymphoma and for differentiating the primary cutaneous form from the systemic form [111,138]. Skeletal scintigraphy is useful for detecting bone involvement, such as with anaplastic large-cell lymphoma [135]. Positron emission tomography (PET)/CT scanning has largely supplanted scintigraphy and is highly recommended for patients with suspected non-Hodgkin lymphoma [139,140,141]. PET/CT scanning is also useful for assessing response to treatment and for identifying occult sites of disease. Whole-body scanning may be helpful in detecting disease sites that would otherwise be unidentified [111,138]. If advanced disease is suspected, MRI or CT of the brain should be done [138].

Classification and Staging

Pediatric non-Hodgkin lymphoma is classified as stage I through IV according to the St. Jude staging system, which is similar to the Ann Arbor staging system for Hodgkin lymphoma [142,143]. These stages are [43,142,143]:

- Stage I: Involvement of a single node

- Single tumor outside of the abdomen or chest

- Stage II: Single extranodal tumor with involvement of regional lymph nodes

- Involvement of two nodal regions or more on the same side of the diaphragm

- Two single extranodal tumors, with or without involvement of regional lymph nodes, on the same side of the diaphragm

- Primary tumor (completely resectable) in the gastrointestinal tract, with or without involvement of associated mesenteric lymph nodes

- Stage III: Two single extranodal tumors on opposite sides of the diaphragm

- Involvement of two or more nodal regions above and below the diaphragm

- Primary intrathoracic tumor (mediastinal, pleural, or thymic)

- Extensive primary intra-abdominal disease

- Paraspinal or epidural tumor, with or without involvement of other sites

- Stage IV: Any finding of stage I, II, or III disease with initial involvement of the CNS, bone marrow, or both

Prognostic Variables

As with Hodgkin lymphoma, advances in treatment for non-Hodgkin lymphoma have made prognostic variables less significant [111]. In addition, factors predictive of outcome vary according to the histologic subtype of non-Hodgkin lymphoma.

For B-cell lymphomas, the most important prognostic factor is tumor burden, as determined by either stage of disease or the serum lactate dehydrogenase level [111]. The tumor burden is high for patients with extensive bone marrow involvement (more than 25%) [111]. Serum lactate dehydrogenase level is a well-recognized risk factor that correlates with tumor burden, and a level of more than 1,000 IU/L has been associated with a poor prognosis [45,144,145].

Age and sex have also been evaluated as prognostic factors in B-cell lymphoma; many studies have not found them to be predictive of outcome [111]. In one study involving children/adolescents with diffuse large B-cell lymphoma, the event-free survival was significantly better for male patients than for female patients and the outcome was better for younger girls than for adolescent girls [132]. Again, the universal applicability of these findings is not established.

In an analysis of pooled data from three multicenter studies of prognostic variables in anaplastic large-cell lymphoma, multivariate analysis demonstrated that the following factors were significantly associated with a risk for treatment failure [111,137,145,146,147,148]:

- Presence of a mediastinal mass

- Involvement of the lung

- Focal lesions of the liver or spleen (and/or hepatomegaly or splenomegaly)

- Skin involvement

There was no significant effect of age, sex, or stage of disease in any of the studies [43].

In a comprehensive analysis of potential prognostic factors for outcome in lymphoblastic lymphoma, no factor was found to be associated with outcome [149].

8. COMMUNICATION WITH THE PATIENT AND FAMILY

The primary care provider is often in the position to tell parents that the clinical findings and initial testing may indicate a diagnosis of leukemia or lymphoma. Primary care practitioners who have established a relationship with their patients and families are the healthcare professionals most likely to understand the overall health status of the family, family dynamics, and cultural context of the family. They should draw on all of this information to help present the diagnosis in a way that the family can understand. Further diagnostic testing in a pediatric cancer center will help to refine the diagnosis by identifying a specific type of leukemia or lymphoma, and prognosis and treatment options will then be discussed by oncology specialists. Primary care providers should have familiarity with key aspects of the diseases, as they may become a resource for the family during the child's/adolescent's treatment in a pediatric cancer care center. Primary care providers must be able to communicate effectively with parents as well as the child/adolescent with leukemia or lymphoma. Effective communication requires basic physician communication skills as well as specialized skills in delivering bad news.

COMMUNICATING EFFECTIVELY

Effective communication is a cornerstone of the family-physician relationship. Some physician communication behaviors that have been found to be positively associated with health outcomes include empathy, reassurance and support, explanations, positive reinforcement, humor, discussion of psychosocial issues, health education and information sharing, courtesy, and summarization and clarification [150]. Other factors essential for effective communication and a successful relationship are knowledge of the language preference of the patient and family; an understanding of and respect for the family's cultural values, beliefs, and practices (referred to as cultural and linguistic competency); and an awareness of the family's health literacy level [151,152,153].

Language, cultural competency, and health literacy are significant issues, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data from 2016, nearly 63.2 million Americans (21.1% of the population) speak a language other than English in the home, with more than 25.4 million of them (8.5% of the population) reporting that they speak English less than "very well" [154]. Clinicians should ask their patients' parents what language they prefer for their medical care information, as some individuals prefer their native language even though they have said they can understand and discuss such information in English [155]. An example of the effect of limited English proficiency is a study of children/adolescents hospitalized for infections, in which a primary caregiver with limited English proficiency was found to be an important independent risk factor for both a longer hospital stay and fewer home health care referrals [156].

The national standards on Culturally and Linguistically Appropriate Services (CLAS) include four standards related to language access services that are mandated for health care organizations [157]. Although these standards are not mandated for individual health care providers, the Office of Minority Health encourages clinicians to meet the standards to make their practices more culturally and linguistically accessible [157]. These standards are:

- Offering and providing language assistance services, including bilingual staff and interpreter services, at no cost to each patient/consumer with limited English proficiency at all points of contact, in a timely manner during all hours of operation

- Providing patients with both verbal offers and written notices (in their preferred language) that inform them of their right to receive language assistance services

- Ensuring the competence of language assistance provided to limited English proficient patients by interpreters and bilingual staff and avoiding the use of the patient's family and friends as interpreters

- Making easily-understood patient-related materials available and posting signage in the languages of the commonly encountered groups and/or groups represented in the practice area

Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (family members, bilingual staff, etc.) leads to better outcomes [158,159,160]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [161]. Despite this clear benefit and preference, a survey of more than 900 pediatricians showed that professional interpreters were the third most commonly used resource; bilingual family members were used most often [162]. According to one study, this practice has only modestly improved since 2004 [163]. Professional interpreters have recommended that clinicians can further enhance the quality of care by meeting with interpreters before discussions of bad news and by explicitly discussing with the interpreter whether strict interpretation or cultural brokering is expected [164].

Knowledge of the family's health literacy is important for achieving treatment goals and good outcomes, yet most individuals lack adequate health literacy. According to the 2003 National Assessment of Health Literacy, 14% of individuals in the United States have "below basic" health literacy, which means they lack the ability to understand health information and make informed health decisions [165]. A systematic review of more than 300 studies showed that an estimated 26% of patients had inadequate literacy and an additional 20% had marginal literacy [166]. Health literacy varies widely, according to race/ethnicity, level of education, and gender, and clinicians are often unaware of the literacy level of their patients and family [153,167]. Predictors of limited health literacy are poor self-rated reading ability, low level of education, male sex, and nonwhite race [167,168].

Several instruments are available to test the literacy level, and they vary in the amount of time needed to administer and reliability in identifying low literacy. A review demonstrated that the two most accurate tools for identifying literacy are the Rapid Estimate of Adult Literacy in Medicine (REALM) and the shortened version of the Test of Functional Health Literacy in Adults (S-TOFHLA) [153]. REALM takes 3 minutes to administer, whereas S-TOFHLA takes 7 to 12 minutes to administer [153]. More rapid testing is available since the development of the Newest Vital Sign (NVS), an instrument named to promote the assessment of health literacy as part of the overall routine patient evaluation. The NVS takes fewer than three minutes to administer, has correlated well with more extensive literacy tests, and has performed moderately well at identifying limited literacy [153,167]. Two questions have also been found to perform moderately well in identifying patients with inadequate or marginal literacy: "How confident are you in filling out medical forms by yourself?" and "How often do you have someone help you read health information?" [153].

Clinicians should adapt their discussions and educational resources to a family's identified health literacy level and degree of language proficiency. The use of plain language (free of medical jargon), asking parents to repeat pertinent information, regularly assessing recall and comprehension, providing educational resources in a variety of formats (e.g., print, oral, web-based, video), and using culturally appropriate and translated educational materials, can all help ensure that parents better understand the diagnosis and other aspects of their child's disease and its management, ultimately leading to higher quality care.

Cultural competency is essential for addressing healthcare disparities among minority groups [151]. The AAP Task Force on the Family noted that "nonjudgmental, culturally sensitive, family-oriented care" should be provided by all pediatricians [169]. The task force further noted that providing such care requires that the "family's history, interactions, and preferred solutions are considered, used, and supported" [169]. To that end, primary care providers should assess the family's beliefs and values associated with illness and health care (Table 10).

Table 10: KEY TALKING POINTS TO ASSESS CULTURAL INFORMATION

- What behaviors and symptoms of the child are of most concern to the parents?

- Why do the parents believe cancer occurred in the child?

- How do the parents believe the child is affected by the cancer?

- What are the family's beliefs and fears about cancer?

- What measures did the parents take to control the symptoms before diagnosis?

- What do the parents expect of the medical team?

- What are the expected roles of various family members in the healthcare setting?

- What are the family's dietary practices?

- What are the religious beliefs and/or affiliations and significant religious persons in the family's lives?

Source: [170]

The status of children within the family and community differs among cultures and is a factor in how parents and other family members will respond to a child's illness [171]. Respect for cultural health beliefs and practices is important for many patients from non-Western cultures, and clinicians should be sensitive to culturally defined beliefs about health care [161]. These beliefs may underlie the degree or quality of the parents' involvement in the child's care or noncompliance with treatment or recommendations [171].

Another factor that varies across cultures is the role of decision-makers; an understanding of the family dynamics with respect to decision making is essential [172]. In most cases of children/adolescents with cancer, the parents will be the primary decision-makers. There are three options for decision making: clinician-centered (the clinician makes the decision), informed (the patient/family makes the decision after becoming informed by the clinician and through other sources), and shared (the clinician and patient/family collaborate in the process). Parents differ in their preferences regarding the level of involvement [173,174,175]. The physician should explore the issue of decision making with parents to ensure that their preferred level of involvement is attained.

One study has underscored the need to engage in the preferred decision-making process; the study found that parents' unhappiness with the decision-making process was correlated with optimism about cure [176]. In the study, 61% of parents were more optimistic than their child's physician about the likelihood of cure. Parents who were unhappy with the decision-making process were more apt to be overly optimistic [176]. Studies have also shown that satisfaction with treatment choices is increased when communication in the diagnosis phase has been effective [173].

Delivering Bad News

A cancer diagnosis presents the dual challenge of being both emotionally and intellectually overwhelming. These feelings are heightened for parents of a child/adolescent with cancer. Parents differ in how much information they want or feel they can handle about the diagnosis. Clinicians should ask how much detail the parents wish to hear [173]. Important points for communicating the diagnosis include:

- Use clear, jargon-free language.

- Check often for understanding.

- Offer reassurance and support.

- Encourage questions.

Clinicians should address parents' and patients' fears and reassure them that they will be available throughout the course of treatment [173]. Eliciting and validating emotional reactions at this time will help parents and patients better understand and comply with further diagnostic testing [173].

Guidelines are available to help clinicians deliver bad news in the childhood cancer setting with sensitivity (Table 11) [176,177,178]. However, the stress of receiving bad news, even if the clinician is compassionate and speaks clearly, can prevent patients and family members from retaining needed information [177]. After relating bad news, clinicians can build a partnership by allowing parents to express their feelings and opinions [179]. A pediatric psychologist or family therapist can assist both the child and family in coping with the impact of the diagnosis.

Table 11: GUIDELINES FOR BREAKING BAD NEWS

- Formulate a plan. Mentally rehearse the steps of the conversation.

- Schedule a time for the discussion to allow all important family members and medical staff to be present.

- Meet in a quiet and private setting.

- Make arrangements for a professional translator if English is not the first language of the family. Meet with the professional translator before the discussion to discuss expectations.

- Preface bad news with a phrase to prepare the family, such as "I wish the results were different, but..."

- Communicate clearly and minimize use of technical language.

- Let the patient's and family's reactions guide the flow of the conversation. Allow silence.

- Be empathetic and acknowledge the family's emotions.

- Explain to parents who are worried about the child hearing bad news that age-appropriate, open communication with children allows the practitioner and family to provide the child with comfort and reassurance while removing uncertainty.

- Determine the family's level of understanding of the illness/situation to assess misconceptions, aspects of news that will be surprising, and their unique information needs.

- Determine if any family members are "numbers people" so they can be provided the type of information with which they feel most comfortable.

- Make parents feel that they are part of the team to help their child and that their efforts will help the medical team take care of their child.

- Explain to patient and family that they are not to blame for the child's cancer.

- Schedule a future meeting to discuss the bad news and options (e.g., in an hour, the next day, the next week).

Source: [176,177,178]

Clinicians should also determine parents' preference for the type and amount of information to be shared with the child. Many parents wish to protect their child by withholding information. This is especially true among some cultures—for example, among Chinese, Japanese, and Greek populations [180]. However, studies have shown that children often recognize the seriousness of their illness and prefer open communication about their disease and prognosis [180,181,182]. Such open exchange of information can help to avoid the fear of the unknown and to preserve the child's trust in his or her parents and/or family and caregivers [180,182]. Even if the child is to be included in the discussion, the best approach may be to sequence some information; that is, to communicate information to parents in separate meetings before communicating it to the child. Parents of children with leukemia have acknowledged the benefits of communicating openly with children, but they noted that their child's presence during discussions of such topics as prognosis, treatment options, and adverse events, restricted their own communication with physicians, made it difficult to concentrate, and interfered with their efforts to care for their child emotionally [183]. Parents also said that separate meetings allowed them to absorb information and to convey it to their child at an appropriate time and in a reassuring way [183].

Parents and clinicians should involve the child in the discussion of the diagnosis using language that is developmentally appropriate for the child, checking often to make sure the child understands. Having the child repeat the information in his or her own words is one way to assess comprehension [180]. The child should also be encouraged to express feelings and concerns. Adolescents and children who are mature enough to understand and reason should be allowed to express their opinions, and healthcare professionals should be advocates for the child's preferences and decisions [175]. Adolescents especially, because of their need for independence, should be given choices about their care, whenever possible, as well as about privacy issues, such as with whom information can be shared [8].

Clinicians should explore ways to best communicate with and educate children/adolescents. Computer-assisted and multimedia educational programs have been shown to enhance cancer-related knowledge among children/adolescents and improve their feelings of control over their health [184].

9. TREATMENT APPROACHES

The goals for treatment of pediatric leukemia and lymphoma have evolved dramatically since the early 1960s, when palliative care was considered to be the rational approach to treatment of leukemia and extensive radiation therapy was used for lymphoma. The search for better curative therapies that do not yield long-term side effects has led to a variety of approaches based on prognostic factors, as well as independent host-related or disease-related factors.

The treatment protocols for pediatric leukemia and lymphoma have been developed and refined by several cooperative groups in the United States and Europe, the most notable of which are COG, the National Cancer Institute, St. Jude Children's Research Hospital, Dana-Farber Cancer Institute Consortium, Medical Research Council Working Party on Childhood Leukemia, European Organisation for Research and Treatment of Cancer—Children's Leukaemia Cooperative Study Group, the French Society for Pediatric Oncology, and the Berlin-Frankfurt-Munster Cooperative Groups. The investigators in these groups are at the forefront of evaluating chemotherapy and radiation doses and combinations to achieve the overall goal of maximizing the potential for cure while minimizing treatment-related toxicity.

The treatment of pediatric leukemia and lymphoma is a complex process that requires the expertise of several pediatric subspecialists, including hematologists/oncologists, diagnostic radiologists, pathologists, radiation oncologists, and surgeons, as well as pediatric nurses, social workers, and other allied healthcare professionals experienced in the care of children with cancer. Superior results have been achieved when treatment is provided at pediatric cancer centers with specialized multidisciplinary teams. Due to these superior results, the AAP developed guidelines recommending that all children and adolescents with cancer be referred to a pediatric cancer center for treatment [54,55]. The AAP notes that, in many cases, all aspects of care should be given at the center but acknowledges that "certain aspects of care may be continued in the office of a primary pediatrician for selected children, after the diagnosis has been established and the treatment plan determined by the pediatric cancer center" [54,55].

Over the years, the treatment of adolescents with leukemia or lymphoma has been the topic of some debate because of the decreased event-free and overall survival among adolescents compared with children [185]. Some adolescents have been treated according to adult protocols, while others have been treated according to pediatric protocols. Almost all retrospective studies comparing outcomes for adult and pediatric protocols have shown a significant benefit to pediatric protocols [67,126,185]. These differences are thought to be related to the substantial differences between adult and pediatric protocols [185].

IMPORTANCE OF CLINICAL TRIALS

Retrospective reviews of data from pediatric cancer clinical trials have demonstrated that the treatment protocols in clinical trials offer a significant survival benefit compared with other treatment approaches [186,187]. Virtually all children with leukemia or lymphoma are eligible for treatment in a clinical trial, yet 40% to 60% do not participate [186,188]. This rate of nonparticipation is even higher outside pediatric cancer centers. In one study of more than 5,000 children/adolescents (birth to 21 years of age), the rate of clinical trial participation was 25% for institutions other than pediatric cancer centers [186]. Participation of children/adolescents in clinical trials, both within and outside of pediatric cancer centers, is higher for leukemia than for lymphoma and for younger children (birth to 5 years) than for older children [186]. The rate of participation among adolescents is substantially lower, ranging from 10% to 15%, and this low rate is of special concern [185].

One systematic review sought to identify the perceptions and attitudes toward clinical trial participation among adolescents and young adults (15 to 39 years of age) [189]. Major themes identified for acceptability of clinical trials included hope for positive clinical affect, altruism, and having autonomy, while potential deterrents included prolonged hospitalization, worry about side effects, and discomfort with experimentation [189]. The findings of one qualitative study suggest that caregivers and providers have work to do in overcoming factors that limit patients' involvement in clinical trial enrollment decision-making [190]. Data from a retrospective study suggest that establishing a joint pediatric/adult oncology program can improve adolescent/young adult enrollment in clinical trials. Fifty-seven patients were referred to an oncology program from 2006 to 2010. Eight were referred for consultation only and not treated. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial; 9 of 27 patients (33%) who received treatment at the adult cancer center were enrolled, an increase from the previous three years [191].

Clearly, more children/adolescents should participate in clinical trials to provide the maximum opportunity for cure and long-term survival. Healthcare professionals should encourage parents to seek care at a pediatric cancer center and to ask about clinical trials if the issue is not raised. This is particularly important for older children and adolescents [192]. Assent for clinical trial participation in the pediatric setting differs from its counterpart in the adult setting (informed consent) in many ways and is a complicated issue. The obvious and primary difference between the two settings is the patient's capacity for decision making. It is generally believed that children/adolescents should be involved in the discussion and decision making about medical treatment (including participation in a clinical trial) if the discussion is developmentally appropriate [180,193,194]. Various ages have been suggested as the threshold for sufficient capacity to reason and understand a discussion about a clinical trial and make a decision to participate. The National Commission for Protection of Human Subjects of Biomedical and Behavioral Research, the California legislature, and the AAP have set the threshold for participating in the assent discussion at 7 years of age [193,194]. However, others have argued that a child at this age cannot understand all aspects of a research trial, and the ages of 9 years, 11 years, and 14 years have all been suggested as thresholds [194,195,196]. The age range of 9 to 14 years has been noted as the "transition period," or the ages at which there is the most variability in the capacities of individual children [194]. Studies involving focus groups of healthy adolescents have shown that research concepts such as placebo and randomization are difficult to understand even for teenagers [197]. Clearly, age is but one of several factors that should be considered when determining the appropriateness of engaging a child in the decision-making process; other factors include level of maturity, physiologic and psychologic state, and the child's reasons for his or her preferences [196,198].

In a study of assent discussions involving children/adolescents with leukemia and their parents, the fewest number of clinicians considered the patient alone to be the primary decision-maker [199]. Most clinicians noted that the parents were the primary decision-makers; others indicated that it was a "family" decision to be made jointly between parents and the patient [199]. According to guidelines established by COG, the clinician and parents should seek the child's perspective in a "developmentally, contextually, and culturally sensitive fashion," and the clinician should encourage the parents and patient to make the decision jointly as a family unit [194]. Furthermore, clinicians should advocate for the child if the parents disregard the child's preferences and should ask to speak to the child alone if they think the child is not expressing his or her true perspective in the presence of the parents [194].

Another factor in the issue of clinical trial assent is the high levels of emotion, stress, and anxiety associated with a diagnosis of cancer in a child. These psychosocial factors have been shown to have an effect on comprehension, which, in turn, influences the ability to make a decision [188]. The complexity of treatment options for pediatric cancer and the swiftness with which most decisions must be made also add to the challenge of decision making about clinical trials. Because of these factors, effective clinician-parent communication is essential [173]. In many cases, the intervention of a psychologist or therapist may also be helpful. A study showed that race and socioeconomic status were associated with less information-sharing and partnership-building cues from clinicians and with less participation in the assent discussion by parents [188].

The importance of respect in obtaining assent has been emphasized. Respectful assent involves providing sufficient information about the trial and encouraging the patient and family to ask questions and express concerns [194,196]. Respectful assent also involves responding to dissent [194,196]. The child's participation in a trial should be monitored, and persistent expressions of distress about continued participation should be addressed [194].

In a study to gain the perspective of parents about clinical trial decision making, parents offered several suggestions to improve the process. The most common suggestion was to give parents more time to decide [200]. Parents also suggested that clinicians should [200]:

- Provide more information and repeat it for understanding

- Offer other resources, such as videos and books

- Communicate honestly and with empathy

- Arrange for parents to speak with other parents who have been through the clinical trial decision-making process

Parents who were not native English speakers noted the importance of having a professional interpreter available during the process [200].

Discussion of the trial should be comprehensive and address all facets of treatment, including side effects, long-term effects, and survival expectancy (Table 12). A focus on providing information in the context of informed consent may come at the expense of other communication exchanges that are important to patients, especially in the context of end-of-life decisions [201]. Many parents wish to avoid these topics in an effort to protect their children, but research has shown that children tend to pose these questions themselves and that they benefit from the assent process [180,199,201].

Table 12: KEY ELEMENTS TO BE DISCUSSED ABOUT PARTICIPATING IN A CLINICAL TRIAL

- Goals of the trial and treatment

- Rationale for treatment

- Prognosis (survival and cure)

- Importance of the child's best interests

- Randomization procedure

- Procedures necessary for the research

- Anticipated risks and benefits of both experimental and standard treatments

- Inconveniences associated with the trial

- Alternative procedures or treatments

- Voluntariness

- Confidentiality

Source: [200,202]

Parents have also noted a need for clearer explanations of the randomization process and of the difference between the clinical trial treatment and standard treatment [202]. Specifically, parents have noted a need to better understand that a clinical trial involves several possible treatment options, one of which is the treatment their child would receive outside of the clinical trial [202]. One analysis identified suggestions for improving the informed consent process by interviewing 57 parents and 20 young adult patients (14 to 21 years of age). A total of 21 suggestions for improvement emerged in three main themes: provision of more information; structure and presentation of the informed consent process; and suggestions for physicians conducting the process. Common suggestions included providing more specific information about the trial, allowing more time for decision making, and using different methods to deliver information [203]. Multimedia approaches to describe research procedures have been shown to enhance overall understanding of both parents and children/adolescents [204].

Although signed assent is not usually required legally, clinicians should document the assent process, including whether the child was invited to participate in the discussion and, if so, the role he or she played in the decision-making process [194].

DISEASE-DIRECTED TREATMENT

As mentioned, treatment regimens for leukemia and lymphoma continue to be refined as the findings of long-term studies demonstrate late effects. For example, high rates of neurocognitive disorders and other effects have been associated with radiation exposure resulting from prophylactic cranial radiation therapy in children with leukemia or radiation to the thorax or head and neck area in children with lymphoma. This has led to the reduction of radiation doses in treatment protocols and/or the use of radiation only for high-risk patients [205,206].

Another well-recognized late effect, anthracycline-related cardiac toxicity, has led to the use of lower doses of anthracycline as well as the use of cardioprotectants (dexrazoxane or enalapril) during anthracycline treatment [207,208,209]. The effects of cardioprotectants require the results of long-term studies, which will not be available for several years.

A detailed discussion of the various protocols that have become standard for the treatment of leukemia and lymphoma is beyond the scope of this course. An overview of the goals and approaches to treatment and the chemotherapy agents used is provided here (Table 13).

Table 13: CHEMOTHERAPY AGENTS USED IN REGIMENS TO TREAT PEDIATRIC LEUKEMIA AND LYMPHOMA

Class of Drug

Name of Drug

Alkylating agents

Busulfan

Carmustine (BCNU)

Chlorambucil

Cyclophosphamide

Ifosfamide

Mechlorethamine

Melphalan

Procarbazine

Antimetabolites

Cytarabine

Mercaptopurine (6-MP)

Thioguanine (6-TG)

Methotrexate

Clofarabine

Cladribine

Fludarabine

Antitumor antibiotics

Bleomycin

Dactinomycin

Anthracyclines

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

Mitoxantrone

Corticosteroids

Dexamethasone

Prednisone

Enzymes

Asparaginase

Pegaspargase

Epipodophyllotoxins

Etoposide

Teniposide

Topotecan

Heavy metals

Carboplatin

Cisplatin

Plant alkaloids

Vinblastine

Vincristine

Vinorelbine

Source: Compiled by Author

TREATMENT OF LEUKEMIAS

The treatment of leukemia varies according to the type and is risk-adapted. This approach prevents overtreatment of children at low risk for relapse and provides sufficient cytotoxicity for children at high risk for relapse or treatment failure. Investigators continue to explore both different doses of chemotherapy agents, timing and intensity, and different drug combinations to achieve better rates of remission, disease-free survival, and overall survival for children/adolescents with ALL and AML.

With one exception, all types of ALL are treated with an approach that includes the following phases [210]:

- Remission induction therapy (at the time of diagnosis)

- Postinduction therapy (after achieving complete remission), including:

- Consolidation/intensification therapy

- Continuation (maintenance) therapy

- CNS prophylaxis

The exception to this approach is B-cell ALL. B-cell ALL is histologically similar to Burkitt lymphoma, and it is, therefore, treated according to protocols for advanced Burkitt lymphoma without marrow involvement, which consists of short-term intensive chemotherapy (high-dose methotrexate, cytarabine, and cyclophosphamide) [144,211].

The biologic and molecular characteristics of childhood leukemia are becoming better understood with the advent of genetic technology. As this enhanced knowledge leads to further distinction of subgroups according to molecular characteristics, research is focusing on the development of novel therapies to target molecular abnormalities, a type of treatment that has dramatically changed treatment and outcomes for several types of cancers in adults. Several such drugs are in early studies of children/adolescents with leukemia [212]. Imatinib (an oral drug that has been successful in adults) received FDA approval in 2013 for treatment of pediatric Philadelphia chromosome-positive (Ph+) ALL [213].

Acute Lymphoblastic Leukemia (ALL)

Risk-adapted treatment protocols developed in the 1990s have achieved a cure rate of 80% [93,214]. Most pediatric study groups classify patients with ALL according to three risk categories: standard, high, and very high; COG uses a fourth category for very low probability of relapse [213,215].

In general, treatment of pediatric T-cell or precursor B-cell ALL consists of intensive multidrug chemotherapy for standard-risk patients, allogeneic HSCT for high-risk patients, and antimetabolites for low-risk or very-high-risk patients [36]. CNS prophylaxis, primarily with intrathecal chemotherapy, is used for patients with high-risk disease [67]. Prophylaxis with cranial radiation is reserved for patients at very high risk of relapse, such as patients with CNS involvement at diagnosis or with T-cell ALL [67,213].

Remission Induction

The goals of remission induction therapy are to induce complete remission (defined as eradication of 99% of the initial burden of leukemia cells), to restore normal hematopoiesis, and to regain a normal performance status [36]. This phase of treatment typically lasts four weeks [210]. The rate of complete remission after induction therapy is high, ranging from 96% to 99% [67,210]. Of the patients in whom complete remission is not achieved within the first four weeks of treatment, approximately 50% will experience a toxic death during induction (usually due to infection) and the remaining 50% will have resistant disease [86,149,216,217]. The protocols for children with high-risk or very-high-risk ALL and all adolescents with ALL involve treatment with at least four chemotherapeutic agents. These agents most often include a corticosteroid (prednisone or dexamethasone), vincristine, and asparaginase and/or an anthracycline (doxorubicin or daunorubicin) [210]. The COG protocols reserve the use of a four-drug induction for patients with high-risk B-cell ALL and T-cell ALL and do not include administration of anthracycline during induction to patients with standard-risk ALL [210]. Patients treated by three other study groups receive an induction regimen with four or more drugs regardless of presenting features [210]. A meta-analysis of studies comparing the use of dexamethasone or prednisone showed that dexamethasone was more efficacious, with lower rates of events (death from any cause, refractory or relapsed leukemia, second malignancy, and CNS relapse) but no difference in bone marrow relapse or overall mortality [218]. Dexamethasone was associated with higher rates of toxicity, however, and it is not clear whether the short-term benefits found will translate to better overall survival [218]. A randomized trial comparing doxorubicin and daunorubicin given during induction found no difference in efficacy between the agents in early response measures [219].

The emergence of targeted therapies for treatment of Philadelphia chrome-positive (Ph+) disorders with tyrosine kinase inhibitors (TKIs) represents an important advancement in ALL therapy. Imatinib mesylate is an inhibitor of BCR-ABL tyrosine kinase and, as stated, is approved by the FDA for treatment-naïve patients with pediatric Ph+ ALL [220]. In one study of early response to TKIs during remission induction in children with Ph+ ALL, TKIs (imatinib and dasatinib) produced a marked drop in minimal residual disease levels. At the end of remission induction, nine of 11 patients who received imatinib or dasatinib and conventional induction chemotherapy had remission, compared with two of 16 patients who received chemotherapy alone. The five-year event-free survival rate was 68.6% for the 11 patients who received TKIs compared with 31.6% for the 19 patients who did not [221].

Consolidation/Intensification Therapy

Consolidation/intensification therapy begins after normal hematopoiesis has been restored. Chemotherapy regimens in this phase usually include methotrexate with 6-mercaptopurine (6-MP) and high-dose asparaginase, followed by reinduction treatment (the same regimen given during the first few months of remission induction therapy) [67]. The doses of drugs are increased according to risk, and studies have been done to evaluate the efficacy of higher doses in preventing relapse. Research reported in 2011 demonstrated a significant improvement in event-free survival for children/adolescents with high-risk B-cell ALL when high-dose methotrexate without asparaginase was used compared with standard-dose methotrexate and asparaginase (82% vs. 75%) [222]. Similarly, compared with standard-dose methotrexate, high-dose methotrexate led to significantly better 5-year and 10-year event-free survival for children/adolescents with high-risk T-cell ALL, with rates of 80% vs. 68% and 77% vs. 66%, respectively [223].

In a landmark multicenter COG study of 92 children (1 to 21 years of age) with Ph+ ALL, investigators evaluated whether imatinib (340 mg/m2 per day) with an intensive postinduction chemotherapy regimen improved outcome. Continuous imatinib exposure improved outcome in patients treated with imatinib for 280 continuous days, with a three-year event-free survival of approximately 80%, more than twice that of historical controls. Three-year event-free survival was similar for patients treated with chemotherapy plus imatinib or sibling donor blood and marrow transplantation. There were no significant toxicities associated with adding imatinib to intensive chemotherapy [224]. A follow-up study found that five-year disease-free survival was similar for patients treated with chemotherapy plus imatinib (70%), sibling donor blood and marrow transplantation (65%), and unrelated donor blood and marrow transplantation (59%). The reinduction rate following relapse was similar to other higher-risk ALL groups [225].

Another study assessed the safety and efficacy of oral imatinib in association with a Berlin-Frankfurt-Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for patients (1 to 18 years of age) with pediatric Ph+ ALL [226]. Patients were enrolled by 10 study groups between 2004 and 2009, and were classified as either good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned to receive postinduction imatinib with chemotherapy or chemotherapy alone. All poor-risk patients received postinduction imatinib with chemotherapy. All patients received four postinduction blocks of chemotherapy, after which they became eligible for stem-cell transplantation. Four-year disease-free survival was 72.9% in the good-risk/imatinib group compared with 61.7% in the good-risk/no imatinib group. Four-year event-free survival for poor-risk patients was 53.5% [226].

Continuation (Maintenance) Therapy

Continuation therapy usually consists of weekly methotrexate and daily 6-MP for a period of 2 to 2.5 years [67]. A review of trials involving more than 10,000 children demonstrated that shorter durations of treatment were associated with a higher risk of relapse and death [227,228].

CNS Prophylaxis

Before the routine use of CNS prophylaxis, relapse involving the CNS occurred in approximately 80% of all patients with complete remission [229]. Preventing relapse of disease in the CNS has led to significant improvement in the rate of isolated CNS relapse, which now ranges from less than 2% to 10% [17,93]. Radiation was first used for CNS prophylaxis, but this approach was associated with significant acute and late morbidity, including neurocognitive impairment, second cancers, and endocrinopathy [67,205]. As such, the use of intrathecal chemotherapy, usually methotrexate or cytarabine, is now used in most cases [210]. Children/adolescents with very-high-risk disease may still benefit from cranial radiation, and most treatment protocols limit the use of radiation to these instances, with the use of lower doses [149,210,230].

Treatment for Relapsed or Refractory Disease

Relapse occurs in approximately 25% of patients with ALL [231]. The most common sites of relapse in ALL are bone marrow, the CNS, and the testicles [231]. For bone marrow relapse, reinduction therapy (usually a four-week course of prednisone, vincristine, and an anthracycline, with perhaps the addition of asparaginase) is followed by postremission chemotherapy [231]. Treatment of CNS relapse usually involves intensive systemic therapy, with cranial or craniospinal radiation delayed for six months [232].

In 2017, the FDA approved the first gene therapy for the treatment of B-cell precursor ALL in children and young adults [233]. Tisagenlecleucel is a genetically modified autologous T-cell immunotherapy used in the treatment of refractory or relapsed disease. With this approach, the patient's T cells are collected and modified to include a chimeric antigen receptor that directs T cells to kill leukemias cells, then infused back into the patient. In one study, the three-month remission rate was 83% [233]. However, tisagenlecleucel is associated with potentially severe side effects, including cytokine release syndrome, neurologic events, serious infections, acute kidney injury, and hypoxia [234].

Isolated testicular relapse usually occurs later than either bone marrow or CNS relapse and is treated with intensive chemotherapy that includes high-dose methotrexate. Patients who do not have a complete remission after induction also receive local radiation therapy [210]. Orchiectomy of the clinically involved testis is performed in some European clinical trial groups, with biopsy of the contralateral testis to determine whether additional local control (i.e., surgical removal or radiation) is needed. One study that examined testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease [235]. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) to achieve antileukemic levels in the testes is being tested in clinical trials [210].

Hematopoietic Stem Cell Transplantation

In 2012, the American Society for Blood and Marrow Transplantation (ASBMT) published an update to its 2005 recommendation that HSCT be done after first complete remission of Ph+ ALL when a matched related donor is available [236,237]. Allogeneic HSCT is recommended for children who [237]:

- Are in their second complete remission following an early marrow relapse for B-cell ALL

- Have had failure of primary induction therapy but subsequent complete remission

- Have T-cell ALL in their second complete remission

- Have ALL in their third or greater remission

Allogeneic HSCT is not recommended for patients with T-cell ALL in their first complete remission; patients with the MLL gene plus ALL when it is the sole adverse risk factor; and patients with isolated CNS relapse in B-cell ALL [237]. In general, HSCT approaches benefit only children at high risk for relapse with standard chemotherapy approaches [238].

Infection prophylaxis during HSCT includes confinement in a HEPA-filtered, positive-air-pressure sealed room, strict hand hygiene, antibacterial prophylaxis with fluoroquinolone, and antifungal prophylaxis with fluconazole [239].

Follow-Up and Surveillance

Several organizations have published consensus guidelines for follow-up for late effects following HSCT; however, these guidelines do not address all pediatric-specific challenges to HSCT [240]. The Pediatric Blood and Marrow Transplant Consortium (PBMTC) published six detailed papers to address the lack of detailed pediatric-specific late effects and guidelines for long-term follow-up after HSCT. The PBMTC summary and guideline recommendations provide the most current outline for following up children for late effects after HSCT (Table 14) [241].

Table 14: SELECTED SCREENING RECOMMENDATIONS FOR LATE EFFECTS AFTER HSCT IN PEDIATRIC POPULATION

Effects

Screening

Management

Iron overload

Annual serum ferritin; if elevated, consider T2-weighted MRI

Phlebotomy or chelation

Gastrointestinal

Annual screening for chronic GVHD and hepatitis virus infection

Annual hepatocellular carcinoma screening for high-risk patients (i.e., those with hepatitis C or B infection, obesity, diabetes, or low platelet count)

—

Renal

Monitor urine for albumin:creatinine ratio at day 80 and then annually. If ratio is >30 and <300 mg/g, confirm with two or more tests in 3 to 6 months and monitor every 3 to 6 months. If ratio is >300 mg/g, monitor every 3 to 6 months.

Treat with ACE inhibitor or ARB if albumin:creatinine ratio is >300 mg/g on one occasion or if patient has persistent ratio >30 g/kg on three occasions in a 6-month period and has hypertension.

Pulmonary

Pulmonary function testing for allogeneic recipients twice per year for two years, with consideration for more frequent screening in recipients of mismatched or unrelated donor grafts, or patients with active chronic GVHD. After two years, consider yearly follow-up pulmonary function tests based on symptoms and past measurements.

With a >15% decrease in pulmonary function test values or new pulmonary infiltrate, evaluate for infection/GVHD. Refer to pulmonologist for disease-specific care as needed.

Cardiac

Annual cardiovascular risk assessment

Blood pressure each visit and at least annually

Electrocardiogram/echocardiogram at least every five years, more frequently if patient received anthracycline, total body radiation, or chest radiation

Refer to cardiologist for abnormal or declining cardiac function.

Metabolic

Lipid profile and fasting glucose at least every five years. If abnormal, screen annually.

—

Thyroid dysfunction

Thyroid-stimulating hormone and free thyroxine annually for 10 years after busulfan and for at least 30 years after total body radiation.

Physical examination of thyroid yearly to screen for tumors after total body radiation.

If thyroid-stimulating hormone is high and free thyroxine is normal, either treat or repeat in two months. Replace thyroid as indicated for low levels. Rare secondary thyroid tumors post-TBI can be cured with surgery.

Growth impairment

Accurate measurement of growth yearly through full growth (age 17 years for girls and 19 years for boys). Bone age as needed.

Bone age and referral to an endocrine specialist for a patient not growing appropriately. GH therapy may unmask hypothyroidism.

Low BMD

Dual-energy x-ray absorptiometry scan before HSCT, one year after HSCT, and yearly if z-score is <–1.

Calcium and vitamin D supplementation

Weight-bearing exercise

Avoid smoking, alcohol, and caffeine

For patients with z-score <–2 and/or history of fractures, refer to endocrine specialist.

Osteonecrosis

Consider MRI screen of asymptomatic patients on high-dose steroids

Early MRI screening of any patients with symptoms of joint pain, pain in groin or anterior thigh, or limping

Minimize steroid and alcohol consumption

Offer analgesics

Recommend non-weight-bearing exercise and physical therapy

Refer to orthopedic specialist.

Reproductive risks

Women: monitor for ovarian failure (FSH, assess cycling)

Men: semen analysis

Women: Anti-Müllerian hormone may assess ovarian reserve. Treat ovarian failure with hormone replacement therapy.

Men: If oligospermia noted, may offer intracytoplasmic sperm injection

ACE = angiotensin converting enzyme; ARB = angiotensin receptor blocker; FSH = follicle-stimulating hormone; GH = growth hormone; GVHD = graft-versus-host disease; MRI = magnetic resonance imaging.

Source: [241]

Acute Myeloid Leukemia (AML)

As noted earlier, the event-free and overall survival rates are lower for children/adolescents with AML than for those with ALL. Due to lack of consistent prognostic factors in AML, risk-adapted treatment is not regularly used as it is for ALL; however, risk-adapted and biologically targeted therapies are being tested to improve treatment while sparing normal tissues [39,242]. Optimal treatment of AML requires control of bone marrow and systemic disease [243]. The four-phase approach is not always followed, as the efficacy of the continuation (maintenance) phase has not been proven for the treatment of AML [17,39,243]. The approach to the treatment of AML is similar for all types except for the M3 subtype (acute promyelocytic leukemia), for which chemotherapy is combined with all-trans retinoic acid (ATRA) [17].

The drugs used to treat AML have primarily remained the same, but regimens and timing of treatment have been refined, with current rates of 80% to 90% for complete remission, 30% to 40% for relapse, 50% for event-free survival, and 60% for overall survival [39].

Induction Therapy

The most effective chemotherapy regimen for induction in AML has been an anthracycline, cytarabine, and etoposide [39,243]. Although the regimens used have differed in many ways, including the cumulative doses of drugs, the choice of anthracycline, and the number of treatment cycles, the results have been relatively similar [39].

Consolidation/Intensification Therapy

Studies and one phase III clinical trial have demonstrated that intensive treatment during the consolidation phase leads to decreased relapse rates and better event-free and overall survival for younger patients with AML [17,244]. High-dose cytarabine, usually given with mitoxantrone, has led to improved outcomes for children with high-risk disease [243].

CNS Prophylaxis

Intrathecal chemotherapy is considered by most to be a standard component of treatment of AML, although no studies have compared CNS prophylaxis with no CNS prophylaxis, and it has not been shown to contribute directly to improved survival [17,243]. Cytarabine, methotrexate, or both, along with hydrocortisone, are the preferred agents for prophylaxis. The rate of isolated CNS relapse is reported to be 2% [39]. Cranial radiation is not used for prophylaxis [39].

Treatment for Relapsed or Refractory Disease

Most relapses occur during the first year, and the most common site of relapse is the bone marrow (92%) [245]. Relapse occurs in the CNS in 10% to 20% of patients and in the skin in 4%.

Remission induction chemotherapy regimens have included high-dose cytarabine in combination with fludarabine or mitoxantrone [39,243]. Anthracyclines are effective, but the increased risk for cardiotoxicity limits their use in the relapse setting if they have been used for primary treatment [245]. Liposomal daunorubicin has been added to fludarabine plus cytarabine in an attempt to limit cardiotoxicity [39]. However, cure is unlikely with chemotherapy alone for relapsed AML [39]. Early studies have shown promise for the addition of targeted immunotherapy with gemtuzumab and clofarabine to standard chemotherapy, but more studies are needed [39,246]. In a report from the COG on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent AML, the combination yielded an acceptable response rate without excess toxicity. The nearly 50% survival rate reported suggests that this combination is an effective bridge to HSCT [247]. HSCT is thought to be the only curative treatment for relapse [39,243,244,245,248].

Stem Cell Transplantation

The issue of HSCT in AML, especially with regard to when it should be done, remains a topic of some debate. A meta-analysis demonstrated that transplantation reduced the risk of relapse and significantly improved disease-free and overall survival among many children/adolescents with AML [249]. The review of evidence by the ASBMT led to its recommendation of transplantation after either first or second remission if a matched related donor is available [250]. However, a later meta-analysis showed that transplantation after first complete remission did not lead to significant differences in relapse or disease-free or overall survival compared with no transplantation [251]. Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission [243]. Due to improved outcomes in patients with favorable prognostic features and lack of demonstrated superiority of HSCT, this patient population typically receives matched-family donor HSCT only after first relapse and achievement of a second complete remission [250,252,253,254].

The absence of published recommendations specific for pediatric AML motivated an international group of pediatric hematologists and oncologists to develop evidence- and expert opinion-based consensus recommendations for the management of AML in children [58]:

- For patients with initial hyperleukocytosis and symptomatic coagulopathy and/or leukostasis, emergency strategies should be initiated to reduce the risk of fatal hemorrhage and leukostasis.

- Antifungal prophylaxis (including trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis jirovecii) should be administered to all children.

- The use of fluoroquinolones may be considered as prophylaxis against Streptococcus viridans and gram-negative sepsis.

Follow-Up and Surveillance

The improved outcome in children with AML over the last 10 years is probably associated with better supportive care strategies [58]. Children with AML who receive treatment with contemporary therapy and remain in remission four years from diagnosis probably are cured. Although late relapses and late deaths from other causes are rare, long-term follow-up of survivors is necessary for the timely management of late adverse effects [255].

TREATMENT OF LYMPHOMA

Hodgkin Lymphoma

Standard treatment options achieve cure in approximately 80% to 90% of children/adolescents with Hodgkin lymphoma. The rates have been better for children 10 years of age and younger than for children older than 10 years of age [110,256]. The German Hodgkin Study Group found that adult treatment protocols were safe and effective treatment options for adolescents with Hodgkin lymphoma [257].

The risk-adaptive approach to the treatment of Hodgkin lymphoma involves planning treatment according to prognostic variables such as stage of disease, presence of B symptoms, and tumor bulk [258]. Disease is classified as being low, intermediate, or high risk. Low-risk disease is defined as localized Hodgkin lymphoma (stage I or II and sometimes IIIA) with no B symptoms or tumor bulk. Intermediate-risk disease usually includes stage I or II disease with unfavorable features (B symptoms, tumor bulk, involvement of three or more lymph node regions, and/or extranodal extension to contiguous structures) [110]. Stages III and IV typically represent high-risk disease.

Evidence Based Practice Recommendation

The American College of Radiology recommends that treatment of patients with favorable-risk pediatric Hodgkin lymphoma typically involve two to four cycles of chemotherapy and low-dose, involved-field radiation therapy. In some regimens, the radiation therapy dose has been reduced based on a favorable response to chemotherapy.

https://acsearch.acr.org/docs/70602/Narrative

Last Accessed: August 22, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Favorable-risk (low-risk) disease is defined differently by different clinical trial groups, but for the most part it encompasses patients with localized stage I and II disease without adverse prognostic features (e.g., "B" symptoms, extranodal extension, mediastinal bulky disease). Favorable-risk disease can be treated with reduced therapy, which consists of two to four cycles of multiagent chemotherapy and low-dose (15–25 Gy), involved-field radiation [258,259]. The regimens used most often include etoposide, which has commonly replaced alkylating agents and anthracyclines. Intermediate-risk disease is treated with three to six cycles of compacted, dose-intensive chemotherapy and low-dose, involved-field radiation, usually as consolidation therapy. For high-risk disease, four to six compacted, dose-intensive cycles of chemotherapy in addition to low-dose (15–25 Gy) involved-field radiation therapy to involved sites of disease are recommended [258]. The dose-intensive regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone led to response within four weeks in 74% of children/adolescents with stage IIB or IIB Hodgkin lymphoma with bulk disease or stage IV disease [260]. When followed by guideline-directed consolidation therapy, the treatment led to overall survival of 97% and five-year event-free survival of 94% [260]. Early response to therapy may be considered in determining the need for radiation in those who have complete remission. Advanced radiation techniques, such as intensity-modulated radiation therapy and proton therapy, may be considered depending on the clinical scenario and if an improvement is expected [258,261].

In addition to disease-related factors, the patient's age and sex are primary considerations. A younger age at the time of diagnosis has implications for musculoskeletal and soft-tissue deformities and cardiovascular dysfunction after radiation and/or chemotherapy with an anthracycline [110]. With respect to the patient's sex, the risk of breast cancer is increased for teenage girls who have radiation to the thorax, and girls are at higher risk of cardiomyopathy as a result of anthracycline use [110]. Alkylating agents lead to a higher prevalence of gonadal dysfunction in boys. The German Paediatric Oncology and Haematology Society pioneered risk- and gender-adapted therapy featuring the vincristine, etoposide, prednisone, and doxorubicin regimen for boys to limit the amount of alkylating agents; girls received vincristine, procarbazine, prednisone, and doxorubicin. The HD-95 trial investigated whether radiation therapy could be omitted in patients achieving a complete remission to chemotherapy. Early results (median follow-up time: three years) indicate a 97% event-free survival rate for favorable-risk patients. There was no difference in outcome between favorable-risk patients treated with chemotherapy alone and those treated with combined-modality therapy [262].

Randomized trials have compared chemotherapy alone with chemotherapy plus low-dose radiation for advanced stage Hodgkin lymphoma. The results have primarily indicated that there is no benefit to the addition of radiation in terms of event-free or overall survival, with one study indicating that the addition of radiation was comparable to the addition of a second chemotherapy regimen [114,263]. Researchers continue to debate the issue of adding low-dose radiation to chemotherapy because of the toxicity associated with each modality [264,265,266]. However, the use of radiation therapy may allow for lower doses of chemotherapy agents. In an effort to cure children with Hodgkin lymphoma with minimal side effects, most treatment approaches entail combined-modality therapy with reduced dose radiation. A number of combined-modality therapy protocols exist, and the decision as to how to incorporate radiation therapy should be made within the context of the protocol followed [258].

Treatment for Relapsed/Refractory Disease

Relapse will occur after first-line treatment in approximately 10% to 20% of children with advanced-stage Hodgkin lymphoma [256]. Relapse occurs most often within four years, but late relapse is not rare [258]. Although chemotherapy with ifosfamide, carboplatin, and etoposide in combination or as single agents is effective, the toxicity profiles of the drugs have led investigators to search for alternative treatments. Vinorelbine, ifosfamide, and high-dose methotrexate have been found to be acceptable, but subsequent relapse after high-dose methotrexate has occurred in as many as 50% of children/adolescents [256]. Nonmyeloablative stem cell transplantation has been used in selected patients with high-risk disease [256]. In addition, two cycles of chemotherapy with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and asparaginase (DECAL) plus maintenance therapy and stem cell transplantation was found to be effective for relapsed Hodgkin lymphoma, with a five-year event-free survival of 26% and five-year overall survival of 31% [267]. The COG has evaluated ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) and its derivatives across all risk groups [268,269,270]. Benefits of this regimen include lower cumulative doses of anthracyclines, alkylating agents, and bleomycin compared with MOPP and ABVD regimens used in prior decades. Lower cumulative doses are expected to translate into long-term reductions in second malignant neoplasms and fewer cardiovascular, pulmonary, and fertility complications [271,272,273].

Stem Cell Transplantation

HSCT is usually limited to patients who have relapse or in whom disease is refractory to primary conventional therapy [110,124].

Follow-Up and Surveillance

Most pediatric patients with Hodgkin lymphoma have a favorable outcome; however, there is increasing concern about risks of carcinogenesis from diagnostic and therapeutic radiation therapy and from post-treatment surveillance imaging. In one study, cumulative radiation dosage from diagnostic imaging examinations and the frequency of relapse detection by these examinations were recorded. In the first two years after therapy, patients in remission received a median of 11 examinations. In 13 of 99 patients who relapsed, approximately 1% of surveillance imaging examinations (e.g., CT scan, positron emission tomography [PET] scan, chest radiographs) identified relapsed disease. Given this very low rate, the financial burden of the tests themselves, the high cure rate, and risks of second malignancy from ionizing radiation exposure, modification of the surveillance strategy is recommended [274].

Non-Hodgkin Lymphoma

With standard treatment options, approximately 75% to 80% of children/adolescents with non-Hodgkin lymphoma will survive at least five years, although the survival rate varies according to subtype [43,132,275]. Age may also be a factor. In one study, the five-year event-free survival rate was approximately 79% for adolescents compared with 85% for patients younger than 15 years of age [276]. However, another study found that age was not a factor in increased risk of treatment failure [145]. Instead, the patient's level of lactate dehydrogenase, mediastinal disease, and combined bone marrow-/CNS-positive involvement were independent risk factors in children with mature B-cell non-Hodgkin lymphoma [145].

As with Hodgkin lymphoma, the treatment of non-Hodgkin lymphoma is based on the extent of disease, with the intensity of treatment being increased for more extensive disease [277]. Because non-Hodgkin lymphoma in children is considered to be widely disseminated from the outset, even when apparently localized, combination chemotherapy is recommended for most patients [43]. The event-free survival has been better in some studies in which surgical resection was done. So, there may be some value to this approach if resection can be readily accomplished, especially in cases of large tumor masses [111]. Treatment often consists of a cytoreduction phase to reduce tumor burden, followed by a consolidation phase.

For most studies of treatments done in the United States, patients are categorized into three risk groups: low-risk, which is completely resected stage I disease or stage II abdominal disease; high-risk, which consists of CNS involvement with or without bone marrow involvement; and intermediate-risk, which encompasses disease that is not eligible for the other two groups [111]. Treatment also varies according to the pathologic subtype.

B-cell non-Hodgkin lymphoma can be treated with two or three cycles of combination chemotherapy after surgical resection if there is no measurable tumor burden [43,277,278]. The combination of vincristine, cyclophosphamide, doxorubicin, and prednisone has been highly effective in this setting [211]. A single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma [279]. A pilot study from the COG added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell non-Hodgkin lymphoma [280,281]. For higher risk disease, the addition of two or three courses of chemotherapy, high-dose methotrexate, and high-dose cytarabine was also effective [211,282,283].

Good outcomes for treatment of lymphoblastic lymphoma have been achieved with use of ALL-type regimens consisting of an induction phase of multiagent chemotherapy (eight drugs) followed by a consolidation phase and a maintenance phase of two years, with cranial radiation for CNS prophylaxis [48,284]. This approach was superior to short, intensive pulsed chemotherapy regimens [285,286,287]. Good outcomes also have been reported by the COG with use of a Children's Cancer Group (CCG)-modified BFM ALL regimen (prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, and reduced number of intrathecal treatments during maintenance) [43]. The study randomized 254 patients to the regimen with intensified intrathecal methotrexate (Arm A1) or an adapted non-Hodgkin lymphoma/BFM-95 therapy with high dose methotrexate in interim maintenance but no intrathecal methotrexate in maintenance (Arm B1). Each cohort was randomized to either more or less intensification (cyclophosphamide/anthracycline) (Arms A2/B2) and CNS radiation therapy for CNS-positive patients only [288]. There was no difference in five-year event-free survival among the four arms. Five-year survival for CNS-positive patients was 63%. There was no difference in outcome based on CNS prophylaxis or intensification for CNS-negative patients [288]. In a COG study of 56 children and adolescents with stages I and II disease who were treated with the modified CCG BFM regimen for two years, the COG reported a five-year event-free survival of 90% and a five-year overall survival of 96% [289].

For patients with a mediastinal mass, radiation targeting the mass is not necessary except as emergency treatment to relieve airway obstruction or superior vena cava syndrome [43,112]. In such cases, low doses of radiation are used. Cranial radiation may be reserved for patients with CNS involvement at the time of diagnosis [287].

Several treatment strategies have been used for anaplastic large-cell lymphoma, and the outcomes have been comparable [43,113,137]. Treatment has been adapted to risk in some cases, usually according to stage of disease [137]. Common agents are corticosteroids, vincristine, doxorubicin, and methotrexate, but the doses have varied substantially. A course of chemotherapy similar to that used for B-cell non-Hodgkin lymphoma, with treatment stratified by stage of disease, was effective for disseminated anaplastic large-cell lymphoma, as was treatment that included a short cytoreduction phase (two chemotherapy cycles) followed by a short maintenance phase (five to seven months) [136,137]. In an international study of systemic childhood anaplastic large-cell lymphoma, 12 of 463 patients had CNS involvement; three of the 12 had isolated CNS disease. Comparative analysis of CNS-positive and CNS-negative patients showed no difference in anaplastic lymphoma kinase positivity, immunophenotype, presence of B symptoms, or other sites of disease. With multiagent chemotherapy, the event-free and overall survival rates of the CNS-positive group at five years were 50% and 74%, respectively [290]. CNS involvement in anaplastic large-cell lymphoma is rare at diagnosis [43].

CNS Prophylaxis

The use of radiation therapy is limited in children with non-Hodgkin lymphoma. Early studies showed that routine CNS prophylaxis had no benefit for patients with low-risk (stage I or stage II) disease [291]. It has been demonstrated that CNS prophylaxis can be omitted in lymphoblastic lymphoma [287,292]. It can also be eliminated for patients with anaplastic large-cell lymphoma and B-cell non-Hodgkin lymphoma, even those who present with CNS disease [137,282]. These findings are supported by data from the Childhood Cancer Survivor Study, which demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors [293].

Treatment for Recurrent or Refractory Disease

Relapse occurs in approximately 12% of children/adolescents with non-Hodgkin lymphoma [275]. Intensive chemotherapy with drugs that were not used in first-line treatment have been utilized, and stem cell transplantation support has been effective for patients with chemosensitive disease [111,294,295,296,297]. Two cycles of chemotherapy with DECAL, maintenance therapy, and stem cell transplantation was found to be effective for relapsed non-Hodgkin lymphoma, with a five-year event-free survival of 23% and five-year overall survival of 30% [267].

Although outcomes in pediatric B-non-Hodgkin lymphoma have improved with intensive chemotherapy protocols, the long-term adverse effects of therapy and poor outcomes for patients who relapse continue to be challenges [43,298]. One study evaluated the potential risks and benefits of routine relapse surveillance imaging after the completion of therapy among 44 patients with non-Hodgkin lymphoma who were diagnosed and treated at Texas Children's Cancer Center between 2000 and 2011 [298]. Only three of the 44 patients had relapse (6.8%) and none of the relapses were initially diagnosed by CT or PET scans. The median effective radiation dose per patient was 40.3 mSv (range: 0–276 mSv). This study highlights the low relapse rate following complete response at the end of therapy among children/adolescents with B-non-Hodgkin lymphoma, the low sensitivity of early relapse detection by surveillance imaging, and the costs and potential increased risk of secondary malignancies from cumulative radiation exposure from surveillance imaging [298].

10. SUPPORTIVE CARE

Supportive care is integral to the treatment of leukemias and lymphomas and addresses the symptoms and potential complications of both the disease and treatment. Children should be followed closely during active treatment; the primary oncologist usually coordinates this care. However, the child's primary care provider may also be involved, especially if the family's home is far from the pediatric cancer center. In addition, routine visits with the primary care provider should continue for overall health maintenance. These visits provide an opportunity to assess symptom management and the development of complications. Good reciprocal communication between the primary care provider and the primary oncologist is essential. The primary oncologist should send a copy of the patient's treatment plan to the primary care provider, and both clinicians should maintain communication about complications as they occur [299].

Supportive care focuses on the treatment of infection, neutropenia, anemia, thrombocytopenia, and other complications, such as metabolic disturbances and deep vein thrombosis. Also essential is symptom management, which centers on enhancing the quality of life.

INFECTION

Of primary concern during treatment for leukemia or lymphoma is the risk of infection, which is the leading cause of morbidity and mortality among children with cancer [17,300]. Infection is a result of the severe immunosuppression caused by both treatment (chemotherapy and radiation therapy) and the disease process itself. Immunosuppression and associated neutropenia increase the risk for opportunistic infection with bacterial, viral, fungal, and protozoal organisms [300,301]. Most infections that occur in children during or after treatment for leukemia or lymphoma are the same as those found in healthy children [301].

Evidence Based Practice Recommendation

According to the Advisory Committee on Immunization Practices, the measles, mumps, rubella, and varicella vaccine should not be administered routinely to children who have leukemia, lymphomas of any type, or altered immunity of any kind.

https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html

Last Accessed: August 22, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Prevention of infection includes general measures such as meticulous hand hygiene (for the patient and all who come in direct contact) and the avoidance of environments where the risk of infection transmission is high. Playing in dirt or gardens or near construction sites may pose a risk of fungal infection [300]. In addition, it is important to protect the integrity of the skin and mucosal surfaces, as they serve as barriers to infectious pathogens [301]. Proper oral hygiene, with daily tooth brushing and use of chlorhexidine mouth rinse, is important, and rectal suppositories and rectal thermometers should not be used [300]. Unless the child is at high risk for fever and neutropenia, routine prophylaxis against viral, bacterial, and fungal agents is not recommended [301,302,303]. One exception is prophylaxis for Pneumocystis jiroveci (formerly Pneumocystis carinii), which occurs in 15% to 20% of children treated for ALL [301,304,305]. Prophylactic treatment consists of trimethoprim-sulfamethoxazole (TMP-SMZ), given either daily or on three consecutive days per week [305,306,307]. Treatment with TMP-SMZ on two consecutive days per week has also been shown to be effective [308].

Several trials have shown the efficacy of antibiotic prophylaxis in reducing the incidence of bacterial infections but not in reducing mortality rates. One systematic review evaluated whether there remains a benefit of reduction in mortality when compared with placebo or no intervention [309]. The review included 109 trials (involving 13,579 patients) that were conducted from 1973 to 2010. The reviewers found that, when compared with placebo or no intervention, antibiotic prophylaxis significantly reduced the occurrence of fever, clinically and microbiologically documented infection, and other indicators of infection. There were no significant differences between prophylaxis with quinolone or TMP-SMZ with regard to death from all causes or infection; however, quinolone prophylaxis was associated with fewer side effects leading to discontinuation and less resistance to the drugs thereafter. The benefits of antibiotic prophylaxis outweighed the harms (e.g., adverse effects, development of resistance) because all-cause mortality was reduced [309].

Children receiving treatment for leukemia or lymphoma who have a fever (38.5 degrees Centigrade or two temperatures of at least 38.0 degrees Centigrade within 24 hours) should be evaluated carefully for infection. Vital signs should be assessed, and physical examination should include evaluation of common sites of infection (respiratory system, ears, sinuses) as well as occult sites (mouth, skin, perianal area) [300]. Laboratory testing should include a CBC, blood cultures, urinalysis, and urine culture [300]. The absolute neutrophil count (ANC) should be determined, as neutropenia is the most significant predisposing factor for infection [300,310]. Approximately 70% to 80% of bacterial infections occur in children who have moderate neutropenia [310]. The presence of fever and neutropenia requires hospitalization for empiric treatment with intravenous administration of broad-spectrum antibiotics [311]. One randomized controlled trial evaluated the use of ciprofloxacin in children younger than 18 years of age with ALL or lymphoma who were scheduled to undergo chemotherapy [312]. A total of 95 children were randomized to receive oral ciprofloxacin 20 mg/kg/day (45 children) or placebo (50 children) from the beginning of their chemotherapy. Rectal swab cultures were taken before and at one and/or two weeks after the intervention. Of the 71 patients who developed neutropenia, the proportion of children who developed fever was significantly lower in the ciprofloxacin group than in the placebo group. Ciprofloxacin significantly reduced the occurrence of febrile episodes in patients with ALL in the induction phase of chemotherapy, but not in patients with lymphoma or in the consolidation phase of chemotherapy. Adverse effects were not different between the groups [312].

Evidence Based Practice Recommendation

The Children's Oncology Group recommends obtaining blood cultures at the onset of fever and neutropenia in children with cancer from all lumens of central venous catheters.

https://www.childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document_Dec_2017.pdf

Last Accessed: August 22, 2018

Strength of Evidence/Level of Evidence: Strong recommendation, low-quality evidence

The risk of infection is also increased for children who have an indwelling central venous catheter. Indwelling venous catheters are used in most children/adolescents with cancer to facilitate the administration of medications, fluids, and blood products. The risk of infection related to these catheters has ranged from approximately 3% to 60%, and the risk is greater with external catheters than with implanted ones [313,314]. Care of external catheters requires strict adherence to aseptic technique, daily flushing of the catheter, and frequent changes of the sterile dressing [301]. If a fever develops, blood for cultures should be obtained through the catheter and from a peripheral site and empiric treatment with antibiotics should be started. Routine removal of the catheter is not necessary, as nearly 75% of catheter-related infections resolve with the catheter intact [315]. However, if signs of septicemia develop and bacteremia persists 48 hours after the start of antibiotic administration, the catheter should be removed [300]. The catheter should also be removed immediately if the infection is fungal.

The presence of a central venous catheter also requires prophylactic antibiotics before invasive procedures, including dental cleaning or procedures. The prophylaxis used is that recommended by the American Heart Association for children with congenital heart disease: amoxicillin, 50 mg/kg (maximum of 3 grams), given one hour prior to the procedure [316].

NEUTROPENIA

Neutropenia is defined as an ANC of less than 1,000/mcL. An ANC of less than 500/mcL is considered to be moderate neutropenia, and an ANC of less than 200/mcL is severe neutropenia [300]. As noted, neutropenia is a significant factor for the development of infection. In the adult setting, neutropenia is prevented and managed with the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). In the pediatric population, clinical protocols for leukemia usually include guidelines for the use of CSFs. Research to evaluate their use has been limited, and the results have varied [313,317,318]. One meta-analysis of 16 randomized controlled trials involving nearly 1,200 children with cancer, primarily leukemia and lymphoma, demonstrated that the prophylactic use of CSFs was associated with a 20% decrease in febrile neutropenia, a lower number of documented infections, and shorter hospital stays [319]. However, other studies, including a meta-analysis, have indicated that CSFs have no significant effect on the incidence of infection [317,320]. It is important also to note that the use of CSFs in children with ALL has been associated with an increased risk for secondary myeloid leukemia or myelodysplastic syndrome [321]. Given these findings, the American Society of Clinical Oncology states that the use of CSFs in children with ALL should be "considered with caution" and recommends that primary prophylaxis with CSFs is "reasonable" for children in whom febrile neutropenia is likely [318]. Secondary prophylaxis with CSFs should be limited to children at high risk [318]. The risk of AML has also led to the recommendation to avoid the routine use of CSFs after induction therapy [313,318]. Pegfilgrastim, a recombinant G-CSF used to prevent neutropenia in adults, has been shown to be safe and effective for children [322].

The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary, multinational group of pediatric oncology and infectious diseases experts. In 2017, the Panel published an updated clinical practice guideline for the management of fever and neutropenia in children with cancer and in HSCT recipients [303]. The Panel addressed risk stratification and evaluation as well as therapeutic interventions, and it made strong or weak recommendations related to initial presentation, ongoing management, and antifungal therapy of pediatric fever and neutropenia. The Panel's strong recommendations are summarized in Table 15 [303].

Table 15: INTERNATIONAL PEDIATRIC FEVER AND NEUTROPENIA GUIDELINE PANEL RECOMMENDATIONS FOR THE MANAGEMENT OF FEVER AND NEUTROPENIA IN CHILDREN WITH CANCER

Recommendation

Level of Evidence

Remarks

Initial Presentation of Fever and Neutropenia: Initial Management

Risk stratification: Adopt validated risk stratification strategy and incorporate into routine clinical management

Low-quality evidence

Strategy choice should be determined by validation in similar context; ability to implement based on complexity, availability of required components (e.g., biomarkers)

Evaluation: Obtain blood cultures at onset of FN from all CVC lumens

Low-quality evidence

—

Evaluation: Obtain chest radiography in patients with respiratory signs/symptoms

Moderate-quality evidence

Patients at High Risk for Fever and Neutropenia: Treatment

Use monotherapy with antipseudomonal β-lactam, fourth-generation cephalosporin, or carbapenem as empirical therapy

High-quality evidence

Monotherapy may be not be appropriate for centers with high rate of resistance, or for patients who present with hemodynamic instability

Reserve addition of second gram-negative agent or a glycopeptide for patients who are clinically unstable, when resistant infection is suspected, or for centers with high rate of resistant pathogens

Moderate-quality evidence

Threshold for when rates of resistance are sufficiently high to support empirical combination or glycopeptide therapy has not been established, will vary by institution

Ongoing Management (Excluding Empirical Therapy)

Modification of treatment: In patients who respond to initial empirical antibiotic therapy, discontinue double coverage for gram-negative infection or empirical glycopeptide (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy

Moderate-quality evidence

Rationale is same as that for recommendation for initial empirical monotherapy. The Panel valued reducing unnecessary antibiotic administration to reduce toxicity, costs, and antibiotic resistance.

Modification of treatment: Do not modify initial empirical antibacterial regimen based solely on persistent fever in children who are clinically stable

Low-quality evidence

Modification of treatment: In children with persistent fever who become clinically unstable, escalate initial empirical antibacterial regimen to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria

Very low-quality evidence

Cessation of treatment: In all patients, discontinue empirical antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of marrow recovery

Low-quality evidence

—

Empirical Antifungal Therapy

Risk stratification: Patients at high risk of IFD are those with AML, high-risk ALL, or relapsed acute leukemia, and children undergoing allogeneic HSCT. Children with prolonged neutropenia and children receiving high-dose corticosteroids are also at high risk of IFD. All others should be categorized as low-risk IFD.

Low-quality evidence

Risk stratification rules are not yet available for prediction of IFD. The Panel recognized that high-risk ALL is a heterogeneous group and this risk may be explained by prolonged neutropenia and corticosteroid administration. No data available to specify which ALL patients is at particular risk of IFD.

Evaluation: Do not use β-D-glucan.

Low-quality evidence

—

Evaluation: Do not use fungal PCR testing in blood

Moderate-quality evidence (new recommendation)

—

Evaluation: In terms of imaging for evaluation of prolonged (≥96 hours) FN in IFD high-risk patients, perform CT of the lungs

Low-quality evidence

Lungs consistently most commonly affected site. Optimal timing of initial and repeated imaging not known.

Treatment: In IFD high-risk patients with prolonged (≥96 hours) FN unresponsive to broad-spectrum antibacterial agents, initiate caspofungin or liposomal amphotericin B for empirical antifungal therapy

High-quality evidence

—

FN = fever and neutropenia; CVC = central venous catheter; IFD = invasive fungal disease; AML = acute myeloid leukemia; ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; PCR = polymerase chain reaction; CT = computed tomography

Source: [303]

ANEMIA OR THROMBOCYTOPENIA

Evidence Based Practice Recommendation

According to the Council of Pediatric Hematology/Oncology Centres across Canada, prophylactic platelet transfusions are recommended at a platelet threshold of 10 x 109/L for clinically stable pediatric patients receiving chemotherapy for leukemia.

https://www.c17.ca/index.php/download_file/view/42

Last Accessed: August 22, 2018

Strength of Evidence/Level of Evidence: 1C (Strong recommendation, poor-quality evidence)

Myelosuppression caused by chemotherapy may lead to anemia and thrombocytopenia. In these cases, blood products may be needed. No hemoglobin level has been established as a threshold for transfusion of blood; the need for transfusion of packed red blood cells (preferred to whole blood) is based on careful evaluation of individual patients [313]. Transfusion was once done for a hemoglobin of less than 10 g/dL, but most clinicians now consider 7–8 g/dL as the threshold due to the risks associated with transfusions [300,313]. Erythropoietin at a dose of 600 units/kg to 900 units/kg once weekly for 16 weeks has been shown to be safe for increasing the hemoglobin level and decreasing the need for transfusion among children 5 to 18 years of age who were being treated with myelosuppressive chemotherapy for nonmyeloid cancers [323].

As with transfusion of blood products for anemia, the need for transfusion of platelets is based on the individual case. Platelet transfusion is rarely indicated during remission induction for ALL, but prophylactic platelet transfusions are usually given during treatment for AML when the platelet count declines to less than 10,000/mcL [313]. If a child has fever, sepsis, a history of bleeding, severe mucositis, coagulopathy, or hyperleukocytosis, prophylactic transfusion of platelets may be given with the presence of a higher platelet count (for example, 20,000/mcL) [313]. If a child is to have an invasive procedure, a transfusion should be given to maintain a platelet count of 40,000–50,000/mcL [300].

METABOLIC DISTURBANCES

The rapid destruction of malignant cells can lead to a build-up of chemicals in the bloodstream. This accumulation of biochemicals can cause several metabolic disturbances, including hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia [310,324]. Collectively, these abnormalities comprise tumor lysis syndrome, which is most commonly associated with high tumor burden [111,112]. Prompt management of tumor lysis syndrome is necessary to prevent renal failure. The management approach has involved increased hydration with a hypotonic solution and administration of allopurinol; however, recombinant urate oxidase has been shown to be more effective than allopurinol [111,112,310,324].

DEEP VEIN THROMBOSIS

The risk of deep vein thrombosis is increased for children with a central venous catheter (CVC), and the likelihood of thrombosis is higher for children who have had catheter-related infection or occlusion of the catheter [325]. Deep vein thrombosis (DVT) in these cases usually develops without signs or symptoms. In a study of 21 children with a catheter-related deep vein thrombosis, signs or symptoms occurred in only five [325]. Repeated complications, primarily occlusions, should prompt investigation for thrombosis [300,325]. Treatment consists of a thrombolytic agent, such as tissue plasminogen activator [300,326]. One prospective registry study found that insertion of peripheral central catheters (specifically, Hickman catheters), insertion in an angiography suite, and proximal-tip location significantly increased the risk of symptomatic CVC-related DVT. Positive family history of thrombosis also significantly increased the risk of CVC occlusion [327].

11. PALLIATIVE AND END-OF-LIFE CARE

The term palliative care is often used synonymously with end-of-life care. However, palliative care is increasingly being defined as care that focuses on enhancing the quality of life for the patient (child or adult) and family, regardless of whether curative treatment is being undertaken. As optimally defined, pediatric palliative care [170,328,329,330,331,332,333]:

- Begins at the time of diagnosis

- Is family-centered and includes the child and the child's family, including siblings

- Is delivered by a multidisciplinary team

- Addresses physical symptoms and psychosocial issues

- Addresses the family's spiritual issues (e.g., faith, culture, religion, clergy, questions about the meaning of pain/suffering and death/dying)

- Enhances the quality of life for the patient and family

- Provides assistance with advance care planning and practical concerns (e.g., location of end-of-life care)

Recognizing the need for more effective pediatric palliative care, the AAP issued a statement recommending that "the components of palliative care are offered at diagnosis and continued throughout the course of illness, whether the outcome ends in cure or death. Palliative care should be accessible in any setting, including home, hospital, and school" and should be patient- and family-centered [331,334]. Despite the calls for a family-focused approach to pediatric palliative care, a gap remains between optimal family care and actual practice, due in part to the ambiguity and ambivalence about the meaning of "caring for the family" [333].

Effective communication among all caregivers and between parents and the patient is essential to providing optimum palliative care. The goals of treatment should be clearly articulated among the palliative care team and the family to facilitate collaboration and delivery of care [170]. As much as possible and appropriate, the child should be allowed to participate in discussions about the direction of care [331,335]. Parents have repeatedly stated that compassionate, honest, and complete information, ready access to staff, emotional expression by staff, and staff support are critically important to their ability to make decisions concerning their children. Family needs in this area are high [336,337,338,339].

ASSESSING AND MANAGING SYMPTOMS

The assessment and management of symptoms represent the cornerstone of palliative care [170,340]. Symptom management is crucial not only to relieve physical and psychologic suffering but also to avoid feelings of mistrust and fear [335]. In general, studies have shown that pain, fatigue, and nausea/vomiting are the most common physical symptoms in children being treated for cancer [170,335,341,342,343]. Symptoms differ, however, according to age, the type of cancer, the type of treatment, and the degree of distress they cause. For example, in one study, 35% of children/adolescents 10 to 18 years of age had clinically significant pain, lack of energy, drowsiness, nausea, cough, lack of appetite, and psychologic symptoms; the most distressing symptoms were pain, insomnia, mouth sores, and difficulty swallowing [344]. A similar study of younger children, 7 to 12 years of age, demonstrated lethargy, pain, or insomnia occurring in approximately 33%, with pain, insomnia, pruritus, nausea, sadness, and worry being the most distressing symptoms [345].

Effective management of symptoms requires careful assessment, physical examination, and functional evaluation, all of which should be repeated at regular intervals to ensure ongoing alleviation. Several tools are available to assess pain. However, such tools are lacking for other symptoms, highlighting the importance of the patient's self-report of symptoms. A symptom checklist for children can help facilitate monitoring and self-reporting of symptoms [343]. Symptom management should be timely and include both pharmacologic and nonpharmacologic strategies [170,328,335]. Because stress and anxiety can exacerbate physical symptoms, attention to psychosocial issues is essential for optimum symptom management.

Pain

Pain may be related to treatment, diagnostic procedures, and/or progressive disease. The patient's self-report of pain, when possible, is the most reliable indicator [50,335]. Assessment of pain must be appropriate for each child's age, developmental level, and cultural context. Pain assessment tools have been developed for several different age groups among children/adolescents, from birth to 18 years of age, and for nonverbal or cognitively impaired children (Table 16) [50,346,347,348,349,350,351,352,353,354,355]. These tools are designed to either provide a score according to a set of behavioral cues, as in the case of infants and young children, or allow the child to self-report on the intensity and location of pain. Several tools have been modified and validated for use among children/adolescents of different races/ethnicities, including black, Hispanic, Asian, and Alaska Native populations [356,357,358,359].

Table 16: INSTRUMENTS USED FOR PAIN ASSESSMENT IN CHILDREN AND ADOLESCENTS

Age of Child

Assessment Tool

Birth to 3 years of age

FLACC (Face, Legs, Activity, Cry, Consolability)

CRIESa

Neonatal Infant Pain Scale

Children's Hospital of Eastern Ontario Pain Scale (CHEOPS)

3 to 7 years of age

Faces Scale

Oucher

Pain thermometers

Body maps

Older than 7 years of age

Visual analog scale

Verbal response scale

aThe five parameters are crying, requires oxygen to maintain saturation greater than 95%, increased vital signs, expression, and sleepless.

Source: [50; 346; 347; 348; 349; 350; 351; 352; 353; 354; 355]

It is also helpful to evaluate behaviors to determine if a young child has pain. Indicators of pain in infants include facial expressions such as frowning, a furrowed brow, a quivering chin, crying, sucking, flexing of fingers and toes, and breath-holding. Behavioral indicators are also important for older children, as they may not admit to having pain because of fear of an injection. Indicators in older children include decreased energy level; decreased eating; lack of interest in usual activities; holding or protecting part of the body; seeking comfort or closeness; and whining or groaning [346,347,348,349,350].

Physical examination and functional evaluation are other components of pain assessment. During the examination, the clinician should watch closely for nonverbal cues that suggest pain. These cues are especially important when examining patients who are unable to verbally communicate. To evaluate how pain may be influencing function, the clinician should watch the patient to see how pain limits movements and should ask the patient or family how the pain interferes with normal activities. Determining functional limitations can help enhance patient compliance in reporting pain and adhering to pain-relieving measures, as clinicians can discuss compliance in terms of achieving established functional goals.

As with adults, using the WHO ladder to manage pain is effective for children [360,361,362]. The WHO ladder involves a three-step approach, with the strength of the analgesic agent increasing according to the severity of pain. There are two important underlying principles of the WHO ladder. First, analgesics should be administered on a regular schedule rather than on an as-needed basis. This approach is not only more effective at controlling pain but also avoids unnecessary pain as a prompt for the next dose. The second principle is that treatment should correspond to the intensity of pain as reported by the patient, regardless of whether treatment at a previous step was carried out [360].

The WHO ladder calls for the use of nonopioid and opioid analgesic agents (Table 17). Rotation of opioids has been found to be effective and can help avoid dose-limiting toxicity [170]. Medications for pain should be given by the easiest, least painful route (oral, sublingual, or parenteral for children with a central venous catheter), avoiding intramuscular injections whenever possible [170,335].

Table 17: PHARMACOLOGIC APPROACHES TO PAIN RELIEF IN CHILDREN AND ADOLESCENTS

Drug (Route)

Typical Initial Dose, Interval

Maximum Dose

Notes

Nociceptive Pain

Acetaminophen (PO, PR)

10–15 mg/kg every 4 to 6 hrs

1.0 g/dose, 4 g/day

Oral form available as tablets, chewable tablets, liquid, and drops

Ibuprofen (PO)

5–10 mg/kg every 8 to 12 hrs

400 mg/dose, 1.2 g/day

Oral form available as tablets, chewable tablets, liquid, and drops

Choline magnesium trisalicylate (PO)

7.5–15 mg/kg every 12 hrs

1.0 g/dose

Oral form available as tablets and liquid

Naproxen (PO)

5–10 mg/kg every 12 hrs

1.0 g/dose

Oral form available as tablets and liquid

Ketorolac (PO, IV, IM)a

0.5 mg/kg every 6 hrs

10 mg/dose (PO);

30 mg/dose (IV)

–

Codeine (PO, SQ, IM)

0.5–1 mg/kg every 3 to 4 hrs

60 mg/dose

Oral form available as tablets and liquid

Tramadol (PO)

1–2 mg/kg every 6 hrs

Titrate

–

Morphine (PO, SL, PR)

0.15–0.3 mg/kg every 3 to 4 hrs

Titrate

Oral form available as tablets and liquid

Morphine (IV, SQ, IM)

0.1 mg/kg every 2 to 4 hrs

Titrate

–

Hydromorphone (PO, PR)

0.03–0.08 mg/kg every 3 to 4 hrs

Titrate

Oral form available as tablets and liquid

Hydromorphone (IV, SQ, IM)

0.015 mg/kg every 2 to 4 hrs

Titrate

–

Methadone (PO)

0.2 mg/kg every 8 to 12 hrs

Titrate

Oral form available as tablets and liquid

Methadone (IV, SQ, IM)

0.1 mg/kg every 8 to 12 hrs

Titrate

–

Fentanyl (Transdermal)

0.5–1 mcg/kg/hr every 48 to 72 hrs

Titrate

–

Fentanyl (Lozenge [sedative])

5–15 mcg/kg every 4 to 6 hrs

Titrate

–

Fentanyl (IV, SQ)

1–2 mcg/kg every 1 to 2 hrs

Titrate

–

Oxycodone (PO)

0.1 mg/kg every 3 hrs

Titrate

Oral form available as tablets and liquids

Neuropathic Pain

Gabapentin (PO)

5 mg/kg every 6 to 8 hrs

3.6 g/day

–

Amitriptyline (PO)

0.2 mg/kg at night

1 mg/kg/night

–

aGive for no more than five days.

PO = by mouth; PR = per rectum; IV = intravenously; IM = intramuscularly; SL = sublingually; SQ = subcutaneously.

Source: [50,335]

There are no randomized controlled trials addressing the management of breakthrough pain in children with cancer. Limited data and considerable experience indicate that breakthrough pain in this patient group is common, underassessed, and undertreated [363]. Clinicians and parents should also be alert to breakthrough pain, which occurred in 57% of children with cancer in one study [364]. The risk of breakthrough pain was higher for younger children (7 to 12 years of age) than older children (13 to 18 years of age). The high rate of breakthrough pain reflects the importance of pain assessment as an ongoing process, with assessment and documentation at regular intervals. The optimum interval varies. In general, patients with more severe disease should be evaluated more frequently. Measures of pain relief should also be documented, especially with regard to efficacy.

An ideal therapeutic agent would be easy to administer and rapid in onset with short duration. The most common and effective strategy seems to be multimodal analgesia that includes an immediate-release opioid (e.g., morphine, fentanyl, hydromorphone) administered intravenously by a patient-controlled analgesia pump, ensuring an onset of analgesic action within minutes. Intranasal fentanyl (or hydromorphone) may be an alternative, but no pediatric data have been published for commercially available fentanyl transmucosal application systems, and these products cannot yet be recommended for use with children with cancer and breakthrough pain [363].

Pain medication should be complemented by nonpharmacologic interventions that are begun early in the course of treatment. These interventions should be age-appropriate. Touch, massage, stroking, and rocking work well for infants, toddlers, and young children; distraction is effective for older children, as are guided imagery, music and art therapy, play therapy, controlled breathing, and relaxation techniques [50].

Fatigue

Fatigue is often described by children as "drowsiness," feeling "sluggish," or having a loss of energy. As many as 70% to 80% of children/adolescents with cancer note one of these feelings, which can be caused by many factors, including medications (chemotherapy agents and opioids), pain, anemia, progressive disease, and psychologic issues [329,335,343]. Tools to assess fatigue, for use by patients (7 to 12 years of age), parents, and healthcare staff, have been developed but require evaluation and validation in prospective studies [365]. Signs and symptoms of fatigue include asthenia, sleep disturbances, low energy level, and decreased participation in activities. Gradual increases in exercise and school activities and cognitive-behavioral approaches to improve coping skills may be helpful.

One study evaluated the change in children's and adolescents' fatigue scores during cancer treatment and described possible causes of fatigue [366]. Forty children 7 to 12 years of age, 29 adolescents 13 to 15 years of age, and one parent were included in the study. Cancer-related fatigue was measured using the Child Fatigue Scale, the Adolescent Fatigue Scale, and the Parent Fatigue Scale. Children, adolescents, and parents reported a statistically significant increase in fatigue scores during their treatment, with medical procedures and the hospital environment reported as major causative factors of the fatigue experienced [366]. Results of another study indicate that cancer-related fatigue results in a low health-related quality of life for pediatric patients [367].

Gastrointestinal Symptoms

Nausea and vomiting are the most common gastrointestinal symptoms in the pediatric cancer setting; other symptoms include constipation, diarrhea, and anorexia/cachexia. Nausea and vomiting can be a challenge to assess, especially in young children who are unable to articulate the feeling of nausea. Inactivity, signs of weakness, and/or lack of appetite may indicate nausea. The choice of antiemetic is based on the likely cause of nausea and vomiting [170,335]. The best agents for nausea and vomiting caused by chemotherapy or radiation therapy are 5-HT3 receptor antagonists, such as ondansetron and granisetron. Other choices are prochlorperazine, scopolamine, dronabinol, and metoclopramide [110,170,335,368]. Anticipatory nausea may be alleviated by benzodiazepines and the use of relaxation techniques [310,335]. Use of a hydration fluid may be necessary to prevent dehydration in a child who is vomiting excessively [335]. Taking medications after meals, when possible; eating small, frequent meals; and avoiding strong smells may also help ease nausea [170].

Constipation is also common among children/adolescents with cancer and is usually related to medications, particularly opioids and vincristine [335]. This symptom is often under-recognized or undertreated by clinicians [170]. The optimum treatment for constipation is prevention through a variety of measures, including movement/exercise, adequate fluid intake, and increased fiber intake. Regular use of laxatives is recommended during treatment with opioids [50].

Mucositis

Mucositis occurs in as many as 50% of children/adolescents receiving chemotherapy. It is often associated with radiation therapy to the head and neck area [310,324]. Mucositis can affect the mouth, esophagus, stomach, duodenum, and colon, and the severity depends on the type of chemotherapy used. High-dose methotrexate and high-dose cytarabine are considered the most damaging to mucosa [324]. Small studies have shown that chlorhexidine is beneficial for alleviating mucositis in children, but the results must be confirmed by larger trials [369]. One literature review focused on randomized clinical trials to evaluate the effectiveness of chlorhexidine mouthwash in alleviating mucositis in children receiving chemotherapy [370]. Control groups consisted of placebo, no intervention, or another intervention group. Mucositis was scored using either the WHO scale or the modified Oral Assessment Guide. Five studies fulfilled the inclusion criteria, in which chlorhexidine was evaluated. Four of the five showed a significant preventive effect on the development or severity or mucositis when chlorhexidine mouthwash was used. The remaining study showed no benefit compared with the placebo group [370]. Other helpful measures include the use of ice chips during administration of chemotherapy, excellent oral hygiene, analgesic agents, and avoidance of irritating foods or fluids, such as citrus fruits and juices [310,324].

Pruritus

Pruritus usually occurs as a side effect of medications, especially morphine and other opiates, and may also be associated with progressive lymphoma [50]. Physical manifestations of pruritus include excoriation, erythema, and lichenification; rubbing of the eyes, nose, or skin may also indicate pruritus [335]. Discontinuing use of the causative medication, if possible, is the preferred treatment approach. Moisturizing creams may be used for dry skin, and systemic corticosteroids or antihistamines may be helpful for more severe cases [335].

PSYCHOSOCIAL AND SPIRITUAL ISSUES

Anxiety, worry, and sadness are among the most frequently occurring psychologic symptoms for children/adolescents with cancer [170,335,344]. These emotions are a normal response to many effects of cancer and its treatment, including pain and other symptoms, disease progression, impaired function, isolation, loss of control, concern about parents and other family members, and loss of a "normal" life [170]. Clinicians and other caregivers should address such fears and concerns honestly and should encourage family members to discuss them openly with each other and the patient.

Specially trained members of the palliative care team can play an important role in helping patients and their families deal with psychosocial issues. Child-life specialists and creative art therapists are available in hospital settings to guide patients in expressing their feelings through creativity and imagination [170]. This process can help foster the patient's sense of control and independence and enhance self-esteem [170]. Psychologists on the palliative care team can assess the psychologic needs of both the patient and family and implement interventions as appropriate.

Spiritual support for the child and family is an important component of palliative care and is usually the primary responsibility of a pastoral care worker on the palliative care team. However, all professional caregivers should provide spiritual support. Spirituality transcends religion and involves such concerns as hope, forgiveness, love, and sense of meaning [335]. Caregivers should talk with the patient about his or her dreams and hopes for the future and encourage the patient and family to express spiritual concerns and engage in their religious traditions [332].

PROVIDING END-OF-LIFE CARE

The high survival rates for children with leukemia and lymphoma has of course led to a decreasing number of childhood deaths. Still, 10% to 30% of patients will have relapsed disease and die. Despite the fact that these children would benefit from hospice care delivered by a multidisciplinary palliative care team, studies have shown that most children with cancer die in the hospital [371]. However, one report indicated a significant increase in the number of children/adolescents who died at home since the late 1990s, and a survey of bereaved parents and pediatric oncologists ranked home as their first choice for end-of-life pediatric cancer care [372,373]. Still, hospice care is used by only 5% to 25% of eligible children in the United States and Canada [374].

The movement to formally develop high-quality palliative care programs began in the late 1990s. The AAP issued the first policy statement on pediatric palliative care in 2000. Then in 2003, the Institute of Medicine recommended specialty training in pediatric palliative care and development of collaborative guidelines and protocols tailored to children [375,376]. In 2006, St. Jude Children's Research Hospital (St. Jude) made development of a pediatric palliative care program an institutional priority, with the mission to "provide each child living with or dying from a catastrophic illness with state-of-the-art patient- and family-centered physical, emotional, and spiritual care with the goal to attend suffering, promote healing, and improve quality of life" [377,378,379]. In 2007, St. Jude initiated a one-year pilot project to evaluate the role of pediatric palliative care expertise as part of the interdisciplinary care team. The pilot program was a success, and in 2008, St. Jude fully implemented the Quality of Life Service (QoLS) program throughout the hospital. The program functioned on a consultative basis, working together with patients' primary care teams. QoLS consults included advanced care planning; symptom control; care coordination and continuity; emotional, social, and spiritual support; end-of-life care; and bereavement support in inpatient, outpatient, and home-based settings. The QoLS also provided more than 200 educational offerings across all professions in the institution and partnered with medical and psychosocial providers [380].

In 2016, members of the St. Jude Department of Oncology, Division of Quality of Life and Palliative Care, in collaboration with others, published results of a study that described the institution's eight-year experience integrating palliative care with cancer care for pediatric patients [380]. According to the results, new consults per year increased from 17 in the pilot year to 115 in 2014. Patient encounters increased from 58 in the pilot year to 1,297 in 2014, indicating that the QoLS not only saw more patients but also followed them more regularly and for longer periods of time. Mean encounters per patient by year of initial consult more than tripled, from 5.1 in 2007 to 16.1 in 2014, substantiating that patients were seen with increasing regularity and sustained continuity from the time of consultation [380]. In the early years of the program, the primary patients' goal of care at initial consultation was focused on "comfort only," but this shifted over time to a "goal of cure," which increased from 25% of patients in 2008 to 58% in 2014. Following the pilot year, there was also a shift in patients' location of death from primarily inpatient settings to increased use of outpatient settings. The authors were unable to determine the preferred location of death, but increased use of outpatient locations suggest that increased availability of palliative care services facilitated outpatient end-of-life care and a greater ability to satisfy the preferences of patients and their families [380]. This led the American Society of Clinical Oncology to recommend palliative care services for all high risk oncology patients. Yet, as stated, both adult and pediatric oncologists refer only a small proportion of patients to palliative care services, and then it is late in the disease course when the goal of cure is no longer an option [381,382,383,384].

There is a significant association between race/ethnicity and hospice enrollment, with Latinos enrolled in hospice significantly more often than patients of other races. However, by the time of death, 34% of Latinos and 50% of non-Latinos had withdrawn from hospice [385]. The lack of appropriate end-of-life care has a high price; one study indicated that 89% of dying children suffered "a lot" or "a great deal" from at least one symptom in their last month of life [386]. The findings of that study and others, including the Institute of Medicine (IOM) report When Children Die: Improving Palliative and End-of-Life Care for Children and Their Families, have prompted further research on the topic [330,340,345].

Several barriers to pediatric end-of-life care have been identified (Table 18) [170,330,335,387,388]. Because of the low rate of mortality, the lack of relevant educational programs, and the paucity of palliative care services across the United States, particularly in pediatric facilities, many healthcare professionals are left inexperienced with pediatric end-of-life care [387,388,389,390]. In addition, the availability of sufficiently trained pediatric hospice professionals is limited because of the low rate of hospice admissions for children/adolescents. One survey found that pediatric palliative care is only offered in 58% of Children's Oncology Group institutions caring for children with cancer [388]. Other challenges to providing high-quality care include growing demands for expansive care, discomfort in providing mental health/bereavement services to families, and reimbursement models that do not support comprehensive care [333]. The increasing demand for expansive care, including palliative care services, led St. Jude to expand the QoLS resources, which included: more clinical and research staff; a hospice and palliative medicine fellowship training program; and creation of a home-based palliative care and hospice program in collaboration with the local children's hospital and community hospice [380].

Table 18: BARRIERS TO PEDIATRIC END-OF-LIFE CARE

- Rarity of death among children

- Immeasurable parental distress at loss of child

- Unrealistic expectations or denial of parents

- Association of palliative care with "giving up" or hopelessness

- Provider sense of failure when a child dies

- Difficulty in determining prognosis

- Lack of symptom assessment tools

- Lack of knowledge regarding pediatric dosing of symptom-relief medications

- Fragmentation of medical and psychosocial/spiritual services for children

- Lack of adequately trained pediatric hospice professionals

- Lack of comprehensive, coordinated pediatric palliative care programs

- Inadequate education for providers and families about palliative care

Source: [170,330,333,335,380,384,387,388,390,391,392]

The potential death of a child goes against the natural order and is associated with feelings of distress and failure for parents as well as clinicians. Parents and family members continue to hope for a cure and often see the end of curative therapy as "giving up" [335,393]. In a survey of pediatric oncologists, the most frequently reported barrier to end-of-life care was unrealistic expectations of the family, noted by approximately 48% of respondents [394]. Family denial was another commonly reported barrier, noted by 36% of respondents [394]. Paradoxically, the high rates of cure and long-term survival associated with most pediatric leukemias and lymphomas foster parents' hope for cure [330,393]. Feelings of denial and hope are also factors in late hospice referrals. Most hospice referrals are made at the time of disease progression (44%), at the end of therapeutic options (26%), or at the time of imminent death (20%) [387]. Earlier hospice referral, such as at the time of disease relapse, would enhance the quality of care for children and their families, yet only 2.5% of referrals are made at that time [387]. A survey of pediatric oncologists found that they were less likely to refer patients after chemotherapy had been stopped and more likely to refer at the time of diagnosis of cancer/incurable cancer. They also preferred that "supportive care" be used in place of "palliative care," because the term was negatively perceived by their patients [384].

Clinicians usually recognize the lack of a realistic chance for cure before parents and should talk openly with parents about discontinuing aggressive treatment and directing attention to enhancing the quality of life that remains for the child [395]. At this point, it is helpful to emphasize the importance of alleviating pain and other symptoms and making the child comfortable [170]. In addition, the family should understand that the primary oncologist and/or primary care provider will remain involved in the child's care [170]. Members of the palliative care team should discuss goals of treatment with the family, outline choices for interventions as the end of life draws near, and establish limits of care as the health status changes [170,328].

The symptoms present at the end of life are similar to those that occur during treatment, although research has shown that some are more common or more intense in the end-of-life period [340]. Pain, nausea, drowsiness, and energy loss have been reported by more than half of children/adolescents (6 to 17 years old) with advanced cancer [340,396]. Other common symptoms include dyspnea, weight loss and anorexia, vomiting, and constipation [340]. Bone marrow failure may occur as a result of progressive disease, leading to infection, fatigue, and bleeding [340]. Transfusion of blood products can provide symptomatic relief, and their use should be considered on an individual basis.

In a study in which symptoms among various types of cancer were evaluated, the symptoms most commonly associated with pediatric leukemia and lymphoma during the end-of-life period were pain (95%), weakness (83%), anemia (76%), bleeding (66%), infection (59%), and weight loss and anorexia (56%) [340]. Overall, symptom management was more effective for children with leukemia or lymphoma than for children with solid tumors, but weakness and anorexia remained intractable among all patients [340]. How aggressively symptoms are treated will depend on many factors, including how close the child is to death and the defined limits of care. The underlying goal is to keep the child as comfortable as possible. In addition to the management of symptoms, "comfort interventions" should be integrated into care (Table 19) [397].

Table 19: COMFORT CARE INTERVENTIONS

Intervention

Description

Quiet presence

Sit quietly to provide calming influence and comfort that family is near

Massage

Ask the child what he or she would like massaged (e.g., feet, back); play quiet music to aid in relaxation

Touch

Hold hand or gently touch or stroke the child in familiar comforting manner

Music/television/DVD

Play child's favorite music, television show, cartoon, movies for familiar comfort and distraction

Toys/blanket

Provide the child with his or her favorite item for comfort

Picture board

Have family and friends gather pictures of fun past events shared with the child and place the pictures on a bulletin board or poster board near the bed

Books

Ask the child which book he or she would like to hear and read aloud

Family, friends, spiritual support person, pets

Honor the child's requests to see family members, pets, etc.

Source: [397]

Dyspnea is particularly present near the end of life, occurring in approximately 30% of children with leukemia and lymphoma [340,386]. Objective measures of dyspnea do not correlate well with subjective sensation. But because the symptom is extremely distressing and frightening to both the patient and the family, treatment should be directed at alleviating the patient's discomfort and distress promptly [335]. The use of oxygen, opiates, and/or benzodiazepines can provide symptomatic relief [170,335]. Nonpharmacologic interventions include relaxation techniques and the use of fans to blow air across the child's bed [170].

The need for spiritual support is heightened during the end of life as children and family prepare for dying [335]. Faith and the involvement of clergy play a critical role in decision making about end-of-life care [332]. A survey of pastoral care workers indicated that more than half of patients and 60% to 80% of parents had spiritual needs [398]. Because the illness experience, primary fears, and concept of death range according to the child's developmental age, appropriate spiritual interventions vary (Table 20) [170,328,335]. Patients grieve because of the isolation and loss associated with the disease, and the palliative care team should provide support for this process [399]. Many parents avoid talking with their ill child about death for many reasons, primarily because they do not wish to acknowledge the fact to themselves or the child. However, most dying children are aware that they are dying, and talking about it with family can help them to express important feelings and to say good-bye [170,330]. One retrospective study showed that parents who talked with their child about death did not regret it, whereas more than 25% of parents who did not talk to their child about death regretted that decision [399]. In addition, levels of anxiety were higher among parents who did not discuss death with their child. Another retrospective study investigated the rationale and consequences of a parent's decision to discuss death with their child [400]. The study involved bereaved parents of a child who died of cancer. Eighty-six parents of 56 children responded to questions about the topic. Of these, 55 parents of 35 children did not discuss the impending death. Their reasons for not discussing death were varied and included: parents' inability to discuss the impending death; their desire to protect their child; their general views about talking with children; their perceptions of their child's characteristics; the child's unwillingness to discuss death; a lack of opportunity to have the discussion; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they discussed the subject directly and briefly. A majority of the parents interviewed felt positive about their ultimate decision [400]. Parents should be encouraged to talk to their spiritual or religious advisor for guidance in how to talk with their child [170]. Strict adherence to Western ethical norms may not always be the best choice for migrant or immigrant patients and their families. Instead, an approach that is based on cultural humility may allow for a greater understanding and improved communication between patient/family and caregivers [401].

Table 20: FEARS, CONCEPTS OF DEATH, AND SPIRITUAL INTERVENTIONS ACCORDING TO DEVELOPMENTAL AGE OF CHILDREN AND ADOLESCENTS

Age

Primary Fears

Concept of Death

Spiritual Interventions

Infant

Separation; strangers

Unable to differentiate death from temporary separation or abandonment

Provide consistent caretakers

Minimize separation from parents and significant others

Decrease parental anxiety

Maintain crib/nursery as "safe place" (no invasive procedures)

Encourage parental presence

Encourage/facilitate use of spiritual support system for the family

Toddler

Separation; loss of control

Recognizes death in terms of immobility

Often viewed as reversible, temporary, or foreign

Minimize separation from parents and significant others

Keep security objects at hand

Provide simple, brief explanations

Explain and maintain consistent limits

Encourage participation in daily care

Provide opportunities for play and play therapy

Reassure the child that disease is not punishment (by God, Higher Power, or other authority figure)

Early school-age child

Bodily injury and mutilation; loss of control; the unknown; the dark; being left alone

Recognizes death in terms of immobility

Often viewed as reversible, temporary, or foreign

Begins to question and develop a mature concept

Do not underestimate level of comprehension

Provide simple, concrete explanations

Provide advance preparation (days for major events, hours for minor events)

Use pictures, models, actual equipment, medical play when providing explanations

When appropriate, initiate discussion of love and caring from Higher Power to relieve anxiety and loneliness

Show behavioral qualities of love, trust, respect, caring, and setting of firm limits and disciplining without anger

School-age child

Loss of control; bodily injury and mutilation; failure to live up to expectations of important others; death

Recognizes all the components of irreversibility, universality, nonfunctionality, and causality

Provide choices whenever possible

Stress contact with school or organized religious peer group

Use diagrams, pictures, and models for explanations

Emphasize the "normal" things the child can do

Reassure child that he/she has done nothing wrong; hospitalization is not punishment

Be alert to anxiety about being punished by deity

Provide appropriate concrete explanations in response to questions regarding spiritual beliefs

Continue spiritual rituals; if appropriate, promote prayer and relationship with child's concept of God

Model behaviors that show forgiveness and acceptance

Adolescent

Loss of control; altered body image; separation from peer group

Speculates on the implications and ramifications of death

Understands effect of death on other people and society as a whole

Future-oriented, difficult to understand reality of death as a present possibility

Allow adolescent to be an integral part of decision making regarding care

Give information sensitively

Allow as many choices and as much control as possible

Be honest about treatment and consequences

Stress what the adolescent can do for himself or herself and the importance of cooperation and compliance

Assist in maintaining contact with peer group

Provide answers without bias and enable participation in discussions of illness in terms of philosophical or spiritual beliefs

Encourage contact with friends and use of spiritual rituals if appropriate

Observe and document verbalizations of adolescent's values and beliefs

Source: [170,328,335]

Bereavement and Grieving

Bereavement and grieving support are other essential components in end-of-life care [170,333,399]. Bereavement care may best address grief by providing family members with outlets to communicate feelings and memories about a dying or deceased child [402,403]. It is important to provide support for siblings, who report often feeling left out and abandoned [333,399]. Despite a growing body of literature substantiating the needs of siblings, they continue to be unmet [404,405,406,407]. Siblings also may experience post-traumatic stress symptoms, poor quality of life, and a sense of aloneness [408]. Healthcare providers can address the needs of siblings by [408,409,410,411]:

- Engaging them in discussions about care

- Providing them with specific caregiving tasks

- Ensuring that they have adequate support (e.g., child life specialist, social worker, support group) and education

- Encouraging them to remain active in activities important to them

- Identifying a "safe adult" in which the sibling can confide

- Making mental health referrals when appropriate

- Asking sibling directly about his or her experiences

Grief can be prolonged and exacerbated by several factors, including the loss of the child's quality of life, the family's dissatisfaction with the provider-family rapport and communication, cultural insensitivity, and lack of follow-up [170]. This finding underscores the need for effective end-of-life care and open, honest, empathic communication from the palliative care team. In addition, caregivers should respect the family's cultural context when designing and discussing treatment plans and goals. Also, it is imperative that family members be allowed to hold their child during and after death and to carry out family, religious, and cultural rituals.

In most cases, the grieving process is considered to be in its end stages when bereaved individuals are comfortable with a restructured lifestyle [412]. However, parental grief related to the loss of a child is generally experienced more intensely and differently than other forms of grief because a child's death is atypical in developed countries [413]. Parents can maintain healthy bonds with their deceased children by sharing memories about their children, writing biographies, performing annual religious rituals, and establishing monetary memorials [414,415]. The maintenance of the connection through conversation appears to aid in healing for grieving parents [415].

Grieving is relieved by the continued involvement and support of the palliative care team and the primary care provider after a child's death [416]. Attendance at a memorial service and handwritten notes of sympathy from the clinician and medical team are valued highly by grieving families [409,417]. The clinician should emphasize the personal strengths of the family that will help them cope with the loss and should offer help with specific issues. The note should also invite the patient to contact the physician or other members of the palliative care team with questions. Provision of bereavement services varies. Programs usually involve contacting the family at regular intervals to provide resources on grieving, coping strategies, professional services, and support groups. Frequent contact with family after death can ensure that families are adjusting to the loss [333]. Referrals for psychosocial and spiritual interventions should be made as early as possible to optimize their efficacy. Bereavement services should extend for at least one year after the patient's death, but a longer period may be necessary.

12. PSYCHOSOCIAL ISSUES FOR THE PATIENT AND FAMILY

In the 1960s, psychosocial interventions focused on bereavement during palliative care because of the low survival rates for common childhood cancers. Today, the excellent survival rates produced by advances in treatment challenge clinicians with more complicated familial psychosocial issues and increase the need for a variety of intervention strategies.

Evidence Based Practice Recommendation

The Cincinnati Children's Hospital Medical Center strongly recommends that primary caregivers of newly diagnosed pediatric oncology patients receive psychosocial interventions of cognitive behavioral therapy or psychoeducational therapy to reduce anxiety, emotional distress, post-traumatic stress symptoms, and negative mood and enhance effective coping skills and adjustment.

https://www.cincinnatichildrens.org/-/media/cincinnati%2520childrens/home/service/j/anderson-center/evidence-based-care/recommendations/specialty-discipline/psychosocialinteroncolbest143psycho-socialinterventionsbest143final11-28-12.pdf

Last Accessed: August 22, 2018

Level of Evidence: High

Addressing psychosocial issues is an integral component of comprehensive cancer care not only to help patients and their families cope with a cancer diagnosis and the stress related to treatment, but also to help alleviate latent psychosocial distress. The diagnosis and course of a child's cancer can detrimentally affect family members' interactions with one another and their social environment. Yet, responding to childhood cancer can prompt positive growth if psychosocial issues are managed effectively. Although many families are resilient, the negative psychosocial consequences for one or more family members touched by a child's cancer can be lasting and severe. Studies have found that the psychologic distress experienced by family members is often greater than that experienced by the patient [418]. For example, parents, who are already distressed by their child's illness also often struggle with conflicted feelings when their role as parent means they must manage the competing needs of various family members. The authors of one qualitative analysis sought to identify parental expectations of support from healthcare providers during a child's life-threatening illness [419]. Based on thematic analyses conducted with data from 31 semi-structured interviews of parents, the authors identified three themes and one overall expectation [419]:

- "Help us survive this."

- "Let's fight together. Please fight with me, not against me, to care for my family."

- "Guide me through the darkness. I am suffering."

The overall expectation was for mutuality with the healthcare providers and healthcare system in order to keep fighting together for the family's survival [419].

Clinicians in the pediatric and family medicine setting are well-positioned to monitor family members' coping abilities and psychosocial states during the trajectory of the illness. Most parents believe that psychosocial issues should be discussed with the child's physician and would find that discussion to be valuable [169]. However, less than 50% of parents raise such topics, and parents report that only 15% to 20% of physicians assess the family's psychosocial issues [169]. Clinicians may be able to provide the auxiliary emotional support and guidance the child and his or her family needs [419,420]. If necessary, they can refer at-risk family members to intervention programs/specialists to improve coping strategies and promote healthy psychologic adjustment.

PSYCHOSOCIAL ISSUES FOR THE PATIENT

The anxiety and stress associated with cancer and its treatment require that patients use effective coping mechanisms. Due to the wide range in age of patients with childhood leukemia and lymphoma, coping mechanisms vary according to a child's level of understanding and stressors. Similarly, the potential late effects and the actions to promote well-being also differ. In addition to disrupting a child's psychologic well-being, the period of cancer treatment affects a child's relationships with peers and school performance. The psychosocial issues discussed in this section focus primarily on issues arising during treatment.

Coping Mechanisms

Coping has been defined as the "constantly changing cognitive and behavioral efforts to manage the specific external and/or internal demands that are appraised as taxing or exceeding the resources of the person" [421]. The two main types of coping are problem-focused and emotion-focused [421]. The goal of problem-focused coping is to change aspects of an event to relieve distress. If the individual cannot manage a stressful event, emotion-focused coping is used to regulate feelings or alter his or her interpretation of the situation. Emotion-focused coping mechanisms intended to alter interpretations are categorized into four control strategies: predictive control, vicarious control, illusory control, and interpretative control [341]. These control strategies are used commonly by children and their parents when coping with cancer [342,343]. Using combinations of problem-solving and emotion-regulating mechanisms to meet each cancer-related challenge decreases short-term distress and promotes healthy social and cognitive development and adaptation [422].

The majority of studies have shown that the psychologic profile of childhood leukemia or lymphoma survivors is similar to population norms, suggesting that most children with leukemia or lymphoma will cope effectively with their cancer experience [423,424]. However, subgroups of these patients are at special risk for poor psychologic outcomes [425,426,427].

As children learn and grow, they construct the world around them differently. Thus, the developmental age at the time of a cancer diagnosis defines the type and complexity of coping mechanisms available to the patient throughout the course of the disease [428,429]. The level of understanding and stressors, coping mechanisms, potential long-term effects, and actions a medical team can take to promote well-being vary according to the developmental age [430,431].

Infants (Birth to 12 Months of Age)

Level of understanding and stressors: The infant's understanding of treatment is limited to pain and comfort. Infants undergoing cancer treatment can have a difficult time developing trust and bonding with parents because medical procedures often separate infants from their parents, disrupt household routines, and cause pain. An infant frequently separated from parents may experience feelings of abandonment [432].

Coping mechanisms: Infants are limited to certain aspects of emotion-focused coping because crying is an emotional release. With few available coping mechanisms, the infant's emotional development and future coping abilities can be affected adversely by cancer.

Potential long-term effects: A child diagnosed with cancer during infancy may experience cognitive delay. Difficulty bonding with parents may affect subsequent developmental stages.

Actions to promote well-being: To offset cancer-related developmental disruptions, the medical team should allow parents to stay in the infant's room and attend to his or her needs, such as feeding, diaper changing, comforting, and bathing. In addition, minimizing the number of staff caring for the child may promote trust and a sense of routine.

Toddler (18 Months to 3 Years of Age)

Level of understanding and stressors: A toddler diagnosed with cancer has different developmental challenges than an infant. However, a toddler still has limited understanding of cancer-related cause and effect and has limited access to coping mechanisms. Because a toddler's sense of time is restricted to the present, the child will likely not grasp that staying still reduces the time and pain associated with treatment. The toddler's level of understanding may exceed his or her ability to communicate, which is another barrier to coping. During this stage of development, a toddler explores his or her sense of self, property, and security. Cancer therapy, however, challenges a toddler's autonomy and feeling of safety. For instance, a toddler will likely say "no" to treatment, only to be vetoed. In addition, the toddler may perceive that his or her parents cannot protect him or her from pain associated with treatment. Although a toddler's understanding of death is minimal, he or she likely has some concept of loss and separation and may fear abandonment when parents are out of sight. The health-related quality of life for toddlers with cancer is significantly worse than that of healthy age-matched controls. Cancer most strongly affects a toddler's sleep, appetite, behavior, and liveliness [433].

Coping mechanisms: A toddler has access to more emotion-focused coping strategies to regulate stress than an infant and has developed some problem-focused strategies. Communication skills, although limited, can be used to express emotions and seek parental support and solace. To gain more control over his or her environment, a child may hold a parent's hand during a painful procedure to know that the parent is near. Pain endured during a procedure may be associated with the staff member providing the respective treatment.

Potential long-term effects: During this stage, a cancer diagnosis may postpone language and motor development as well as bladder and bowel control. Toddlers' development in these areas may regress.

Actions to promote well-being: Parental handling of a toddler's cancer-independent needs should be made routine to minimize the child's feelings of abandonment or insecurity. Motor skill development accelerates at this age; therefore, safe levels of physical activity should be promoted. Also, giving a toddler limited choices, even in the smallest matters, supports their sense of autonomy. For instance, a provider could ask a toddler, "Would you like a bandage with cartoon characters or a regular one?"

Early School-Age (4 to 7 Years of Age)

Level of understanding and stressors: Although the degree of development of a child at 4 years of age may be much different from that of a child at 7 years of age, children of these ages have surpassed the cognitive and emotional development of toddlers. Concepts of empathy and guilt are developing. Injury and death may be believed to be magically reversible, as in many children's cartoons. Patients who are 6 to 7 years of age at the time of a cancer diagnosis have been shown to have poor health-related quality of life with respect to autonomy, motor skills, and cognitive functioning two months after treatment [433].

Coping mechanisms: Early school-age children can cope using emotion-focused methods and some problem-focused strategies. A child in this age category can communicate feelings and needs more clearly than a toddler and has a better understanding of cause and effect. Both of these factors elevate the child's ability to cope actively with stressors and express negative emotions. Children understand the concept of hopefulness during this stage, which can promote a positive outlook and adaptive coping [434]. Regardless of the cancer stressors experienced, patients with a high sense of humor have better psychosocial adjustment and fewer infections [435].

Potential long-term effects: Experiencing leukemia can interfere with the proper development of an early school-age child's social and academic skills [436,437,438,439]. Without honest, age-appropriate discussions about the child's prognostic information and death, the development of thinking based on logic rather than fantasy may be delayed [440]. Children in whom cancer is diagnosed after 5 years of age are more likely to experience post-traumatic stress symptoms because they are able to understand the seriousness of their illness. However, they are also more likely to experience post-traumatic growth, characterized by a positive shift in perspective and priorities, because they can appreciate their inner strength and others' support [441].

Actions to promote well-being: A child may believe that his or her cancer diagnosis and treatments are punishments for bad behavior. Parents should be advised that rewarding good behavior during and after procedures with praise and small rewards (e.g., stickers) can promote a child's healthy development and ability to cope with cancer. Negative behaviors should not receive extra attention. To avoid developmental delay of reality-based thinking, parents should also be advised to answer a child's questions about the cancer honestly and in an age-appropriate manner [440]. Role-play discussions should be performed to assist in understanding how to best tell an individual child distressing news [177]. Discussions should be tempered by the expression of hope, which is a very important coping strategy in any pediatric cancer situation. School attendance should be encouraged because social and academic skills can be developed and peers can serve as an important support system for children with cancer [437]. Animal therapy programs may reduce a young child's emotional distress and promote socialization [442].

School-Age (8 to 12 Years of Age)

Level of understanding and stressors: Compared with self-reports in other developmental age groups, self-reports of children with cancer who are 8 to 12 years of age and secondary assessments were more likely to emphasize emotional distress over physical distress. Emotional stressors include confinement, feelings of alienation, and worries before medical procedures. The pain associated with diagnostic procedures and treatments is the most frequently mentioned physical aspect of cancer-related distress [443]. By 9 years of age, children understand that death is irreversible; however, their concept of the future is still very limited [444]. Some children may try to "protect" their parents from fearing death by avoiding conversations about the subject. However, avoidance of these discussions causes a child to suffer in isolation [182,440].

Coping mechanisms: Communication and logical reasoning skills available to children in this age range promote the development of problem-focused coping. Children may be more interested in learning about their cancer and its treatment because they want to master social and cognitive skills; intellectualizing the problem is one coping strategy children of this age may use. Emotion-focused coping skills are also more advanced because a school-age child is more likely to communicate emotions to seek others' support [443].

Potential long-term effects: Intensive treatments may interrupt the development of social and academic skills. Although the child's communication skills are more sophisticated, sharing concepts that are "too adult" for the child can affect socialization with peers and personality development.

Actions to promote well-being: A cancer diagnosis poses a challenge to a child's desire for equality and fairness. Its effects on schoolwork and physical activity may leave the child feeling inferior to peers, angry, and frustrated [437]. Such emotions may manifest as withdrawal or depression; the child may hide these feelings from parents. Thus, listening carefully and discussing feelings is imperative to understanding the child's problems. Art, writing, music, and dance/movement therapy can provide the child with expressive outlets [445,446,447]. Although children may desire to know all about their illness, parents and the treatment team must provide age-appropriate education. Too much exposure to decision making and adult responsibilities may disrupt a child's socialization with peers. As for any school-age child, school attendance is beneficial for social and academic development, and children should therefore be given the tools necessary to transition back into a school routine [437].

Adolescent (13 to 18 Years of Age)

Level of understanding and stressors: During this stage, adolescents are attempting to individualize themselves. However, identity formation in adolescents with cancer may revolve around their illness. Although adolescents understand death, they may feel it only happens to others. The most frequently reported emotional stressors are worries before medical procedures and feelings of alienation [344,443,448]. Compared with age-matched controls, children 12 to 15 years of age with cancer have a significantly lower health-related quality of life with respect to motor functioning [433].

Coping mechanisms: Coping strategies commonly used by adolescents during treatment include positive thinking, avoiding thoughts of treatment, keeping busy, focusing on positive outcomes, and staying relaxed [448,449,450]. One study found that better problem-solving skills were associated with lower adolescent distress [451]. A systematic review analyzed how childhood cancer patients and survivors communicate about their cancer with family and peers [452]. Participants were adolescents and young adults 16 to 34 years of age. Communication occurred on a spectrum with variations in who the youth shared information with, how often they shared information, and the amount and type of information they shared. The reviewers found that communicating about cancer was a beneficial coping strategy and that it prompted social support and appeared central to significant relationships. Barriers to communication (e.g., fear of stigma, poor peer reactions) hindered the participants' willingness to disclose [452]. Post-treatment coping strategies include negotiating to regain/gain autonomy, cognitive reliving of the cancer experience with peers or the medical team, and forgetting the negative aspects of treatment [449]. Potential long-term effects: One large, retrospective study has suggested that adolescents with cancer achieve autonomy, psychosexual development, and social development at an older age than peers [453]. Diagnosis at adolescence has been linked to an increased risk for the development of post-traumatic stress disorder [426]. However, one study found that personality factors, such as adaptive style, were a stronger determinant of post-traumatic stress than health history [454]. Another study of 435 youth (253 with cancer, 182 healthy controls) found that the relationship between post-traumatic stress symptoms and post-traumatic growth depended on contextual factors and that the majority of the youth (83%) were resilient and able to find benefit from stressful life events [455].

Actions to promote well-being: The physical and emotional changes of this final stage of childhood are conjoined with a desire for private space. However, honoring an adolescent's desire for privacy can be difficult during hospitalizations. A sense of privacy and respect, as well as cooperation, can be maintained by knocking before entering an adolescent's room, asking permission when introducing new people, and being mindful of the adolescent's physical modesty during examinations. To promote treatment compliance in older adolescents, equal medical information should be provided to patients and their parents. Adolescents should have the option to lead treatment discussions in order to enhance feelings of respect, control, and independence. Getting to know others with the same disease, treatment, or situation—especially those who are cured—may help adolescents cope, and emerging technology, cancer-related video games, and social networking are helping adolescents with cancer to better understand their disease, comply with treatment, and connect with one another [9,448,456]. Parents should be dissuaded from controlling treatment discussions and decision making without the adolescent's approval, which can lead to acting-out (externalizing) or internalizing behaviors in the patient.

Gender Differences in Coping Mechanisms

Some studies have shown differences in the coping styles of male and female children/adolescents with cancer. One study found that older female children (12 to 18 years of age) use a wider repertoire of emotion-focused and problem-focused coping strategies than their male counterparts [457]. Among male participants in the study, use of emotion-focused coping was linked to a disposition to experience anger and anxiety but not depression. Emotion-focused coping in the female participants was not associated with these variables. Depressive symptoms were less likely to develop in female participants who used problem-focused strategies.

In another study, male children 11 to 18 years of age were found to use disengagement coping strategies, such as problem avoidance, wishful thinking, social withdrawal, and self-criticism, more often than female children did [458,459]. Engagement coping strategies include problem-solving, cognitive-restructuring, social support, and expression of emotions. Male children were also found to use humor coping significantly more often than girls in a study of children 7 to 14 years of age who had ALL [435,460]. Healthy psychosocial adjustment was strongly correlated to humor coping [435].

Relationships with Peers

Mothers are the most commonly reported source of social support by children/adolescents with cancer. As a child with cancer develops into an adult, however, his or her social support needs extend beyond the family. Socialization with peers contributes to coping abilities and psychologic adjustment of children/adolescents with cancer [461,462,463]. For adolescents 12 to 14 years of age, family-independent social networks are significantly smaller than those of adolescents 15 to 18 years of age, which may contribute to less effective coping. The emotional support of peers is particularly important for continued participation in school and social activities [463]. Hospitalizations, poor physical health/appearance, academic difficulties, and poor parental coping skills can also limit the patient's development of relationships with peers [437,464].

School-Related Issues

Regular attendance at school is difficult during cancer treatment, but clinicians should emphasize to patients and their parents that going to school is an important part of normal life. School can help to reduce the social isolation associated with cancer and enhance the child's self-esteem [300]. School reintegration programs have been found to improve children's psychosocial well-being (anxiety and depression), social well-being (social competence and social support), behavioral problems, and physical competence, but more research is needed to investigate the effects of these and other related interventions [184,465].

In preparing for the child/adolescent to re-enter school, the primary care provider should guide parents in developing questions and issues to discuss with teachers and other personnel at the school. Topics that should be addressed with school personnel include [466]:

- Child's diagnosis and treatment plan

- Information on low blood counts and the risk of infection

- Central venous line issues

- Importance of contacting the parents when the child has a fever

- Immunization restrictions

- Attendance issues

- Administration of medicine

- Activities that the child cannot participate in

- Whether special permission is required to wear a hat or scarf in school

- Whether the child may take extra time to move between classrooms

- Possibility of tutors in specific subjects

Cancer and its treatment are often associated with learning problems, and parents should be aware for the potential for difficulties with handwriting or spelling, reading comprehension, remembering math facts, copying information after seeing it, and completing tasks on time [466].

Psychosocial Interventions

A meta-analysis of the effects of psychosocial interventions on psychologic outcomes in children with cancer showed that patient-oriented therapies do not effectively reduce child distress or improve child adjustment [467]. The authors of the study suggested several reasons for this finding: children with cancer have psychologic outcomes similar to those of healthy children; the average length of follow-up of the studies analyzed was only four months; and most studies used a waitlist/standard care control group instead of a control group with a generic psychosocial intervention providing nonspecific support or attention. Waitlist control groups do not control for nonspecific treatment variables such as social support from other group members or facilitators. One systematic review identified a broad range of psychosocial interventions that could benefit cancer survivors and their families, but concluded that more high-quality studies are needed to optimize the healthcare services that can best support children and their families [468].

PSYCHOSOCIAL ISSUES FOR THE FAMILY AND FAMILY DYNAMICS

Childhood cancer can place every family member at risk for the development of psychosocial problems. Several studies have been conducted to explore the psychosocial dynamics within family units.

Patient and Parents

Parental factors linked to the psychologic outcomes and quality of life for a child with cancer include education, communication styles, and coping strategies [437,458,465,469,470,471,472,473].

- Parental education: Children with cancer are more likely to experience poor psychologic adjustment if their parents' education level does not exceed high school.

- Parental communication styles: Most healthcare professionals agree that parents should talk openly, honestly, and age-appropriately to a child about his or her illness. Open lines of communication protect children with cancer from suffering emotional distress in isolation and promote high-quality care. In addition, poor cancer-related communication is linked to children's and adolescents' noncompliance with cancer treatments.

- Parental coping strategies: Coping mechanisms of parents can be reflected by children with cancer. A correlation study demonstrated similarities in the use of disengagement coping—in particular, problem avoidance—by parents and their adolescent child. Three months after diagnosis, parental differences in information-seeking were correlated with lower quality of life for children with cancer. However, other dissimilarities in maternal and paternal coping mechanisms, such as religious or support-seeking coping styles, do not appear to affect patients' quality of life.

Patient and Siblings

From the diagnosis through the course of a child's cancer, cancer-free siblings of all ages are affected emotionally and often physically. Siblings may suffer from unattended emotional responses, including anger, anxiety, jealously, resentment, depression, and loneliness; difficulties related to the absence of their parents; and reduced school achievement [474]. Immature thinking in young children can lead to thoughts that they caused their sibling's illness. Adverse physical problems experienced by cancer-free siblings are headaches, sleep disruption, and poor eating habits [475]. Most siblings who experience these emotional and physical responses do not suffer long-term problematic outcomes; however, a subset of siblings does experience difficulties [476].

Risk Factors for Poor Psychologic Outcomes for Cancer-Free Siblings

A meta-analysis of 50 studies involving siblings of children with chronic illness showed that internalizing behaviors, especially anxiety and depression, placed healthy siblings at a higher risk of poor psychologic adjustment [477]. The risk of unhealthy psychologic adjustment is also amplified if the ill sibling's cancer alters day-to-day family function. Warmth or closeness between cancer-free siblings (8 to 15 years of age) and their siblings with cancer increases the risk of poor psychologic adjustment; these intimate relationships are associated with decreases in social competence [478]. In addition, the incidence of poor psychologic outcomes in response to guilt and heightened fear of death increases if the sibling with cancer dies [479]. The psychologic adjustment of cancer-free siblings, however, improves with age as a result of the development of protective factors such as increased maturity and capacity to empathize [478,480].

A post-traumatic stress model may best fit the potential psychologic outcomes of cancer-free siblings up to five years after treatment. As a component of the Surviving Cancer Competently Intervention Program randomized trial, 78 sibling participants completed a Post-traumatic Stress Disorder Reaction Index [481,482]. Post-traumatic stress symptoms were experienced by almost half of cancer-free siblings. Moderate-to-severe post-traumatic stress disorder was reported by one-third of cancer-free siblings. Cancer-free siblings who were 7 years of age or older at the time of their sibling's cancer diagnosis reported more severe post-traumatic stress symptoms than those who were 6 years of age or younger at the time of diagnosis. In the same study, cancer-free female siblings indicated more post-traumatic stress symptoms than cancer-free male siblings.

One study explored bereaved siblings' advice to healthcare professionals working with children with cancer and their families [483]. Of the 174 siblings that participated, 108 answered an open-ended question about what advice they would give. The most common advice (given by 56% of siblings) related to their own support. Another one-third wanted professionals to provide them with better medical information. Some siblings wanted to be more involved in their brother's/sister's care and asked that healthcare professionals provide their parents with guidance on how to achieve this. Other common threads were related to psychosocial aspects, for example, siblings' wish for professionals to mediate hope without sacrificing realism and understanding the importance of asking the ill child about the kind of care they wanted [483].

Factors that promote healthy psychologic outcomes in cancer-free siblings are related to support and functioning of the entire family. Specifically, these factors include [484,485,486]:

- More family cohesion and adaptability with less family disruption

- Increased family support resources

- Enhanced communication within the family

Cancer-Free Siblings' Feelings During Treatment

Cancer-free siblings tend to identify themselves through the experiences of other family members during the course of their ill siblings' cancer [487]. When encouraged to discuss their personal experiences and feelings, cancer-free siblings focused primarily on their ill siblings' or parents' experiences, diminishing their sense of self. These patterns were more evident during the ill siblings' hospitalizations and as the physical appearance of their ill siblings worsened. Although cancer-free siblings experience stress similar to their brothers or sisters with cancer, most participants reinforced that their suffering was not justified because they were not experiencing the illness. Healthy siblings worried about the physical and emotional needs and abilities of their ill brothers or sisters following a cancer diagnosis. They said that they often "felt good" during the times they helped the ill sibling feel more comfortable. Yet, most of the cancer-free siblings also indicated that they experienced guilt because they had minimal involvement in taking care of their ill sibling. Although feelings of guilt in cancer-free siblings have not been correlated to negative psychologic outcomes, these feelings should be addressed by parents and clinicians [487].

Parents and Siblings

Numerous studies have shown that cancer-free siblings of children with cancer have the most unmet emotional needs relative to all other members of the family [488]. For children, the family is the primary social support system, and cancer-free siblings receive the least attention when childhood cancer disrupts everyday household life. Cancer-free siblings' emotional responses (e.g., fear, anger, guilt, jealousy, sadness) and health-related responses (e.g., sleeping difficulties, eating problems) are often overlooked or underestimated by parents [475]. These responses are compounded by cancer-free siblings' sensitivities to the parents' cancer-related emotional and practical burdens.

Parental and Self-Reports of Cancer-Free Siblings' Health

Parental and self-reports regarding cancer-free siblings' emotional and physical states also differ. Parents generally report better statuses for their cancer-free children than the children report themselves [489]. However, parents of children with cancer also report that their cancer-free children are "less healthy" than age-matched and sex-matched controls. Despite these reports, parents utilized health care for their cancer-free children less than the parents of matched controls [475]. The relative health of a cancer-free sibling to that of a child with cancer may cause parents to minimize the significance of the cancer-free sibling's health issues. Lack of time, energy, and financial resources may also reduce the parent's efforts to seek health care for a cancer-free child. Furthermore, most cancer-free children attempt to protect their parents' emotions by hiding their own negative emotions and health issues. The findings of a qualitative study suggested that cancer-free siblings valued keeping the family together and the survival of the sibling with cancer similarly [487].

Compared with matched controls, cancer-free siblings of children with cancer report significantly more trouble sleeping (72% compared with 53%) and problems eating (42% compared with 26%) [475]. These complaints are reported more frequently by cancer-free siblings who also report internalizing behaviors than those who engaged in externalizing coping strategies. Cancer-free siblings who present emotional or behavioral problems before the cancer diagnosis are more prone to somatic symptoms and poor psychologic adjustment. Therefore, healthcare practitioners should ask parents if their cancer-free children acted-out or had emotional problems prior to the development of cancer in the ill sibling to help assess the cancer-free child's level of risk for psychosocial issues. Also, clinicians should ask if the cancer-free sibling has any physical complaints in order to evaluate whether he or she needs additional interventions to avoid long-term psychologic repercussions. Parents who understand that their cancer-free child is at risk for psychosocial problems due to a sibling's cancer are more likely to have the child participate in a therapeutic program [489].

Parents

Although parental emotional distress and psychosomatic complaints are high shortly following a child's cancer diagnosis, prospective studies have shown that most survivors' parents adjust within 1 to 10 years [490,491,492]. Still, approximately 25% to 33% of parents face long-term psychologic issues [346,490,492,493]. Healthcare professionals' attention to the specific needs of the family can enhance the family's resilience [494,495,496,497]. Post-traumatic stress disorder is the most common psychologic disturbance for parents of childhood cancer survivors [493,498].

In a prospective and longitudinal study to assess psychologic functioning, parents' somatic symptoms and feelings of anxiety gradually decreased to control group levels by five years after diagnosis [499]. However, 27% of parents still had clinically elevated scores for psychologic distress at that time. When the data were analyzed according to the treatment outcome for the child, psychologic distress was manifested in 23% and 29% of parents of survivors and deceased children, respectively. Fifty percent of parents of children with relapsed disease continued to experience psychologic distress after five years. Higher levels of psychosomatic complaints at the time of the cancer diagnosis and the child's relapse were indicators of higher long-term psychologic risk. The same study found that mothers had higher levels of anxious feelings than fathers; however, all other measures were similar between mothers and fathers. Support-seeking coping strategies have been found to significantly reduce anxiety levels in mothers [500].

Psychosocial Interventions for Families

Therapies that holistically address the family's or the parents' emotional distress and coping skills are most effective for curtailing the intensity of unhealthy psychologic outcomes caused by childhood cancer [467,501,502]. Of interventions that have been studied in randomized trials, two have been shown to offer significant benefit [467]. Mothers of children recently diagnosed with cancer were better able to cope with their cancer-related stressors after receiving problem-solving skills training in conjunction with standard psychosocial care, compared with mothers who received standard psychosocial care alone [501]. The effectiveness of the training was better for Spanish-speaking mothers than English-speaking mothers, and single mothers derived the greatest benefit from the training.

The second intervention with proven efficacy is the Surviving Cancer Competently Intervention Program, a one-day, four-session, family-centered treatment intervention designed to teach coping skills to mothers, fathers, and adolescent survivors [502]. Compared with the control group, fathers derived the most benefit from the program, followed by the adolescent survivors. The coping strategies taught to fathers and survivors allowed them to reframe their reactions to the cancer and to speak more openly with their families about the cancer experience. Mothers did not show improvements with the intervention.

Interventions for siblings have also been effective. A therapeutic peer support camp was shown to improve mental health outcomes for siblings (8 to 13 years of age) of children with cancer [503]. The camp program was designed to decrease stress levels, improve social competence, and enhance knowledge of cancer and its treatment. According to standardized self-report measures, participants in the program demonstrated significantly decreased anxiety, improved social competence, greater social acceptance, and significantly reduced fear of disease [503]. Another study found that structured teaching and psychosocial sessions at a five-day residential summer camp led to significant improvements in knowledge about the sibling's cancer, behavior, social support, self-esteem, attitude, and mood [504]. The improvements represented increases of 5% to 25% over the baseline values and were sustained over a period of one year.

Resources for Patients and Their Families

Several resources are available to help patients and their families become more knowledgeable about cancer and treatment options, gain support from other families, and obtain help with practical concerns. Educational materials developed by several advocacy organizations are available online, and a list of potentially useful resources is available at the end of this course.

13. LONG-TERM HEALTH CARE FOR CHILDHOOD CANCER SURVIVORS

Approximately 1 in 640 adults 20 to 39 years of age is a survivor of pediatric cancer [505]. There are 126,752 survivors of pediatric leukemia and lymphoma, of whom 81,580 are at least 20 years of age [14]. The high (and increasing) number of survivors, as well as the emerging results of myriad late effects of treatment, led to the IOM report Childhood Cancer Survivorship: Improving Care and Quality of Life, published in 2003 [506]. Among the recommendations in that report were:

- Develop evidence-based clinical practice guidelines for the care of survivors of childhood cancer.

- Define a minimum set of standards for systems of comprehensive, multidisciplinary follow-up care that link specialty and primary care practitioners and ensure the presence of such a system within institutions treating children with cancer.

- Evaluate alternate models of delivery of survivorship care.

- Improve awareness of late effects and their implications to long-term health among childhood cancer survivors and their families.

- Improve professional education and training regarding late effects of childhood cancer and their management for both specialty and primary care practitioners.

The long-term follow-up care of childhood cancer survivors is important both to maintain routine care and to monitor for the occurrence of late effects of cancer treatment. Children and adolescents need continuity of routine pediatric care throughout and following their cancer treatment. This need has been emphasized by the AAP, which stated that each child must have a "medical home" for maintenance of health care [507]. Pediatricians, family practitioners, and nurses have an important role in the follow-up care for children with cancer [299,300,505,508]. Children with cancer should have regularly scheduled visits for routine preventive care, such as immunizations and the monitoring of growth and development [300]. In addition, routine pediatric care provides the opportunity to assess the effectiveness of symptom management, monitor treatment-related toxicity, confirm cancer remission, evaluate the psychosocial needs of the patient as well as the family, and promote healthy lifestyle behaviors [299]. Lastly, primary care providers are valuable resources for education and support for the patient and family.

Long-term follow-up healthcare is also crucial for ensuring appropriate surveillance, screening, and preventive care for childhood cancer survivors. The advances in survival for pediatric cancer have allowed investigators to evaluate survivors' health over time. Since the 1980s, long-term studies have identified several, widely varying late adverse effects of treatment. These long-term studies have served two valuable purposes: by identifying the most common treatment-related effects, clinicians can provide better follow-up care and investigators can modify treatment protocols to minimize toxicity for future patients. Many of the studies have involved the Childhood Cancer Survivor Study (CCSS) group, a cohort of more than 20,000 survivors who have survived for more than 5 years after treatment at various institutions and have been followed for 16 to 32 years. The group also includes sibling controls for comparison studies.

Research with the CCSS group has led to the development of evidence-based clinical practice guidelines for childhood cancer survivors [509,510]. The guidelines were developed by an expert panel within COG and are available online [510]. The guidelines facilitate creating a surveillance and follow-up care plan that is individualized according to treatment exposure and risk. The COG Late Effects Committee, in conjunction with Baylor School of Medicine, has developed a web-based interface, Passport for Care, that generates personalized recommendations based on an individual's specific risks [511]. Updates on this interface will be posted on the guidelines website.

LATE EFFECTS AMONG CHILDHOOD CANCER SURVIVORS

Late effects are usually defined as those occurring at least two years after completion of treatment and are chronic and sometimes progressive [49]. These late effects are primary contributors to mortality and morbidity for survivors. Among 20,483 five-year survivors in the CCSS group, mortality was 8.4 times higher for survivors than for the age-, sex-, and year-matched U.S. population [5]. The overall absolute excess risk of mortality was 7.36, which represents an additional seven deaths per 1,000 individuals who were followed up for one year [5]. The leading cause of mortality was recurrent and/or progressive disease (approximately 58%), followed by subsequent neoplasms (19%), circulatory system diseases (7%), and respiratory system diseases (3%) [5]. The cause of mortality varied by sex, with a higher proportion of deaths related to a subsequent neoplasm among female survivors and a higher proportion of cardiac deaths among male survivors [5]. The morbidity related to pediatric cancer treatment has a substantial impact on the health status and quality of life for survivors. Studies have shown that 63% to 75% of childhood cancer survivors have at least one physical or psychosocial late effect and that 28% to 40% have a severe or life-threatening condition [3,4]. However, one study found the incidence of severe or life-threatening conditions to be much higher. Researchers evaluated 14,359 five-year survivors in the CCSS cohort for risk of severe, disabling, life-threatening, and fatal events, and 4,301 siblings were included for comparison [512]. The cumulative incidence of a severe, disabling, life-threatening, or fatal health condition was greater among survivors than siblings (53.6% and 19.8%, respectively) by 50 years of age [512]. Correlation of late effects with primary diagnosis has indicated that leukemia and non-Hodgkin lymphoma are associated with lower burdens of adverse events, whereas the burden associated with Hodgkin lymphoma is often higher than the average burden (Table 21) [3,4,513].

Table 21: COMPARISON OF LATE EFFECTS ACCORDING TO PRIMARY DIAGNOSIS

Measure of Late Effect

Overalla

Leukemia

HL/NHL

Moderate or extreme adverse effect in at least 1 of 6 health status domains

44%

40%

44%/37%

Burden of Adverse Events

None

20%

26%

19%

High or severe

23%

12%

16%

Chronic Health Condition (Relative Risk)

Any

3.3%

2.2%

4.6%/3.2%

Severe or life-threatening

8.2%

4.1%

10.2%/6.8%

Two or more

4.9%

2.8%

8.7%/4.3%

aIncludes all childhood cancer diagnoses.

HL = Hodgkin lymphoma; NHL = non-Hodgkin lymphoma.

Source: [3,4,513]

Among the most common late effects are [3,4,206,259,299,505,510,513]:

- Subsequent neoplasm

- Cardiac abnormalities

- Abnormal growth and development

- Gonadal dysfunction

- Neurocognitive impairment

- Dental problems

- Psychosocial disorders

Many other less common late effects are also associated with cancer treatment, and survivors at risk should be evaluated accordingly (Table 22 and Table 23). The morbidity rates related to these late effects vary substantially according to many factors, primarily the type of treatment and the primary cancer diagnosis. Knowledge of the specific diagnosis and details of treatment can help clinicians provide preventive care, establish early diagnosis, and implement appropriate interventions.

Table 22: NONMALIGNANT ADVERSE EFFECTS ASSOCIATED WITH CHILDHOOD LEUKEMIA OR LYMPHOMA AND ITS TREATMENT

Organ/System Affected

Late Effect

Causative Agent or Therapy

Blood

Hepatitis B or C, human immunodeficiency virus (HIV)

Transfusion of contaminated blood producta

Bone marrow

Myelodysplasia

Alkylating agents

Acute myelogenous leukemia

Epipodophyllotoxins

Endocrine glands

Pituitary and/or thyroid dysfunction

Radiation

Bones and joints

Abnormal skeletal growth, chronic pain

Radiation

Osteopenia, osteoporosis, avascular necrosis

Radiation, corticosteroids, methotrexate, cyclophosphamide, ifosfamide

Reproductive system

Testes/ovaries dysfunction

Alkylating agents, radiation

Lungs

Fibrosis

Bleomycin, BCNU, radiation

Diffusion abnormalities

Radiation

Cardiovascular System

Heart

Cardiomyopathy, left ventricular dysfunction (subclinical), congestive heart failure

Anthracyclines

Cardiac failure, cardiac arrhythmias

Cyclophosphamide (high dose)

Myocardial infarction, valve disorders, cardiac arrhythmias, constrictive pericarditis

Radiation

Blood vessels

Coronary artery disease

Radiation

Central Nervous System

Brain

Neurocognitive impairment, motor problems, seizures, behavior changes

Methotrexate, cytarabine, radiation

Ears

Scarring of eardrum, build-up of ear wax, damage to middle ear (sense of balance)

Radiation

Hearing loss

Cisplatin

Eyes

Dry eyes, light sensitivity, keratoconjunctivitis, retinopathy

Radiation

Cataracts

Radiation, corticosteroids, busulphan

Nerves

Neuropathy

Cisplatin, vincristine, vinblastine

Digestive System

Oral cavity, teeth

Xerostomia, abnormal dentition, cavities, gingivitis, periodontal disease

Radiation

Intestines

Malabsorption, strictures, chronic diarrhea

Radiation

Liver

Hepatitis, fibrosis, cirrhosis

Methotrexate, BCNU, 6-mercaptopurine, radiation, contaminated blood productsa

Urinary System

Bladder

Hemorrhagic cystitis, cancer

Ifosfamide, cyclophosphamide

Scarring

Radiation

Kidneys

Nephropathy

Radiation, ifosfamide

Fanconi syndrome

Ifosfamide, cisplatin

Reduced filtration

Cisplatin, carboplatin

Hypertension, renal insufficiency

Radiation

Kidney failure (rare)

BCNU, CCNU, methotrexate (high dose)

aFor transfusions given before 1972 (hepatitis B), between 1977 and 1985 (HIV), and before 1993 (hepatitis C).

Source: [3,4,206,259,299,505,510,513,514,515,516,517,518,519]

Table 23: RECOMMENDED SCREENING FOR SURVIVORS OF CHILDHOOD LEUKEMIA AND LYMPHOMA ACCORDING TO CHILDREN'S ONCOLOGY GROUP GUIDELINES

Late Effect

Therapy or Cause

Recommended Screening

Cardiac abnormalities (cardiomyopathy, left ventricular dysfunction [subclinical], congestive heart failure, arrhythmias, myocardial infarction, valve disorders, pericarditis, coronary artery disease)

Anthracyclines, cyclophosphamide (high dose), radiation (mantle, mediastinum, thorax, axilla, abdomen)

Yearly history and physical examination with attention to presence of murmur, S3, S4, increased P2 sound, pericardial rub, rales, wheezes, peripheral edema, jugular vein distention

Baseline echocardiography and electrocardiography, repeated as clinically indicated

Fasting glucose and lipid profile every three to five years

Education about risk of strenuous exercise

Cataracts

Alkylating agents, corticosteroids, cranial, orbital, or eye radiation

Yearly eye examination

Dental problems (abnormal dentition, cavities, gingivitis, periodontal disease, microdontia)

Cranial radiation, bone marrow transplantation, chemotherapy (any)

Dental cleaning every six months

Yearly oral examination

Dyslipidemia

Heavy metals

Baseline fasting lipid profile every two years

Gonadal dysfunction

Alkylating agents, radiation (whole abdomen, pelvis)

Yearly evaluation of puberty stage and pace, sexual function, Tanner assessment, testicular volume (male patients)

Baseline levels of FSH, LH, and estradiol (female patients) or testosterone (male patients) at 13 years age (female patients) and 14 years of age (male patients)

Hearing loss, tinnitus, vertigo

Heavy metals

Yearly assessment of hearing difficulties and otoscopic examination

Hepatic dysfunction

Antimetabolites, methotrexate, radiation (abdomen)

Yearly examination with attention to jaundice, ascites, hepatomegaly, splenomegaly

Baseline levels of ALT, AST, and bilirubin, repeated as clinically indicated

Hepatitis B or C; HIV

Transfusion of blood products before 1972 (hepatitis B), between 1977 and 1985 (HIV), and before 1993 (hepatitis C)

Hepatitis B surface antigen and core antibody once

HIV 1 and 2 antibodies once

Hepatitis C antibody once

Neurocognitive deficits

Cranial radiation, methotrexate, cytarabine

Formal neuropsychologic evaluation at baseline

Yearly assessment of educational or vocational progress

Peripheral sensory neuropathy

Heavy metals, plant alkaloids

Yearly neurologic examination for two to three years after therapy completed

Psychosocial disorders

Cancer experience

Yearly assessment for depression, anxiety, post-traumatic stress syndrome, and social withdrawal

Pulmonary toxicity (fibrosis, interstitial pneumonitis, obstructive lung disease)

Alkylating agents, bleomycin, radiation (mantle, mediastinum, thorax)

Yearly pulmonary examination with attention to history of cough, shortness of breath, dyspnea, wheezing

Baseline chest x-ray and pulmonary function tests, repeated as clinically indicated

Renal/bladder damage

Alkylating agents, heavy metals, antimetabolites, radiation (abdomen, pelvis)

Yearly blood pressure, urinalysis

Baseline levels of BUN, creatinine, electrolytes, calcium, magnesium, and phosphate, repeated as clinically indicated

Sinusitis (chronic)

Cranial radiation

Yearly sinus examination with evaluation for history of rhinorrhea and postnasal discharge

Thyroid gland dysfunction

Radiation (head and neck, thorax)

Yearly thyroid function studies and evaluation for thyroid hyperplasia

Bone Disorders

Osteopenia, osteoporosis

Radiation, corticosteroids, methotrexate, cyclophosphamide, ifosfamide, hematopoietic cell transplant

Baseline bone density

Yearly musculoskeletal examination

Avascular necrosis

Corticosteroids, hematopoietic cell transplant

Abnormal Growth and Development

Impaired growth

Cranial radiation, corticosteroids, chemotherapy (any), radiation (neck, thorax, whole abdomen)

Yearly height measurements on standardized growth charts

Yearly determination of height, weight, body mass index, and blood pressure

Fasting glucose, serum insulin, and lipid profile every two years (overweight or obese individuals) or five years (normal-weight individuals)

Overweight or obesity

Cranial radiation, diagnosis of acute lymphoblastic leukemia

Second Cancers

Acute myelogenous leukemia, myelodysplasia

Epipodophyllotoxins, alkylating agents, hematopoietic cell transplant

Yearly dermatologic examination (pallor, petechiae, purpura) with evaluation for history of fatigue, bleeding, or easy bruising up to 10 years after treatment

Yearly CBC with differential up to 10 years after treatment

Bladder cancer

Cyclophosphamide, radiation (whole abdomen, pelvis)

Yearly urinalysis and evaluation for history of hematuria, urinary dysfunction

Breast cancer

Radiation of 20 Gy or more (mantle, mediastinum, thorax, axilla)

Yearly clinical breast examination beginning at puberty until 25 years of age, then every six months

Mammography beginning eight years after radiation or at 25 years of age, whichever occurs last

Colorectal cancer

Radiation of 30 Gy or more (whole abdomen, pelvis)

Colonoscopy every five years beginning at 10 years after radiation or at 35 years of age, whichever occurs last

Lymphoma

Hematopoietic cell transplant

Yearly physical with attention to lymphadenopathy and splenomegaly

Skin cancer

Radiation (any field)

Yearly dermatologic examination of radiated fields with evaluation for history of skin lesions or changing moles

Solid tumors

Hematopoietic cell transplant

Yearly evaluation for benign or malignant tumors

FSH = follicle-stimulating hormone; LH = luteinizing hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count.

Source: [510]

Subsequent Neoplasms

The occurrence of subsequent neoplasms as a late effect among childhood cancer survivors has been well-documented. Multiple studies have demonstrated that these cancers are a major source of morbidity and mortality for 30 years or longer after treatment [3,259,505,520,521,522,523,524]. The 30-year cumulative incidence is 20.5% for a subsequent neoplasm and 7.9% for a second malignant neoplasm (excluding nonmelanoma skin cancer) [7]. The highest cumulative incidence is associated with Hodgkin lymphoma (18.4%); the incidence is similar for non-Hodgkin lymphoma and leukemia (5.8% and 5.6%, respectively) [7].

The greatest risk factor for a subsequent neoplasm is radiation therapy (relative risk: 2.7), followed by female sex and childhood Hodgkin disease (relative risk: 1.5 for both), and older age at the time of childhood cancer diagnosis (relative risk: 1.3) [7]. It is important to note, however, that changes to treatment protocols over time (e.g., the move to limited use of radiation therapy) may affect risk among children/adolescents treated within the past decade. Overall, the most frequently occurring subsequent solid tumors among childhood cancer survivors are breast, thyroid, and CNS cancers and soft-tissue sarcoma [7,519].

The authors of one study sought to find the incidence and excess risk for breast cancer in women after chest radiation; differences between the clinical characteristics of breast cancer and the outcomes after therapy among these women and in the general population; and potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation. The cumulative incidence of breast cancer by 40 to 45 years of age ranged from 13% to 20%. The risk for breast cancer increased linearly with radiation dose. The evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population [518]. Authors of another study evaluated cumulative breast cancer risk in 1,230 female childhood cancer survivors treated with chest radiation. Survivors who were treated with lower delivered doses of radiation (2–20 Gy) to a large volume (i.e., whole-lung field) had a high risk (43.6%) of breast cancer. The cumulative incidence of breast cancer by 50 years of age was 30%, with a 35% incidence among Hodgkin lymphoma survivors. Breast cancer-specific mortality at 5 and 10 years was 12% and 19%, respectively [516].

The rate of cancer screening among childhood cancer survivors has been lower than optimal, and clinicians should emphasize the importance of screening, given the high risks [525]. Second cancers among childhood cancer survivors call for vigilant screening and surveillance according to individual risk [510,526]. A prospective one-arm study was conducted among a random sample of 72 Hodgkin lymphoma survivors, 27 to 55 years of age, who were at increased risk for breast cancer and/or cardiomyopathy and had not had a screening mammogram or echocardiogram within the prior two years. A one-page survivorship care plan with recommendations for surveillance was mailed to participants. In addition, survivors' primary physicians were contacted and provided patient-specific information. A web-based virtual information center was made available for both survivors and physicians. Outcomes were assessed by telephone six months after the intervention. At six months, 41% of survivors reported having completed the recommended mammogram; 20% reported having an echocardiogram (women 30%, men 10%) [519].

Cardiac Abnormalities

The greatest risk of cardiac abnormality is associated with a high cumulative dose of anthracycline, which is used in treatment regimens for approximately 60% of children and adolescents with cancer [207,208,505,517,527]. In a study of more than 1,300 childhood cancer survivors, the relative risk of cardiac abnormality was reported to be 3.53 in association with use of an anthracycline and 7.41 in association with the combination of an anthracycline and an alkylating agent [4]. The risk of anthracycline-induced cardiac abnormality is increased further by several factors, including female sex, younger age (younger than 5 years) at the time of treatment, and black race [510]. Examples of nonanthracycline agents used in pediatric populations that have been associated with cardiotoxicity include cyclophosphamide, cytarabine, cisplatin, and ifosfamide [528].

A wide range of cardiac abnormalities have been noted in survivors [3,4,206,299,505]. It is well-established that the development of congestive heart failure can occur at any anthracycline dose, but the risk increases with increased cumulative doses, especially doses ≥300 mg/m2 [529,530,531,532]. A systematic review indicated a rate of subclinical cardiotoxicity of approximately 16% to 28% associated with an accumulated dose of anthracycline of more than 200 mg/m2[4]. Among survivors who had been treated with an anthracycline, cardiomyopathy has been identified in as many as 57% and clinical heart failure (usually asymptomatic) in as many as 39% [206,505]. In a study of more than 10,000 survivors, the relative risk of congestive heart failure was 15.1 compared with sibling controls [3]. The more time that has passed since a patient has received treatment with an anthracycline, the higher the patient's risk for developing changes in cardiac function [207,533,534].

Radiation therapy to the thorax has also been associated with cardiac damage, including decreased left ventricular mass, end-diastolic wall thickness, valve defect, and early, significant decline in left ventricular shortening fraction, with elevated body mass index and Hispanic ethnicity identified as independent risk factors [206,505,517]. The use of lower doses of radiation for children with lymphoma has decreased the occurrence of radiation-related cardiac toxicity [206].

The COG guidelines suggest yearly history and physical examination for survivors at risk for cardiac abnormality related to either chemotherapy or radiation [510]. In addition, an echocardiography and electrocardiography should be done at baseline (the beginning of long-term follow-up) and periodically, depending on risk. Survivors should be educated about the risks of strenuous sports or exercise.

Abnormal Growth and Development

The most common abnormalities in growth and development among childhood cancer survivors have been impaired growth (short stature) and obesity.

Impaired Growth

The use of chemotherapy and radiation therapy in children has been associated with impaired growth and short stature as a result of effects on growth centers in the spine and long bones and endocrine organs [259,535,536,537]. Cranial radiation at a dose of more than 18 Gy has been linked to the greatest loss in height. This loss can be caused by several factors, including growth hormone deficiency, precocious or delayed puberty, or hypothyroidism [259,299,510]. Other factors, such as age younger than 4 years, female sex, obesity, concomitant use of corticosteroids, and radiation dose, contribute to risk [259,510,535].

Cranial radiation alone is not the only causative factor, as final height has been compromised in children with ALL regardless of whether radiation was given in addition to chemotherapy [535,536]. Growth is impaired primarily during remission induction therapy, and so-called "catch-up growth" will occur in approximately 70% of children after induction therapy has been completed [505,535,536,537]. However, maintenance therapy with methotrexate and 6-MP may prevent catch-up growth [538]. Catch-up growth does not occur with radiation-induced impairment [536].

Radiation therapy to the head and neck or cerebral cortex can cause hypothyroidism, leading to short stature and poor growth [259,539]. This risk has been somewhat decreased by the use of lower cumulative doses of radiation therapy in treatment protocols for childhood lymphoma [206]. Bone marrow transplantation is also associated with a high risk for severe growth impairment, especially when the conditioning regimen involves total body radiation [259].

Survivors should have regular growth assessment consisting of measurement of height on standardized growth charts [510]. Growth hormone therapy may be beneficial if growth hormone deficiency is found to be the cause of impaired growth [299,505,510]. Although the use of growth hormone therapy was once thought to confer an increased risk of second neoplasms, evidence of this risk has not been demonstrated in large studies [259,299].

Obesity

Obesity is another well-recognized long-term complication in survivors of ALL, occurring in as many as half of long-term survivors [259,299,505]. Weight gain is increased the most during the first year after the end of treatment, and gains continue with time. Several factors have been suggested as the cause of obesity, including treatment with corticosteroids (especially dexamethasone) and cranial radiation [259,505,510].

A meta-analysis of survivors of pediatric ALL found a high prevalence of obesity in ALL survivors regardless of survivors' receipt of cranial radiation, gender, or age at diagnosis [540]. Another study indicated a relative risk of obesity of 1.97 in association with radiation therapy to the head and neck, cranium, or thorax [4]. However, other investigators found no difference in the prevalence of overweight and obesity among survivors and the general population [541]. In this latter study, an age of younger than 6 years and overweight and obesity at the time of diagnosis were stronger factors than cranial radiation for overweight and obesity in adulthood [541].

Childhood cancer survivors should be weighed yearly at the time of routine history and physical examination and a body mass index should be determined. The patient's height should be considered when reviewing the body mass index, as a high body mass index may be the result of normal weight gain but relative loss of height. Primary care practitioners should emphasize the importance of weight control through healthy eating habits and exercise in preventing the development of such chronic conditions as diabetes, hypertension, dyslipidemia, and cardiovascular disease [299,505,510].

Gonadal Dysfunction

Gonadal dysfunction can occur in both boys and girls as a result of alkylating agents or radiation therapy [259,505,510]. In boys, testicular dysfunction may include delayed or arrested puberty, oligospermia, azoospermia, or infertility. In girls, ovarian dysfunction may include delayed or arrested puberty, premature menopause, or infertility [206,259,299,505,510]. The risk is dose-dependent and is increased when an alkylating agent is used in combination with radiation or an anthracycline [206,510]. The majority of these late effects arise from radiation-induced uterine injury. Such injuries are reported at higher incidence in adult survivors of childhood cancers who were exposed to uterine radiation (i.e., pelvic, spinal, or total-body) during childhood. Findings from long-term follow-up studies of the reproductive performance of female survivors provides some reassurance to them by documenting that pregnancy and live birth rates were not significantly compromised in survivors, including those who had been treated with alkylating agents and had not received pelvic, cranial, and total-body irradiation [542]. The relative risk for male infertility has been reported to be 9.03 in association with use of an alkylating agent and 10.6 in association with both an alkylating agent and an anthracycline [4]. Cranial radiation is correlated with an increased risk for premature puberty, especially for girls treated before 8 years of age [259]. The risk of infertility is low and is directly related to gonadal exposure to radiation and age at the time of treatment [543,544]. The possibility of maintaining gonadal function in the presence of higher cumulative doses of alkylating agents is greater in girls than for boys [510].

The annual history and physical for survivors at high risk for gonadal dysfunction should include evaluation of the puberty stage and pace, sexual function, and Tanner assessment [510]. Baseline levels of follicle-stimulating hormone, luteinizing hormone, and estradiol (girls) or testosterone (boys) should be determined at 13 years of age for girls or 14 years of age for boys and as clinically indicated [510].

Neurocognitive Impairment

Neurocognitive impairment is among the most common and distressing late effect of pediatric cancer treatment [4,299,437,505,545,546,547]. In one study, the relative risk of severe cognitive dysfunction among more than 10,000 survivors was 10.5 compared with sibling controls [3]. In another study, cognitive or psychosocial disorders represented approximately 8% of all severe, life-threatening, or disabling events [4]. A cancer experience alone increases the risk for neurocognitive impairment, and the interruption of regular schooling during treatment can have serious effects on academic performance [510]. Cranial radiation is the greatest contributor to the risk for neurocognitive deficits. The highest risk is associated with cranial radiation in combination with an age of younger than 3 years at the time of treatment or female sex [510]. The intensity of treatment and the time since treatment are also factors [510]. The replacement of prophylactic cranial radiation with intrathecal chemotherapy has led to a decrease in neurocognitive toxicity, but intrathecal chemotherapy (primarily methotrexate) is associated with some level of deficit in approximately 30% of survivors [545,546,547].

A variety of impairments have been reported, and the most common deficits are related to [49,299,440,510,546]:

- Attention

- Memory

- Mathematic reasoning

- Reading comprehension

- Executive function (planning and organization)

- Visual-motor coordination

- Written expression

- Delays in academic achievement

The deficits in survivors of leukemia and lymphoma are more often related to information processing [510].

The findings of studies on the academic status of survivors support the high reported rate of neurocognitive impairment. In a Childhood Cancer Survivor Study involving 12,430 survivors and 3,410 siblings, significantly more survivors used special education services (23% compared with 8% for siblings) [547]. The results indicated that the greatest differences were found for survivors who were younger than 6 years of age at the time of treatment or who had a diagnosis of CNS tumors, leukemia, or Hodgkin lymphoma [547]. Survivors of leukemia and non-Hodgkin lymphoma were among those who were least likely to finish high school [547]. In addition, a Canadian survey of parents of childhood cancer survivors showed that significantly more survivors than controls had educational or other school problems (46% compared with 23%), had repeated a grade (21% compared with 9%), had attended a learning disability program (19% compared with 7%), or had participated in a special education program (20% compared with 8%) [437]. Leukemia survivors were among the subgroups that were more likely to have educational problems.

The COG long-term follow-up guidelines recommend that the annual examination for all childhood cancer survivors include an assessment of educational and/or vocational progress [510]. A baseline formal neuropsychologic evaluation is recommended, with follow-up testing for survivors who demonstrate evidence of impaired progress. Primary care practitioners should alert parents to signs of neurocognitive impairment, emphasizing the importance of evaluating any learning-related problems [49]. In addition, primary care practitioners should refer patients with neurocognitive deficits to a school liaison or community service to facilitate access to educational services or vocational rehabilitation.

Dental Problems

Dental abnormalities have been associated primarily with radiation to the head and neck area or brain and also with chemotherapy. Abnormalities include tooth agenesis, enamel dysplasia, blunting of roots, incomplete calcification, high plaque index, arrested tooth development, and tooth discoloration [206,259,299,505]. The maturity of the teeth appear to be a substantial factor, as the most severe abnormalities have been found in children who are younger than 5 years of age at the time of treatment [259]. Dental caries and periodontal disease are also associated with bone marrow transplantation with chronic graft-versus-host disease [510].

Despite the prevalence of dental abnormalities, the rate of routine dentist visits among survivors of childhood cancer is lower than that recommended for the general population [548]. Primary care practitioners should encourage patients and parents to maintain regularly scheduled dentist visits, with dental cleaning every six months and an oral examination yearly [510].

Psychosocial Disorders

Psychosocial disorders are thought to be related to physical function, well-being, and anxiety related to future health needs [424]. As such, survivors of childhood cancers would be vulnerable to such disorders. However, long-term studies have shown contrasting results with respect to the psychologic health of childhood cancer survivors. In general, the psychologic health of survivors is similar to that of the general population, but a small percentage of survivors and family members have difficulty with coping and with personal and social skills [440].

A meta-analysis of 20 studies showed no deficits in measures of anxiety, depression, and self-esteem when results for survivors were compared with those for population norms or matched controls [424]. Following that study, the CCSS reported on the psychologic outcomes for survivors of pediatric leukemia and lymphoma [425]. That study indicated that survivors were approximately 1.7 times more likely to report symptomatic levels of depression or somatic distress compared with sibling controls, but the rate of depression and distress were similar to those among the general population [425,549].

In another Childhood Cancer Survivor Study, the percentage of leukemia and lymphoma survivors who reported an adverse effect on mental health or anxiety was similar to the overall population of survivors. One exception was a greater likelihood for Hodgkin lymphoma survivors to report cancer-related anxiety [513]. The authors of the report suggested that the older age at the time of Hodgkin lymphoma diagnosis may account for this difference, as the patient is better able to understand the seriousness of the cancer diagnosis [513]. This rationale supports the finding of post-traumatic stress disorder symptoms in approximately 20% of adolescent survivors [550].

Age and time since diagnosis may be factors in reported levels of post-traumatic stress disorder [551]. In one study, 255 children with cancer, stratified by time since diagnosis, and 101 demographically matched peers were assessed for post-traumatic stress disorder using structured interviews by both child and parent reports and survey measures of post-traumatic stress symptoms by child report. Cancer was identified as a traumatic event by 52.6% of children with cancer, declining to 23.8% in those who were five years or more from diagnosis [551].

The authors of one study sought to estimate the prevalence of emotional distress in a large cohort of adult survivors of childhood cancer and to evaluate the inter-relationship of risk factors, including cancer-related late effects. A total of 1,863 adult survivors of childhood cancer (median age at follow-up: 32 years) completed comprehensive medical evaluations. Elevated global distress was reported by 15.1% of survivors, and childhood cancer-related morbidities, including pain and learning or memory problems, appear to be directly and indirectly associated with elevated distress symptoms decades after treatment [552].

Sociodemographic factors related to psychosocial disorders among childhood cancer survivors are similar to those of the general population, with higher rates associated with female sex, lower level of educational attainment, and lower socioeconomic status [425,513]. One systematic review assessed unemployment in adult childhood cancer survivors compared with the general population, and its predictors [553]. Overall, approximately one in six survivors was unemployed and survivors were more likely to be unemployed than controls. Survivors of brain tumors were more likely to be unemployed. Younger age, female sex, radiotherapy, and physical late effects were predictors of unemployment [553]. Because the effects of prolonged psychologic distress can be severe, assessment for depression, anxiety, post-traumatic stress, and social withdrawal should be carried out annually [510]. Special attention should be directed toward female survivors, Hispanic survivors, and survivors with low socioeconomic status. Primary care practitioners should refer patients with emotional difficulties for psychologic consultation.

Other Late Effects

The CCSS cohort was used to compare the incidence rates of infections among five-year survivors of pediatric cancer with the rates of siblings [554]. Compared with that of the U.S. population, survivors were at an increased risk of death from infectious causes, with girls/women and those exposed to total body radiation being at greatest risk. Survivors also reported higher rates of overall infectious complications than siblings [554]. As part of the Swiss CCSS, a questionnaire was sent to all registered survivors (20 to 40 years of age), all aged younger than 16 years at diagnosis who had survived five or more years [555]. Fewer survivors than siblings had life partners, and fewer survivors were married than siblings and participants in the Swiss Health Survey. Older and female survivors were more likely to have life partners. Survivors who had undergone radiotherapy, bone marrow transplants, or who had a CNS diagnosis were less likely to have life partners [555].

HEALTH PROMOTION AND EDUCATION

Surveys of childhood cancer survivors have shown knowledge deficits regarding the late effects of cancer and cancer treatment [556,557]. More than half of the participants in a Childhood Cancer Survivor Study survey could not accurately report their anthracycline exposure or site of radiation therapy, information that is essential for appropriate long-term follow-up care [557]. In addition, 46% of respondents said that previous treatment did not pose a serious health issue, and 19% did not know that previous treatment was related to adverse events [557].

Given the lack of knowledge about the risk for adverse effects and the need for long-term follow-up care, education is essential and should focus on the importance of:

- Obtaining documentation of cancer type and treatment

- Understanding the risk of specific late effects according to a specific cancer diagnosis and specific therapies

- Engaging in healthy lifestyle behaviors to reduce the risk of treatment-related morbidity

- Seeking routine follow-up care and recommended screening

When developing or recommending educational resources for patients and family members, clinicians should consider the native language and literacy level, as appropriate materials will facilitate comprehension.

Documentation of Cancer Type and Treatment

It is imperative that every childhood cancer survivor have written documentation of his or her specific diagnosis and all diagnostic and treatment details. The concept of survivorship care plans has been developed as a way to facilitate better follow-up care for all survivors [558,559]. Among the basic elements of a survivorship care plan are [559]:

- Diagnostic tests performed and results

- Disease characteristics (e.g., histologic type, stage, grade, site)

- Start and end dates of treatment

- Type of treatment (chemotherapy and radiation therapy regimens, including doses and schedules)

- Indicators of treatment response

- Treatment-related toxicities

- Psychosocial and other supportive services provided

- Information on possible late and long-term effects of treatment and symptoms of such effects

- Information on possible signs of recurrence

- Description of recommended cancer screening and other periodic testing and examinations, their performance schedule, and which provider should perform them

- Specific recommendations for healthy behaviors (e.g., diet, exercise, healthy weight, sunscreen use, immunizations, smoking avoidance/cessation, osteoporosis prevention)

- List of cancer-related resources and information (e.g., web-based sources and telephone listings for major cancer support organizations)

- Identifying number and title of clinical trial (if applicable)

- Full contact information on treating institutions and key individual practitioners

- Identification of a key contact and a coordinator of continuing care

One study suggests, however, that a majority of cancer survivors and their physicians have not yet embraced survivor care plans [560]. From April to July 2012, researchers conducted in-depth telephone interviews with 53 adult survivors (average age: 39.1 years) recruited from the Utah Cancer SEER Registry. Participants were randomly selected from sex, age, and rural/urban strata and were younger than 21 years of age at the time of diagnosis. Participants were asked if they had a primary care physician, if they discussed their cancer history with their physician, and if they had interest in a survivor care plan. Most (83%) survivors had a current primary care physician; nearly 50% were not concerned about their health despite having had cancer; and few had a follow-up care plan, although more than half felt that a survivor care plan could empower their medical decision making. However, more than 30% of survivors were skeptical about the usefulness of a survivor care plan and some expressed concern about healthcare costs [560].

The National Children's Cancer Society has introduced a new online Late Effects After Treatment Tool (LEATT), which is available online at https://leatt.thenccs.org. The tool was designed to help survivors learn about potential late effects of childhood cancer. The LEATT provides personalized results, based on the information that the survivor enters, and it takes less than 10 minutes to complete. The results describe potential late effects and symptoms to look for, provide recommendations for follow-up care, and offer preventive tips to help reduce the risk of further health issues [561].

Understanding Risks of Late Effects

A valuable resource for patient and family education is Health Links, a series of educational handouts based on the COG guidelines for long-term care of childhood cancer survivors. The handouts address more than 40 topics within the guidelines, and each handout contains a brief overall description of a specific late effect, as well as [509,510]:

- Explanation of risk factors

- Description of common symptoms

- Explanation of exacerbating conditions

- Recommended screening

- Next steps after positive screening

- Brief explanation of the treatment

- Health-promoting behaviors and interventions

Healthy Lifestyle Behaviors

The health behaviors of childhood cancer survivors have not been well-studied, but overall, young cancer survivors report lifestyle behaviors that are at least as healthy as the age-matched population [49,508]. Behaviors have been shown to vary according to race/ethnicity; overall, black survivors have reported better preventive practices and have been less likely to engage in risky behaviors such as smoking and alcohol consumption [562]. In one study, 40% of survivors reported eating a nutritious diet, 64% said they practiced sun protection, and 94% said they did not smoke [563]. In a later and much larger study, the rate of physical inactivity was high (52% to 72%), with the lowest rate for Hispanic male survivors and the highest rate for black female survivors [562]. In that same study, the rates of smoking among black and Hispanic survivors were lower than the rates among their peers in the general population [562].

In a case-control study published in 2014, researchers sought to identify factors other than cancer-related treatment and presence/severity of chronic health conditions that might be associated with late mortality risk among adult survivors of pediatric cancer [564]. A total of 445 participants who died from causes other than cancer recurrence/progression or non-health-related events were compared with 7,162 surviving participants matched for primary diagnosis, age at baseline questionnaire, time from diagnosis to baseline questionnaire, and time at risk. Exercising fewer than three days per week, being underweight, increased medical care use, and self-reported fair-to-poor health were associated with an increased risk for all-cause mortality [564].

Primary care practitioners should make sure that childhood cancer survivors understand that the risks associated with unhealthy lifestyle behaviors may be increased because of their previous cancer treatment. In addition, clinicians should ensure that survivors know the importance of a healthy diet, regular exercise, routine sun protection, avoidance of tobacco, and moderation in alcohol consumption. Survivors should also be educated about the signs and symptoms of depression and of ways to alleviate stress and anxiety.

Routine Follow-Up Care and Recommended Screening

The cancer screening practices and compliance with healthcare recommendations have been less than optimal among childhood cancer survivors, and most survivors have contact with primary care practitioners rather than oncology specialists or follow-up clinics [508,526,544,558]. These findings indicate the importance of primary care practitioners assuming responsibility for the long-term follow-up care of childhood cancer survivors; however, barriers to doing so remain. In one study, a minority of primary care physicians perceived that their medical training was adequate to recognize late effects of chemotherapy (27.6%), cancer surgery (36.6%), and radiation therapy (38.1%). Most (93%) had never used the COG guidelines, but 86% would follow their recommendations. Most (84% to 86%) stated that they had never received a cancer treatment summary or survivorship care plan, but more than 90% thought these documents would be useful [565]. Although most general internists report involvement in the care of pediatric cancer survivors, many are unfamiliar with surveillance guidelines and uncomfortable caring for survivors, citing access to guidelines and treatment summaries as the most useful resources in caring for survivors and preferring to care for survivors in collaboration with a cancer care center [566]. A survey of U.S. and Canadian family physicians involved in the care of pediatric cancer survivors revealed similar attitudes. Clinicians also cited surveillance recommendations and clinical care guidelines as being the most useful in assisting them with survivor care and were willing to care for survivors in consultation with a cancer care center [567].

Due to their heightened risk of developing late-occurring adverse outcomes, pediatric cancer survivors are advised to receive follow-up care in specialized survivor clinics. Research indicates that most survivors (71%) who do not attend a specialized clinic were "not aware" of their availability [568]. Clinicians should use every opportunity (e.g., acute care visits, parental or sibling visits, annual examinations) to emphasize the importance of long-term follow-up care in a survivor care clinic and adherence to recommended screening guidelines for survivors.

CHALLENGES IN PROVIDING HEALTH CARE

Approximately one in every 640 young adults (20 to 39 years of age) in the United States is a childhood cancer survivor [505]. This large and increasing population, with its increased risk of adverse events, creates a substantial healthcare burden. As such, there are several challenges to providing long-term care for childhood cancer survivors.

The first challenge is related to the overall age of childhood cancer survivors. Because survival rates have improved over the years, the population of survivors is young and will require close follow-up for several years. The primary responsibility for follow-up care has typically been assigned to oncologists, but many have suggested that primary care practitioners are best equipped to provide the full spectrum of health care to cancer survivors [49,300,505,558,569]. This shift in responsibility may be especially important given the predicted shortage of oncologists by the year 2020, as well as the predisposition of survivors to seek care with primary practitioners [570].

The increasing age of childhood cancer survivors also creates many challenges to maintaining long-term follow-up care. First, over the course of childhood, adolescence, and young adulthood, individuals are more likely to be mobile, which makes continuity of long-term follow-up difficult. Second, as children/adolescents mature, the primary responsibility for their care shifts from their parents to themselves and they begin to make their own decisions. Third, most pediatric cancer centers do not have programs for follow-up into adulthood, which means that when survivors become adults, they must seek follow-up care elsewhere [569]. Lastly, long-term follow-up centers that are in existence are confronted with many barriers, including inadequate funding, lack of capacity of the growing population of survivors, and lack of awareness or interest among survivors [505].

Models of care that take into account the transition of care into the adult setting are needed. Until such programs are available, it becomes incumbent on pediatric oncologists to share treatment plans with pediatricians and family practitioners and for oncologists and primary care practitioners to collaborate on survivorship care plans. With emerging technology, the use of electronic media to store health information will facilitate maintenance of important documentation in a portable format.

Lack of awareness of diagnosis, treatments, and potential late effects among childhood cancer survivors also presents a challenge. Such information is essential for appropriate long-term care, and primary care practitioners have an important role in providing educational resources to help survivors better understand their health and receive optimal long-term care.

14. CASE STUDIES

CASE STUDY 1

Patient A, a bright, energetic boy, 8 years of age, had shown less enthusiasm for his normal activities for a few days. He told his mother he felt tired and was sometimes nauseated, and his mother found that he had a low-grade fever (37.8 degrees Centigrade). Mrs. T, the patient's mother, took Patient A to his pediatrician, who noted no abnormalities on physical examination. He told Mrs. T that the patient probably had a virus. A week later, Patient A was still not feeling better, and Mrs. T took him to the pediatrician again. On physical examination, the pediatrician noted that the patient appeared pale and had slight lymphadenopathy. Suspecting infection, the pediatrician prescribed a 10-day course of an antibiotic. After completing the course of antibiotics, Patient A still did not feel better and continued to have a low-grade fever. At that time, the pediatrician noted ecchymoses of the skin and slight splenomegaly, findings that had not been previously evident. He ordered laboratory and imaging studies to rule out leukemia. The complete blood count demonstrated slight anemia and leukopenia; the chest x-ray was normal, and computerized tomography confirmed splenomegaly.

The signs and symptoms of pediatric leukemia are often insidious and persistent. The most common symptom associated with ALL is a low-grade fever of unknown etiology. Many symptoms related to leukemia are associated with other diseases and conditions, and care is needed in making a differential diagnosis. Reactive lymphadenopathy is common in children and adolescents, and clinicians should first rule out infectious or inflammatory conditions. Because of this, symptoms of ALL are present for an average of four to six weeks before the diagnosis is made. Further evaluation for leukemia is warranted when fever persists for more than two weeks and when findings on physical examination include pallor, petechiae, ecchymoses of the skin or mucous membranes, or lymphadenopathy. Splenomegaly (or hepatomegaly) at the time of diagnosis of ALL is common. Imaging studies should be carried out to determine the presence of leukemic involvement.

The pediatrician talked with Mr. and Mrs. T privately (without Patient A present) and carefully explained that their son may have leukemia and that he was referring Patient A to a pediatric cancer care center in a neighboring city. Patient A's parents were both devastated by the news. The pediatrician encouraged them to express their emotions and to ask questions. He patiently answered all questions, checking often to make sure they understood. He also reassured Mr. and Mrs. T that he would be available to talk with them or their son at any time. Mr. and Mrs. T told the pediatrician that they did not want Patient A to know about the diagnosis until it was confirmed. The pediatrician tried to persuade them to carefully consider this decision.

A cancer diagnosis is overwhelming for parents, and clinicians discussing the diagnosis should use clear language, encourage questions, check often for understanding, and offer reassurance and support. In addition, clinicians should elicit and validate parents' and patients' emotions. The American Academy of Pediatrics recommends that clinicians refer children to pediatric cancer centers for diagnostic testing for leukemia (and lymphoma), where the availability of appropriate technology and subspecialists helps to ensure an accurate diagnosis. Many parents wish to protect their child by withholding information about the diagnosis, but clinicians should encourage parents to share information with their child, as studies have shown that children often recognize the severity of their illness and wish to be included in discussions about diagnosis and treatment. Open discussion can help a child feel less fear about the unknown and feel trust for their family and caregivers.

After much discussion, Mr. and Mrs. T decided not to tell Patient A the suspected diagnosis, but they did tell him he would need to see another physician and possibly have more tests. Patient A was concerned about the tests and wanted to know if they would be painful. The patient and his parents met with the pediatric oncologist, who performed a bone marrow aspiration, ensuring that Patient A was comfortable during the procedure. Examination of the bone marrow sample showed the presence of leukemic blast cells consistent with ALL. A lumbar puncture was performed, again ensuring that the patient was comfortable, and there was no evidence of leukemic involvement of the CNS. Cytogenetic examination of bone marrow cells demonstrated hyperploidy.

Pain interventions during diagnostic procedures are important, and the goal is to achieve unconsciousness, amnesia, and analgesia to ensure optimum comfort and cooperation. Preventing pain during diagnostic procedures is also important to avoid a child's fear of future diagnostic testing and to avoid post-traumatic stress years later. The sample obtained during bone marrow aspiration should be enough for both cytogenetic examination and immunophenotyping.

The pediatric oncologist met with Patient A and his parents to discuss the findings. Before the oncologist could discuss the diagnosis, Patient A's mother requested that the oncologist speak with only her and her husband before telling the patient. Both Mr. and Mrs. T seemed to be masking their emotions. The oncologist noted that Patient A should be included in the conversation, but Mr. and Mrs. T were adamant. Reluctantly, the oncologist discussed the diagnosis and prognostic factors with the parents only; he told them that the prognostic factors were favorable and noted that a clinical trial would be the best option. Mr. and Mrs. T began to express strong emotions, with Mrs. T crying and Mr. T becoming angry. They did not ask any questions, and Mr. T said he did not want his son to be a "guinea pig" in a clinical trial. The oncologist encouraged them to consider the decision carefully and to talk about the diagnosis with Patient A. When the oncologist suggested that Patient A be involved in the decision about participating in a clinical trial, both parents argued that he was too young to make such a decision. The oncologist provided Mr. and Mrs. T with educational resources and the names of some parents who had agreed to talk with parents of children with newly diagnosed leukemia. He also told them that a decision would need to be made quickly, as treatment should begin as soon as possible.

The emotional behavior of Mr. and Mrs. T indicates that they are having a difficult time dealing with their son's diagnosis. It is important for the clinician to be empathic and to encourage them to express their emotions. The clinician should also reiterate the importance of Patient A being involved with discussions about the diagnosis and treatment. Among the favorable prognostic factors are Patient A's age; age at the time of diagnosis is a strong prognostic factor, and disease-free survival is better for children 1 to 9 years of age than for other age groups. In addition, hyperploidy is associated with a highly favorable prognosis. These factors will allow treatment with a standard-risk protocol. Clinical trial participation should always be encouraged, as it provides the maximum opportunity for cure and long-term survival. The age threshold for a child participating in a discussion about a clinical trial has been debated, but most agree that individual decisions should be made on the basis of the child's level of maturity and physiologic and psychologic state. The Children's Oncology Group recommends that the clinician and parents seek the child's perspective and that the clinician should encourage the parents and patient to make the decision jointly as a family. During the clinical trial discussion, the clinician should discuss all facets of the clinical trial, emphasizing that a trial involves several possible treatment options, one of which is the treatment their child would receive outside of the clinical trial. Parents of children with cancer have suggested that providing educational resources and arranging for discussions with other parents are helpful for making decisions about a clinical trial.

Mr. and Mrs. T met with other parents and gained support for their emotional reactions. They also decided that Patient A should know about the diagnosis. He had many questions, and they arranged a meeting with the oncologist. The oncologist also discussed the possibility of a clinical trial, and Patient A said he wanted to participate; his parents supported his decision.

Patient A received induction therapy, CNS prophylaxis, consolidation therapy, and three years of maintenance therapy. Throughout his treatment, the patient received support from his extended family, friends, and classmates. He was tutored at home and managed to keep up with his school work. Four years after diagnosis, Patient A has no evidence of disease and he has returned to a "normal" life of school and activities. The pediatric oncologist documented the patient's complete diagnosis and a comprehensive account of treatment in a survivorship care plan, which he forwarded to the patient's pediatrician.

As Patient A continues routine health care, the survivorship care plan will provide the information his pediatrician and subsequent physicians need to understand his health risks according to his cancer type and its treatment. His physicians should also consult the Children's Oncology Group's evidence-based guidelines for the long-term follow-up care of childhood cancer survivor to provide individualized follow-up care and screening. Lastly, Patient A's physicians should use every healthcare visit as an opportunity to educate Patient A (and his parents) about his specific health risks and the importance of appropriate prevention measures, engaging in healthy lifestyle behaviors, and avoiding risky behaviors.

CASE STUDY 2

E is a Puerto Rican girl, 10 years of age, whose brother, Patient M, 5 years of age, is in the second year of his three-year course of chemotherapy for ALL. Before Patient M was diagnosed with cancer, E enjoyed helping her mother with his care and teaching him how to count and to say the alphabet. E also enjoyed taking dance classes, and she and her classmates would visit each other's homes to practice. E's mother, Mrs. P, does not work outside the home and had been very involved in E's activities before the diagnosis. E's father, Mr. P, works full-time on the weekdays and paints houses on the weekends to ensure that the family can live in a nice neighborhood outside of the city. Several Puerto Rican families live in the neighborhood, and the P family enjoys close ties within this community. Both Mr. and Mrs. P speak Spanish as a first language and use English sparingly.

Because of the financial strain and the long drive to the hospital, the family moved into a two-bedroom condominium closer to the hospital. E's family is the only Hispanic family in the complex, and E spends much time at home alone, as Mr. P continues to work two jobs and Mrs. P spends most of each day at the hospital. E's grades begin to drop, and she does not complete assignments or closely follow directions. E's teacher feels that she is disinterested in academics and her classmates. At home and at the hospital, E argues frequently with Mrs. P and cries often, saying that she wants to live with her friends in her former neighborhood because she feels "bored." In general, Mrs. P is embarrassed and frustrated by E's behavior. She often physically handles E following outbursts, resulting in E's crying and embarrassment. Conversely, Mrs. P is very kind to the staff and her son. If E is not present, Mrs. P does not exhibit signs of emotional distress.

E has lost many things that were important to her: dance lessons, familiar school, and friends, and her behavior and outbursts may be indicative of loneliness as well as jealously and resentment she feels against the time and attention Mrs. P provides Patient M. Cancer-free siblings are often reactive to the loss of day-to-day family routine, restrictions on their social activities, and inability to help their siblings with cancer. In addition, cancer-free siblings receive the least attention in the family, and their parents often overlook or underestimate their emotional and health-related responses [475]. E's feelings and behaviors increase the risk of unhealthy psychosocial adjustment and lower educational achievements.

Noting the emotional behaviors of E and her mother, Patient M's healthcare team seeks to provide psychosocial support for the family. A female member of the medical team who has been involved with Patient M's treatment and a professional interpreter arrange to talk with Mr. and Mrs. P and E independently so that they can share their concerns and express their emotions openly. The team member reassures the parents that E is expressing feelings and behaviors typical of cancer-free siblings. She acknowledges that the move has been difficult for the entire family, and points out that it is particularly so for E because of the social support she lost in addition to the time lost with her family. In the discussion with E, the team member acknowledges how difficult the adjustment is for E and emphasizes that her parents love her. E says that she misses being with her mother and brother and wishes she could be more involved. She also misses her father and wishes he could spend more time with the family. On the basis of the discussions with the family, the team member recommends several interventions, including a problem-solving skills training program for Mrs. P, family therapy, and a sibling program for E. The team member also encourages Mrs. P to involve E in Patient M's care and helps Mr. and Mrs. P seek additional practical resources to help them meet the challenges associated with Patient M's illness.

Family-centered care is essential in pediatric cancer, and the healthcare team must emphasize the importance of family cohesion and communication [484,485,486]. Helping Mr. and Mrs. P understand the reasons for E's behavior enhances the likelihood that they will agree to have her participate in a psychosocial intervention [489]. The use of a professional interpreter helps to make Mr. and Mrs. P more comfortable and provides for better comprehension [160]. The recommendation for a problem-solving program for Mrs. P is especially appropriate as such training has been shown to have increased effectiveness for Spanish-speaking mothers [501]. Family therapy will help Mr. and Mrs. P and E communicate more openly with each other, and the therapeutic peer support group can help E with psychosocial adjustment.

Four months after the intervention, E says that she feels she has more of an active role in Patient M's treatment and that she is helping him with pain and emotional management. E is able to speak with her mother and father about problems at school and emotional aspects related to Patient M's cancer and the move. Mrs. P is noticeably affectionate with E. The family has received financial assistance with help from a cancer society, and Mr. P has negotiated with his employer to be off on every Friday and has quit his second job, allowing him to spend more time with his family. The family also makes arrangements to see friends in their former neighborhood occasionally. E is interacting with schoolmates again and is also performing better academically.

15. CONCLUSION

The diagnosis, treatment, and follow-up care for children and adolescents with leukemia and lymphoma are complex. Although pediatric oncologists and a host of oncology specialists will provide treatment, primary care practitioners should be familiar with the signs and symptoms indicative of the most common types of hematologic cancers to ensure timely detection and early treatment, when the chances for cure are best. The types of leukemia and lymphoma differ from each other according to patient factors (age, sex, and race/ethnicity), clinical features, cancer biology and histology, approaches to treatment, late effects, and rates of overall and disease-free survival.

Diagnosing childhood leukemia and lymphoma is challenging because of the similarity between their symptoms and the symptoms of other common childhood conditions, especially infection. Careful history and physical examination targeted to suspicious symptoms is the first step of testing to confirm the diagnosis and determine the biology and histology of the cancer.

The diagnosis of cancer in a young person is devastating for patients and families. Therefore, clinicians should follow the tenets of "breaking bad news" and use clear, simple language, show empathy, and allow the patient and family to express concerns and emotion. As in all healthcare encounters, communicating the diagnosis should be done with consideration of the family's cultural context, with a professional interpreter used if English is not the family's native language.

Children and adolescents with leukemia or lymphoma should be treated in a pediatric cancer center and should be encouraged to participate in a clinical trial, which provides the opportunity for the most advanced care. The discussion of clinical trial participation should include all the pertinent information necessary for decision making. When possible, the family should make a decision together, with involvement of the patient. Treatment for leukemia and lymphoma is centered on chemotherapy, and several regimens have been evaluated for each type of disease. Radiation therapy is also a cornerstone of treatment, especially for lymphoma. The underlying principle of treatment is to maximize the potential for cure while minimizing the toxic effects of chemotherapy and/or radiation therapy. As such, treatment is risk-adapted according to prognostic variables. Research focused on adverse events related to chemotherapy and radiation therapy has demonstrated a variety of acute and late effects of treatment, and investigators continue to modify treatment regimens to avoid toxicity.

Disease-directed treatment is only one component of the overall treatment of children and adolescents with pediatric leukemia or lymphoma. Treatment also includes supportive, palliative, and psychosocial care. Supportive care involves the evaluation and treatment of potential complications of both the disease and treatment. The most common complications are infection, neutropenia, anemia, and thrombocytopenia. Palliative care focuses on the careful assessment and treatment of symptoms to enhance the quality of life. The prevalence of such symptoms as pain, fatigue, gastrointestinal disturbances, mucositis, and pruritus are high among children/adolescents with leukemia or lymphoma, and clinicians should implement both pharmacologic and nonpharmacologic interventions to relieve discomfort.

As a result of advances in treatment, the five-year overall survival for a child/adolescent with leukemia or lymphoma is approximately 80% [4]. Despite this high rate of success, some children and adolescents will die of the disease or complications. Pediatric end-of-life care is a challenge for several reasons and does not need to exclude curative therapy. Parents often have unrealistic expectations or optimism about cure, and clinicians should talk openly with the family to ensure that the priority in decision making is the patient's quality of life. Throughout all treatment, children and adolescents with cancer should be allowed to express opinions about the direction of care in a way that is appropriate for their developmental age.

Addressing the psychosocial and spiritual needs of children and adolescents with cancer is an integral component of comprehensive care. Evaluating these needs and providing referrals for interventions help patients and their families cope with the diagnosis and treatment of cancer and help to avoid later psychosocial distress. By definition, pediatric health care is family-centered, and it is important for clinicians to ensure that the psychosocial and spiritual needs of parents, siblings, and other family members are also met.

The advances in treatment for children/adolescents with pediatric leukemia or lymphoma have led to a substantial number of childhood cancer survivors, and the health burden caused by the late effects of treatment is substantial for this growing population. Close follow-up care is essential to ensure the early detection and/or prevention of such late effects as second cancers, cardiac abnormalities, abnormal growth and development, gonadal dysfunction, neurocognitive impairment, and psychosocial disorders. Follow-up care should be individualized according to treatment exposure and risk, and evidence-based guidelines are now available for care.

There are many challenges inherent in providing long-term follow-up care to childhood cancer survivors. Patient and family education is necessary to heighten awareness of the importance of follow-up care and the potential late effects. Primary care practitioners are uniquely poised to provide the full spectrum of care for childhood cancer survivors and can play a pivotal role in ensuring the long-term health of this growing population.

16. RESOURCES FOR FAMILIES WITH A CHILD OR ADOLESCENT WITH LEUKEMIA OR LYMPHOMA

GENERAL EDUCATION AND ADVOCACY

American Cancer Society

https://www.cancer.org

American Childhood Cancer Organization

https://www.acco.org

The Leukemia and Lymphoma Society

http://www.lls.org

The National Children's Cancer Society

https://www.thenccs.org

13Thirty Cancer Connect

http://13thirty.org

The Ulman Cancer Fund for Young Adults

https://ulmanfund.org

SURVIVORSHIP

Cancervive

http://www.cancervive.ca

Children's Oncology Group

http://www.survivorshipguidelines.org

Stupid Cancer

http://stupidcancer.org

National Coalition for Cancer Survivorship

https://www.canceradvocacy.org

Office of Cancer Survivorship (of the National Cancer Institute)

https://cancercontrol.cancer.gov/ocs

INSURANCE, LEGAL, AND EDUCATIONAL ISSUES

International Center for Disability Resources on the Internet

http://www.icdri.org

Patient Advocate Foundation

https://www.patientadvocate.org

FREE WEEKLONG AND WEEKEND CAMPS

Big Sky Kids

https://eaglemount.org/volunteer/volunteer-opportunities/big-sky-kids

Camp Mak-A-Dream

https://www.campdream.org

Camp Sunshine

https://www.campsunshine.org

First Descents

https://firstdescents.org

Special Love for Children with Cancer

Camp Fantastic

http://www.specialove.org/camps/patients-survivors/camp-fantastic

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527. Lipshultz SE, Adams MJ, Colan SD, et al. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. 2013;128(17):1927-1995.

528. Fulbright JM. Review of cardiotoxicity in pediatric cancer patients: during and after therapy. Cardiol Res Pract. 2011;2011:942090.

529. Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. Journal of Clinical Oncology. 2001;19(7):1926-1934.

530. Pein F, Sakiroglu O, Dahan M, et al. Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy. Br J Cancer. 2004;91(1):37-44.

531. Pinarli FG, Oğuz A, Tunaoğlu FS, Karadeniz C, Gökçora N, Elbeg S. Late cardiac evaluation of children with solid tumors after anthracycline chemotherapy. Pediatric Blood Cancer. 2005;44(4):370-377.

532. Sorensen K, Levitt GA, Bull C, Dorup I, Sullivan ID. Late anthracycline cardiotoxicity after childhood cancer: a prospective longitudinal study. Cancer. 2003;97(8):1991-1998.

533. Hudson MM, Rai SN, Nunez C, et al. Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors. J Clin Oncol. 2007;25(24):3635-3643.

534. Rathe M, Carlsen NLT, Oxhøj H, Nielsen G. Long-term cardiac follow-up of children treated with anthracycline doses of 300 mg/m or less for acute lymphoblastic leukemia. Pediatric Blood Cancer. 2010;54(3):444-448.

535. Vilela M, Viana MB. Longitudinal growth and risk factors for growth deficiency in children treated for acute lymphoblastic leukemia. Pediatric Blood Cancer. 2007;48(1):86-92.

536. Haddy T, Mosher RB, Nunez SB, Reaman GH. Growth hormone deficiency after chemotherapy for acute lymphoblastic leukemia in children who have not received cranial radiation. Pediatric Blood Cancer. 2006;46(2):258-261.

537. Viana MB, Viela MI. Height deficit during and many years after treatment for acute lymphoblastic leukemia in children: a review. Pediatric Blood Cancer. 2008;50(2 Suppl):509-516.

538. Groot-Loonen JJ, Otten BJ, van t'Hof MA, Lippens RJ, Stoelinga GB. Chemotherapy plays a major role in the inhibition of catch-up growth during maintenance therapy for childhood acute lymphoblastic leukemia. Pediatrics. 1995;96(4 Pt 1):693-695.

539. Adams J, Lipshultz SE. Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatric Blood Cancer. 2005;44(7):600-606.

540. Zhang FF, Kelly MJ, Saltzman E, et al. Obesity in pediatric ALL survivors: a meta-analysis. Pediatrics. 2014;133(3):e704-715.

541. Razzouk BI, Rose SR, Hongeng S, et al. Obesity in survivors of childhood acute lymphoblastic leukemia and lymphoma. J Clin Oncol. 2007;25(10):1183-1189.

542. Oktem O, Kim SS, Selek U, Schatmann G, Urman B. Ovarian and uterine functions in female survivors of childhood cancers. Oncologist. 2018;23(2):214-224.

543. Horning S, Hoppe RT, Kaplan HS, Rosenberg SA. Female reproductive potential after treatment for Hodgkin's disease. N Engl J Med. 1981;304(23):1377-1382.

544. Oeffinger KC, Mertens AC, Hudson MM, et al. Health care of young adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med. 2004;2(1):61-70.

545. Nathan PC, Patel SK, Dilley K, et al. Guidelines for identification of, advocacy for, and intervention in neurocognitive problems in survivors of childhood cancer: a report from the Children's Oncology Group. Arch Pediatr Adolesc Med. 2007;161(8):798-806.

546. Butler RW, Mulhern RK. Neurocognitive interventions for children and adolescents surviving cancer. J Pediatr Psychol. 2005;30(1):65-78.

547. Mitby P, Robison LL, Whitton JA, et al. Utilization of special education services and educational attainment among long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer. 2003;97(4):1115-1126.

548. Yeazel M, Gurney J, Oeffinger K, et al. An examination of the dental utilization practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Public Health Dent. 2004;64(1):50-54.

549. Mertens AC, Brand S, Ness KK, et al. Health and well-being in adolescent survivors of early childhood cancer: a report from the Childhood Cancer Survivor Study. Psychooncology. 2014;23(3):266-275.

550. Hobbie WL, Stuber M, Meeske K, et al. Symptoms of posttraumatic stress in young adult survivors of childhood cancer. J Clin Oncol. 2000;18(24):4060-4066.

551. Phipps S, Klosky JL, Long A, et al. Posttraumatic stress and psychological growth in children with cancer: has the traumatic impact of cancer been overestimated? J Clin Oncol. 2014;32(7):641-646.

552. Oancea SC, Brinkman TM, Ness KK, et al. Emotional distress among adult survivors of childhood cancer. J Cancer Surviv. 2014;8(2):293-303.

553. Mader L, Michel G, Roser K. Unemployment following childhood cancer. Dtsch Arztebl Int. 2017;114(47):805-812.

554. Perkins JL, Chen Y, Harris A, et al. Infections among long-term survivors of childhood and adolescent cancer: a report from the Childhood Cancer Survivor Study. Cancer. 2014;120(16):2514-2521.

555. Wengenroth L, Rueegg CS, Michel G, et al. Life partnerships in childhood cancer survivors, their siblings, and the general population. Pediatric Blood Cancer. 2014;61(3):538-545.

556. Bashore L. Childhood and adolescent cancer survivors' knowledge of their disease and effects of treatment. J Pediatric Oncol Nurs. 2004;21(2):98-102.

557. Kadan-Lottick NS, Robison LL, Gurney JG, et al. Childhood cancer survivors' knowledge about their past diagnosis and treatment: Childhood Cancer Survivor Study. JAMA. 2002;287(14):1832-1839.

558. Earle C, Schrag D, Woolf SH, Ganz PA. The survivorship care plan: what, why, how, and for whom. In: Perry MC (ed). ASCO 2006 Educational Book. Alexandria, VA: American Society of Clinical Oncology; 2006.

559. Earle CC. Failing to plan is planning to fail: improving the quality of care with survivorship care plans. J Clin Oncol. 2006;24(32):5112-5116.

560. Kirchoff AC, Montenegro RE, Warner EL, et al. Childhood cancer survivors' primary care and follow-up experiences. Support Care Cancer. 2014;22(6):1629-1635.

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562. Castellino SM, Casillas J, Hudson MM, et al. Minority adult survivors of childhood cancer: a comparison of long-term outcomes, health care utilization, and health-related behaviors from the childhood cancer survivor study. J Clin Oncol. 2005;23(27):6499-6507.

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Evidence-Based Practice Recommendations Citations

1. Terezakis SA, Metzger ML, Constine LS, et al. ACR Appropriateness Criteria: Pediatric Hodgkin Lymphoma. Reston, VA: American College of Radiology; 2012. Available at https://acsearch.acr.org/docs/70602/Narrative. Last accessed August 22, 2018.

2. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atlanta, GA: Centers for Disease Control and Prevention; 2015. Available at https://www.cdc.gov/vaccines/pubs/pinkbook/meas.html. Last accessed August 22, 2018.

3. Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem cell transplantation: 2017 update. J Clin Oncol. 2017;35(18):2082-2094. Available at https://www.childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document_Dec_2017.pdf. Last accessed August 22, 2018.

4. Barnard D, Portwine C, Members of the C17 Standards and Guidelines Group. Guideline for platelet transfusion thresholds for pediatric hematology/oncology patients. Edmonton: C17 Council, Children's Cancer & Blood Disorders; 2010. Available at https://www.c17.ca/index.php/download_file/view/42. Last accessed August 22, 2018.

5. Cincinnati Children's Hospital Medical Center. Patient Services/Primary Care Givers of Oncology Patients/Psycho-Social Interventions: BESt 143. Available at https://www.cincinnatichildrens.org/-/media/cincinnati%2520childrens/home/service/j/anderson-center/evidence-based-care/recommendations/specialty-discipline/psychosocialinteroncolbest143psycho-socialinterventionsbest143final11-28-12.pdf. Last accessed August 22, 2018.

30722 • Lung Cancer: Diagnosis and Management

Marilyn Fuller Delong, MA, BSN, RN

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Lung cancer is the second most common cancer affecting both men and women in the United States. Although it has been linked primarily with smoking and environmental factors, this disease can affect patients regardless of their occupation or lifestyle. Within the general diagnosis of lung cancer, there are several types, each with its own clinical course and prognosis. It is important that healthcare professionals understand these differences as they care for patients with the diagnosis of lung carcinoma. Multiple treatment options are available to the lung cancer patient. Traditional methods, such as surgery, chemotherapy, and radiation, continue to be the mainstays, but alternative methods are also being increasingly developed and used. Many of the treatment options available to lung cancer patients have extensive side effects, which should be discussed and minimized as much as possible.

Table of Contents

30722 • Lung Cancer: Diagnosis and Management

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

ALTERABLE RISK FACTORS

NONALTERABLE RISK FACTORS

3. PREVENTION AND SCREENING

4. PATHOPHYSIOLOGY OF LUNG CANCER

TYPES OF LUNG CANCER

5. SIGNS AND SYMPTOMS

6. DIAGNOSIS

RADIOLOGIC IMAGING

LABORATORY ANALYSIS

VISUALIZATION AND BIOPSY

7. CLASSIFICATION AND STAGING

STAGING CRITERIA

CLASSIFICATION OF SMALL CELL LUNG CANCER

CLASSIFICATION OF NON-SMALL CELL LUNG CANCERS

8. TREATMENT

SURGERY

CHEMOTHERAPY

RADIATION THERAPY

PHOTODYNAMIC THERAPY

ALTERNATIVE THERAPIES

9. THE CLINICAL COURSE OF LUNG CANCER

METASTASIS

10. CONDITIONS CAUSED BY ADVANCED LUNG CANCER AND CANCER TREATMENTS

RESPIRATORY DISTRESS

FATIGUE

NAUSEA, VOMITING, AND WEIGHT LOSS

PAIN

SUPERIOR VENA CAVA SYNDROME

SPONTANEOUS PNEUMOTHORAX

HEMOPTYSIS

11. VASCULAR ACCESS DEVICES

TROUBLESHOOTING VASCULAR ACCESS DEVICES

12. THE TERMINAL PATIENT

STAGES OF GRIEF: THE KÜBLER-ROSS MODEL

ADVANCE DIRECTIVES

HOSPICE

13. CASE MANAGEMENT OF THE PATIENT WITH LUNG CANCER

CLINICAL PATHWAYS

NURSING OUTCOMES

14. PATIENT TEACHING GOALS

PATIENT TEACHING FOR SURGERY

PATIENT TEACHING FOR CHEMOTHERAPY

PATIENT TEACHING FOR RADIATION THERAPY

CASE MANAGEMENT AND PATIENT TEACHING

15. CASE STUDY

16. CONCLUSION

17. RESOURCES

18. APPENDIX 1: SAMPLE CASE MANAGEMENT CARE PLANS

Works Cited

Evidence-Based Practice Recommendations Citations

30722 • Lung Cancer: Diagnosis and Management

Education Category. Medical / Surgical

Release Date. 09/01/2018

Expiration Date. 08/31/2021

Course Overview

Lung cancer is the second most common cancer affecting both men and women in the United States. Although it has been linked primarily with smoking and environmental factors, this disease can affect patients regardless of their occupation or lifestyle. Within the general diagnosis of lung cancer, there are several types, each with its own clinical course and prognosis. It is important that healthcare professionals understand these differences as they care for patients with the diagnosis of lung carcinoma. Multiple treatment options are available to the lung cancer patient. Traditional methods, such as surgery, chemotherapy, and radiation, continue to be the mainstays, but alternative methods are also being increasingly developed and used. Many of the treatment options available to lung cancer patients have extensive side effects, which should be discussed and minimized as much as possible.

Audience

This course is designed for all nurses, especially those involved in the care of patients with lung cancer.

Course Objective

The purpose of this course is to address the various aspects of diagnosis, treatment, disease management and appropriate patient care for healthcare professionals caring for patients with lung cancer.

Learning Objectives

Upon completion of this course, you should be able to:

1. Discuss the risk factors and incidence of lung cancer.

2. Explain the pathophysiology of lung cancer.

3. Identify the signs and symptoms of lung cancer.

4. Discuss the various tests used to diagnose lung cancer.

5. Describe the lung cancer classification and staging system.

6. Discuss the treatment options available to the patient with lung cancer, including potential adverse effects.

7. Discuss the clinical course of a patient with lung cancer.

8. Describe conditions caused by advanced lung cancer and lung cancer treatments.

9. Identify the vascular access devices (VADs) commonly used in the treatment and management of lung cancer.

10. Define grief and loss and identify measures to facilitate the grieving process.

11. Differentiate between advance directives, physician directives, and do not resuscitate (DNR) orders.

12. Explain the hospice concept.

13. Discuss nursing case management and clinical pathways of the patient with lung cancer.

14. List patient teaching goals that are useful for patients with lung cancer.

Faculty

Marilyn Fuller Delong, MA, BSN, RN, received her basic nursing education at St. Luke's School of Nursing in Cedar Rapids, Iowa, her BSN from Coe College and her MA from California State University, Long Beach. She has worked throughout the United States both clinically and as an educator. Her continuing education classes have focused on the case management aspects of the care of orthopedic and pulmonary patients, with particular focus on the long-term care needs of the elderly and disabled.

Faculty Disclosure

Contributing faculty, Marilyn Fuller Delong, MA, BSN, RN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Lung cancer is the second most common cancer affecting both men and women in the United States, accounting for an estimated 13.5% of all new cancer diagnoses [1,2]. Although it has been linked primarily with smoking and environmental factors, this disease can affect patients regardless of their occupation or lifestyle. Within the general diagnosis of lung cancer, there are several types, each with its own clinical course and prognosis. It is important that healthcare professionals understand these differences as they care for patients with the diagnosis of lung carcinoma.

Multiple treatment options are available to the patient with lung cancer. Traditional methods, such as surgery, chemotherapy, and radiation, continue to be the mainstays, but alternative methods are being increasingly developed and used. Many of the treatment options available to patients with lung cancer have extensive side effects, which should be discussed and minimized as much as possible.

By first understanding lung cancer and how it is diagnosed and treated, healthcare professionals will best know how to implement measures to save costs. The realities of healthcare costs in the last few decades have caused changes in the practice of medicine. Perhaps now more than ever before, the nurse has a vital role as patient advocate. When concerns exist about quality of care, the case manager can be a pivotal influence to keep all components of the process functioning.

2. EPIDEMIOLOGY

Early in the twentieth century, lung cancer was rare. One report from 1912 found only 374 cases of lung cancer described in international medical literature; one man commented that it seemed of little value to write about such an "insignificant problem" [3]. However, in the 1930s, cigarette smoking became a socially acceptable trend for men in the United States. By the 1950s, lung cancer rates had risen significantly in the male population. In the 1960s, women began to embrace the trend and started smoking cigarettes in increased numbers. Ten years later, the rate of lung cancer among women had increased as well [2].

Among men in the United States, the number of new lung cancer cases and the number of deaths from lung cancer have decreased over the last several decades due to a decline in the number of men who smoke. Although men develop lung cancer more often than women, the incidence of new lung cancer cases among men has been steadily declining since the 1970s, with a reduction in lung cancer incidence of 2.5% per year from 2005 to 2014; this is compared with a 1.2% per annum decrease in women in the same period [2]. Overall, lung cancer death rates among men in the United States have declined 45% since 1990, with a decrease of 3.8% each year from 2005 to 2014 [2]. While the death rates for U.S. men continue to decrease and are lower than the death rates for men in several other countries, more men die from lung cancer than women [2,5]. In 2015, 83,645 men died from lung cancer, compared with 70, 073 women [1].

Among women in the United States, reductions in smoking began in the late 1970s. As noted, the incidence of lung cancer among women decreased 1.2% per year from 2005 to 2014, and death rates have steadily decreased by 2.3% per year from 2011 to 2015 [2]. Lung cancer death rates for women in the United States are among the highest in the world; however, likely due to a decline in smoking rates, there has been a 19% reduction in lung cancer deaths among women in the United States since 2002 [2,6]. Also, large state and regional variations in lung cancer trends among U.S. women persist [1,2,7].

The American Cancer Society estimates that 234,030 new cases of lung cancer (121,680 men and 112,350 women) will be diagnosed in the United States in 2018 [2]. Lung cancer deaths for the same year are estimated to be 154,050 (83,550 men and 70,500 women), accounting for approximately 25% of all cancer deaths [2].

ALTERABLE RISK FACTORS

Several risk factors for lung cancer have been associated with lifestyle choices, meaning that the risks can be either managed or avoided in many cases. The most common lifestyle risk factor in the development of lung cancer is smoking. A 1954 study was one of the first to substantiate the connection between smoking and lung cancer. This study demonstrated that a person who had smoked for 20 years, the equivalent of two packs per day for 10 years or one pack per day for 20 years, was, on average, 20 times more likely to have died from lung cancer than a nonsmoker [8]. Approximately 80% of lung cancer deaths in the United States each year are related to smoking [2,9].

There are several other risks that contribute to the development of lung cancer besides smoking, including involuntary or secondhand smoking, industrial and environmental hazards, and geography. Smoke that is breathed in from the environment is not as concentrated as if it was inhaled directly, but it contains the same harmful materials. Secondhand smoke, also known as environmental tobacco smoke, is a complex mixture of gases and particles that includes smoke from the burning cigarette, cigar, or pipe tip (sidestream smoke) and exhaled mainstream smoke. Secondhand smoke contains at least 7,000 chemicals, 250 or more that are known to be toxic, including more than 70 that cause cancer. Secondhand smoke exposure causes lung cancer in nonsmoking adults. Nonsmokers who are exposed to secondhand smoke at home or work increase their lung cancer risk by 20% to 30% [10,11,12]. Secondhand smoke exposure also causes respiratory symptoms in children and slows their lung growth. There is no risk-free level of secondhand smoke exposure. Even brief exposure can be dangerous [10].

The role of particulate air pollution in the incidence of lung cancer was the source of serious debate and contention for many years. Between 1982 and 2006, the American Cancer Society conducted a study (the Cancer Prevention Study II [CPS-II]) to examine the impact of environmental and lifestyle factors on cancer etiology in men and women in the United States. Researchers determined that fine particulate and sulfur oxide-related pollution, from vehicle and industrial sources, was associated with an increased incidence of cancer, heart disease, and all-cause mortality. Long-term exposure to these pollutants was determined to be a significant environmental factor in lung cancer incidence and mortality [13]. Another study published in 2017, the Adventist Health and Smog Study-2 (AHSMOG-2), followed more than 80,000 participants for an average of 7.5 years and determined that there was a positive incremental association between ambient fine particulate air pollution and the incidence of lung cancer and associated mortality [4].

Those who work around certain industrial substances, such as asbestos, have been found to have an increased risk for developing lung cancer, as well as mesothelioma and nonmalignant lung and pleural disorders [14]. In the late 1970s, the U.S. Consumer Product Safety Commission imposed a limited ban on the use of asbestos. This was followed by a 1989 ban on all new uses of asbestos by the U.S. Environmental Protection Agency [15]. Studies have shown that cigarette smoking combined with asbestos exposure is particularly hazardous. Smokers who are exposed to asbestos have a risk of developing lung cancer that is greater than the individual risks from asbestos exposure and smoking added together [14,15].

In addition to asbestos, many other materials have been linked to the development of lung cancer, including [4,11,16]:

- Radioactive ores (e.g., uranium)

- Inhaled chemicals or minerals (e.g., arsenic, beryllium, cadmium, vinyl chloride, nickel compounds, chromium compounds, coal products, mustard gas, chloromethyl ethers)

- Myristic acid

- Petroleum products

- Wood dust

- Radon

- Diesel exhaust

These substances are handled in many occupations, including by workers in chemical factories, automobile maintenance, uranium mining/processing, copper smelts, foundries, shipyards, mines, and glass, pottery, and linoleum factories [17]. Individuals in any of these occupations who also smoke cigarettes have an increased risk of developing lung cancer [11].

Geography has also been shown to be a significant risk factor for lung cancer. A report compiled by the American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries found large geographic variations in smoking that are delaying a decrease in lung cancer death rates in women and slowing the decrease in men. For example, the average percentage decrease in the lung cancer death rate among men in California was more than twice that of many Midwest and Southern states during the period 2008 through 2012 [18]. In women, the lung cancer death rate increased in 3 states (Vermont, South Dakota, and North Dakota) and decreased in 28 states for the same time period [18]. Rates remained stable in 20 states. Another report from the American Cancer Society shows that, between 2011 and 2015, death rates attributable to lung cancer were highest for men (in order of highest to lowest) in Mississippi, Arkansas, West Virginia, Tennessee, and Alabama, and highest for women in Kentucky, West Virginia, Arkansas, Tennessee, and Maine [2]. State variations have been attributed to several factors, including the level of public awareness about the harmful effects of smoking, social norms (e.g., acceptability of smoking), state educational levels, racial/ethnic variations among states, tobacco control activities, industry promotional activities, and economic dependency on tobacco farming and production [2,7].

NONALTERABLE RISK FACTORS

The risk factors mentioned so far have all been manageable or preventable (i.e., the decision to smoke or where to work is generally a personal choice). Race, gender, socioeconomic status, and family history are not factors that can be changed, but they nevertheless influence an individual's likelihood of developing lung cancer.

Significant racial and ethnic differences in the smoking-related incidence and progression of lung cancer have been reported [17]. Tobacco use varies within and among racial/ethnic minority groups and sex. In 2016, American Indian/Alaska Native adults had the highest prevalence of tobacco use (31.8%), followed by non-Hispanic individuals of multiples races (25.2%), whites (16.6%), blacks (16.5%), Hispanics (10.7%), and Asians (9%) [5]. The overall rate of cigarette smoking is higher among men (17.5%) than women (13.5%). In regards to sex, American Indian/Alaska Native women and men have the highest prevalence (34.3% and 29.3%, respectively) of smoking, with the lowest rates seen among Asian men and women (14% and 4.6%, respectively) [5,19]. Traditional uses of tobacco in ceremonial, religious, and medicinal roles in native cultures may affect behaviors and attitudes toward commercial tobacco use, leading to the high prevalence in this group.

Differences in the magnitude of disease risk are directly related to differences in patterns of smoking. No single factor determines patterns of tobacco use among racial/ethnic minority groups; these patterns are the result of complex interactions of multiple factors, such as socioeconomic status, cultural characteristics, acculturation, stress, biologic elements, targeted advertising, price of tobacco products, and varying capacities of communities to mount effective tobacco control initiatives [19].

There seems to be an identifiable trend of lung cancer in persons who have a family history of lung cancer, particularly in those cases where the patient was young. Studies have shown that there may be a specific gene that predisposes a person to lung cancer. Researchers studying the genetics of familial lung cancer have found strong evidence linking a major lung cancer susceptibility region of chromosome 6, specifically 6q23-25, to lung and other tobacco-related cancers [20,21].

3. PREVENTION AND SCREENING

Most risk factors can be minimized by establishing goals to prevent the disease whenever possible. The majority of these efforts have been focused on educating the public to never begin smoking, decrease exposure to secondhand smoke, and/or stop smoking if already smoking. Educational efforts to prevent new smokers from beginning have been heavily aimed at teenagers and young adults. Many programs have been established in schools, on television, and in print media.

Smoking cessation is beneficial in the following ways [19,22]:

- It lowers the risk for lung and other types of cancer; the risk declines with the number of years of smoking cessation.

- It reduces an individual's risk of dying prematurely.

- It reduces respiratory symptoms (e.g., coughing, wheezing, dyspnea).

- It slows the rate of decline in lung function and may improve lung tissue.

Patients who stop smoking continue to have a greater risk of developing lung cancer than those who never smoked at all, and the benefits are greater the earlier cessation occurs; however, cessation is beneficial at all ages.

Among adult U.S. smokers, 68% report that they want to quit completely [19,23]. Brief clinical interventions by healthcare providers can increase the chances of successful cessation, as can counseling and behavioral cessation therapies [24]. Treatments with more person-to-person contact and intensity (e.g., more time with counselors) have been shown to be more effective. Effective pharmacologic therapies include nicotine replacement products (e.g., gum, inhaler, patch) and non-nicotine medications, such as bupropion SR (Zyban) and varenicline tartrate (Chantix); however, the U.S. Food and Drug Administration (FDA) has required manufacturers to add a black box warning regarding a reported association between the use of these medications and neuropsychiatric adverse effects [19,24,25].

Several screening tools have been explored for the early detection and subsequent treatment of lung cancer, the most common being chest x-rays, sputum cytology, and computed tomography (CT) scans of the lungs. The tests involve risks, such as false-positive diagnoses, which may account for as much as 5% to 25% of total diagnoses [26]. False-positive results may lead to overtreatment, unnecessary invasive procedures, and exposure to radiation.

There is little evidence that chest x-ray or sputum cytology affect lung cancer mortality [26]. However, low-dose helical CT scans in high-risk patients do result in reductions in lung cancer-specific (20% reduction) and all-cause (nearly 7% reduction) mortality, mostly due to cancers being at an earlier stage at the time of diagnosis [26,27]. Based on these findings, the U.S. Preventive Services Task Force (USPSTF) recommends that adults 50 to 80 years of age who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years be screened annually with low-dose CT scan [28]. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

4. PATHOPHYSIOLOGY OF LUNG CANCER

To understand the pathophysiology of lung cancer, it is necessary to examine normal tissue cells and how they function. Normal cells are differentiated. That is, they undergo structural changes that make them different from cells in other parts of the body; these differences allow the cells to operate optimally in a given environment.

Malignant cells divide at an uncontrolled rate; they may grow at a frenzied pace, accumulating many more cells than are needed and disrupting homeostasis. They also have the ability to undergo innumerable doublings without dying. These new cells are not the same as the original cells. Therefore, they cannot perform the same tasks, and function is altered. One example of malignant cell reproduction causing abnormal function is small cell lung cancer (SCLC) cells, which can produce adrenocorticotropic hormone (ACTH) in such large amounts that the patient may develop Cushing syndrome, characterized by upper body weight gain, hypertension, and loss of potassium [29]. Cells that are close in appearance and function to healthy cells are well-differentiated, while tumor cells that are dramatically unlike healthy lung cells are undifferentiated or anaplastic.

Carcinogenesis is the process by which a normal cell is changed into a malignant cell. Many steps are involved, beginning with damage to the genes that regulate cell growth or inactivation of tumor suppressor genes. The substance or factor that initiates these cellular changes is referred to as a carcinogen. In some cases, an oncogene may be the initiating agent. These bits of genetic code within the cell may allow the cell to be altered. When this is the case, a cocarcinogen enhances the work begun by the oncogene initiator [30,31].

The second stage of carcinogenesis is promotion. In this phase, cells have an increased opportunity to become malignant. The effects of promotion are linked to the level and duration of exposure to the cocarcinogen (e.g., the number of years as a smoker and number of cigarettes smoked per day). This step of the process is reversible, so cancer prevention efforts are most effective when aimed at evading promoters. The length of time between exposure to the cocarcinogen and the development of the malignancy is referred to as the latency period [30,31].

The next step is progression, during which the tumor cells proliferate and undergo changes in their microscopic structure. Progression occurs as the malignant cells divide faster and develop the ability to invade, metastasize, and resist normally limiting agents [30,31].

TYPES OF LUNG CANCER

According to the World Health Organization (WHO), there are two main categories of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), each with their own pathology. NSCLC accounts for approximately 85% of all lung cancers and is further divided into two types: non-squamous carcinoma (this includes adenocarcinoma, large cell carcinoma, and other cell types) and squamous cell (epidermoid) carcinoma, each with distinct histologic and clinical characteristics [24,32,33,34].

Cellular Pathophysiology of Small Cell Lung Cancers

SCLC accounts for approximately 10% to 15% of all lung cancers [32,71]. It initiates in the basal cell lining of the bronchial mucosa, often in the central part of the chest. Because the cells resemble oat grains, SCLC was once called "oat cell carcinoma." SCLC is aggressive and grows rapidly, causing postobstructive pneumonia and atelectasis. It produces arginine vasopressin (AVP) and ACTH, which causes Lambert-Eaton syndrome, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and Cushing syndrome. SCLC metastasizes very early and to distant sites such as the brain, liver, and bone marrow. It is more responsive to chemotherapy and radiation than other types of lung cancer; however, because it has a tendency to be widely disseminated by the time of diagnosis, it is difficult to cure [35,36].

Cellular Pathophysiology of Non-Small Cell Lung Cancers

Squamous cell carcinoma accounts for approximately 25% to 30% of all lung cancers. It can be well-differentiated, moderately differentiated, or poorly differentiated. The cells are stratified squamous epithelium that line the airways and have receptors for growing epidermal tissue. This carcinoma tends to begin in the medial portion of the lung, which makes it difficult to detect with a chest x-ray. Squamous cell carcinoma of the lung also produces a substance similar to parathyroid hormone and may cause sudden hypercalcemia [32,33,37,69].

The non-squamous cell carcinoma of adenocarcinoma accounts for approximately 35% to 40% of all lung cancers and may manifest as a "scar carcinoma." It has a glandular appearance when viewed under a microscope and is comprised of acinar, papillary, solid, and bronchoalveolar types of cells. This cancer type begins, and usually remains, in a peripheral site of the lung, which makes it easy to visualize on chest x-ray, but difficult to reach through bronchoscopy. It metastasizes easily, often to the brain, liver, adrenal glands, or bones [32,33,38,69].

Approximately 10% to 15% of all lung cancers are large cell anaplastic carcinoma, which is clinically similar to adenocarcinoma. Microscopically, the large cells lack distinctive features. It can start in any part of the lung, and it tends to grow and spread quickly, which makes it difficult to treat [32,69].

5. SIGNS AND SYMPTOMS

Lung cancer rarely gives an early indication of its presence. It may be detected accidentally, when viewing a routine chest x-ray, or it may be suspected by symptoms presented by the patient (Table 1).

Table 1: SYMPTOMS OF LUNG CANCER

Cough, especially one that changes or becomes productive

Unilateral wheezing

Dyspnea

Pneumonia

Chest pain or pain in shoulder and arm

Hemoptysis

Vocal cord paralysis

Atelectasis

Neurologic changes

Lethargy

Unexplained weight loss

Source: [39]

Evidence Based Practice Recommendation

For all patients with lung cancer who have troublesome cough, the American College of Chest Physicians recommends that they be evaluated for treatable causes in addition to cancer-related etiologies.

https://journal.chestnet.org/issue/S0012-3692

Last Accessed: August 21, 2018

Strength of Recommendation: 1C (Strong recommendation based on low-quality evidence that the benefits outweigh the risks/burdens)

One of the most common symptoms experienced by patients with lung cancer is cough, which occurs when the airways become irritated (as from smoking) [2,32,35]. Those patients who have a cough related to their smoking may recognize a change in the type of cough but are not as likely to realize the significance of that change, particularly if the change occurs slowly over decades [35]. The cough may be more frequent, more irritating, of a different tone, or may feel as if it is arising from a different site than a normal cough. A cough that has always been dry may suddenly become productive as the obstructed bronchus develops an infection [2,35,39]. Persistent wheezing that occurs in one location in a smoker may also indicate lung cancer [35,39].

Pain that arises from lung abscess or tumor is often difficult to describe. It may not be severe, if present at all. With metastasis to the chest wall or lymph nodes, the patient may feel some tightness or a constant ache, which may be mistaken for a pulled muscle related to coughing. When a tumor invades the brachial plexus, there is usually pain in the arm and shoulder. Pain that originates in the chest wall may worsen with deep breathing or coughing [35,39,40].

Smokers may have emphysema and therefore be familiar with and accustomed to the feeling of dyspnea (shortness of breath) that accompanies that disease. The emphysematous patient may only feel a more frequent need for oxygen, or perhaps if already receiving oxygen continuously, his or her rate of O_2 flow may have to be increased. Because this change is more subtle, it may not be brought to the physician's attention as promptly. In contrast, when an otherwise healthy person becomes winded easily with exercise, he or she is more likely to investigate the cause and/or avoid exertion. If lung cancer is diagnosed, dyspnea may occur even at rest as the disease progresses [35].

Hemoptysis, bright red blood in the expectorant, is a symptom that generally prompts a rapid response from patients. Infection is the most common cause; however, lung cancer tumors account for approximately 20% of cases of hemoptysis [35]. Symptoms such as recurrent bouts of bronchitis or pneumonia that do not clear quickly may cause the patient to question whether there is an immune response problem but may never cause the patient to link the illness to cancer.

Metastasis has been shown to produce hoarseness, vocal cord paralysis, dysphagia, head and neck swelling, weakness, weight loss, loss of appetite, anorexia, and anemia [40]. Other symptoms that are indicative of metastatic spread of the disease include Horner syndrome, abdominal discomfort, nausea and vomiting, unexplained fever, jaundice, and cardiac symptoms. Elevated liver function tests may be signs of liver metastasis. Bone pain may signify bone metastasis, and severe, unrelenting headache may be caused by increased intracranial pressure from metastasis to the brain [40].

An estimated 10% to 20% of patients with lung cancer experience paraneoplastic syndromes. These symptoms may develop when substances (e.g., hormones, cytokines) released by cancer cells disrupt the normal function of surrounding cells and tissue [35,40,41]. SCLC is the most frequent cancer histology associated with paraneoplastic syndromes, including [40,42,43,44]:

- SIADH

- Blood clots

- Cerebellar degeneration (e.g., loss of balance, unsteady limb motion)

- Hypercalcemia

These syndromes are common lung cancer complications. They have been most frequently associated with advanced stages of the disease but may also occur at early stages [43,44].

6. DIAGNOSIS

When lung cancer is suspected, a complete history and physical examination is required. The history should inquire into any health problems, work history, smoking history, and family history. The physical examination should include listening to respiration, checking for fluid in the lungs, and feeling for swollen lymph nodes or swollen liver. If the exam results suggest lung cancer, additional tests should be done [32,37].

RADIOLOGIC IMAGING

Chest x-rays help find masses or lesions on the lungs. When anteroposterior and lateral films are taken, a peripheral tumor at least 1 cm in diameter can be visualized. Additionally, there will be evidence of a widened mediastinum or hilar adenopathy visible with this view [37].

CT scans film cross-sectional soft tissue images of the body to analyze tissue for density and reveal tumors or displaced organs. A CT scan of the chest with contrast has been recommended for patients with known or suspected lung cancer who are eligible for treatment [45]. A chest x-ray and chest CT scan with contrast material has also been recommended for staging locoregional disease [46].

The patient may be asked to take nothing by mouth (NPO) prior to the procedure and may be asked to drink, or receive intravenously, a contrast solution to help outline structures in the body. The images can provide precise information about the size, shape, and position of tumors and can help find enlarged, potentially cancerous lymph nodes. The test can also be used to detect masses in the adrenal glands, brain, and other internal organs [32]. While CT of the chest is the reference standard for detecting focal lung disease, missing lung lesions during CT is a well-recognized phenomenon. The computer-aided detection system has been shown to increase the overall accuracy of lesion detection when used as a second reader on chest CT studies [47,48].

Spiral CT uses a faster, continuously rotating machine. The spiral CT allows for a more rapid collection of images than the standard CT. It also reduces blurred images, lowers the dose of radiation received, and produces thinner images that yield a more detailed picture for analysis [32].

A CT-guided needle biopsy is another option for analyzing suspected cancer. In this method, a CT scan is used to guide a biopsy needle into the suspected area. The scans are repeated until the physician is certain that the needle is within the mass. A biopsy sample is then removed and reviewed under a microscope [32].

Newer imaging techniques, such as four-dimensional computed tomography (4DCT), are being explored to help in diagnosis and improved treatment. 4DCT continuously scans the chest for about 30 seconds, as the patient breathes, and shows where the tumor is in relation to other structures. This can help practitioners to deliver radiation more precisely and can also show if a tumor is interfering with any other structures in the chest [79].

Magnetic resonance imaging (MRI) is a noninvasive radiologic procedure used in some cases to aid in diagnosing lung carcinomas. It is more commonly used to stage lung cancers and identify possible metastases, particularly of the brain and spinal cord [33]. However, it may also be employed to visualize areas of the lungs not well demonstrated on axial images. Head CT or MRI brain imaging has been recommended for use in patients with signs or symptoms of central nervous system disease as well as for patients with stage III disease who are being considered for aggressive local therapy [33,46].

Positron emission tomography (PET) scans may also be useful in the diagnosis of lung cancer. An 18F-deoxyglucose PET scan should be performed to investigate solitary pulmonary nodules or mass, particularly in cases where a biopsy is not possible or has failed, depending on nodule size, position, and CT characterization [45,46,49,50]. This study may also be useful in detecting metastatic spread of the disease but is not intended to replace conventional imaging techniques. The American College of Chest Physicians (ACCP) does not recommend PET scanning in the routine staging of SCLC, although the National Comprehensive Cancer Network (NCCN) guideline recommends combined PET-CT if limited-stage disease or metastasis is suspected [49]. PET has been recognized as a valuable tool in developing a treatment plan in the management of lung cancer [49,51].

Endobronchial ultrasound (EBUS) uses sound waves to produce images [52]. EBUS has been found to be a useful adjunct in the diagnosis of lung cancer, particularly when the lesions occur in the periphery of the respiratory tract [53]. Additionally, EBUS has been shown to have a high sensitivity and specificity for node staging compared to CT or PET scans and may be considered in staging lesions [54]. Endoscopic esophageal ultrasound is similar to EBUS, except it involves passing an endoscope down the throat into the esophagus. Ultrasound images taken inside the esophagus may help find cancerous lymph nodes inside the chest [55].

LABORATORY ANALYSIS

Blood work is done to assess the respiratory status and to look for metastasis to other organs. These tests may include arterial blood gases, complete blood count, serum calcium, alkaline phosphatase, and liver function studies [33].

Sputum specimens for cytology are completed in order to microscopically identify any malignant cells that may have been sloughed off and expectorated. This requires collecting three early morning specimens in an attempt to obtain deep sputum production, not just saliva from the mouth. Samples are placed in a fixative and processed before viewing. Sputum cytology is not routinely recommended and should be reserved to investigate patients with centrally placed nodules or masses and who are unable to tolerate or unwilling to undergo bronchoscopy or other invasive tests [33,49].

VISUALIZATION AND BIOPSY

A bronchoscopy is performed routinely on patients suspected of having lung cancer. This procedure allows an opportunity to visualize the lung structure for possible narrowing, inflammation, bleeding, or tumors (Table 2). The ability to actually see some tumors permits a more representative tissue sample to be obtained. A sample of the tissue may be obtained through needle aspiration (transbronchial), brush or forceps biopsy, bronchoalveolar lavage, or bronchial washings. There is some controversy regarding the use of bronchoscopy and fine-needle aspiration. While some have challenged the practice as unsafe and useless, based on instances of complications and false-negative results, use of these procedures remains a recommended approach to diagnosis [49,56,57,58]. The additional use of ultrasound imaging when using fine-needle aspiration is often utilized.

Table 2: BRONCHOSCOPY

Definition

The visualization of the pharynx, larynx, trachea, and bronchi through a rigid or flexible fiber optic bronchoscope.

Purpose

To collect specimens, visualize possible tumors, and obtain biopsies.

Procedure

Bronchoscopy may be performed at a patient's bedside if necessary but is usually done in the operating or procedure suites. Baseline vital signs are taken prior to beginning the procedure and are reassessed during and after the procedure. General anesthesia will be ordered for bronchoscopy performed with a rigid bronchoscope. Bronchoscopy performed with a flexible bronchoscope requires only local anesthetic, which is sprayed on the patient's throat and nares to reduce discomfort and override the gag reflex. Atropine may be ordered to decrease secretions. Patients are placed in a supine position with neck hyperextended. Patients should be constantly reassured and reminded to breathe through the nose and not cough, if possible. The bronchoscope is moved through the nares or mouth into the trachea and bronchial tree. Biopsy forceps may be used to remove tissue specimens, and a bronchial brush may be used to obtain cells from tissue surfaces.

Postprocedure

Withhold food and fluids until the local anesthetic has worn off, as the patient's ability to cough if aspirating will be inhibited.

Complications

Hypoxemia, hemorrhage, respiratory distress, hypertension, arrhythmia, tachycardia, and pneumothorax are all possible complications. Frequent observation of the patient is required until he or she is totally recovered from the procedure and the effects of the medications.

Source: Compiled by Author

The patient is kept NPO prior to the procedure and given mild sedation. There are different types of bronchoscopes available; the fiber optic bronchoscope is generally less uncomfortable than the rigid type. The tube is inserted through the nares in most patients, or through the mouth in those whose nasal passages are obstructed. Once inserted, the bronchoscope allows visualization of the tracheobronchial tree down to the finer branches. It is customary in this procedure to obtain washings, brushings, and possibly even a biopsy.

While the bronchoscopy can easily find tumors that lie in or on the main airways, those that are more peripheral are not easily accessed. In these cases, a percutaneous fine-needle aspiration biopsy may be done with the assistance of the CT scan, ultrasound, or fluoroscopy to direct the needle [32,49]. Ninety-five percent of the time this procedure is sufficient to diagnose the lesion, but there are some disadvantages as well. A pneumothorax or hemorrhage may occur. Also, if the tumor is cancerous, those malignant cells may be drawn along the path of the biopsy needle [59]. Bronchoscopy should be performed on patients with central lesions who are able and willing to undergo the procedure. Chest CT should be performed before an intended fiber optic bronchoscopy [49].

Mediastinoscopy and mediastinotomy may be done in instances when mediastinal lymph nodes must be assessed for possible metastasis. These are invasive procedures, involving incisions made over the sternal notch to allow access into the mediastinum with a mediastinoscope. The primary difference between the two procedures is in the size and location of the incision [32]. Biopsies may be taken from the nodes or other suspicious structures. Mediastinoscopy is considered to be the long-standing "criterion standard" for evaluating mediastinal lymph nodes; however, it is a high-risk procedure, typically used prior to surgery to confirm or exclude the presence of tumor in enlarged nodes [60,61,96]. Studies have shown that mediastinoscopy may be replaced by newer, more well-tolerated technologies, such as EBUS, which are safer and generally preferred by patients. Training to either maintain mediastinoscopy procedures skills or to elevate levels of accuracy for technologies such as EBUS is necessary to ensure a consistent level of accuracy between mediastinoscopy and other evaluation options [137].

Thoracenteses are done to obtain pleural fluid for analysis. They are most often performed when the patient has a pleural effusion. In this procedure, fluid is removed, thereby improving the patient's comfort while also allowing that fluid to be sent to the laboratory for examination [32]. Local anesthetic is given to allow insertion of a trocar into the chest. In some cases, fluoroscopy is used to direct the needle insertion. Table 3 provides more detail regarding thoracentesis.

Table 3: THORACENTESIS

Definition

The removal of fluid from the pleural space.

Purpose

To relieve pressure on the lungs by removing accumulated fluid; to withdraw fluid for laboratory analysis.

Procedure

Thoracentesis is usually performed at the patient's bedside. Baseline vital signs are taken before the procedure begins and are reassessed during and after the procedure. A narcotic or sedative may be administered prior to the procedure to relieve pain and/or relax the patient. Most often, patients are positioned sitting on the edge of the bed with legs supported and their head resting on their arms, atop a pillow, which has been positioned on an overbed table. This allows the physician access to the patient's back. The patient should have each step explained and should be reassured during this uncomfortable procedure. Patients should be reminded not to cough, sigh, or jerk away during the procedure, as this could cause an inadvertent puncture of other organs. If a patient needs to cough, he or she should be told to signal, so that the procedure can be stopped momentarily and the needle pulled back slightly. Local anesthetic is injected at the site of the insertion. A 17- or 18-gauge needle is inserted into the pleural space and fluid withdrawn. If more than a few milliliters of fluid are removed, tubing may be attached for drainage.

Complications

Hypovolemic shock is possible if large amounts of pleural fluid are removed rapidly. Pneumothorax may occur and happens frequently enough that chest x-rays are routinely taken postprocedure as a precautionary measure.

Source: Compiled by Author

In 2004, the FDA approved a CT system called the superDimension/Bronchus system (SDBS), a minimally invasive device used to diagnose lung cancer. The SDBS uses overlaid CT images to navigate to lesions in the lungs in real time and has a greater capability to reach peripheral masses, lymph nodes, and areas outside the range of a traditional bronchoscopy [62,63]. The procedure is proven to be safe, effective, and useful in establishing a diagnosis of lung cancer, especially when combined with other biopsy modalities [62,63,64].

7. CLASSIFICATION AND STAGING

Four histologic types account for more than 95% of all primary lung neoplasms; they are SCLC and the NSCLCs of squamous cell carcinoma, adenocarcinoma, and large cell carcinoma [65].

Bronchogenic carcinoma cells have the ability to differentiate into squamous, glandular, or neuroendocrine structures. A patient may be diagnosed with one particular cancer, perhaps adenocarcinoma, but within that tumor more than one type of cell may be found (mixed cell type). As a result, when a biopsy is taken, although one particular sample may indicate a certain diagnosis, another sample may indicate something else. It is important that a larger sample be taken so that all possible mutations may be seen.

Even more enigmatic is the propensity for the cells to alter their cell type after being treated with chemotherapy or radiation. To avoid total confusion when keeping tumor registry records and other studies, the type of tumor first listed as the diagnosis is the one that will be kept throughout the patient's illness.

STAGING CRITERIA

Staging of any tumor is done to determine the extent of the disease and the prognosis, to select patients for surgical or other intervention modalities, and to decide on a plan of treatment. The extent of the disease is the most important prognostic indicator. To determine this, a staging system has been developed by the American Joint Committee on Cancer (AJCC). This widely used TNM tumor classification system examines and classifies three different aspects of the cancer's development and growth: tumor, regional lymph node involvement, and metastasis (Table 4). "T" indicates the features of the primary tumor; "N" indicates metastasis to regional lymph nodes; and "M" indicates the presence or absence of distant metastases. Based on the presence and extent of these three aspects, the cancer may be staged (Table 5). It is this set of criteria that tumor registrars use to classify cancers and compile statistics for study and research [36,66,67].

Table 4: ELEMENTS OF LUNG CANCER STAGING

Code

Description

Primary Tumor (T)

TX

Primary tumor cannot be evaluated or malignant cells detected in sputum or bronchial washing, but not visualized through x-rays or bronchoscopy

T0

No evidence of primary tumor

Tis

Carcinoma in situ (only be diagnosed after resection of tumor)

T1: Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura; no invasion beyond lobar bronchus

T1a(mi)

Minimally invasive, irrespective of size

T1a

Tumor 1 cm or less in greatest dimension

T1b

Tumor more than 1 cm but 2 cm or less in greatest dimension

T1c

Tumor more than 2 cm but 3 cm or less in greatest dimension

T2: Tumor more than 3 cm but 5 cm or less in greatest dimension, or tumor with any of the following features: involves main bronchus without carina, regardless of distance; invades visceral pleura (PL1 or PL2); associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a

Tumor more than 3 cm but 4 cm or less in greatest dimension

T2b

Tumor more than 4 cm but 5 cm or less in greatest dimension

T3

Tumor more than 5 cm but less than 7 cm or that directly invades any of the following: parietal pleural (PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe

T4

Tumor more than 7 cm in greatest dimension with extensive invasion of the mediastinum, diaphragm, heart, great vessels, trachea, esophagus, recurrent laryngeal nerve, carina, or vertebral body; or tumor with malignant pleural effusion; or satellite tumor nodule(s) within the ipsilateral primary lobe of the lung

Regional Lymph Node Involvement (N)

NX

Regional lymph nodes not assessable

N0

No regional lymph node metastasis

N1

Metastasis to ipsilateral peribronchial and/or ipsilateral hilar nodes and intrapulmonary nodes, including direct extension

N2

Metastasis to ipsilateral mediastinal and/or subcarinal nodes

N3

Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or any supraclavicular nodes

Distant Metastasis (M)

MX

Distant metastasis not assessable

M0

No distant metastasis

M1: Distant metastasis

M1a

Separate tumor nodule(s) in a contralateral lobe, tumor with pleural nodules or malignant pleural (or pericardial) effusion

M1b

Single extrathoracic metastasis, including single non-regional lymphnode

M1c

Multiple extrathoracic metastases in one or more organs

Source: [36]

Table 5: STAGES OF LUNG CANCER

Stage

Primary Tumor

Node Involvement

Metastasis

Occult

TX

N0

M0

Stage 0

Tis

N0

M0

Stage IA1

T1mi or T1a

N0

M0

Stage IA2

T1b

N0

M0

Stage IA3

T1c

N0

M0

Stage IB

T2a

N0

M0

Stage IIA

T2b

N0

M0

Stage IIB

T1a, T1b, T1c, T2a, or T2b

N1

M0

T3

N0

M0

Stage IIIA

T1a, T1b, T1c, T2a, or T2b

N2

M0

T3

N1

M0

T4

N0

M0

T4

N1

M0

Stage IIIB

T1a, T1b, T1c, T2a, or T2b

N3

M0

T3 or T4

N2

M0

Stage IIIC

T3 or T4

N3

M0

Stage IVA

Any T

Any N

M1a or M1b

Stage IVB

Any T

Any N

M1c

Source: [36]

The Veterans Administration Lung Study Group has been the basis for treatment recommendations for SCLC for decades. This system classifies patients as having either limited-stage disease (i.e., tumor confined to one hemithorax and to the regional lymph nodes) or extensive-stage disease (i.e., tumor beyond this area in contralateral lung or extrathoracic sites). In 2009, the International Association for the Study of Lung Cancer (IASLC) launched a lung cancer staging project (using the sixth edition of the AJCC TNM staging system) designed to analyze clinical TNM staging for SCLC. The IASLC found a better correlation of patient survival when the TNM staging system was used and recommended that the AJCC TNM staging system be adopted more uniformly. These recommendations were incorporated into the seventh edition of the AJCC staging manual, and all cancer cases diagnosed between 2010 and 2017 use the seventh edition criteria. In 2017, updates based on new evidence in clinical cancer care were incorporated into the eighth edition of the AJCC TNM staging system, and all cases of cancer diagnosed after January 1, 2018, use the updated staging criteria [36,37,66].

CLASSIFICATION OF SMALL CELL LUNG CANCER

There are two subtypes of SCLC: small cell carcinoma and combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components). The classification of "SCLC combined" is used when at least 10% of the tumor bulk is composed of an associated non-small cell component. "SCLC" is reserved for tumors with pure SCLC histology [68].

As previously noted, SCLC accounts for approximately 10% to 15% of all bronchogenic carcinomas in the United States [34,68,71]. Without treatment, it is a highly aggressive malignancy with a median survival rate of only two to four months from the time of diagnosis. The overall survival at five years if 5% to 10% [68]. Approximately two-thirds of patients with SCLC have bilateral lung involvement at the time they are diagnosed [68]. Because distant metastasis is often present, SCLC is almost always considered metastatic. When found early, it is particularly sensitive to chemotherapy and radiation therapy; however, a cure is difficult to achieve. As discussed, SCLC is the cancer most commonly associated with paraneoplastic syndromes [68].

CLASSIFICATION OF NON-SMALL CELL LUNG CANCERS

There are several types of NSCLC, each with a different kind of cancer cell that grows and spreads in different ways [69]. Squamous cell carcinoma, also called epidermoid carcinoma, arises from the flat, scaly, stratified columnar epithelial cells that line the airways. It is almost always related to smoking and accounts for about 25% to 30% of all diagnosed cases [33,37,70]. Squamous cell carcinoma tends to be located centrally, causing atelectasis and pneumonia before it metastasizes. Squamous cell cancers grow slowly and are easier to surgically resect than some of the other types. Because of this, the prognosis is better for these patients [69]. One lesion most often caused by squamous cell carcinoma is Pancoast tumor. This cancer is located high in the lung apex, causing pain in the shoulder and radiating down the ulnar nerve distribution path [33].

Adenocarcinoma is the most common lung cancer. It represents approximately 40% of all cases and is increasing in frequency [33,70,69]. It is easy to diagnose, as it is most often located peripherally and can be readily visualized on chest x-rays. Adenocarcinoma metastasizes rapidly, and patients are often found to have distant lesions at the time of diagnosis [69]. Common sites for metastasis include the brain, bone, liver, kidneys, and the other lung [16]. A subtype of adenocarcinoma, adenocarcinoma in situ, is characterized by pneumonia-type infiltrates present on chest x-ray films. Patients with this subtype often have a better prognosis than those with other types of lung cancer [33].

Large cell carcinoma is the least common of the three major types of lung cancer, accounting for about 10% to 15% of cases [33,70,69]. It has characteristics similar to adenocarcinoma, but microscopically, the cells appear different. Metastasis occurs frequently, with the gastrointestinal tract being the most common site of metastatic symptoms. With improved histopathologic procedures and the use of electron microscopy, most NSCLCs that would previously have been classified as large cell carcinomas are instead identified as undifferentiated adenocarcinomas or SCCs. Large cell undifferentiated carcinomas have the same prognosis as adenocarcinomas [33].

Other less common types of NSCLC include [37]:

- Pleomorphic

- Carcinoid

- Salivary gland carcinoma

- Unclassified carcinoma

Malignant mesothelioma is a type of lung cancer that tends to be grouped into the "other" category, mainly because there are fewer patients with the disease. Asbestos has been identified as the main carcinogen involved in the development of mesothelioma. Even when exposure is brief and occurs many years prior to the tumor development, a link may often be found. In most cases, the exposure was heavy and patients often have a history of asbestosis prior to the appearance of the mesothelioma [72]. Approximately 80% of patients diagnosed with mesothelioma also report a history of asbestos exposure [72,73].

Prognosis in mesothelioma is difficult to assess because of the variability in the time before diagnosis and the rate of disease progression. The latency period between a patient's first exposure to asbestos and the manifestation of disease is generally between 20 to 40 years [73,74,75]. On a cellular level, mesothelioma is similar to several different cancer types, including adenocarcinoma and metastases [74]. Immunohistochemistry and electron microscopy are the most common tools used to identify malignant mesothelioma and to distinguish between it and lung adenocarcinoma [24,72]. It may be difficult to differentiate mesothelioma from adenocarcinoma on small tissue specimens; therefore, obtaining a tissue sample, usually through thoracoscopy, is generally necessary for diagnosis [72]. Because it is usually advanced by the time it is diagnosed, prognosis in mesothelioma is poor. For patients with malignant pleural disease, the median survival time with trimodal treatment is 16 to 19 months; for those with extensive disease, the median survival time is four to eight months [72].

8. TREATMENT

After the tissue type has been confirmed and the stage has been determined, treatment options may be discussed with the patient and the patient's family. It is critical that all healthcare professionals thoroughly understand each type of treatment in order to answer questions posed by the patient and family as they work through the decision-making process.

Patients commonly ask about the quality of life that can be anticipated after the treatment decision has been made. The components of treatment, such as discomfort, pain, nausea, hospitalization, and loss of time with friends and family, should all be weighed against the possibility of a longer life. The course of treatment is ultimately the patient's decision, and it is helpful to answer questions and provide acceptance no matter what choice is made.

SURGERY

Evidence Based Practice Recommendation

The American College of Chest Physicians recommends that patients with lung cancer be assessed for curative surgical resection by a multidisciplinary team, which includes a thoracic surgeon specializing in lung cancer, a medical oncologist, a radiation oncologist, and a pulmonologist.

https://journal.chestnet.org/issue/S0012-3692

Last Accessed: August 21, 2018

Strength of Recommendation: 1C (Strong recommendation based on low-quality evidence that the benefits outweigh the risks/burdens)

Surgery is a frequent and logical choice for removing a cancer. Many patients respond to the announcement of their diagnosis with comments indicating that they want the cancer removed from their body immediately. While this is not always an option, it is the best choice for many patients (e.g., those with stage I or stage II disease) [24,76]. In general, the type of surgery performed depends upon the extent of the disease [24].

The surgical procedures used to remove lung cancers include wedge resection, lobectomy, pneumonectomy, and sleeve resection. Wedge resection removes the tumor and a small amount of the normal surrounding tissue (called "segmental resection" or "segmentectomy" when more tissue is taken). Lobectomy removes the affected lobe of the lung, whereas pneumonectomy removes an entire lung. The sleeve resection removes only part of the bronchus [24,37]. According to the American College of Surgeons Oncology Group, a complete mediastinal lymphadenectomy should obtain one or more lymph nodes from each mediastinal station [77]. For cancers on the right side, lymph nodes should be removed from stations 2R, 4R, 7, 8, and 9; in cases of left-sided cancers, stations 4L, 5, 6, 7, 8 and 9 should be sampled.

Surgery may be performed for the treatment of [24,37]:

- Occult NSCLC (depending on where the cancer has spread)

- Stage 0 (carcinoma in situ) NSCLC

- Stage I or stage II NSCLC

- Stage IIIA NSCLC, with or without radiation therapy

Approximately 20% of NSCLC patients are at stage I or stage II at the time of diagnosis [78]. These patients have traditionally been treated with surgical resection alone; however, adjuvant treatment in these early-stage patients has shown promise [78]. A few stage IIA patients may be helped by surgical resection, but those at stage IIB or beyond are not considered surgical candidates. NSCLC is considered inoperable when there is distant metastasis, esophageal obstruction, or involvement into the chest wall or mediastinum. Sleeve lobectomy is generally preferred over pneumonectomy when anatomically appropriate. In patients with severely reduced pulmonary function who are otherwise not candidates for surgery, the use of lung-sparing surgeries (i.e., wedge resection) is controversial [24]. Surgical resection of a solitary metastasis (particularly a brain metastasis) may improve survival in select patients with stage IV disease. Resection of metastasis in other sites remains controversial [24].

Patients who are diagnosed with SCLC are generally considered to be metastatic at diagnosis and therefore are not usually advised to consider surgery. Fewer than 1 out of 20 patients with SCLC will have cancer in only one localized tumor nodule, with no spreading. Those who do have surgery combine it with another treatment, such as chemotherapy [68]. Preoperatively, patients should be advised of what to expect with the surgical experience. Patients tend to do better postoperatively if, prior to surgery, they are told or shown [80]:

- The extent and exact location of the wound

- The purpose and necessity of chest tubes

- Pain medication procedures

- How to splint the chest for proper coughing and deep breathing

- To refrain from smoking both before and after surgery

- That oxygen will be provided postoperatively

- Leg exercises to complete while recovering in bed

If there are critical pathways in place in the hospital where the patient will be admitted, these should be reviewed to allow the patient to anticipate the flow of postoperative events. For nurse case managers working inside the hospital, the primary postoperative focus will be on maintaining the patient's immediate bodily functions: airway, secretions management, intravenous (IV) fluids and medications, wound care, and chest tube maintenance. As the patient progresses, an increase in activity and dietary intake should be encouraged, with the anticipated outcome of discharging to home.

Case managers working outside the hospital setting may or may not have direct contact with patients before surgery or communication with the hospital case manager during the patient's hospitalization. If contact is established, these case managers will help to coordinate the postdischarge plans and will follow the patient to home, hospice, or other facility as necessary.

CHEMOTHERAPY

Non-Small Cell Lung Cancer

The patient with NSCLC may receive chemotherapy in combination with radiation and/or surgery, as determined by the stage of the disease and the patient's overall health status [37]. Research has indicated that adjunctive chemotherapy, in addition to surgery, radical radiotherapy, or supportive care, is effective in improving overall survival rates and disease-related symptoms [37]. However, it is not recommended for use in patients with stage IA or stage IB NSCLC [37,81]. The agents most commonly used for initial chemotherapy with NSCLC are [24,82,138]:

- Cisplatin

- Carboplatin

- Paclitaxel

- Docetaxel

- Gemcitabine

- Vinorelbine

- Irinotecan

- Etoposide

- Vinblastine

- Pemetrexed (as maintenance therapy with advanced or metastatic NSCLC)

Surgery, chemotherapy, and radiation therapy may all be used to treat stage III NSCLC; however, there is ongoing debate about which modalities to use and in what sequence. For example, combined modality therapy (chemoradiation) has been shown to be more effective than radiation alone for patients with unresectable stage IIIA or stage IIIB disease, and concurrent chemoradiation has been shown to be superior to radiation alone and sequential chemotherapy followed by radiation. Concurrent chemoradiation regimens include: cisplatin/etoposide (preferred); cisplatin/vinblastine (preferred); carboplatin/pemetrexed; and cisplatin/pemetrexed. Other concurrent regimens may also be used (e.g., cisplatin with etoposide) [24]. Preoperative (i.e., neoadjuvant) chemotherapy has shown promise of increasing survival in patients with stage III disease. Cisplatin/etoposide is the preferred regimen [24]. Combined-modality therapy with neoadjuvant chemotherapy has been recommended for patients with good overall health status and stage IIIA NSCLC. Patients with poor health status are best managed with chest radiation therapy [37]. Patients who meet certain criteria may benefit from the addition of targeted therapy drugs (e.g., bevacizumab, cetuximab) to initial treatment [24].

Targeted Therapy for NSCLC

Targeted therapy drugs work differently than standard chemotherapy drugs by specifically targeting the gene changes in cells that cause cancer. They are most frequently used in conjunction with chemotherapy or when chemotherapy is no longer working. They produce different side effects than standard drugs (e.g., bleeding with bevacizumab) [37]. Chemotherapy generally consists of adjunctive treatment with two or more medications. Cisplatin or carboplatin in combination with radiotherapy have traditionally been the most common medications used to treat NSCLC [16,33]. Adjuvant cisplatin-based chemotherapy has been recommended for patients with stage IIA, stage IIB, and stage IIIA disease [33,37,81]. Newer drugs that are active against stage IV NSCLC include the taxanes (i.e., paclitaxel, docetaxel), vinorelbine, the camptothecin analogs (i.e., irinotecan, topotecan), and gemcitabine. Combinations of these drugs have produced one-year survival rates greater than those produced by single agents alone [24]. Common chemotherapy regimens for stage IV NSCLC include carboplatin/paclitaxel, cisplatin/paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, and docetaxel/cisplatin. Additional regimens include gemcitabine/carboplatin, docetaxel/carboplatin, and gemcitabine/docetaxel [24]. In instances where at least one prior chemotherapy regimen has failed, the FDA has approved the use of erlotinib, atezolizumab, and durvalumab for the treatment of patients with locally advanced or metastatic NSCLC [24].

Since 2013, advancements in the identification of gene deletions, rearrangements, and mutations has led to several new medications being approved for the treatment of NSCLC and updated guidelines for first-line treatment. Newer targeted therapy has been rapidly developed for several gene mutations involved in cancer, including [24,41,139,149]:

- Epidermal growth factor receptor (EGFR): Protein found on the surface of some cells to which EGF binds, causing the cell to divide

- Anaplastic lymphoma kinase (ALK): Protein involved in cell growth

- ROS1: Protein involved in sending signals in cells and cell growth; similar structure to ALK

- BRAFV600E: Gene that produces protein involved in sending signals in cells and cell growth

- Programmed death-ligand 1 (PD-L1): Protein found on cancerous cells that suppresses immune activity

- Mesenchymal-epithelial transition (MET) gene: Proto-oncogene implicated in 25% to 70% of all NSCLC

First-Line Treatment of NSCLC with EGFR Mutation

In 2013, the FDA approved the first automated molecular assay that is able to differentiate metastatic NSCLCs that are or are not susceptible to erlotinib [83]. The EGFR Mutation Test is approved to detect and identify mutations of the EGFR gene in DNA derived from NSCLC tumor tissue, allowing for personalized medical treatment for the 10% to 30% of patients with lung cancer known to have one of these mutations. Also in 2013, the EGFR inhibitor afatinib was approved for the treatment of patients with metastatic NSCLC that expresses EGFR gene mutations, followed by gefitinib in 2015 and osimertinib in 2018 [84,139,140,141]. In 2019, the FDA approved osimertinib as an adjuvant treatment for NSCLCs with EGFR mutations [151]. Among these drugs, gefitinib and erlotinib are generally regarded as the standard of care; however, studies of osimertinib have shown a higher response rate and response duration [85,141]. The 2018 National Comprehensive Cancer Network (NCCN) guidelines recommend erlotinib, afatanib, gefitinib, or osimertinib as a first-line therapy in patients with NSCLC with EGFR mutation [24].

First-Line Treatment of NSCLC with ALK Rearrangement

Crizotinib, an ALK-inhibitor, was approved by the FDA for ALK-positive NSCLC in 2011 [143]. In 2014, another ALK-inhibitor, ceritinib, received accelerated FDA approval for patients who were intolerant or whose disease progressed while taking crizotinib. In 2017, ceritinib was granted regular FDA approval with the addition of approval as a first-line treatment [144]. In 2015, alectinib was granted accelerated FDA approval for treatment of patients with ALK-positive NSCLC, and the drug received regular FDA approval in 2017 [143]. The 2018 NCCN and American Society of Clinical Oncology (ASCO) guidelines recommend alectinib as the preferred drug of choice for ALK-positive NSCLC due to evidence of halting cancer growth longer while also causing fewer side effects than crizotinib in phase III clinical trials [142]. It should be noted that ALK-inhibitors are only considered FDA-approved after an FDA-approved test for ALK returns positive [142].

First-Line Treatment of NSCLC with ROS1 Rearrangement

As of 2018, crizotinib is the only FDA-approved approved drug for treatment of NSCLC with ROS1 rearrangement–positive disease. Because of the similar structure of ALK and ROS1 genes, the NCCN guidelines also list ceritinib as a first-line treatment, although crizotinib is the preferred treatment [145].

First-Line Treatment of NSCLC with BRAFV600E Mutation

In 2017, dabrafenib and trametinib were granted approval for NSCLC with BRAFV600E mutation when administered in combination. This is the first approved chemotherapy for this type of gene mutation disease process, and these agents are recommended in the 2018 NCCN treatment guidelines [146].

First-Line Treatment of NSCLC with PD-L1 Rearrangement

In 2016, pembrolizumab was FDA approved as a first-line treatment for NSCLC with expression of PD-L1 on at least 50% of the tumor cells [86,139]. The 2018 NCCN treatment guidelines and 2017 ASCO guidelines recommend pembrolizumab alone as first-line treatment in patients with this gene mutation. Additionally, the FDA granted accelerated approval in 2017 for pembrolizumab in combination with pemetrexed and carboplatin for patients with previously untreated, advanced nonsquamous NSCLC, regardless of whether PD-L1 is present [147].

First-Line Treatment of NSCLC with MET Gene Exon 14 Skipping

In 2020, the FDA approved the first medication (capmatinib) for the treatment of NSCLC with mutations leading to MET or MET exon 14 skipping [150]. Capmatinib is a kinase inhibitor administered at an oral dosage of 400 mg twice daily. Common side effects include peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite [25,150].

Small Cell Lung Cancer

SCLC, which is often considered a systemic disease due to its common metastasis, is customarily treated with chemotherapy. It is not unusual to administer radiation to shrink the tumor and chemotherapy to discourage the growth of metastatic cells. While chemotherapy often increases survival time, actual remission is rare. Research has indicated that increased doses or more intensive chemotherapy has no correlation to survival rates for patients with SCLC [68]. A combined modality treatment that includes chemotherapy and thoracic radiation therapy (TRT) is considered to be the standard treatment for patients with limited-stage disease SCLC (the optimal dose and timing of TRT is a subject of ongoing controversy). The combination of chemotherapy/TRT has been shown to produce an improvement in survival of 5% at three years when compared to chemotherapy alone [68]. The most common combined chemotherapy regimens for initial use with SCLC are [32]:

- Cisplatin and etoposide

- Carboplatin and etoposide

- Cisplatin and irinotecan

- Carboplatin and irinotecan

Chemotherapeutic drugs are considered to be either cell cycle phase specific or cell cycle phase nonspecific. The cell cycle phase-specific drugs work on cells undergoing cell division and are therefore more efficient in cases of rapid cell division. This class includes antimetabolites and vinca plant alkaloids. Examples of cell cycle phase-nonspecific drugs are alkylating agents, antitumor agents, hormones, and nitrosoureas. This class of chemotherapy is generally indicated for cells with longer division times. Some drugs may be both specific and nonspecific. Corticosteroids are often used concomitantly with other chemotherapeutic medications due to their anti-inflammatory and appetite stimulatory effects [87]. Chemotherapeutic agents that are cell cycle phase specific are given on a schedule to maximize their effect on the particular cell being treated. Some are given daily for one to three weeks, then stopped for one week before repeating the schedule again. Others are given daily for longer periods of time.

Although a single drug may work, drug combinations have an improved result. The combinations of drugs are commonly known by their initials or as acronyms; however, these acronyms can be confusing and potentially dangerous, as they are sometimes used to define more than one regimen. It is for this reason that the Institute for Safe Medication Practices has recommended against the use of acronyms or abbreviations when prescribing and has placed chemotherapeutic agents on its List of High-Alert Medications [88,89].

In addition to these combination regimens, several agents that specifically target lung tumors are being investigated [90]. Physicians and pharmacists should have a good understanding of the most common and current regimens in use and be able to answer any questions the patient may have.

Chemotherapy may be administered orally, intracavity, or intrathecal. However, most drugs are administered intravenously, and some (e.g., vincristine) must only be administered intravenously [91]. Chemotherapy is administered in a variety of settings, including the acute hospital, outpatient ambulatory care centers, physicians' offices, subacute care centers, or patients' homes with the assistance of home health nurses.

Chemotherapeutic agents are destructive to tissue cells, so care should be taken in handling the solution to avoid spills or extravasation, which would be harmful to the patient. When handling chemotherapeutic agents, healthcare professionals should wear protective eyewear, gowns, and gloves [92]. Gloves should be changed between preparation and administration and again every half hour throughout the process.

When etoposide is given, either a glass bottle and non-polyvinyl chloride (PVC) tubing or PVC equipment may be used [25]. Some facilities have opted to use non-PVC tubing as a means of minimizing diethylhexyl phthalate (DEHP) exposures. Paclitaxel and docetaxel have an incompatibility with PVC and require the use of either glass or non-PVC containers [25]. All supplies used in the administration of chemotherapy should be sealed in a leak-proof container that has been marked as "chemotherapy" and discarded using regulated hazardous waste disposal procedures [25].

Side Effects

Although extensive research has been undertaken in an effort to minimize the adverse effects of chemotherapy, nausea and vomiting remain among the stressful side effects of treatment. Antiemetics are generally given immediately prior to the chemotherapy infusion; they may also be ordered after treatment to help prevent delayed emesis. It is often helpful for patients to avoid foods with strong scents or spiciness, as they may encourage nausea [35]. It is important that patients be made aware of the seriousness of dehydration. If unable to keep food or fluids down, they should notify a physician to begin intravenous rehydration. Adequate hydration is of particular importance when patients are receiving cisplatin, which is nephrotoxic. Patients receiving cisplatin should be encouraged to increase fluid intake to at least 2,000 cc per day [25]. Cisplatin, vinorelbine, docetaxel, or paclitaxel may damage nerves, which can lead to peripheral neuropathy [32].

Alopecia, or hair loss, generally occurs two to three weeks after chemotherapy is initiated. Because hair follicle cells divide rapidly, they are affected by the cell cycle specific forms of chemotherapy. Hair grows back (generally within two to three months) after the treatment is discontinued. However, while enduring treatment, patients may be sensitive regarding their appearance. The use of a hat, scarf, or wig may help raise spirits [93]. Chemotherapy agents that seem to have the greatest tendency towards alopecia include cyclophosphamide, doxorubicin, etoposide, and vincristine. Some hair thinning may also occur with mitomycin and vinblastine [25].

Other side effects from chemotherapy include anorexia, constipation, cystitis, diarrhea, fatigue, allergic reactions, and neurotoxicity [32,35]. Cisplatin has been specifically associated with ototoxicity [25].

Clinical Trials

Some patients may be asked to participate in clinical trials of chemotherapeutic drugs. Government agencies, such as the National Institutes of Health (NIH), National Cancer Institute, Department of Defense, and Department of Veterans Affairs, as well as physician organizations, medical institutions, foundations, and pharmaceutical companies, sponsor, conduct, and fund research into the treatment of cancer of all types and test possible chemotherapy medications [94]. These trials may be performed either within the NIH campus (intramural research studies) or at participating facilities around the country (extramural research studies).

Clinical trials in the United States undergo four phases. Phase I determines the maximum tolerated human dose and the method of administration. Phase II evaluates the antitumor properties of a drug and the safety and efficacy of the drug. Phase III establishes the value of the treatment by random and comparative study with a current standard therapy, and phase IV evaluates the long-term safety and efficacy of the treatment [94]. It is vital to ensure that patients understand the rules of participation. This is done by explaining the protocol that will be used for conducting the trial and by adhering to the trial's specific eligibility criteria. Additional areas under evaluation include [94]:

- Combining local treatment (surgery)

- Regional treatment (radiation therapy)

- Systemic treatments (e.g., chemotherapy, immunotherapy, targeted agents)

- Developing more effective systemic therapy

Aside from chemotherapy, several alternative modalities, such as stem cell and bone marrow transplantation, are in clinical trials to determine their effectiveness in the treatment of lung cancer.

RADIATION THERAPY

Radiation therapy is defined as the use of ionizing radiation to kill cancer cells. It is usually considered local therapy because it treats only the cells at which the radiation is directed; however, systemic radiation therapy, or introduction of radioactive material (i.e., radiopharmaceuticals) into the circulatory system, is also available. When healthy cells surrounding the cancerous lesion are exposed to radiation, they may also be destroyed; however, they are better able to repair DNA damage than are cancer cells. Radiation treatments may be administered IV or orally, whichever is determined most effective to treat the specific tumor type and magnitude [95,98].

External beam therapy, or teletherapy, can be delivered by several different types of machines, depending on the type and extent of the tumor [95]. The linear accelerator is the most commonly used machine. With the linear accelerator, electrons bombard a target and produce high-energy photons. Because the electrons have both mass and charge, they lose energy more quickly than, for example, x-rays. This limits their ability to penetrate and minimizes damage to surrounding tissue. An extension of external beam therapy is conformal radiation therapy, which uses a three-dimensional CT scan of the affected area in order to better target the tumor. An extension of conformal therapy and a more advanced method is intensity-modulated radiation therapy (IMRT). The IMRT facilitates shaping of the intensity of the radiation beam, which allows for a more precise distribution of the desired dose around the target site [95,98].

Prior to beginning any type of external radiation therapy, CT scans, MRIs, and/or other imaging results are studied to determine the exact area for the best effect of the radiation. The patient is tattooed or marked to ensure that the technician will correctly position the beam each time the treatment is given. Patients may also be fitted with a support to help them hold the correct position during the radiation therapy treatments [95,98]. Patients should be told to allow one to two hours for the initial planning session prior to beginning treatment. Daily treatments usually take less than five minutes, but positioning may take a few minutes longer [98].

Both NSCLC and SCLC patients are likely to have courses of radiation therapy. NSCLC is treated most commonly with five treatments, also called "fractions," of external beam radiation per week for five to eight weeks. The amount of radiation and the duration of treatment with this therapy is dependent on the stage of the cancer and its responsiveness to treatment [98]. Research has supported the use of hyperfractionated accelerated radiotherapy, in which smaller radiation doses are administered several times a day five times a week, or continuous hyperfractionated accelerated radiotherapy, in which radiation is given several times a day every day, especially in later stages of lung cancer [99].

Intraoperative external beam radiation therapy may be an option for some patients, depending on the inaccessibility of their tumors or metastasis. During surgery, organs may be moved out of the line of radiation and treatment given directly to the affected site [95,98].

Internal radiation, known as brachytherapy, is the temporary or permanent implantation of radioactive isotopes. It provides an opportunity to deliver a large amount of radiation to a small site in a relatively short period of time. The usual procedure involves surgery to insert the wires, tubes, or needles into the tumor. After the tubes are sutured into place, the patient is returned to the hospital room and the radioactive isotopes are loaded into the receptacles [95,100].

Patients undergoing brachytherapy should be informed prior to the procedure that the staff caring for them will be maintaining precautions to prevent overexposure to the radioactive source. Nurses and other healthcare professionals should keep the time spent in close contact to a minimum and should encourage the patient to do as much self-care as possible. Shielding is placed in the room to protect workers from being exposed when doing tasks not directly involving the patient. When the radioactive substances have been removed from the patient, these precautions are no longer necessary.

Radiation therapy may cause a variety of side effects, including [95,98]:

- Skin irritations (e.g., erythema, dryness, itching, flaking), which may progress to sloughing

- Fatigue and depression

- Anorexia, with weight loss and increased fatigue

- Stomatitis or painful, ulcerated areas in the mouth

- Bone marrow suppression (may be worse when bones are treated due to metastasis)

- Esophagitis, especially when the esophagus is within the area being irradiated

- Cough, often caused by material that had been trapped by the tumor being released into the alveoli

- Radiation pneumonitis, which generally occurs one to three months after the beginning of treatments

- Radiation fibrosis, which may occur 6 to 12 months after the treatments have been completed

Skin Care Issues

Skin reactions are normal and temporary side effects to radiation treatment. They are not the burns historically associated with radiation, but rather dryness, itchiness, and peeling. Some patients also experience increased tanning or pigmentation [95,98].

As treatment continues, moist desquamation may occur in areas where skin surfaces meet. When this is the case, patients should be given a few days break from radiation therapy in order to allow for normal tissue healing. Desquamated areas are potential sites of infection and should be kept as clean as possible. The area can be gently irrigated with normal saline, and an ointment may be applied to soothe the exposed skin surfaces. The following are general skin care guidelines for patients receiving radiation therapy [98,102]:

- Wash the skin with warm water and pat dry. For patients who do not have permanent ink dots, they should take care not to wash off skin markings.

- Use a mild soap that does not contain perfume or deodorant.

- Avoid the use of creams or lotions that contain perfumes or deodorants. These products may contain a heavy metal-ion residue that can irritate the skin.

- Hydrophilic creams and lotions may be used on the skin surface to prevent dryness. Petroleum jelly is not water-soluble and should be avoided.

- Avoid the use of cornstarch in the groin and buttock folds.

- Avoid tight-fitting garments that can rub or press against the skin. Loose-fitting cotton garments are the best.

PHOTODYNAMIC THERAPY

Evidence Based Practice Recommendation

For patients with superficial limited mucosal lung cancer in the central airway who are not candidates for surgical resection, the American College of Chest Physicians recommends endobronchial treatment with photodynamic therapy, brachytherapy, cryotherapy, or electrocautery.

https://journal.chestnet.org/issue/S0012-3692

Last Accessed: August 21, 2018

Strength of Recommendation: 1C (Strong recommendation based on low-quality evidence that the benefits outweigh the risks/burdens)

Photodynamic therapy (PDT) (also called photoradiation therapy, phototherapy, or photochemotherapy) combines a photosensitizing agent with a specific type of light. The FDA has approved porfimer sodium for use in PDT to treat symptoms of certain cancers, including endobronchial NSCLC. Porfimer is administered intravenously and retained in cancer cells at a greater concentration than healthy cells. A light source (e.g., laser, light-emitting diodes) is used to illuminate, via bronchoscopy, the photosensitized cells, which results in increased laser light uptake, photochemical reaction, and the subsequent death of cancer cells. Both primary and metastatic tumors present in the tracheal or bronchial passages respond to PDT. However, this treatment is not appropriate and not effective for all tumors (e.g., large tumors, those located in areas difficult to expose to light). The advantages of this therapy are that no resistance has been found and there are no significantly adverse side effects. Due to increased skin photosensitivity, patients who have undergone PDT should avoid sunlight for at least six weeks following treatment [103,104].

ALTERNATIVE THERAPIES

Alternative therapy encompasses any method used to treat cancer that is out of the mainstream of medical protocol. Patients who have a poor prognosis or who have not responded to conventional treatments may look to these methods as a source of hope. Some alternative therapies offer psychologic comfort, others are being investigated as possible advances in the treatment of lung cancer, and many are seriously questionable. Patients may feel they have nothing to lose by trying these methods, but alternative treatments may prove to be harmful if they result in [105]:

- Delaying legitimate treatment in lieu of questionable treatment

- Interference with legitimate treatment, such as a megadose of folic acid interrupting the antifolate action of methotrexate

- Great financial loss that leaves the patient and/or the patient's family impoverished

- Actual physical harm or poisoning

False therapies that should be avoided include devices that supposedly rid the body of tumors, hyperoxygenation products, diets that espouse only one or two foods and thereby deprive the body of needed nutrients, and psychic surgery.

Dietary approaches to cancer treatment have not been proven to diminish or eliminate cancer in the body. However, good nutrition strengthens the immune system, which in turn may help patients withstand the rigors of legitimate therapy.

It is helpful to be able to discuss these methods while encouraging adherence with the established protocol. Any question regarding the safety of herbs, foods, or other ingested substances should be referred to the physician and/or pharmacist immediately.

9. THE CLINICAL COURSE OF LUNG CANCER

The clinical course and outcomes for patients diagnosed with lung cancer may vary widely from one patient to another. Prognosis is dependent on the extent of the disease, the cell type, and the patient's physical condition at the time of diagnosis.

The overall five-year survival rate for all patients not differentiated by type is 18.6% [9]. Because 57% of all patients have metastasis at the time of diagnosis, their prognosis is greatly impacted [37]. Women generally have a better prognosis than men [16,37].

As mentioned, cell type is a prognostic indicator. The data provided in Table 6 illustrate the differences in survival according to stage at diagnosis.

Table 6: FIVE-YEAR RELATIVE SURVIVAL RATES BY CANCER TYPE AND STAGE

Stage

Survival Rate

Small Cell Lung Cancer

Limited stage

31.4%

Extensive stage

1.5% to 8.4%

Non-Small Cell Lung Cancers

Squamous cell carcinoma

Stage I

51.3%

Stage II

35.1%

Stage III

9.9%

Stage IV

1.9%

Adenocarcinoma

Stage I

63.8%

Stage II

34.4%

Stage III

10.2%

Stage IV

2.2%

Large cell carcinoma

Stage I

50.2%

Stage II

33.7%

Stage III

9.5%

Stage IV

1.7%

Source: [106]

Patient condition impacts prognosis in that an immunocompromised individual who is weakened by chronic illness may not have the immune reserves stored away to fight another battle. Also, comorbidities, especially comorbid lung conditions such as chronic obstructive pulmonary disease, are common in smokers and may complicate diagnosis, limit treatment options, and lengthen recovery times. Similarly, elderly patients may be less likely to withstand rigorous treatment programs.

Unfortunately, many persons with lung cancer have a difficult and obstacle-strewn path to negotiate. Metastases, results of advancing disease, and complications from treatment are all part of disease management.

METASTASIS

Metastasis presents a very real concern and complication for the patient with lung cancer. Distant metastasis is the most common reason for failure to cure. A vital portion of the role of the healthcare professional is to maintain close contact with the patient to be alert for early signs of metastasis.

Brain Metastasis

Approximately 48% of all brain tumors are metastatic from lung cancer; therefore, it is important to be alert for even vague symptoms of central nervous system involvement [107]. If a patient complains of headache, nausea, vomiting, confusion, memory loss, mood swings, or other neurologic problems, there should be immediate contact with the physician [108]. Treatment is generally palliative rather than curative [109]. Patients may be given steroids to decrease the intracranial pressure being exerted by the metastatic lesion(s). Resection of the brain metastasis followed by radiation therapy is indicated in some cases; however, most patients are not candidates for the procedure based on the number, location, or type of lesions [109].

Brain metastases are an increasingly important cause of morbidity and mortality in cancer patients, and coping with brain metastasis is a major task for a patient's family or significant other. Patients may display personality changes, bizarre behavior, anger, and/or confusion, making it difficult for loved ones to understand what is happening. Guidance and explanations can assist in the coping process during this heart-wrenching period.

Bone Metastasis

Metastasis occurring in the bones is common, particularly for patients with lung cancer. It is possible for patients to have pathologic fractures, hypercalcemia, and spinal cord compression. Symptoms may be mild initially, with pain that comes and goes and increases in intensity with time [110]. The most common sites for bone metastasis, in approximate order of frequency, are the vertebrae, pelvis, proximal femur, proximal humerus, ribs, and skull [110]. These locations account for more than 90% of all bone metastases [111]. Patients who have extensive bone metastasis over a large percentage of their skeleton have a poor prognosis [16,110].

Treatment options include pain control measures, prophylactic fixation of bones that have lesions, or chemotherapy [110]. The biggest challenge for bone metastasis remains pain control. It is important that pain relief measures are undertaken and that pain is effectively managed.

Liver Metastasis

Liver metastasis is also common and a poor prognostic sign. The liver is the second most commonly involved organ (after the lymph nodes). In 77% of patients, both lobes are involved [112]. Symptoms of this metastasis include an enlarged liver, elevated liver function tests, abdominal pain or tenderness, an abnormal liver scan, anorexia, nausea, and vomiting. Hepatic metastasis is generally treated palliatively with radiation and chemotherapy [112]. In the case of localized masses, hepatic resection may be an option for some patients. A celiac plexus block may be necessary to alleviate pain.

Cardiac Metastasis

Due to its close physical proximity, lung cancer may metastasize to the heart. When it invades the muscle, a pericardial effusion can result and, when enough fluid accumulates, cardiac tamponade will develop. Symptoms are nonspecific and include cardiac enlargement, dyspnea, cyanosis, cough, chest pain, palpitations, and venous distention. In many cases, cardiac metastases are identified only on autopsy. Treatment includes chemotherapy and/or pericardiocentesis. When cardiac tamponade occurs, surgery for a cardiac window is the usual treatment [113].

10. CONDITIONS CAUSED BY ADVANCED LUNG CANCER AND CANCER TREATMENTS

In addition to the direct effects produced by metastasis, advancing disease and treatments can result in several other symptoms, including respiratory distress, fatigue, nausea and vomiting, anorexia, and pain. These effects should be managed in order to minimize their effects on the patient's quality of life.

RESPIRATORY DISTRESS

Progressive lung cancer ultimately involves respiratory distress of some degree. Obstruction of airways and/or restriction of lung expansion results in dyspnea. Also, postobstructive pneumonitis, atelectasis, or pleural effusions may occur.

Pleural fluid accumulates when the lymphatic drainage system is obstructed. This results in poor lung expansion and decreased gas exchange. Treatment consists of thoracentesis or a chest tube. Some patients may require the insertion of a sclerosing agent through the chest tube into the pleural space (i.e., pleurodesis). The pleura's reaction to the sclerosing agent causes scarring, which will help to keep the lung inflated [114].

Dyspnea may be alleviated by several nursing measures. Patients and healthcare staff should be encouraged to schedule activities that require exertion so that they do not follow one another and are spaced with rest periods. Relaxation techniques may help and can be demonstrated to most patients. Pursed lip breathing is advantageous to some patients. Still others find that opioid inhalers provide relief; early use of opioids for dyspneic cancer patients has been associated with a reduction in stress and improved quality of life. Whenever possible, assessing and treating the underlying cause of the condition is recommended [115].

When oxygen is required, several factors should be considered before choosing the best system for the patient. Most patients use a concentrator at home. This small device converts normal room air into a higher concentration of oxygen. The system is electrical and generates a sound that may be annoying to some patients. Its main advantage is that the oxygen is supplied continuously with no need to change tanks or have deliveries. It works well for patients who require a high flow rate.

Oxygen cylinders are used for backup for concentrators in the case of power failure. They are also useful for patients who need only occasional oxygen. They are large, heavy, and require replacement as the oxygen is consumed. However, they are quiet and require no electricity to run.

Liquid oxygen systems are also available in some areas. A larger tank is filled by a delivery truck; small portable units can be replenished by the patient as needed. This type of system requires some physical strength but is preferred by many patients.

It is important to note that most insurance providers do not reimburse for the amount of oxygen used, but rather pay a monthly fee. Insurance carriers also require documentation of the need for oxygen, most often in the form of arterial blood gas reports or oximetry records. It is necessary to report the blood gas that shows the oxygen pressure (pO_2) when the patient has desaturated the most; usually, this is after ambulation or other activity.

When a patient on oxygen reports increased shortness of breath, it is advisable to have the oxygen delivery system examined to make sure that everything is functioning properly before deciding that the patient is deteriorating. Holes may appear in tubings, gauges can operate incorrectly, or any number of mechanical problems can be the cause of decreased effectiveness.

Evidence Based Practice Recommendation

In adult patients with lung cancer experiencing cough despite anticancer treatment, the American College of Chest Physicians suggests cough suppression exercises as alternative or additional to pharmacologic therapy where such services are available.

https://journal.chestnet.org/article/S0012-3692

Last Accessed: August 21, 2018

Strength of Recommendation: 2C (A weak and conditional recommendation based on low-quality evidence that the benefits outweigh the risks/burdens)

Some patients feel dyspneic, but their blood gases are normal. The potentially correctable underlying causes of dyspnea include hypoxia, anemia, bronchospasm, respiratory muscle dysfunction, poor oxygenation, muscle fatigue, abnormal cortisol and catecholamine levels, circulating cytokines, tumor obstruction, superior venal cava obstruction, pleural effusions, pericardial effusions, cardiac failure, and pulmonary embolism. Lack of understanding about the pathophysiologic mechanisms underlying dyspnea may hamper a clinician's ability to effectively manage it [115].

Coughing may be caused by an infection or inflammation in the lung or by the tumor pressing against the bronchial tree. Severe cough may result in major suffering for the patient in the form of lost sleep, fractured ribs, worsened fatigue, and hemoptysis. The optimal therapy is treatment of the underlying disorder. Hydration and humidification of the air may provide symptom relief. However, if the cough persists, an order may be obtained for a cough suppressant [115].

FATIGUE

Debilitating fatigue may be a problem for the patient with lung cancer and has been associated with a diminished quality of life [116]. It is different from the fatigue experienced by healthy individuals and may be so severe that it is difficult to deal with treatment or to carry out simple activities of daily living [117]. The fatigue may be directly related to chemotherapy treatments, or it may be solely a result of the cancer. Fatigue related to cancer treatment is categorized as chronic fatigue that is not relieved by sleep and rest, and it has been reported in 14% to 96% of patients undergoing cancer treatment and in 19% to 82% of patients post-treatment [117]. Cancer-related fatigue is prevalent in 75% of patients with metastatic disease and affects cancer survivors for months to years after cessation of treatment [117].

The best method to combat severe fatigue is to increase both rest and exercise. Even mild exercise can improve endurance and decrease stress from normal activities. The exercise may be an activity that encourages the patient to socialize, such as golfing or walking with others. Companionship may improve mental outlook and relieve some depression, which may also be part of the cause of the fatigue [117].

Patients may benefit from scheduling their activities to maximize their strength. For example, if a patient is exhausted simply by showering, shaving, and getting dressed each morning, it may be helpful to suggest that the patient shave and shower upon rising, then read the newspaper over coffee and breakfast while still wearing a bathrobe. The rest will ease the strain of dressing, which can be done later. This type of division of activities can ease shortness of breath and decrease fatigue [117].

NAUSEA, VOMITING, AND WEIGHT LOSS

This triad of complications is often linked to treatment with either radiation or chemotherapy but may occur solely from the cancer. The most common causes are chemotherapy drugs and radiation therapy directed at the gastrointestinal (GI) tract, liver, or brain. Nausea and vomiting that result from cancer therapy occur in up to 80% of patients and have been classified as [118]:

- Acute: Occurring within 24 hours of start of chemotherapy

- Delayed: Occurring more than 24 hours after start of chemotherapy

- Anticipatory: Expecting it to occur if it has previously occurred

- Breakthrough: Occurring within five days of prophylactic use of antiemetics, requiring rescue

- Refractory: Does not respond to treatment

- Chronic: Not well understood, but it appears to affect many patients with advanced cancer

Previous severe episodes, female sex, age (50 years and older), fluid and/or electrolyte imbalance, tumor location (e.g., GI tract, liver, brain), constipation, certain drugs (e.g., opioids), infection, blood poisoning, kidney disease, and anxiety all indicate the likely occurrence of nausea and vomiting [118].

Anorexia-cachexia syndrome occurs in patients with advanced cancer. As a response to the stress of the disease and/or treatment, the body's immune system triggers the development of increased metabolism, decreased intake, and wasting. Anxiety and depression may also worsen the problem in some patients. Treatment depends upon the type of nausea and vomiting (e.g., acute, delayed, anticipatory, chronic) and is more likely to be effective when the symptoms are recognized and treated early [119].

Patients may have gluconeogenesis to meet the demands for nutrients by the cancer cells. There may also be vitamin deficiencies and fluid and electrolyte imbalances caused by decreased intake. A nutritional assessment from a dietitian is recommended for most patients. The measurements and calculations made by a dietitian may be used to develop a plan of care to improve the patient's nutritional status. Being well-nourished has been linked to a better prognosis [119].

Simple counseling may be very helpful. Dietitians can often suggest ways to increase the caloric content of simple foods without requiring the patient to eat a great deal more food. Adding dry milk powder to milk, ice cream, or puddings, for example, can substantially increase calorie intake.

For patients experiencing nausea, soda crackers and ginger ale may help settle their stomachs. For some patients, simply eliminating spicy foods or foods with strong odors may make a tremendous difference. Encouraging the family to eat with the patient and making it a social event can be helpful. Antiemetics taken regularly before meals can often relieve symptoms of nausea and vomiting.

Antiemetics commonly given alone or in combination include prochlorperazine, droperidol/haloperidol, aprepitant, netupitant, rolapitant, and lorazepam. Other agents include metoclopramide (an antiemetic and motility agent); ondansetron, granisetron, dolasetron, and palonosetron (antiemetics and serotonin receptor antagonists); dexamethasone and methylprednisolone (synthetic steroids); dronabinol and nabilone (synthetic forms of tetrahydrocannabinol [THC]); midazolam, lorazepam, and alprazolam (benzodiazepines used to treat anxiety); and olanzapine (an antipsychotic) [118].

For those who do not have relief, enteral nutrition may be required. Whether using a nasogastric tube for feeding or total parenteral nutrition via an intravenous line, the patient may be given the nutrients required to decrease wasting and maintain a strong immune system [119]. A brief overview of the care of patients receiving nutrition by nasogastric or gastrostomy tube is provided in Table 7.

Table 7: CARE OF THE PATIENT WITH TUBE FEEDINGS

Nasogastric Tube

1. Change tape daily.

2. Cleanse and lubricate nostrils daily.

3. Check the amount of residual remaining in the stomach before each intermittent feeding.

4. Elevate head of bed to semi-Fowler's position during feeding and for one hour after the feedings.

5. Flush the tube with 20–30 cc of water or carbonated beverage (room temperature) before and after each feeding.

6. Observe for nausea, cramping, diarrhea, or aspiration.

7. Maintain accurate intake and output records.

8. Weigh regularly.

9. Continue to maintain good oral hygiene.

Gastrostomy Tubes

1. Observe tube and surrounding skin for possible tube migration daily.

2. Cleanse area around tube and the tube itself, starting at base and moving outwards.

3. Secure tube with hypoallergenic tape.

4. Follow points 3 through 9 above.

Source: Compiled by Author

PAIN

One of the primary concerns voiced by patients who are given a diagnosis of cancer is that they will be in severe pain. Some patients are so certain their diagnosis equates to suffering that they are willing to forego treatment that would prolong their life. It is vital that patients and their families be assured that pain will be relieved effectively.

It has been estimated that pain occurs in 20% to 50% of patients with cancer; 70% to 90% of these patients can experience pain relief when properly treated. Nonetheless, studies also indicate that approximately 30% to 60% of cancer patients fail to receive adequate pain relief, with more than one-third experiencing moderate-to-severe pain [121,122]. Pain usually occurs due to the location and stage of the tumor. For example, a tumor that is compressing a nerve or other organ will cause a great deal of pain. A late stage tumor produces more pain than one in the early stages. There are several different types of cancer pain. Table 8 is provided to assist in the identification of a patient's type of pain.

Table 8: TYPES OF LUNG CANCER PAIN

Pain Type

Definition

Somatic

Caused by stimulation of afferent nerves in skin, connective tissue, muscles, joints, or bones. Characterized by localized, throbbing, sharp, or aching pain. Responds well to analgesics.

Visceral

Caused by pressure or distention. Pain is deep, more diffuse.

Neuropathic

Caused by peripheral or central sensory nerve trauma. Characterized by burning, shooting, or tingling sensations and poor response to analgesics.

Paraneoplastic syndrome

Several different types of pain, caused by bony metastasis, peripheral nerve compression, brachial plexus pressure (Pancoast tumor), or epidural spinal cord compression

Postoperative

Normally anticipated pain following a surgical procedure

Mucositis

Inflammation of the oral mucosa as a result of cancer therapies

Postradiation

The result of radiation fibrosis

Source: [122]

How a patient responds to pain is highly individualized and should be managed accordingly by considering the patient's diagnosis, stage of disease, responses to pain and treatments, and personal likes and dislikes [122]. Anxiety will affect the patient's ability to cope with pain, and measures taken to reduce anxiety are often helpful in also reducing pain. Culture and background may play a role, as some cultures view the expression of pain as a weakness, while others more openly express it. The patient's level of pain should be measured at regular intervals, such as after the start of treatment and at each new report of pain. Patient self-reporting of pain should also be considered [122].

The WHO has developed a three-step approach for the management of cancer-related pain based upon the severity of the patient's pain. Patients who experience mild-to-moderate pain (a rating of 1–3 on a scale of 1 to 10) should receive a Step 1 pain medication, such as aspirin, acetaminophen, or a nonsteroidal anti-inflammatory drug (NSAID). Patients who experience moderate pain (4–6 on scale of 1 to 10) while already taking a Step 1 medication should receive a Step 2 medication, such as tramadol or acetaminophen products containing hydrocodone, oxycodone, and codeine. Step 3 indicates severe pain (7–10 on a scale of 1 to 10) and treatment includes strong pain medication, such as opioids (e.g., morphine, hydromorphone, oxycodone, methadone, fentanyl, oxymorphone, levorphanol). This will apply to most patients with cancer-related pain. Patients should be monitored for any side effects of opioids, such as nausea, sleepiness, constipation, vomiting, and breathing problems [122].

Analgesics may be administered in many ways. Oral administration is preferred because it is noninvasive and convenient. If the patient is unable to swallow, the medications may also be given in the form of rectal suppositories or infusions, transdermal patches, subcutaneous injections, intravenous drips, patient-controlled analgesia (PCA), or intramuscular injections [122]. Due to the pain and unreliable absorption associated with intramuscular administration, it is not usually used. If one route does not prove effective, another may be tried.

It is recommended that patients take pain medication regularly, as prescribed, to maintain a constant level of the drug in the body and to prevent pain from becoming so severe that it cannot be controlled [122]. Prevention of pain is more effective than trying to eradicate it once it has a grip on the patient.

Nonpharmacologic techniques for relief of pain include cutaneous stimulation, applications of heat and cold, transcutaneous electrical nerve stimulation (TENS), relaxation techniques, distraction, humor, music, prayer, biofeedback, and hypnosis. Other, more invasive techniques, in the form of nerve blocks, alcohol injections, or acupuncture, may also be employed to control pain [122].

Even when the prognosis is not good, pain should not be overwhelming. It should be controlled or alleviated for nearly every patient, allowing them to spend quality time with loved ones.

SUPERIOR VENA CAVA SYNDROME

As lung cancer progresses, there may be obstruction of the venous drainage, which in turn produces dilation of the veins of the upper chest and neck. Symptoms of superior vena cava syndrome (SVCS) are edema of the face, neck, and chest, dyspnea, headache, visual disturbances, and a depressed level of consciousness [123].

Prompt evaluation is necessary to determine if the cause of SVCS can be corrected. Chest x-rays will usually show a mediastinal mass. A CT scan is useful to obtain more exact information on the tumor's location and anatomy. MRI, contrast or nuclear venography, and ultrasound may be useful, depending on expertise of the healthcare provider. A sputum specimen should be obtained when bronchogenic carcinoma is suspected. A bronchoscopy with biopsy may allow diagnostic tissue to be removed in an attempt to establish a treatment plan [123].

Treatment of SVCS depends upon the etiology of the obstruction, the severity of the symptoms, the prognosis of the patient, and patient preferences. Radiation therapy is often used to treat SVCS because it is easily given and has minimal side effects. However, it should be withheld until the etiology of the obstruction is clear. Relief of symptoms following administration of radiation therapy is reported to be 62% to 80% in patients with SCLC and 46% in patients with NSCLC [123]. The treatment course involves a low dose of radiation, given daily for five to seven weeks [57]. Chemotherapy is effective for some patients (e.g., those with lymphoma or SCLC). Thrombolytic agents may also be used. A few patients (generally those with a benign obstruction) may require surgical resection of the tumor and bypass grafting of the vessels involved. Some patients will require no treatment [123]. The prognosis is not good for patients whose lung cancer causes SVCS; the 24-month survival rate is 9% in patients without SVCS and 3% in those with the syndrome [123].

SPONTANEOUS PNEUMOTHORAX

A pneumothorax occurs when the pleura is ruptured and the lung and chest wall separate as air enters. Lung volume is reduced as the air in the pleural space compresses the lung. A primary spontaneous pneumothorax is one with no obvious underlying lung disease; a secondary spontaneous pneumothorax is one with underlying lung disease. Iatrogenic pneumothorax is traumatic but typically smaller and more easily managed. Up to 10% of patients may be asymptomatic; some may have symptoms that are mild. Symptoms of acute, sudden onset of sharp chest pain and dyspnea occur in approximately 64% to 85% of patients. An estimated 80% to 90% of primary spontaneous pneumothoraces occur in smokers [124].

When a pneumothorax is greater than 20% of the lung, insertion of a chest tube is the usual treatment [124]. The chest tube is left in place until the lung has fully re-expanded and there is no evidence of an air leak. When a patient has a chest tube connected to a water-seal chamber, fluctuations that occur in the fluid level with each respiration should be checked. The tube should be clamped off if it becomes disconnected, as the pressure differences would be disturbed in such a case [125].

Respiratory distress resulting from pneumothorax may cause increased fatigue in the patient. If all of a patient's strength is required to breathe, there will be little energy left for activity. When respiratory distress becomes significant, decisions should be made as to whether the patient desires to have intubation with ventilator support.

HEMOPTYSIS

It is not uncommon for the patient with lung cancer to experience some degree of hemoptysis, ranging from mildly blood-tinged sputum to major hemorrhage. The cause of the bleeding can be capillary trauma, tumor sloughing, or even a pulmonary infection. Bronchitis, bronchiectasis, tuberculosis, and necrotizing pneumonia or lung abscess account for 70% to 90% of cases [35].

One objective of treatment is to protect the uninvolved lung, which may be achieved with positioning maneuvers and selective intubation and obstruction of the bronchus going to the bleeding lung. Massive hemoptysis (i.e., production of ≥600 mL of blood) is an indication for rigid bronchoscopy, which allows for better suctioning and therapeutic interventions, such as laser therapy. Embolization of a pulmonary segment is the preferred method to stop massive hemoptysis. Success rates with this method have been reported at 90% [35,148]. Bronchial adenoma or carcinoma may indicate the need for early resection. Treatment with antibiotics is important, as bronchiectatic bleeding is usually the result of infection [35]. Most patients suffering even mild hemoptysis worry that they will have a major hemorrhage, so it is important that an emergency plan is developed. This plan will help both the patient and the patient's loved ones feel more comfortable and less anxious.

11. VASCULAR ACCESS DEVICES

There are several vascular access devices (VADs) that may be used for the administration of nutrients, fluids, and/or medications during the course of lung cancer management. They have different types of catheters and ports. The type of VAD used depends upon the length of treatment, the administration time, the patient's and physician's preferences, the required maintenance care, and the cost [126].

Nontunneled catheters are inserted through neck or chest veins and include central venous catheters (CVCs), subclavian catheters, and central venous pressure (CVP) lines. They are inserted in the neck area into the high internal jugular, external jugular, low internal jugular, supraclavicular, or infraclavicular veins. The lines are then sutured in place and are used for a maximum of two to three months. They may have single, double, or triple lumens and may be used for multi-infusional therapy when the capabilities of an existing CVC or implantable port has been exceeded. They are often used when emergency CVC is needed and they may augment existing VADs that have been dedicated for acute care or long-term use [127].

Peripherally inserted central catheters (PICCs) may be used long-term (i.e., several weeks to months) to fill the gap that exists between the trauma of subclavian catheters and the cost of long-term tunneled catheters or ports. PICCs are the most easily inserted long-term CVC; however, they require one-handed self-care capabilities, or a caregiver, which may limit patient mobility. PICCs are small-gauge, thin-walled catheters that are inserted through the peripheral venous system of the hand, arm, or foot into the cephalic or basilic vein. Some state boards of registered nursing permit nurses to insert PICC lines if they have had appropriate education and training. Advantages of these catheters include: a nurse may insert them; elimination of the risk of neck and chest insertions; easy removal at completion of therapy; and no surgery is required [127]. Midline catheters are used for intermediate-term therapy when a short-term IV is either unavailable or not advisable. No surgery is required [128].

Tunneled central venous catheters (i.e., Broviac, Hickman, Groshong, Neostar) are radiopaque silicone rubber catheters characterized by a cuff that holds the line in place. These catheters are tunneled into the subcutaneous tissue, which begins to adhere to the line in 7 to 10 days, providing a mechanical barrier against infection. Tunneled central venous catheters are available in single, double, or triple lumens. Advantages of this type of catheter are secure placement, safe and reliable long-term access, decreased risk of infection (due to its unique design features), use without pain (due to external access site), ease of removal when no longer needed for care, and swimming and bathing may be allowed. Disadvantages include the external portion of the catheter is visible outside the chest, the need for daily dressing changes and heparin flushes, and the cost of equipment (i.e., needles, syringes, heparin or saline, dressing materials) [127].

Implanted ports are dense, self-sealing, silicone septums in a metallic or plastic housing with a catheter. They are surgically implanted, accessed intermittently, and intended for long-term use [126]. The entire system is subcutaneous, requiring no dressings and providing the freedom to swim, if desired. Implanted ports require flushes once a month when not in use and greatly increase patient mobility [126]. Disadvantages include the need for surgical insertion and removal, discomfort from the needle stick when the port is used, and the awkwardness of self-access [127]. Implantable titanium pumps are surgically implanted. A refillable reservoir provides for continuous infusions, usually at the patient's home [127].

TROUBLESHOOTING VASCULAR ACCESS DEVICES

Whether caring for patients in a hospital or outpatient setting, the nurse is likely to encounter questions about the use of VADs.

The inability to withdraw blood or infuse fluids may be the result of migration of the catheter, causing the tip to rest in a smaller vessel or against a vessel wall. Having the patient change position, breathe deeply, cough, or walk around to move the catheter is often effective. In some cases, the catheter is damaged between the clavicle and the first rib or within the subcutaneous tunnel. A gentle flush of 10–20 cc of normal saline solution may solve the problem [127]. Other problems may be a kink or knot in the catheter or clot formation within the tubing. In these cases, a physician should be notified to consider x-ray and/or removal of the VAD [126].

Arm or neck edema may indicate extensive thrombosis or SVCS. These conditions require the prompt attention of a physician [126].

Local infection may occur when poor technique is used for site care or when the needle is not well secured. This is evidenced by a reddened, edematous, and/or painful insertion site. If drainage is present, a culture should be taken. Do not use occlusive dressings until the infection resolves. If necessary, remove sutures. If not resolved, the VAD may require removal [126,127]. A physician should be alerted of any infections.

Systemic infection is usually caused by a local infection that was not treated, by contaminated solutions or hubs, or by a cause unrelated to the VAD. Symptoms include fever, chills, diaphoresis, malaise, hypotension, oliguria, and change in mental status. A physician should be notified immediately of signs or symptoms of systemic infection [127].

12. THE TERMINAL PATIENT

Some patients may equate the diagnosis of any type of cancer with death. This is unfortunate, as there are many patients for whom cancer has become more of a chronic illness. Lung cancer, however, generally does not have a good prognosis. As previously noted, many patients with lung cancer have metastases at the time of diagnosis, which decreases survival time. For these patients, dealing with impending death is a reality to be considered. This is not to say that the patients should not be fighting the disease and, indeed, some do win the battle. Unfortunately, the overall five-year survival rate for lung cancer is only about 18.6% 2].

While patients with terminal lung cancer face tremendous psychologic and emotional anguish, it may also be a time for connection and personal growth [129,130]. The time of life when the cancer strikes may be relevant to the degree of grace the patient exhibits. When occurring so as to interrupt plans of travel, marriage, child rearing, career, or other major events, the impact of cancer may be even more devastating to the patient and the patient's family. When hope begins to fade and it becomes apparent that the end is approaching, changes will occur in the patient and the patient's family. Ideally, this is a time when they can realize how important they are to one another and say those things that should be said.

Also at this time, palliative care will replace more aggressive therapies. Desperation may grip some individuals, while others seem resigned and content. This diversity of feelings may be the first step toward separation. Loved ones may be angry with what they perceive as the patient giving up and leaving them without a harder fight. Patients may want to make the transition as emotionally pain free as possible for their family members.

Through all of this, it may be helpful and even therapeutic if patients have an open dialogue with their loved ones. Occasionally, a family will insist that nothing be said to the patient regarding the terminal nature of the cancer. They may believe that they are protecting or somehow strengthening the patient. However, avoiding a discussion of the reality of the condition serves no healthy purpose. It is comforting to the dying patient to know that personal affairs are in order. Patients may want to talk about cremation versus burial or other topics that are difficult for families to confront. When the family avoids talking, they are depriving the patient of this comfort. Intervention may serve as a catalyst to open communication.

Family members may become exhausted by the increased need for care that their loved one now requires. They may not have realized how demanding the care would become, how long it would continue, or how rapidly the patient's needs would change. Dealing with feelings of anxiety is important to the well-being of patients and their families.

STAGES OF GRIEF: THE KÜBLER-ROSS MODEL

Learning about and recognizing the stages of grief may be helpful in developing a deeper understanding of death and dying. Dr. Elizabeth Kübler-Ross has identified the five stages of grief as [131]:

- Denial and isolation

- Anger

- Bargaining

- Depression

- Acceptance

These emotions do not necessarily occur in any particular order, and a patient may move back and forth between stages within a relatively short period of time [132].

Denial is, however, often the first response. It may be the initial reason there was a delay in seeking medical treatment or assessment. Patients may have known that their cough was very different from anything they had ever before experienced; they also know their smoking history and may be acquainted with others who have been diagnosed with cancer. Delays in treatment regardless of this knowledge may, in many cases, be attributed to denial. Patients who are deeply in denial may have a difficult time making wise decisions about health care. Ideally, patients will work through this stage quickly, so that there is time to accomplish goals before dying.

Anger is another step in the grief process. In this stage, patients still have plans for the future, family to care for, and work to accomplish. They may be angry that their lives are being disrupted and that the cancer is demanding so much time.

Bargaining is a toned-down response to anger. It is generally characterized by the patient promising to make a change in exchange for some improvement in their condition. Patients may want the disease to go away completely, or they may just want more time; in any case, it is all considered bargaining. Often, bargaining is linked to religion or to a relationship with religious figures.

Depression is an understandable and normal response. It should not be treated as something for which the patient should be ashamed, nor should the patient be told to cheer up. Feeling depressed is appropriate for the patient who has suffered losses and is coping with a terminal diagnosis. Patients in this state are sad that this is their fate and wish it could be different.

Acceptance comes when the previous four stages have been worked through and the patient accepts and calmly acknowledges the reality of the situation. Patients in this stage do not seem fearful of death but may instead see it as a welcome rest from a long and tiring struggle [132].

Achieving acceptance does not necessarily mean that the patient will cease to feel anger or depression. Also, more than one stage can be felt at any one time. The patient's loved ones, particularly caregivers, will also experience disbelief, anger, bargaining, and depression. Acceptance is generally not as easily achieved by those who will be left as it is for those who are dying.

ADVANCE DIRECTIVES

As a result of medical technologic advancements, patients are living longer and in different circumstances than ever before. The introduction of life-sustaining treatments, such as parenteral feeding and hydration and mechanical ventilation, has also produced vigorous debate regarding care decisions. Several landmark court cases regarding these issues have prompted the creation of laws to protect the right of patients (or the designated proxy) to make their own medical decisions.

In 1990, the U.S. Congress passed the Patient Self-Determination Act (PSDA), which requires hospitals and other healthcare facilities to recognize the living will and durable power of attorney for health care to provide patients with written information about their rights [133,134]. Facilities cannot require a patient to sign an advance directive, but they must make the information available. Because physicians will direct the care the patient receives, they should participate in the discussion, answer questions the patient may have, and when the forms are signed, be given a copy of the advance directive. An advance directive may help to eliminate family dissension about what steps should be taken during the course of a patient's care. This can be a great relief to many patients.

Advance directives vary based on state law and individual preferences within the states' legal requirements. Advance directives include the durable power of attorney for health care (also called the health care power of attorney or health care proxy), physician directives (living wills), and do not resuscitate (DNR) or "no code" orders [133]. All healthcare professionals should understand these documents in order to successfully discuss the options they offer patients.

The durable power of attorney for health care allows the patient to authorize another individual, called a proxy or agent, to make healthcare decisions if the patient becomes incapacitated. Some states restrict the ability of the agent to carry out some requests (e.g., to stop feeding). The durable power of attorney must specifically list the designated person(s) by name. It must also be in writing, signed by the patient choosing the proxy, and witnessed. A backup proxy is often named in case the first choice becomes unable or unwilling to act on the patient's behalf [133,134].

Physician directives (also referred to as living wills) are designed to control future healthcare decisions at a time when the patient is unable to make them. They are guides for physicians that are meant to ensure that the care the patient desires is provided. Physician directives may specify that all measures be taken to save the patient's life, or they may allow the physician to stop trying to prolong life in a terminally ill patient. If a patient has hope of recovery, the living will generally does not apply. There are endless variations on this, but the more specific a directive is, the easier it is to follow. Most states require that the document be witnessed and notarized by someone other than heirs, the attending physician, or employees of the healthcare facility. Where no written advance directive exists, some states recognize oral advance directives; others require a written and notarized form [133].

DNR orders are written by physicians only, in accordance with the wishes of the patient and the family, and added to the patient's medical record [133]. As required by the Joint Commission, all healthcare facilities must have a DNR policy [135]. Laws vary from state to state as to when physicians may write these orders, but they are not advance directives in the strict definition. They are merely outward signs that the advance directive is being followed. Because a DNR order is valid only while the patient is hospitalized, some states have advance directives called "do not attempt resuscitation (DNAR)" orders that may be used outside the hospital, such as when emergency medical teams respond to 911 calls. This order allows the patient to refuse resuscitation in advance, even when emergency personnel have been summoned. This order must be signed by the patient and the patient's physician [133].

It is important for the patient to understand that these directives do not eliminate the provision of normal care. For example, a request for no cardiopulmonary resuscitation (CPR) means only that no chest compressions or mechanical breathing would take place should the patient have a cardiac arrest. It does not mean that the patient will be denied antibiotics for potential infections or refused hospitalization when necessary [133].

HOSPICE

Evidence Based Practice Recommendation

The American College of Chest Physicians recommends that all physicians caring for patients with advanced lung cancer should initiate conversations about the goals of care, the pros and cons of life-sustaining treatment, and end-of-life care options.

https://journal.chestnet.org/issue/S0012-3692

Last Accessed: August 21, 2018

Strength of Recommendation: 1B (Strong recommendation based on moderate-quality evidence that the benefits outweigh the risks/burdens)

Many patients with lung cancer are cared for at home with the assistance of a home health agency. There may be nurses coming in on an intermittent basis to check the patient's condition, monitor TPN, change dressings, or any number of other interventions. There will come a time, however, when hospice should be considered.

The term hospice is used in this country to refer to a program, not necessarily an institution. Hospice is a type of care provided not only to the terminally ill patient, but to the patient's family as well. Hospice strives to meet physical, psychologic, and spiritual needs through an interdisciplinary team of physicians, nurses, social workers, therapists, and volunteers. The goal of hospice is to allow the patient to die comfortably, surrounded by family, with the support that is needed to provide the best possible quality of life and death. Hospice nurses are adept in aggressive pain management and also in communicating effectively with family [130,136].

It is not uncommon for a family caregiver to be afraid of not knowing what to do when death finally does occur. Hospice is able to educate the caregiver to relieve that anxiety, but will also have someone there to physically help with care when the time comes. The hospice team is attuned to the needs of the family and the patient and may provide support to all involved parties. This can be very comforting to patients who may be concerned about the effect their death will have on loved ones [136].

Hospice has certain rules for participation, but they are not rigid rules and may be adapted to a patient's special needs. The entrance requirements state that the patient's physician must certify that the disease is terminal and that the patient is in the last six months of life [130,136]. The six-month time frame is simply an attempt to define the type of patient participating in the program; if a patient lives seven months, the hospice service is not cut off.

Another guideline is that there is a caregiver. This also is not an ironclad rule, but it certainly facilitates the program [136]. Under normal circumstances, a spouse, adult child, close friend, or significant other will step in to provide care for the last days.

Medicare hospice programs require the patient to switch their standard Medicare benefits for the Medicare hospice package. This provides broader coverage for the patient, including health problems unrelated to the terminal illness. It also requires that hospice care be given by a Medicare-certified hospice program [136]. Medicare coverage primarily provides for care at home but will allow hospitalization for illnesses other than the terminal illness. It also allows respite care, which is temporary relief to the caregiver.

13. CASE MANAGEMENT OF THE PATIENT WITH LUNG CANCER

Physicians, nurses, and other healthcare workers have all had to acknowledge the influence of finance on patient care. In an effort to work within the financial constraints that have been imposed, yet continue to deliver quality care, the concept of case management has evolved.

Defining case management may help to shape understanding of what it really is. Some confusion occurs with the term "managed care," partially because case management is based on similar ideas, but also because the two concepts rose in popularity at about the same time.

Managed care is a method of delivering health care that is focused on cost-effective, patient outcome-oriented concepts. It keeps costs under control and manages resources while continuing to strive for good quality in patient care. It encompasses the health maintenance organization, the preferred provider organization, and other methods of healthcare delivery [120].

Case management is a reorganized nursing structure that gives more responsibility and decision-making capacity to nurses. A nurse case manager follows all aspects of a patient's care and becomes more intensely involved in the creation of positive outcomes. A case manager may function in any number of settings, each of which will substantially differ in regards to daily operations. In each setting, however, the patient remains at the center of concern [120].

The hospital-based case manager is also called a "within the walls," or WTW, case manager. WTW case managers may deliver bedside nursing care for a small group of patients, or they may supervise the case management program. Whatever the assignment, the WTW case manager monitors adherence to critical pathways as well as cost- and time-effective delivery of care, with an emphasis on positive outcomes for the patient. Depending on the facility, nurse case managers may also complete discharge planning and utilization review functions [120].

Due to the nature of the disease, patients with lung cancer may have many hospitalizations. Having the same case manager for each admission helps patients feel a continuity of care that allays anxiety and promotes a more effective therapeutic relationship. The following case study and discussion illustrate the role of case management in the care of a patient with lung cancer.

Patient H is a man, 60 years of age, who has been admitted twice previously to City Memorial Medical Center for treatment of his small cell lung cancer. Nurse S has been his WTW case manager each time. This admission, she greets Patient H like an old friend. She knows his history, family situation, and health insurance plan from past admissions, plus she has been kept informed regarding his status by telephone calls. Now, she has only to assess his current status and be apprised as to what has been happening to him recently. This not only reassures Patient H that he is in familiar and caring hands, but it eliminates the time required for Nurse S to learn about him.

WTW case managers not only start IVs and administer medications, they also check with radiology about the delay in chest film reports, call physicians with lab results, and ask dietitians to see patients about their weight loss. These interventions and others not only improve the quality of care, but decrease the length of stay, saving the hospital and insurance companies unnecessary expenses. The WTW case manager will also interface with other case managers.

Those who are employed outside the acute care hospital are called "beyond the walls," or BTW, case managers. The majority of working BTW case managers are employed by insurance companies or some sort of managed care group, but they may also be found in home healthcare agencies and other organizations [120]. It should be noted that some progressive hospitals have established BTW case managers to remain with patients after the patients have been discharged. These case managers do not provide hands-on care, but they do assess patients who have returned home and make referrals to home health or other agencies as necessary. This has proven to be cost-effective to hospitals by reducing the number of readmissions.

When Patient H was admitted to City Memorial, the information about his admission was transmitted from the admitting department to his insurance carrier, Western States Preferred Provider Organization (WSPPO). The particular policy, a PPO, reimburses at a better rate when those providers that are part of a network of hospitals, physicians, and other healthcare agencies listed in his provider directory are used. These providers have signed contracts with WSPPO to accept a lower reimbursement in exchange for the increased number of patients they will be receiving because of being included in the PPO provider directory.

Nurse M, a BTW case manager for Western States, contacted the hospital asking to speak with the patient's case manager, Nurse S. From this conversation she garnered enough information about the patient's condition to authorize the insurance company to pay for the admission. She was able to determine that Patient H met the criteria established by WSPPO for admission to an acute care hospital.

Nurse S will not only be doing traditional nursing activities, but will provide the utilization review information to Nurse M. This reassures Patient H that his care is being paid for, and it allows Nurse S to maintain authorization for her patients.

As soon as a patient is admitted to the hospital, and perhaps before, if it was a scheduled admission, the WTW case manager will work with the patient and the patient's family to meet the discharge planning needs. A WTW case manager assesses the patient's physical, emotional, psychologic, and financial status. Then, using this assessment as a basis, he or she will identify potential needs for continued care posthospitalization. WTW case managers ask physicians, patients, and families many questions that will help them develop a discharge plan. Important discharge planning questions may include [101]:

- Will there be a need for home health care? (This may include nursing, home medical equipment, therapy services, social services, or nutritional support.)

- Do you know where you will get care and who will be helping you after you are discharged?

- Do you understand your health condition?

- Does the patient have transportation needs? Will assistance be required to get to radiation therapy appointments? Physician appointments? Pharmacy? Supermarket?

- Do you know what each of your prescription drugs does? Do you know how to take them and what side effects to watch for?

- Is placement in a long-term care facility indicated?

- Is a referral to hospice warranted?

After the discharge planning questions were answered, Nurse S began to formulate a plan for Patient H. Before the discharge plan could be put into effect, however, it had to be authorized by Nurse M at WSPPO. In order for referral to be made for durable medical equipment, home health care, or any other of a number of services, the authorization had to come from Nurse M.

One of the helpful aspects of BTW case management is the flexibility BTW case managers are given in an effort to control costs. As previously noted, WSPPO has contracts with specific providers (e.g., they have an agreement with a specific rental company to provide hospital beds to WSPPO patients for a discounted rate). This saves both Nurse M and Nurse S from searching for a hospital bed provider; they both know immediately that they must first check with the designated rental company.

BTW case managers may also take advantage of the substitution of benefits. This means that if a patient needs a hospital bed at home, but the patient's healthcare plan does not include a benefit provision for durable medical equipment, a bed may still be provided if it can be proven that the equipment would shorten the hospital stay. BTW case managers often have the authority to approve a bed as a method of controlling costs; it is less expensive for insurance providers to pay for a bed rental than to pay for an additional day or more of acute hospitalization.

Some third-party payers have developed programs for disease management. This is essentially case management with patient participation in the program based solely on their diagnosis. The patient may have asthma, diabetes, heart disease, acquired immunodeficiency syndrome (AIDS), cancer, or other major illness. The purpose of a disease management program is to teach patients methods to control their chronic illness, recognize possible complications so early intervention can be provided, and reduce costs from frequent hospitalizations and costly treatments [97].

CLINICAL PATHWAYS

Whether they are called clinical pathways, critical pathways, case management plans, treatment plans, or care maps, they are all similar methods for managing patient care. As a vital part of the managed care environment, clinical pathways have often been the catalyst for hospitals to move to a case management type of nursing. It is important to note that the clinical pathway may or may not be part of the medical record.

Clinical pathways are multidisciplinary, sequential guides to patient care that are created through a collaboration of healthcare professionals. Anticipated events are included in a day-by-day grid, allowing the nurse, patient, and family members to know what can be expected on any given day [120]. This serves many purposes:

- Routine procedures are not overlooked, which could delay discharge.

- Communication between staff members, as well as between staff and patient, is facilitated.

- Daily goals help motivate patients to achieve better results.

- Awareness of quality management goals is increased.

- Teaching goals are enhanced.

Factors to consider when creating clinical pathways include [16]:

- Leadership of the staff

- Design format

- Patient population

- Assignments for implementation

- Variance reporting

- Method of documentation

Although each of these factors may vary to meet the specific needs of the individual hospital, they all have certain common traits.

The pathway is usually posted within patients' rooms, so they and their families can follow along to see if their progress is as expected. It is motivating to a patient to see, for example, that he or she is expected to walk from the bed to the bathroom the afternoon of surgery or to successfully self-administer an insulin injection by the third day of instruction. Whatever the task, most patients make an effort to do what is expected of them.

The pathway may also be useful to the nurse case manager. For example, a patient's culture and sensitivity report comes back from the laboratory indicating that the patient is receiving the incorrect antibiotic. The report is ordinarily left on the patient's chart for the physician to review during the next rounds, but this might not occur for several hours or into the next day. However, if the nurse sees on the pathway that the patient is expected to be afebrile by the next day and homeward bound the day after, the nurse might be motivated to contact the physician for orders for a new antibiotic.

Clinical pathways are also particularly helpful to the relief nurse. It is always difficult to be the nurse called in to substitute for a nurse who has the day off, is ill, or is on vacation. The patients are new to the relief nurse, and it takes time to learn about the idiosyncrasies and needs of each one. The clinical pathway provides a way for the relief nurse to quickly determine each patient's point on the route to recovery.

Not every patient will have a clinical pathway. They are normally assigned by common diagnosis or diagnosis-related group (DRG) or by clinical unit. Most often, those patients who have been chosen for inclusion are those with high risk and/or high cost illness that can effectively use clinical resources for cost savings. The more generic the pathway, the more patients that may be included [120].

The pathway may be a tool for the nursing staff; however, just as important is its ability to increase security and confidence for patients who are part of a case management program [120].

NURSING OUTCOMES

Evaluating the efficacy of WTW or BTW case management programs depends on how well the chosen outcomes have been met. If outcomes were thoughtfully considered, they should be indicative of the success of case management. For example, if one of the chosen standards of care is that the patient admitted for chemotherapy is educated about exposure to hazardous waste, and procedures are used to reduce that possibility, then a desired daily outcome may be, "No spills of chemotherapeutic agents." Whether this goal was met will be recorded in the medical record and/or in the clinical pathway. If the desired outcome is not met, it is identified as a variance [120].

Patients are not removed from the case management program or even from the use of clinical pathways if there is a variance. Ideally, the pathway will tend to be more generic than specific and will be applied to a homogeneous group of patients. Within that group of patients, however, there may be a wide range of differences. For example, chemotherapy patients may be considered a homogeneous group, but within that group are men, women, young adults, the elderly, those on their first course of chemotherapy, and those on their sixth course. These patients may live in their own home with several loving relatives, or they may live in a nursing home and have no one. It is natural and expected that there will be variances among them.

Variances should be analyzed to determine why the outcomes were not met [120]. Was it a patient problem (e.g., refusal to cooperate)? Was it a clinical problem (e.g., the patient's condition changed)? Was it a staff problem (e.g., failure to give the chemotherapeutic agent as scheduled)? Or was it a facility problem (e.g., the equipment failed)? If, when checking variances, something stands out as preventable, then that is an opportunity to change either the practice or the pathway.

After all the data has been collected, it can be reviewed while considering the various components of the quality improvement program [120]. For example, if it is found that 61% of all patients developed a nosocomial infection, then practice patterns should be reviewed and evaluated.

Good quality health care is less costly in the long run. It only makes sense to deliver the best care possible while also taking into consideration the cost benefits. Reviews and evaluations of variances are easy ways to assess costs associated with errors, misuse of staff, delays, or dissatisfaction [120].

14. PATIENT TEACHING GOALS

Nurses are teachers in every sense of the word, constantly teaching patients about their disease, their medications, possible complications and side effects, testing and treatment procedures, and other aspects of care. The case manager is also very much an educator, whether in a WTW or BTW role. The WTW case manager should discuss the immediate issues facing patients as well as the long-range implications of their disease. A patient cannot be taught everything on the first admission; early goals are different from the follow-up that occurs during subsequent visits. Appendix 1 contains nursing care plans for various teaching and disease management goals, including those for patients with nausea and vomiting, mucositis, and myelosuppression.

PATIENT TEACHING FOR SURGERY

Preoperative teaching can be done prior to admission. In the past, patients were admitted the evening before surgery, partially in order to carry out teaching before the patient went to surgery. Now, with patients being admitted the morning of surgery, very little time is available for teaching, let alone for allowing patients to absorb and understand what to expect. A better time for patient teaching is at the preoperative visit, when the electrocardiogram (EKG), lab work, and other testing are done. Nurses can use this visit as an opportunity to meet with the patient, begin preoperative teaching, and obtain useful history, which can assist in an early start to discharge planning. It has been found that preoperative patient teaching is very useful and comforting for the patient. This establishes a connection that will continue through future admissions as well.

There is a great deal of fear experienced by the patient and the patient's family when lung cancer is diagnosed. On the first admission, when pathology and staging have not been completed, there is anxiety associated with not knowing what the prognosis may be. There is also an understanding that this may be the beginning of the end. The rapport that is built between the nurse and the patient/family can greatly reduce anxiety and facilitate teaching goals.

Prior to surgery, patients should be able to explain the reasons for their surgery and the benefits of the particular type chosen. They should also be able to articulate what is involved in the type of surgery, whether it is a lobectomy, pneumonectomy, or wedge resection. This method of testing gives nurses confidence in patient knowledge. When patients explain what they believe is happening, misconceptions become evident and may be corrected.

Surgery that involves the lung can easily result in postoperative respiratory distress. It will be painful to breathe, cough, and move; yet, all of these activities will be vital to the patient's well-being. A thorough discussion and practice sessions prior to surgery will help the postoperative transition go more smoothly.

Ideally, patients will have stopped smoking preoperatively. This will enable them to have maximum ventilatory capability at the time of surgery. Patients should know that they will be expected not to smoke after the procedure is completed. Additionally, they should be trained in how to turn, cough, and breathe deeply, so these maneuvers will seem more natural after the procedure.

Positioning for lung surgery involves moving the arm on the affected side out of the surgical field. This usually results in a very painful shoulder and/or arm. It is helpful to warn the patient about this and stress the importance of exercising the affected arm. A review of exercise techniques may be done preoperatively and should include information about the leg exercises that will be required to prevent thrombophlebitis.

Patients will most likely have thromboembolic deterrent or pneumatic inflating stockings on their legs after surgery to discourage clot formation. These stockings may be fitted prior to surgery, which will then present an opportunity to teach the patient about their purpose and let the patient know that they will be changed during each shift.

Patients are often concerned about the amount of pain that they will encounter postoperatively. Some are fearful of it, while others present a stoic demeanor. It is beneficial for patients to know that there will be pain, but that measures will be taken to alleviate it as much as possible. Patients should be told what type of analgesia will be ordered and that it should be taken or requested before their pain becomes so severe that it depresses their ability to fully expand their lungs during respiration. If a patient will be receiving PCA, the patient should be taught how to use it and reassured that it will eliminate any delay in relief.

A chest tube is not pleasant but is more tolerable if the patient is prepared to have one. Teaching should include a simple explanation of its necessity and how it will be handled when moving about in bed and ambulating in the room. Some patients are fearful that the tube may fall out or be pulled into their chest, causing damage. Nurses should provide reassurance that neither will happen, and exercise should not be restricted because of the tube. Patients should also be encouraged to seek assistance to correctly position or move the tube.

Specific routine postoperative procedures should also be discussed with the patient. Patients will feel better if they know where their family will be during and immediately after surgery. It is also helpful for patients to know that they will go to the recovery room and, in most cases, continue on to the intensive care unit (ICU). If a patient is unaware that he or she is expected to be in ICU, the placement may cause apprehension regarding the severity of the condition. Understanding vital sign monitoring, dietary restrictions, and other routine care will also make for a more confident and relaxed patient. These procedures should be outlined on the clinical pathway, if possible.

There should be a reinforcement of the applicable teaching goals in the first few hours after surgery. Patients should be reminded about the necessity of coughing, breathing deeply, exercising in bed, ambulating, and being properly medicated for pain. The transitional time will go more quickly and smoothly if the patient is well prepared for this period.

When a patient is thoroughly awake and has the ability to communicate and concentrate, more extensive training can take place. This usually begins the first postoperative day and may be expanded and reinforced as the patient progresses. Teaching should be repeated often in order for the patient to absorb all of the information completely during such a stressful time.

Dressings and wound care are of primary importance to most patients. They may be concerned about the amount of drainage on the dressing, especially if blood is present, or about the risk of infection. Reassurance during wound care is helpful to the patient's overall well-being. If, however, there is a wound infection or complication, there should be reassurances given that home health care can address these issues at the time of discharge, if necessary.

Some patients suffer emotionally from the sight of the wound and the fear that the scar, as well as the diagnosis, will have an adverse effect on relationships and sexuality. Patients can be reassured, allowed to explore feelings, and, if necessary, referred to a social worker or staff psychologist for counseling.

Prior to discharge, it is important to reinforce several teaching points. Primarily, patients should know which medications have been prescribed for them at the time of discharge, their purpose, the correct dosage, administration schedule, and side effects. Signs of possible complications, emergency telephone numbers, and other safety information should also be provided.

PATIENT TEACHING FOR CHEMOTHERAPY

Chemotherapy creates additional patient education needs. The chemotherapeutic agents that will be used should be discussed, including details regarding their mechanisms of action and instructions on how to use verbal information and written instructions. Booklets or pamphlets that might be available should be reviewed and distributed.

Patients and families should be taught about the side effects that can be anticipated with chemotherapy. They should understand that there are immediate side effects as well as delayed symptoms, which may arise one to two weeks after treatment. They should also be taught which effects can be expected as normal and which should be reported to the physician.

Emotional support is also extremely important during this time. Patients and families will have questions, fears, and misunderstandings that should be discussed. They should be encouraged to express those feelings and articulate the worries, anger, or frustrations they feel.

All of this information will obviously not be given to the patient in the first chemotherapy session. The education process takes time. Some patients are eager to learn all they can about their disease and treatment, while others must be encouraged. If a patient is not receptive to learning, it makes the process more difficult; however, teaching can still progress if clues are taken and acted upon. For example, when the patient complains of nausea, this is the cue to discuss prevention and treatment of nausea.

Patients involved in clinical trials will also require teaching to assist them through the process. They should know about the drug, its action, method and time of administration, side effects, and other information that would be available with the use of any drug. Due to the nature of clinical trials, there will likely be a diary to be kept or other special instructions from the group that is conducting the trial.

PATIENT TEACHING FOR RADIATION THERAPY

Radiation therapy treatments provide similar opportunities for teaching. Again, the first concept that patients will learn is when and where their appointments are scheduled. There may already have been a preliminary session in which the positioning and markings are accomplished. Patients should be alerted that subsequent sessions will be shorter. This will help with planning and transportation arrangements.

Patients who have been taught well will understand the process of radiation therapy, be aware of potential side effects, and know how to combat the symptoms of those side effects. These patients will know to notify a healthcare professional when there are symptoms that should be addressed in order to prevent those symptoms from escalating into a more serious problem. Furthermore, they will recognize that the amount and duration of radiation will affect their response. For example, skin changes are expected, as are fatigue and myelosuppression. Radiation to the chest can lead to local problems such as esophagitis, dysphagia, or radiation pneumonitis [91]. The combination of both radiation and chemotherapy treatments will undoubtedly lead to symptoms that must be controlled.

CASE MANAGEMENT AND PATIENT TEACHING

As soon as the BTW case manager has been notified of the diagnosis, he or she will contact the patient and the WTW case manager to begin the teaching program. This contact should include an explanation of the program to the patient and/or family, stressing that the goals are to improve the quality of care, reduce hospitalizations, and smooth the logistics of care. Some individuals will be anxious to participate; others will not want the intervention of a stranger into their lives. Depending on the specifics of the insurance carrier, those patients who choose not to participate may still be case managed, but indirectly and less extensively. The case manager will still work to approve care providers, but will not be conducting the interviews and teaching required with a fully participating case management patient.

BTW case managers often have an initial admission questionnaire to assist in providing a baseline as to the disease stage and progression, patient understanding, and potential knowledge deficit and opportunities for teaching. The case manager will alert the patient that there will be future contact and provide a telephone number for any questions.

15. CASE STUDY

Nurse W is the WTW nurse case manager at City Memorial Hospital. She is assigned to the Oncology Unit on the day shift. Nurse B is a BTW case manager working in the oncology disease management division of Western States Health Maintenance Organization. This case study will examine how each of the case managers works to help care for the patient with lung cancer.

Patient P is a white man, 58 years of age, who worked as a sales representative for a nationally known greeting card company. He traveled by car over a wide area and spent a great deal of his time driving and smoking. The patient was first seen at his primary care physician's office for a routine physical that his wife had insisted he schedule.

When Patient P met the physician for the first time in September, he denied any major complaints and stated that he was there to appease his wife. His medical history revealed no major illness or injuries, apart from an appendectomy at 14 years of age. He admitted he had smoked two packs of cigarettes every day for the last forty years.

When the office nurse observed a frequent, nonproductive cough, she questioned Patient P about it. The patient claimed it was simply a tickle in his throat that came about every spring due to an allergy to budding trees and flowers. Because it was no longer spring and the cough remained, the office nurse made a note for the physician to check into the cough when he examined the patient.

The physician found nothing remarkable on Patient P's physical examination, even though he listened to the patient's chest to assess the cough. As a precaution, however, he ordered a chest x-ray and some routine lab work.

Three days later, the results of the exams were returned. The chest film showed an infiltrate in the patient's right lower lobe. Laboratory work showed mild anemia with a hemoglobin of 10.0 and hematocrit of 31. The patient was contacted and asked to return to the office to discuss the findings.

The next day at the office, the physician explained the results and showed Patient P and his wife the x-rays. He said that while he suspected lung cancer, he hoped he was wrong. A definitive diagnosis required further testing. The physician ordered sputum for cytology, an MRI of the chest, and scheduled a bronchoscopy with biopsy for later in the week, contingent upon approval from the insurance company.

Nonetheless, Patient P and his wife were cheerful when they left the office. They were sure that the physician was wrong, but glad that he was being so thorough. Patient P also agreed that it was time to stop smoking and begin a healthier lifestyle.

Patient P was given instructions for collecting the sputum specimens. The Western States HMO utilization review office approved both the MRI and bronchoscopy as "urgent," which meant it was not routine, but also not an emergency. The diagnosis on the authorization request was possible lung cancer, so a copy was automatically routed to Nurse B in the oncology disease management division.

Three days later, Patient P, accompanied by his wife, went to the outpatient department at City Memorial, the contracted hospital for Western States HMO. Patient P had been NPO since midnight. Once out of his clothes and into a gown, Patient P was taken into the procedures suite for the bronchoscopy.

After the bronchoscopy was completed, the physician explained to Patient P's wife that everything appeared normal with the procedure, but he still wanted the MRI. After the MRI was completed, Patient P recovered from the procedure and sedation and was ready for discharge. Just before they left, the physician came back into the room with a frown on his face.

The MRI showed a peripheral lung tumor. Based on the lung scan, the physician believed the mass was likely cancer, but he also wished to get a consult from a thoracic surgeon and obtain a biopsy to determine exactly what they were dealing with.

The biopsy was scheduled for the following Wednesday, but on Sunday evening the patient's wife, sounding frantic, called the physician. She related that Patient P had had a seizure and that she had called the paramedics. By the time the ambulance had arrived, her husband was awake and had refused to go with them. The paramedics insisted that the family physician be contacted immediately. Per the physician's instructions, Patient P was driven to the emergency room at City Memorial where he was examined and admitted to the Oncology Unit.

Monday morning, when Nurse W arrived on duty, she found she had a new patient, Patient P, who carried the diagnosis of probable adenocarcinoma of the right lung with brain metastasis. At their initial meeting, she noted that he was 6 feet 2 inches tall, weighed 220 pounds, and seemed physically fit. He was awake and cheerful. He told Nurse W that he had a spot on his lung but that he was here now because he had "some sort of freak seizure or something." He thought it was due either to the medication he had taken for the bronchoscopy or perhaps just stress. He repeated several times that he believed he was fine. The patient also expressed a need to get everything settled so he could concentrate on the impending birth of his first grandchild, who was due to be born in December.

Shortly after their conversation, a transporter arrived to take Patient P to the imaging department for a MRI of the brain. While having the procedure, Patient P suffered another tonic-clonic seizure. That afternoon, the physician, accompanied by Nurse W, went to the patient's room to speak with him and his wife. The physician related the findings of the brain MRI, which showed several areas in the brain that appeared to be metastases. He also emphasized the need to begin medication and radiation treatments. First, Patient P would be referred to a neurosurgeon for further examination and possible surgical intervention.

When Patient P's wife asked about the lung tumor, the physician stated that the first priority for treatment would be the brain metastases. The neurosurgeon would determine whether a biopsy would be necessary.

After having the physician write specific orders on the patient's chart, Nurse W returned to Patient P's room. She found both the patient and his wife smiling and upbeat. Patient P's wife expressed relief that they did not need to worry about the patient's lung tumor and stated that they would be happy when the neurosurgeon had Patient P's epilepsy under control.

Unsure whether the couple was in total denial or simply had misunderstood what the physician had said, Nurse W attempted to explain the physician's recommendations. She clarified that the physician did not say he had found epilepsy. She also asked the couple if they knew what metastasis was. The couple looked confused and Patient P shook his head.

Nurse W explained that metastasis occurs when a tumor from one place in the body, for example the lung, sends out cells that grow in another part of the body, such as the brain. She also elaborated that the physician believed that the abnormalities in the brain were caused by Patient P's lung cancer. Although it was confusing to the couple that the physician stated that they would not be treating the lung tumor, Nurse W emphasized that they would still be treating the cancer; the brain metastasis was just considered a more urgent matter.

Patient P sat stunned through the entire conversation. When Nurse W returned to the nurses' station, she noted the variances on the clinical pathway for lung cancer. Patient P was not following the path at all, but his variances were not due to mistakes or omissions; they were due to a changing clinical status.

The neurosurgeon saw Patient P later in the day and scheduled a biopsy of the brain using stereotactic surgery for Tuesday, the next day. Results from the biopsy confirmed metastatic adenocarcinoma from the lung.

Patient P was discharged from the hospital two days later. Before leaving, the physician spoke with the patient and his wife regarding immediate plans. He told them that there was no way Patient P could return to work. The physician stated that he would fill out the forms to declare the patient disabled for Social Security and that he wanted them to proceed with the forms the applicant needed to fill out.

Nurse W had extensive conversations with the couple to assess their home situation. She discovered that the patient's wife was no longer able to drive due to a visual problem, and now, because of the seizure disorder, Patient P could not either. She contacted the local branch of the American Cancer Society, where a volunteer arranged for daily transportation to the hospital outpatient department where the patient would receive his chemotherapy and radiation treatments. The supermarket and pharmacy were only one block from the couple's home, so they were able to walk there, and their two married children volunteered to help with other shopping on the weekends when they were available.

There did not seem to be a need for any durable medical equipment. Nurse B called Nurse W daily during the hospital admission to collect information to authorize the stay and also to begin to obtain baseline data for the oncology case management program.

The day after Patient P returned home, Nurse B called the house and spoke with him on the telephone. She explained who she was and that Western States was interested in having him participate in their oncology case management program. She told him that hopefully this would lead to fewer hospitalizations and a more supportive atmosphere during his illness.

Patient P agreed and asked Nurse B to explain everything to his wife, who also thought it sounded like a good program. By the end of the conversation, Nurse B had completed preliminary forms that recorded the best times to call and basic demographic information. She also set an appointment for a phone visit every Wednesday morning at 11 o'clock. During those calls she would complete questionnaires that were aimed at identifying signs and symptoms of possible complications or problems. It also gave her an opportunity to educate Patient P regarding lung cancer, brain metastasis, radiation therapy, chemotherapy, and other issues that presented. She gave Patient P and his wife her telephone number and asked them to call whenever they had questions or concerns.

Early on a Monday morning, two weeks into radiation, the patient's wife called Nurse B crying. She was concerned about her husband. He was sitting in his recliner watching sports on television all day. He said he was tired, but never would go to bed. He only left his chair to go for his treatment and to go to the bathroom. His wife had tried to talk with him about their future, but Patient P refused to answer. He was also eating poorly, and she believed he had lost weight.

Nurse B arranged to have a contracted home health agency send out a nurse for an assessment and then report back with the results. The home health nurse reported that Patient P weighed 208 pounds, a 12-pound loss since he had been in the hospital. He had sores in his mouth and seemed depressed. Nurse B then spoke again to both the patient and his wife on the telephone. She reinforced the oral hygiene measures that the home health nurse had shared with them and also spoke to them about measures to ease the mouth pain. She stressed the importance of adequate food and fluid intake and offered to send a dietitian to the home. They declined. Nurse B reported her findings to the patient's physician. Chemotherapy was ending, and the physician felt it probably was not advisable to begin another course.

A month later, Patient P was still in a decline. Still depressed, he was watching endless hours of television and eating poorly. His weight was now down to 196 pounds. His fatigue was a continued problem, and now he was having some shortness of breath, even at rest. At his doctor's appointment, arterial blood gases were drawn, and he was found to have a pO_2 of 78 mm Hg. Home oxygen was ordered, which was arranged by Nurse B.

The next week when Nurse B called, she inquired about the status of the oxygen system. The patient was angry and asked when they were actually going to help him. He did not feel that he was getting adequate care. The patient's wife was also annoyed when she spoke to Nurse B. She was fed up with Patient P's bad attitude and said she was sick of being treated like hired help. She wondered why this had to happen to them. After speaking to the couple for several minutes, Nurse B could see they were both at the anger stage of grief. Frustration over Patient P's condition and an underlying fearfulness were apparent.

Nurse B was also concerned about the breathlessness that seemed to persist, despite the oxygen concentrator that was delivering oxygen at 2 liters per minute. She once again called the home health agency, which arranged for an initial assessment, followed by twice weekly nurse visits. The home health nurse recommended physical therapy to improve the patient's strength and endurance, as well as a hospital bed, as he refused to use his own bed. She felt that he liked the recliner because he could have his head up, which eased his respiratory effort. Nurse B approved both the physical therapy and the bed after consulting with the patient's physician.

Right before Thanksgiving, Patient P experienced marked swelling in his face and neck. The patient's wife contacted the physician, who authorized transport to the hospital for evaluation of possible superior vena cava syndrome.

After determining that the lung tumor had spread to the area blocking the flow through the superior vena cava, the physician, along with Nurse W, presented several options to Patient P, including surgery, more radiation and chemotherapy, or returning home with hospice to help with the final days.

The patient's wife was tearful, but said she wanted everything possible that could be done to save or prolong the patient's life. Patient P's demeanor had changed from the last time Nurse W had seen him. He was no longer upbeat, depressed or angry; he seemed tired, resigned, and at peace. He refused further treatment, stating that he wanted to go home for the holidays and enjoy his family. He had things he wanted to say to his children and he wanted to see his grandchild.

Nurse W stayed with the couple after the physician left the room. She reassured them both that if that was their choice, they would be given all the support and assistance they needed. Later, Nurse W spoke with Nurse B to obtain the needed authorization for hospice.

A hospice case manager came to the hospital and spoke with Patient P and his wife prior to discharge. She arranged for daily nurse visits to assess for pain control, respiratory problems, nutrition, and medications. She also spoke to them about advanced directives. Patient P told her that he had already signed a durable power of attorney for health care, appointing his wife as his spokesperson, and specifying that he wished to have no intubation or ventilator support. Both Nurse W and Nurse B followed the patient regularly by telephone. They answered questions and recommended nursing measures for problems that arose.

Christmas was a bittersweet time for Patient P's family. On December 21, his first grandchild, a girl, was born. She met her grandfather the next day and then spent a wonderful Christmas day with the extended family. During the early morning of December 27, Patient P died as he slept. His wife was at his bedside, as was the hospice nurse.

Throughout this illness, the patient was kept informed of all the tests, treatments, procedures, and processes that occurred. Patient P was allowed to express his feelings, make choices, and exert some control over his life that had, in actuality, become very out-of-control. Because of this, he was better able to cope with the illness, his wife was better able to cope and to help him, and costs were kept to a minimum. Numerous hospitalizations were avoided and minor problems were prevented from escalating.

16. CONCLUSION

Although advancements in the diagnosis and treatment of lung cancer have been made in the last few decades, it remains the deadliest cancer in the United States 2]. Identifying risk factors and screening for lung cancer at the earliest possible point is one of the most effective ways to improve the clinical course and survival time associated with the disease. The two main categories of lung cancer, SCLC and NSCLC, have distinctive pathophysiologies, which also affect the available treatment and management options. A comprehensive understanding of the different lung cancer types, how they present, and how they may be treated is an important step in providing the best possible care for patients. Disease progression and/or cancer treatments may result in various conditions, which should be discussed and managed with the patient as much as possible. Eventually, many patients will require palliative or hospice care. A knowledge of lung cancer and its effects on patients will better prepare healthcare professionals for the realities of the disease process and the necessity for compassionate care and patient teaching.

17. RESOURCES

A number of resources are available for healthcare providers and patients diagnosed with lung cancer and their caregivers. These resources cover a wide range of services and are located throughout the United States. Although every community has programs available, those listed here are available nationwide. National organizations listed may have local branches, so it may be useful to check with their headquarters or your local directory. All are nonprofit organizations.

University of Colorado Cancer Center Fund

13001 East 17th Place

Mail Stop F-500

Aurora, CO 80045

303-724-7823

http://cucancercenterfund.org

Provides direct fundraising support for cancer research.

American Cancer Society

800-227-2345

https://www.cancer.org

Provides many services to patients with a diagnosis of cancer, including information, classes, support groups, transportation for medical appointments, home care products, and more.

American Lung Association

55 West Wacker Drive

Suite 1150

Chicago, IL 60601

202-452-1805 or 800-LUNGUSA

http://www.lung.org

Offers programs to reduce the hazards of lung disease, such as classes to stop smoking, as well as information, support groups, and research programs. Some local groups have oxygen concentrators on loan.

CancerCare

275 Seventh Avenue

New York, NY 10001

800-813-4673

https://www.cancercare.org

Includes educational programs, psychologic counseling, and financial support for patients with cancer.

Corporate Angel Network, Inc.

Westchester County Airport

One Loop Road

White Plains, NY 10604-1215

914-328-1313 or 866-328-1313

http://www.corpangelnetwork.org

Provides free air transportation for patients traveling to receive cancer treatment.

National Cancer Institute

BG 9609 MSC 9760

9609 Medical Center Drive

Bethesda, MD 20892-9760

800-4-CANCER (800-422-6237)

https://www.cancer.gov

Answers questions, provides information, and makes resource referrals for those with cancer.

National Hospice and Palliative Care Organization

1731 King Street, Suite 100

Alexandria, VA 22314

703-837-1500 or 800-658-8898

https://www.nhpco.org

Offers information nationwide on local hospices to assist patients in finding the service in their community or nearby.

Lung Cancer Alliance

1700 K Street NW

Suite 660

Washington, DC 20006

202-463-2080 or 800-298-2436

https://www.lungcanceralliance.org

Provides information and referral services for patients and caregivers, and facilitates a peer support network.

18. APPENDIX 1: SAMPLE CASE MANAGEMENT CARE PLANS

Table 8: SAMPLE CASE MANAGEMENT CARE PLANS

ALTERATION IN NUTRITION—DEFICIENCY DUE TO ANOREXIA, NAUSEA, VOMITING, DIARRHEA, WEIGHT LOSS

GOALS: Maintain appropriate weight; prevent nutritional depletion; treat existing nutritional deficiencies; meet increased need for nutrition; maintain/improve patient's quality of life.

ACTION

RATIONALE/DESIRED OUTCOME

Assess patient/family understanding of prescribed diet.

Obtain baseline knowledge level upon which to build.

Assess presence of anorexia, nausea, vomiting, and diarrhea and cross-reference symptoms to medications/treatments.

Report to physician.

Instruct patient/family in maintaining food diary as needed.

Identify trends of poor intake and be able to intervene.

Assist patient/family to identify ways to maintain adequate nutrition. Identify preferred high carbohydrate foods and drinks.

Take antiemetics before meals.

Review sample menus with patient/family. Recommend small, frequent meals. Identify bland foods to eat when nauseated.

Assist in problem solving to provide means of easing discomfort while increasing oral intake.

Encourage good oral care before and after meals.

Will enhance the taste of food.

Instruct patient to weigh daily at same time of day with same clothing.

Monitor weight.

Instruct in monitoring intake and output.

Monitor and report to physician as necessary.

Refer to nutritional consultation as necessary.

Will have appropriate support systems in place.

KNOWLEDGE DEFICIT—RELATED TO DISEASE PROCESS OF LUNG CANCER

GOAL: Demonstrate understanding of disease process by complying with treatment regimen and identifying significant signs and symptoms.

ACTION

RATIONALE/DESIRED OUTCOME

Assess present level of understanding, desire, and ability to learn.

Obtain baseline data upon which to build; dispel fears and misconceptions.

Assess level of compliance with treatment regimen and any reasons for noncompliance.

Emphasize importance of compliance with prescribed plan.

Teach risk factors, disease process, complications, usual treatment modalities, and treatment options.

Provides basis for understanding importance of being an active partner in managing care.

Discuss follow-up care during and after treatments.

Will be actively involved in monitoring condition.

Identify and review with patient/family pertinent education plans.

Modification of controllable risk factors may result in better management of disease process.

Assist patient/family to identify community resources that may be of value.

Will have adequate support systems in place.

KNOWLEDGE DEFICIT—RELATED TO MEDICATIONS

GOAL: Understand prescribed medication regimen through compliance.

ACTION

RATIONALE/DESIRED OUTCOME

Assess level of patient/family understanding of medication plan.

Obtain baseline to determine precise knowledge deficits.

Assess level of compliance with medication regimen and any reasons for noncompliance.

Obtain baseline data upon which to build.

Assess patient/family level of understanding of actions and side effects of medications.

Obtain baseline data upon which to build.

Teach importance of following prescribed medication regimen. Ask patient to record when medications are given.

Adequate information will enhance compliance. Documentation may prevent inadvertent misuse of medications.

Teach actions, common side effects, signs, and symptoms requiring physician attention.

Medical attention will be obtained in a timely manner.

Teach questions to ask physician.

Patient will be prepared to discuss medications with physician.

Assess compliance and knowledge in follow-up visits/telephone calls.

Ongoing monitoring and education will enhance management of lung cancer.

HIGH RISK FOR INFECTION—RELATED TO IMMUNOSUPPRESSION, BONE MARROW SUPPRESSION, AND/OR POOR NUTRITION

GOAL: Remain free of infection.

ACTION

RATIONALE/DESIRED OUTCOME

Assess patient/family level of understanding regarding importance of avoiding infection and ways to prevent infection.

Obtain baseline knowledge and skill level upon which to build.

Teach patient/family to monitor temperature in presence of chills, increased fatigue, dyspnea, and presence of body fluids of unnatural color or with odor.

Will recognize early symptoms of infection and obtain prompt medical attention.

Assist patient/family to identify ways to prevent infections, including:

Maintain adequate nutrition.

Maintain adequate oral and skin care.

Practice good handwashing technique.

Avoid exposure to people with colds or other infections.

Obtain adequate rest.

Obtain flu and pneumonia vaccines per physician's advice.

Take temperature if symptoms present.

Take full course of antibiotics as ordered.

Maintain clean environment.

Maintain highest activity level possible.

Cough and deep breathe regularly if sedentary.

Will understand how to avoid infections; will participate in methods to avoid infections.

Reinforce with patient/family the signs and symptoms to report to physician when infection is suspected.

Will obtain medical attention promptly through precise communication of signs and symptoms of infection.

KNOWLEDGE DEFICIT—RELATED TO TREATMENT MODALITIES USED

GOAL: Improve understanding of treatment modalities by asking appropriate questions and actively participating in management of the treatment process.

ACTION

RATIONALE/DESIRED OUTCOME

Assess patient/family present level of understanding, desire, and ability to learn.

Obtain baseline data upon which to build. Dispel fears and misconceptions.

Assess level of compliance with treatment regimen and any reasons for noncompliance.

Emphasize importance of compliance with treatment regimen.

Teach risk factors, disease process, and complications of patient's treatment modalities and treatment options.

Provides basis for understanding importance of being an active partner in managing care.

Teach signs and symptoms that require physician attention.

Early detection of acute episode allows medical attention to be obtained in a timely manner.

Discuss follow-up care during and after treatments.

Patient will be actively involved in monitoring his or her condition.

Assist patient/family to identify community resources that may be of value.

Will have adequate support systems in place.

Schedule follow-up visits or telephone calls.

Provides for continued support.

ALTERED ROLE PERFORMANCE—DISEASE HAS CHANGED PATIENT AND FAMILY ROLES

GOAL: Patient and family will exhibit empathy and a supportive environment to assist one another in making role changes.

ACTION

RATIONALE/DESIRED OUTCOME

Encourage patient to make a list of individual strengths, goals, and responsibilities.

Identifies realistic perception of abilities, accepts limitations, and discusses ways to change lifestyle to assist in attaining goals.

Assist to explore new ways to accomplish goals with existing limitations.

Fosters new ways to perceive patient and family roles.

Refer to counseling as needed.

Assist with mastery of new role.

ANTICIPATORY GRIEF—RELATED TO POTENTIAL LOSS OF WELL-BEING AND/OR LIFE

GOALS: Have adequate support systems in place; make decisions regarding care.

ACTION

RATIONALE/DESIRED OUTCOME

Assess stages of grief. Acknowledge normalcy of feelings and concerns.

Identify baseline stage of grief. Provide sense of control.

Assess patient/family mental and emotional status noting signs of denial, depression, noncompliance, dependency, etc.

Will determine level of support required.

Provide opportunity for expression of feelings.

Verbalization will assist in the grieving process.

Set limits with maladaptive coping mechanisms and provide positive support for effective coping.

Reinforces adaptive coping mechanisms.

Reinforce the value of treatment.

Provides sense of realistic hope.

Encourage patient/family to make simple decisions regarding care.

Provides a sense of control.

Provide follow-up visits or calls.

Provides for continued support and reassurance.

ANXIETY—RELATED TO CHANGE IN HEALTH, THREAT OF DEATH

GOAL: Effectively cope with identified lifestyle changes.

ACTION

RATIONALE/DESIRED OUTCOME

Assist patient/family in identifying sources of stress.

Obtain baseline data upon which to build.

Identify level of stress and follow appropriate action:

Mild stress – increased awareness and able to focus. No action required.

Moderate stress – decreased awareness of environment and concentration span. May have difficulty thinking clearly.

Severe stress – major decrease in awareness of environment. May focus on one detail at a time. Refer to physician.

Panic – is unable to attend to or integrate environment, unable to function. Refer to physician. Identify effective manners to cope with stress (e.g., assertive techniques, creative problem solving, expression of feelings).

Determine if patient/family is ready and willing to learn. Assess ability as related to stress to actively participate in management of chronic illness. Provide support by conveying attitude of acceptance and through active listening. Develop individualized plan to effectively cope with situation.

Identify relaxation techniques and alternative ways to relax (e.g., exercise, progressive relaxation, guided imagery, hobbies).

Develop individualized plan to assist patient to relax.

Monitor progress with follow-up visits or telephone calls.

Management of stress is an ongoing process.

ALTERATION IN COMFORT—RELATED TO CHRONIC PAIN FROM NEOPLASM, METASTASIS, ETC.

GOALS: Verbalize relief from discomfort; identify resources to assist in pain management.

ACTION

RATIONALE/DESIRED OUTCOME

Assess patient/family complaints of discomfort in terms of frequency, location, intensity, and how relief is obtained.

Patient/family will identify source of discomfort.

Assist patient/family to identify alternative methods of pain relief including: position changes, relaxation techniques, guided imagery, diversionary activities, rest, etc.

Enhances nonpharmacologic methods of pain relief.

Evaluate use and effect of pain medications. Encourage compliance with medication regimen.

Determine if follow-up with the physician is warranted for good pain management.

Assist patient/family to identify community resources that may be of assistance.

Will have adequate support systems in place.

Schedule follow-up visit or telephone call.

Monitor discomfort as an ongoing process.

ALTERED ORAL MUCOUS MEMBRANE—CAUSED BY TREATMENTS, INFECTIONS, POOR ORAL INTAKE

GOALS: Demonstrate ability to maintain good oral hygiene; maintain adequate fluid and nutritional intake; oral mucous membranes intact and without lesions.

ACTION

RATIONALE/DESIRED OUTCOME

Assess condition of oral membranes.

Obtain baseline status.

Instruct patient/family in proper technique to maintain good oral hygiene, such as: use soft toothbrush, do not use mouthwash with alcohol, keep lips well-lubricated, avoid spicy, citrus, or hot foods.

Patient/family will be able to demonstrate/explain proper technique.

Encourage patient to drink adequate fluids.

Helps to maintain membranes in good condition.

IMPAIRED PHYSICAL MOBILITY—RELATED TO FATIGUE, GENERALIZED WEAKNESS, MALNUTRITION, INFECTION, IMBALANCE BETWEEN OXYGEN SUPPLY AND DEMAND, BRAIN METASTASIS

GOAL: Maintain optimal level of physical activity and functional ability.

ACTION

RATIONALE/DESIRED OUTCOME

Assess patient baseline level of activity in terms of type, response, and emotional response.

Obtain baseline data upon which to build. Determine compliance with prescribed activity level.

Assist patient in setting daily schedules/goals as needed.

Promote sense of control.

Help to prioritize and pace activities, providing for rest periods.

Tailor activity level to patient's lifestyle and needs.

Assist patient/family to identify energy-conserving techniques.

Will develop skills to increase strength and endurance.

Assist patient/family to identify activity tolerance by monitoring pulse and respiration before activity and assessing during and after for shortness of breath.

Will accurately identify activity tolerance and precisely report changes to physician to monitor progress.

Instruct patient/family to slowly increase activity.

Will progressively build strength and endurance, as tolerated.

Assist patient/family to recognize signs of activity intolerance that may necessitate need for medical attention.

Early medical attention may prevent exacerbation of acute episode.

Monitor progress with follow-up visit or telephone call.

Progress will be monitored and support provided to attain goals.

INEFFECTIVE BREATHING PATTERN—RELATED TO ACTUAL LOSS OR POTENTIAL LOSS OF VENTILATION

GOALS: Exhibit improved respiratory status; cooperate with care that reduces dyspnea.

ACTION

RATIONALE/DESIRED OUTCOME

Assess rhythm, depth, and quality of respirations.

Obtain baseline data.

Identify factors that contribute to breathing difficulties.

Assist in problem solving for sources of dyspnea.

Assess level of compliance with methods of reducing dyspnea, complying with oxygen regimen, and any reasons for noncompliance.

Obtain baseline data.

Teach signs and symptoms that may require physician attention.

Early detection of acute episode allows medical attention to be obtained in a timely manner.

Instruct patient/family to suction as necessary to remove secretions.

Facilitates breathing.

KNOWLEDGE DEFICIT—RELATED TO OXYGEN DELIVERY SYSTEMS

GOAL: Demonstrate understanding of prescribed oxygen regimen through compliance.

ACTION

RATIONALE/DESIRED OUTCOME

Assess level of patient/family understanding of oxygen system.

Obtain baseline data.

Assess level of compliance with oxygen data.

Obtain baseline regimen and any reasons for non-compliance.

Teach signs and symptoms that may require physician intervention.

Medical attention will be obtained in a timely manner.

Instruct in emergency safety procedures.

Patient/family will be able to avoid and/or properly respond to emergency situations.

Assess compliance in follow-up visits or telephone calls.

Ongoing monitoring will enhance management of cancer.

BODY IMAGE DISTURBANCE—RELATED TO SURGERY, WEIGHT LOSS, EDEMA, AND/OR TREATMENT REGIMENS

GOAL: Develop a realistic, accepting, and positive self-concept regarding body image.

ACTION

RATIONALE/DESIRED OUTCOME

Allow patient to verbally express feelings about the changes seen.

Discussion will help to identify areas of concern.

Suggest ways to improve body image, such as grooming, posture, etc.

Involvement in improving the situation will motivate patient.

IMPAIRED SKIN INTEGRITY—RELATED TO RADIATION THERAPY AND/OR SURGICAL INTERVENTION

GOAL: Skin will remain intact and free of lesions, rashes, or other irritations.

ACTION

RATIONALE/DESIRED OUTCOME

Assess status of skin condition.

Obtain baseline information.

Suggest methods of improving dry, itching, or peeling skin, such as:

Use a mild soap without perfumes or deodorants;

Avoid creams or lotions with perfumes or deodorants;

Avoid the use of cornstarch or petroleum jelly;

Avoid tight-fitting garments that rub against the skin;

Use hydrophilic creams or lotions to ease dryness.

Maintain or restore skin integrity.

Avoid exposure to sun, heat, or cold and use sunblock when sun exposure is not avoidable.

Prevent exacerbation of skin problems.

Treat moist desquamation with saline irrigations or cool compresses.

Prevent skin breakdown and infection.

Monitor progress with follow-up visits or telephone calls.

Provides continued monitoring of progress.

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90772 • Skin Cancers

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

The key to reducing the morbidity and mortality associated with skin cancers is prevention and early detection. Dental professionals involved in the care of adults and children are in a unique position to routinely evaluate patients for skin cancer as well as to educate their patients about self-examination and preventive measures. This course provides an overview of the various types of nonmelanoma and melanoma skin cancers, including a description of the populations at high risk for these cancers and the criteria for distinguishing between benign and malignant melanomas. The course also includes details on diagnostic techniques, treatment options, prognosis, and follow-up care. The importance of patient education pertaining to proper preventive measures and the current recommendations concerning screening are also highlighted.

Table of Contents

90772 • Skin Cancers

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. OVERVIEW OF SKIN CANCERS

TYPES OF SKIN CANCERS

EPIDEMIOLOGY

ROLE OF UV RADIATION IN THE DEVELOPMENT OF SKIN CANCER

3. NONMELANOMAS

RISK FACTORS

DEVELOPMENT OF NONMELANOMAS

DETECTION AND DIAGNOSIS

BIOPSY

STAGING

TREATMENT OPTIONS

PROGNOSIS AND FOLLOW-UP

4. MELANOMA

RISK FACTORS

DEVELOPMENT OF MELANOMA

DETECTION AND DIAGNOSIS

BIOPSY

STAGING

TREATMENT OPTIONS

SENTINEL LYMPH NODE BIOPSY AND LYMPH NODE DISSECTION

PROGNOSIS AND FOLLOW-UP

5. SKIN CANCER SCREENING

6. PREVENTION

PROTECTION FROM UV RAYS

SELF-EXAMINATION AND MONITORING MOLES

ADDRESSING PATIENTS' EDUCATIONAL NEEDS

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

90772 • Skin Cancers

Education Category. Medical / Surgical

Release Date. 03/01/2019

Expiration Date. 02/28/2022

Course Overview

The key to reducing the morbidity and mortality associated with skin cancers is prevention and early detection. Dental professionals involved in the care of adults and children are in a unique position to routinely evaluate patients for skin cancer as well as to educate their patients about self-examination and preventive measures. This course provides an overview of the various types of nonmelanoma and melanoma skin cancers, including a description of the populations at high risk for these cancers and the criteria for distinguishing between benign and malignant melanomas. The course also includes details on diagnostic techniques, treatment options, prognosis, and follow-up care. The importance of patient education pertaining to proper preventive measures and the current recommendations concerning screening are also highlighted.

Audience

This course is designed for physicians, physician assistants, nurses, surgical professionals, and other healthcare providers seeking to enhance their knowledge about the prevention, screening, diagnosis, and treatment of nonmelanoma skin cancers and melanoma.

Course Objective

The purpose of this course is to enhance knowledge about the clinical presentation of skin cancers in order to help primary healthcare providers detect skin cancer and make appropriate referrals early, when treatment is most successful.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the etiology and epidemiology of skin cancers.

2. Discuss the role of UV radiation in the development of nonmelanomas and melanomas.

3. Describe the clinical features, treatment, and prognosis of basal cell carcinomas and squamous cell carcinomas.

4. Describe the clinical features, treatment, and appropriate follow-up care of melanoma.

5. Outline skin cancer screening guidelines.

6. Discuss effective preventive measures for skin cancers, including resources to educate patients about skin cancers and prevention.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Approximately 5.3 million cases of nonmelanoma skin cancer are diagnosed each year, making it the most common cancer in the United States [1,2]. The cost of treating newly diagnosed skin cancers is estimated at $8.11 billion each year [2]. The two most frequently occurring nonmelanoma skin cancers are basal cell carcinoma and squamous cell carcinoma, and the prevalence of these two skin cancers has been increasing worldwide. Since the 1980s, the incidence of squamous cell carcinoma has increased 3% to 10% each year, and the incidence of basal cell carcinomas has increased by as much as 80% [2,3,200,201]. The third most common skin cancer, melanoma, was the fifth leading type of cancer diagnosed in both men and women in 2018, accounting for 5% of all cancers; it will be diagnosed in an estimated 96,480 individuals in 2019 [1]. The prevalence of melanoma has increased at a rate faster than any other malignant disease, with slightly greater increases among men compared with women [4,202]. If the current trend continues, skin cancer will develop in one of five Americans during his or her lifetime [5,6].

The reason for the dramatic increases in these three types of skin cancers is thought to be related to increased exposure to the sun through outdoor recreation beginning in childhood. It has been estimated that nearly 90% of nonmelanoma skin cancers can be attributed to exposure to ultraviolet (UV) rays, especially UV-B rays [6,203]. Thus, many cases of nonmelanoma and melanoma could be avoided through appropriate behavioral changes.

This course provides an overview of skin cancers, with a description of the various types of skin cancers and the demographic variations in their incidences and mortality rates. The role of UV radiation in the development of skin cancers is discussed, as are other risk factors for nonmelanomas and melanoma. The focus of the course is on the detection, diagnosis, treatment, prognosis, and follow-up for basal cell and squamous cell carcinomas and melanoma. Also addressed in detail are guidelines for screening and the importance of patient education in preventing skin cancers.

2. OVERVIEW OF SKIN CANCERS

TYPES OF SKIN CANCERS

A wide variety of tumors and lesions arise in the skin, and most are benign. However, it is important to evaluate all suspicious lesions to distinguish benign tumors from nonmelanomas and melanomas. Skin cancers primarily comprise melanoma and two types of nonmelanomas—basal cell carcinoma and squamous cell carcinoma. Basal cell carcinoma is far more common, accounting for approximately 70% to 80% of nonmelanoma skin cancers, while squamous cell carcinoma accounts for nearly 20% [7,8].

Several less common types of skin cancers together account for less than 1% of nonmelanoma skin cancers [9]. These cancers include Kaposi sarcoma, adnexal tumors, cutaneous lymphoma, sarcomas, and Merkel cell carcinoma.

Kaposi sarcoma (Image 1 and Image 2) became more common with the introduction of the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) but has become rare again as a result of treatment of these conditions with protease inhibitors [10]. Most adnexal tumors, which originate in the hair follicles or sweat glands, are benign. Lymphomas and sarcomas usually originate in lymph nodes, viscera, and connective tissue but develop in the skin on rare occasions. Cutaneous T-cell lymphoma (mycosis fungoides) is the most common primary cutaneous lymphoma, while dermatofibrosarcoma protuberans and angiosarcoma are among the various types of sarcomas that arise from the skin. Merkel cell carcinoma arises from neuroendocrine cells in the skin, and the estimated incidence is 0.7 cases per 100,000 people; however, the incidence appears to be rising [11,12,13,14]. As with basal cell carcinoma and squamous cell carcinoma, Merkel cell carcinoma is caused in part by exposure to the sun and is found on the head or neck in about half of cases and on the extremities in about 40% of cases [11,14]. Unlike the other nonmelanomas, Merkel cell carcinoma is aggressive and has a strong tendency to recur, to spread to regional lymph nodes, and to metastasize [15].

Image 1:

Kaposi sarcoma in the mouth of a patient with AIDS.

Source: National Cancer Institute

Image 2:

Kaposi sarcoma on the skin of a patient with AIDS.

Source: National Cancer Institute

Melanomas occur less frequently than nonmelanoma skin cancers, but they are associated with greater morbidity and mortality due to their propensity to metastasize. Melanomas account for approximately 1% of all skin cancers, but for approximately 65% of all deaths related to skin cancers [1,2,23].

EPIDEMIOLOGY

Demographic Variation

The risk for skin cancers varies among several populations defined by sex, age, ethnicity, comorbid conditions, and geographic location. It is difficult to know the true incidence of nonmelanomas, as they are not documented in cancer registries, as melanoma is. In an early attempt to determine the incidence, researchers studied approximately 10 million people in four geographic regions of the United States (Dallas/Ft. Worth, Minneapolis/St. Paul, Iowa, and San Francisco/Oakland) in the early 1970s and found that 300,000 cases of nonmelanoma skin cancer were diagnosed in a six-month period [16].

Nonmelanoma skin cancers are more common in men, with squamous cell carcinoma affecting two to three times as many men as women and basal cell carcinoma occurring at a ratio of 3:2 (men to women) [17,18]. Melanoma also occurs more frequently in men. The American Cancer Society estimates that, in 2019, an estimated 57,220 cases of melanoma will be diagnosed in men and 39,260 cases in women [1]. The incidence of melanoma is higher among men across most racial/ethnic populations (Figure 1) [19].

Figure 1: MELANOMA INCIDENCE RATES BY SEX AND RACE/ETHNICITY, 2015

Source: [19]

Because most cases of skin cancer are linked to sun exposure, the incidence increases with age [2,17]. Similarly, the incidence of melanoma steadily increases after age 19 years, peaking at more than 311.8 per 100,000 population for individuals older than 85 years of age (Figure 2) [20]. The median age at the time of diagnosis of cutaneous melanoma was 64 years in 2011–2015 [21]. The age and sex distribution of melanoma among children and adolescents (1 to 19 years of age) differs from that among adults. Between 2011 and 2015, the rate of melanoma among children was 1.6 per 100,000 (1.2 per 100,000 in boys and 1.7 per 100,000 in girls) [22].

Figure 2: MELANOMA OF THE SKIN, SEER INCIDENCE 2003–2005 VS. 2013–2015, WHITE PATIENTS, BY AGE AND SEX

Source: [20]

The incidences of specific types of skin cancer vary according to race/ethnicity, and the risk is more than 20 times higher for the white population than for populations with darker skin, such as black, American Indian/Alaska Native, Hispanic, and Asian/Pacific Islander populations [9,23]. This large disparity is the result of the photoprotection provided by increased melanin in the epidermis of individuals with darker skin, which can filter up to twice as much UV radiation than the epidermis of white individuals [25,26].

As is true for the white population, basal cell carcinoma is the most common skin cancer among the Hispanic and Asian populations [27,28]. In fact, among Hispanic individuals, basal cell carcinoma is six times more likely than squamous cell carcinoma [28]. In contrast, squamous cell carcinoma is the most common skin cancer in the black population [25,28]. Melanoma is the third most common skin cancer among all racial/ethnic populations [25,28]. The highest rate of melanoma is found among white men and the lowest is among black women [29,202]. Although melanoma is predominant among white men compared with white women, the incidence of melanoma in men and women is similar in black, Hispanic, and Asian/Pacific Islander populations [29,202]. The clinical features of skin cancers (i.e., appearance and anatomic site) also vary according to race/ethnicity, as will be discussed later.

The risk of skin cancer is also influenced by comorbid or previous conditions. One substantial risk factor is a compromised immune system (because of either drugs or disease). Due to immunosuppression, skin cancers develop in 30% to 70% of patients who have a transplanted organ, with a 100-fold increased risk for developing squamous cell carcinoma, a 24-fold increased risk for Merkel cell carcinoma, a 6-fold increased risk for basal cell carcinoma, and a 2-fold increased risk for melanoma [9,30,134]. The prevalence of skin cancers is also high among individuals infected with HIV, and lesions in this population tend to be more aggressive [9,30]. A higher risk of squamous cell carcinoma is significantly associated with seropositivity for human papillomavirus (HPV) types 16 and 18, but a direct causal relationship has not been established [31]. In addition, individuals with a history of skin cancer are at increased risk for another skin cancer, and survivors of childhood cancers are at increased risk for nonmelanoma skin cancers, primarily basal cell carcinoma, particularly in an anatomic site that had been treated with radiation therapy [9,32,33,34,205].

Geographic area of residence also plays a role in the risk of melanoma, with a higher risk for individuals who live near the equator, where the sun's rays are most intense [9,35].

Trends in Prevalence and Mortality

As noted, the incidence of all types of skin cancers in adults has been increasing over the past few decades. In 1930, the likelihood of melanoma was 1 in 5,000 Americans; by 2013–2015, that rate increased to 1 in 27 for men and 1 in 40 for women [36,222]. Overall, the rate of skin cancers has increased 3% to 8% per year since the 1960s [37]. In addition, the incidence of pediatric melanoma increased at a rate of 2% to 2.9% per year since the 1970s [38]. The demographics of skin cancer are also changing. Both basal cell and squamous cell carcinoma are occurring in an increasing percentage of people younger than 40 years of age, and one study found a disproportionate increase in basal cell carcinoma among women in that age-group [39,201]. These two types of skin cancer have nearly tripled in frequency among women younger than 40 years of age since the 1970s [9,40].

When detected and treated early, most skin cancers are associated with an overall survival rate of 97.7% [41]. Squamous cell carcinoma is associated with the greatest number of deaths attributed to nonmelanomas, and a 2013 study estimated that squamous cell carcinoma was responsible for 3,900 to 8,800 deaths in the United States in 2012 [42]. Previous estimates for annual nonmelanoma deaths have been closer to 2,000. As noted, of the three most common skin cancers, melanoma accounts for the most skin cancer-related deaths, and an estimated 7,230 people will die of the disease in 2019 [1]. Mortality rates associated with melanoma vary according to demographic factors; the rate is higher for men than for women (3.9 vs. 1.6 per 100,000), is highest for white men (4.5 per 100,000), and is lowest for Asian/Pacific Islander men and women (0.4 and 0.3 per 100,000, respectively) (Figure 3) [43].

Figure 3: MORTALITY RATES FOR MELANOMA ACCORDING TO SEX AND RACE/ETHNICITY

Source: [43]

Since the 1970s, the relative five-year survival rate for melanoma has increased significantly, from approximately 82% (1975–1977) to 94% (2008–2014), with a 10-year survival rate of greater than 92% [1,41]. However, this rate is lower among racial/ethnic minority populations; for example, the five-year survival rate rose from 57% to 66% for the black population during the same time period [1,43]. This disparity in survival is the result of melanoma being diagnosed at later stages in black individuals [24,134].

ROLE OF UV RADIATION IN THE DEVELOPMENT OF SKIN CANCER

UV radiation is a known carcinogen in humans [44]. Sources of UV radiation include the sun, as well as sunlamps, sunbeds, and other types of tanning devices. Exposure to UV radiation, primarily sun exposure, has been the most significant factor associated with the three primary types of skin cancers. Approximately 90% of nonmelanomas and 65% of melanomas are associated with sun exposure [45].

In the United States, the incidence of basal cell carcinoma has increased in states with a higher UV index (an estimate of the amount of UV radiation reaching the surface of the earth), with a greater difference for squamous cell carcinoma [46]. The risk of melanoma, however, was not found to differ with variations in the UV index, with only a few of the states with the highest numbers of melanoma cases associated with higher rates of sun exposure year-round (Table 1) [1,46,47]. These findings may be explained by many factors, including exposure to the sun in other locations (e.g., during vacation), changes in residence, frequency of exposure, and genetic susceptibility to the effects of UV radiation [48]. The findings also point to the need for enhanced awareness and attention to sun protection regardless of the geographic location of residence.

Table 1: STATES WITH THE HIGHEST NUMBER OF CUTANEOUS MELANOMA CASES, 2019

State

No. of Cases

California

10,710

Florida

8,360

New York

5,150

Pennsylvania

4,340

Texas

4,270

Illinois

3,750

Ohio

3,750

North Carolina

3,550

Michigan

3,300

Georgia

3,050

Source: [1]

Mechanism of Carcinogenicity

Both the epidermis and the underlying dermis are susceptible to damage from UV exposure. UV-A rays penetrate to the dermis, where they alter structural and matrix proteins, leading to the aged appearance associated with chronic sun exposure. UV-B rays are readily absorbed in the outer epidermal layer and are the primary cause of sunburn. UV-B rays are more carcinogenic than UV-A rays, and UV-B rays are thought to act as tumor initiators, while UV-A rays act as tumor promoters [32]. An early target of UV radiation is thought to be the p53 suppressor gene, which is often mutated in skin cancers [49].

The exposure to UV rays from the sun has increased as the protection afforded by the atmosphere has decreased because of the depletion of the ozone layer [50]. Cloud cover protects only 20% to 40% of UV rays, glass blocks UV-B rays but only half of UV-A rays, and regular clothing provides little protection [17]. Sunscreen provides a chemical or physical barrier to UV rays, but only when applied correctly [17].

Patterns of Exposure

Although UV exposure is the primary factor in the development of nonmelanomas, data are conflicting about the pattern of exposure (i.e., cumulative exposure versus intense, intermittent exposure). Exposure to UV radiation begins in early childhood, and 23% of lifetime exposure is reached by the age of 18 years (Table 2) [51,52]. The greatest accumulation occurs between the ages of 41 and 59 years, which would account for the increase in rates of skin cancers with advancing age [36,51].

Table 2: LIFETIME EXPOSURE TO ULTRAVIOLET (UV) RAYS IN THE UNITED STATESa

Age-Group

Average Accumulated Exposure

1 to 18 years

23%

19 to 40 years

47%

41 to 59 years

74%

60 to 78 years

100%

aBased on lifespan of 78 years

Source: [51]

The risk of basal cell carcinoma has been found to be higher with episodic acute overexposure to the sun (sunburn) than with a similar degree of continuous exposure [53,54]. In contrast, chronic (cumulative) exposure to the sun has been associated with a higher risk of squamous cell carcinoma [54,55]. The findings of a study of Asian individuals demonstrated that lifetime sun exposure was primarily associated with higher risk of squamous cell carcinoma among women, while early-age sun exposure was associated with a greater risk among men [56].

The pattern of exposure associated with melanoma has been debated, with some researchers finding a higher risk with episodic overexposure to the sun and other investigators finding a higher risk with chronic exposure [57,58,59,60,61,62]. One study found that the exposure pattern depends on the anatomic site; melanomas on the head and neck were associated with chronic exposure, and melanomas on the trunk were related to episodic exposure [63]. A meta-analysis of 57 studies published before 2002 supported a relationship between sunburn history and an increased risk for melanoma (relative risk: 2.03); the analysis also demonstrated an inverse relationship between continuous exposure and high risk [64]. Studies have shown that the risk of melanoma is doubled for an individual who had one blistering sunburn in childhood or adolescence or five or more sunburns at any age [6,65,66]. Additionally, a cohort study published in 2014 noted that individuals experiencing five or more blistering sunburns between 15 to 20 years of age have an 80% increased risk of developing melanoma and a 64% increased risk of developing non-melanoma skin cancer in their lifetimes [6,227].

Artificial UV Radiation

Through widespread education and legislation regarding the dangers of indoor tanning, exposure to artificial UV radiation has decreased in recent years, but nearly 8 million adults still tan each year. Among adults, the rates of indoor tanning declined from 5.5% in 2010 to 3.5% in 2015 [69]. Among women, the prevalence decreased from 8.6% in 2010 to 5.2% in 2015, and the rates were 2.2% in 2010 and 1.6% in 2015 among men [69]. The national Youth Risk Behavior Survey also indicates a continued decrease among adolescents, with 15.6% indicating that they used indoor tanning in 2009, compared with 7.3% in 2015 [67,68]. The highest rates of indoor tanning are among white women 18 to 21 years of age (20.4%). Among white adults who reported indoor tanning, 40.8% reported at least one sunburn in the past 12 months, compared with 33.9% of non-indoor tanners [69].

The high use of devices with known carcinogenicity has led to much research on the association between indoor tanning and skin cancers. More than 419,000 cases of skin cancer are diagnosed annually due to indoor tanning, including 245,000 basal cell carcinomas, 168,000 squamous cell carcinomas, and 6,200 melanomas [2]. Studies have shown an increased risk for basal cell (29%) and squamous cell carcinoma (67%) and melanoma (34%) associated with overuse of a tanning device [2,70]. The direct cost of medical care for indoor tanning-related skin cancers is $343.1 million annually in the United States.

As of 2018, 19 states and the District of Columbia have passed legislation prohibiting indoor tanning for children younger than 18 years of age. In addition, 44 states have passed legislation to regulate indoor tanning among minors, including limiting exposure time, providing eye protection, and requiring parental consent [71]. The Society of Behavioral Medicine, the American Academy of Dermatology, and the American Academy of Pediatrics have all issued statements supporting the ban of indoor tanning for minors [224,225,226]. The World Health Organization and the FDA have declared indoor tanning devices to be carcinogenic, and the Surgeon General issued a first-time warning on the dangers of UV radiation and indoor tanning in 2015 [2,72,73].

3. NONMELANOMAS

RISK FACTORS

In addition to the risk factors already mentioned (age, sex, race/ethnicity, comorbid or previous conditions, and geographic location), other individual risk factors associated with the development of nonmelanoma skin cancers include physical characteristics that influence the response to UV rays, such as complexion and eye and hair color. A personal or family history of skin cancers also adds risk (Table 3) [9,32,33]. A low percentage of nonmelanomas are the result of industrial agents such as hydrocarbons, arsenic, coal tar, and ionizing radiation [9,32]. Exposure to UV rays is the most common risk factor for basal cell carcinoma across all racial/ethnic populations [28]. In the black population, the most important risk factors for squamous cell carcinoma are chronic scarring processes (occurring in 20% to 40%) and areas of chronic inflammation [27,28].

Table 3: RISK FACTORS FOR SKIN CANCER

Type of Skin Cancer

Risk Factors

Nonmelanomas

Fair complexion

Light-colored eyes (blue, green, or gray)

Blond or red hair

Tendency to burn or freckle with exposure to the sun

History of exposure to the sun

Family history of skin cancer

Weakened immune system

Exposure to arsenic, coal tar, paraffin, or ionizing-radiation

Xeroderma pigmentosum

Previous basal cell carcinomaa

Nevoid-basal cell carcinoma syndromea

Personal or family history of squamous cell carcinomab

Actinic keratosesb

Chronic skin ulcersb

Human papillomavirus (types 16 and 18)

Melanomas

Changed or persistently changing mole

Dysplastic nevi

Family history of melanoma

Immunosuppression

Sun sensitivity or increased exposure to the sun

aRisk factor specifically for basal cell carcinoma

bRisk factor specifically for squamous cell carcinoma

Source: [9,32,33]

DEVELOPMENT OF NONMELANOMAS

Basal Cell Carcinoma

Basal cell carcinoma arises from the basal layer of keratinocytes in the epidermis. These lesions are most often localized and will gradually destroy healthy surrounding tissue if left untreated. Basal cell carcinoma is classified in histologic subtypes according to the degree of invasion, from superficial basal cell carcinoma to nodular, micronodular, and morpheaform (fibrosing or sclerosing) types. The most common form is a mixed type, followed by nodular, superficial, and micronodular [74]. The superficial and nodular subtypes generally follow a less aggressive clinical course than the other subtypes [33]. Basal cell carcinoma is slow growing and rarely metastasizes, with a rate of metastasis of 0.0028% to 0.55% [33].

Squamous Cell Carcinoma

Squamous cell carcinoma, which originates in keratinizing epidermal cells, differs from basal cell carcinoma because of its potential to grow rapidly and invade fatty tissues beneath the skin and to metastasize. The risk of metastasis for squamous cell carcinoma varies widely, with an average rate of 2% to 6% [7,75,76]. However, the rate of metastasis is 11% to 15% for lesions on the lip and is nearly 30% for tumors larger than 2 cm with poor cell differentiation [32]. Other risk factors associated with metastasis include increasing depth of invasion, location in old scars or areas of chronic radiation dermatitis, and the presence of a compromised immune system [32].

As many as 60% of squamous cell carcinomas evolve from actinic keratoses [77]. These premalignant growths develop as a result of epigenetic changes caused by chronic exposure to sunlight [76]. Actinic keratoses are slow growing, usually asymptomatic, and frequently resolve on their own, but may recur. If left untreated, actinic keratoses become malignant in 0.25% to 20% of cases [9]. Another precursor lesion is squamous cell carcinoma in situ (also called Bowen disease), in which malignant cells are confined to the epidermis[9,32].

Historically, squamous cell carcinomas have not been classified into subtypes; however, they exhibit a range of clinical behaviors from indolent to aggressive with significant metastatic potential. Researchers have recommended a risk-based classification system based on malignant potential, with categories of low (metastatic rate of 2% or less), intermediate (metastatic rate of 3% to 20%), high (metastatic rate of more than 10%), and indeterminate [78,228]. Examples of low-risk squamous cell carcinomas are those arising from actinic keratosis and those associated with HPV. Intermediate-risk subtypes include adenoid (acantholytic) squamous cell carcinoma and intraepidermal epithelioma with invasion. The high-risk subtypes include de novo squamous cell carcinoma, squamous cell carcinoma associated with predisposing factors (e.g., radiation, burn scars, immunosuppression), invasive Bowen disease, adenosquamous carcinoma, and malignant proliferating pilar tumors. Signet ring cell, follicular, papillary, and clear-cell squamous cell carcinomas are classified as indeterminate [78,228].

DETECTION AND DIAGNOSIS

The early detection and diagnosis of skin cancers is crucial for selecting the appropriate treatment approach and to an optimum outcome. Early studies suggested that dermatologists were best at identifying skin cancers, but it is appropriate for primary care providers to conduct skin examinations and to evaluate suspicious lesions, especially given that 51% of all healthcare visits are to a primary care provider [79,80,81]. According to a survey of family physicians, as many as 74% of respondents said they treat skin cancers in their offices [82]. Identification of melanomas is essential for reducing their associated morbidity and mortality, as melanomas detected by primary care providers have a greater likelihood of being less invasive than those found by self-examination or examination by family members [81,83]. In general, referral to a dermatologist is appropriate for borderline or larger lesions, and review of pathology reports should include a dermatologist and/or surgical oncologist [75].

The primary challenges in diagnosing skin cancers are to distinguish between benign and malignant lesions and to identify lesions with malignant potential. The first steps in diagnosing skin cancers involve obtaining a history and physical examination and evaluating the clinical features of the lesion. Symptomatology does not play a large role in the detection and diagnosis of skin cancers, as early stage lesions are usually asymptomatic. Preliminary diagnoses for nonmelanomas can be based on the clinical appearance of the lesion, but biopsy should be performed to determine a definitive diagnosis.

History and Physical Examination

When evaluating a patient with a suspicious lesion, it is important to obtain a history of relevant risk factors and to perform a physical examination, with systematic inspection of the entire skin surface to determine the presence of other lesions. If squamous cell carcinoma is suspected, regional lymph nodes should be evaluated clinically and with imaging studies, when indicated [84]. Advanced lesions may be associated with nonhealing ulceration, bleeding, or pain [9,76]. A sore that does not heal may be a sign of either basal cell or squamous cell carcinoma.

The examination room should be brightly lit, and full-spectrum halogen light or combined incandescent and fluorescent light may be useful. A hand lens with a 7 to 10 times magnification is helpful for evaluating variation in pigment pattern, and dermoscopy has been shown to provide more accurate assessment of lesions than examination with the naked eye, resulting in fewer excisions of benign lesions [9,85,86,87,88]. In one study, instructing primary care physicians on how to use dermoscopy and the subsequent use of dermoscopy within the standard clinical examination significantly increased the sensitivity of referrals to dermatology specialists [89]. Photographs may be helpful for documenting changes in moles and dysplastic nevi over time.

Clinical Features

Examination to identify skin cancers includes evaluation of such clinical characteristics as shape, elevation, nature of the surface, color, and type of border. When evaluating nonmelanomas, clinicians should consider differences in some clinical features among racial/ethnic populations to avoid incorrect diagnoses [28].

Basal Cell Carcinoma

The classic appearance of basal cell carcinoma is a pearly, waxy, or translucent papule or nodule with small telangiectatic vessels on its surface; this is the nodular type (Table 4) [7,8,9,32,33,76,90]. This type may occasionally appear similar to large pores or pits of the sebaceous skin of the central portion of the face (Image 3) [91]. Superficial basalthe superficial and the nodular types may look brown, blue, or black as a result of the presence of melanin. The morpheaform type usually presents as a whitish or yellowish, indurated scar-like plaque, often with indistinct borders [9,32,33].

Table 4: CLINICAL FEATURES OF BASAL CELL CARCINOMAS

Type of Basal Cell Carcinoma

Surface

Color

Border

Common Anatomic Sites

Similar in Appearance

Superficial

Scaly erythematous patch or plaque

Usually lacks pigment, but can be brown, blue, or black

Threadlike

Face, upper extremities, posterior trunk, lower extremities

Inflammatory skin disorder (psoriasis or nummular eczema)

Nodular

Pearly papule or nodule, frequently with small telangiectatic vessels

Brown, blue, or black

Rolled

Face, upper and lower extremities, neck, posterior trunk

Large pores or pits of sebaceous skin of central portion of face

Morpheaform (sclerosing)

Indurated scar-like plaque

Whitish or yellowish

Indistinct

Head and neck, trunk, arms and legs

—

Source: [7,9,32,33,76,90]

Image 3:

Nodular basal cell carcinoma, presenting as a small, reddish/brownish papule, often with telangiectatic blood vessels. This type of skin cancer may appear translucent (described as "pearly") and may have a central depression with rolled borders.

Source: National Cancer Insitute

The most common sites for basal cell carcinomas are the head and neck (85% of cases) and the trunk [8,33]. The clinical features and most common anatomic sites of basal cell carcinoma are similar across all racial/ethnic populations. One difference is the prevalence of pigmentation in the lesion; pigmentation is present in more than half of basal cell carcinomas in individuals of color, compared with approximately 5% in the white population [28]. Among the Asian population, basal cell carcinomas often appear brown to glossy black and have a black, pearly appearance [28].

Squamous Cell Carcinoma

Squamous cell carcinoma usually presents as an ulcerated erythematous nodule, scaling patch, or superficial erosion on the skin or lower lip, but the clinical features of this nonmelanoma vary widely (Table 5) [7,9,32,33,76]. These lesions may also appear as a verrucous papule or plaque. Color also varies, and lesions may be reddish-brown, pink, or flesh-colored. Squamous cell carcinomas typically present as exophytic tumors, ranging in size from a few millimeters to centimeters. Larger lesions may appear crusted, erythematous, or eroded (Image 4). In contrast to basal cell carcinoma, overlying telangiectasias are uncommon. The margins may be ill-defined, and the lesion may be fixated to underlying structures [9,32].

Table 5: CLINICAL FEATURES OF SQUAMOUS CELL CARCINOMAS

Surface

Ulcerated erythematous nodule or superficial erosion; verrucous papule or plaque; larger lesions may appear crusted, erythematous, or eroded

Color

Reddish-brown, pink, or flesh-colored

Border

Ill-defined, may be fixed to underlying structures

Common Anatomic Sites

Head and neck (especially lip and ear), hands, forearms, upper trunk, lower legs

Similar in Appearance

Keratoacanthoma (usually dome-shaped papule with a central keratotic crater)

Premalignant Lesions

Squamous cell carcinoma in situ (reddish patch, often scaly and sometimes crusted)

Actinic keratosis (hyperkeratotic papules)

Source [7,9,32,33,76]

Image 4:

Squamous cell carcinoma tends to arise from premalignant lesions, actinic keratoses; the surface is usually scaly and is often ulcerated (as shown here).

Source: National Cancer Institute

Actinic keratosis (a premalignant form of squamous cell carcinoma) appears as small (size of a pinhead) rough spots that may reach several centimeters in diameter. They are typically pink-red or flesh-colored and feel rough to the touch. Changes such as pain, erythema, ulceration, induration, hyperkeratosis, and increasing size may suggest evolution of an actinic keratosis to squamous cell carcinoma. Some evolving lesions may become clinically indistinguishable from invasive squamous cell carcinoma during their development [92]. Squamous cell carcinoma in situ appears as a reddish patch that is usually larger than actinic keratoses, more scaly, and sometimes crusted.

Cutaneous squamous cell carcinoma may develop anywhere on the body but usually arises on sun-damaged skin. However, in individuals of color, the lesions develop primarily in areas of the body that are not exposed to the sun (such as the legs) [28]. Approximately 50% to 60% of squamous cell carcinomas occur on the head and neck (especially the lip and ear), and other common sites are the hands, forearms, upper trunk, and lower legs [7]. Actinic keratoses typically develop on the face, ears, back of the hands, and arms.

BIOPSY

A biopsy should be performed on any suspicious lesion. Excisional biopsy is preferred for most cases [75,84,93]. A shave biopsy can be done for lesions that appear to be benign or for elevated, nodular lesions suggestive of basal cell or squamous cell carcinoma [75,76]. An incisional or punch biopsy may be considered for large lesions or when maximum preservation of tissue is desired (e.g., lesions on the palm or sole, a digit, the face, or an ear). An incisional biopsy should be performed through the thickest portion of the lesion and should include the vertical growth phase of the primary tumor, if present [9].

In cases of suspected squamous cell carcinoma, an open biopsy or fine-needle aspiration should be done on regional lymph nodes that are either palpable or appear abnormal on imaging studies [84].

STAGING

Nonmelanoma skin cancers are staged according to the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) classification [94]. Basal cell carcinomas are rarely staged due to limited risk of metastasis. However, because of the higher risk of metastasis of squamous cell carcinoma, staging criteria were provided in the seventh edition of the AJCC manual, published in 2009. The 2009 classification for cutaneous squamous cell skin carcinomas and a first-time separate classification for Merkel cell carcinoma provided a method of staging nonmelanoma skin cancers [94,229]. However, research showed that the tumor (T) classification for cutaneous squamous cell carcinoma failed to accurately stratify disease-related outcomes. As a result, the eighth edition of the AJCC TNM classification features a revised tumor classification that applies to only the head and neck of those with nonmelanoma skin cancers and includes the requirement to measure the maximum dimension (usually diameter) of every potential invasive cancer before assigning a T1–T3 category, which have also been updated depending on the size of the lesion. This has since been shown effective in the stratification of staging these diseases [229,230,231].

According to the 2017 AJCC system, early stage cutaneous squamous cell carcinoma is defined as no evidence of regional or distant metastasis, with stage I assigned to tumors 2 cm or less and stage II disease to tumors larger than 2 cm but smaller than 4 cm [94,230]. Stage III disease is defined by a tumor larger than 4 cm or by tumor extension into bone, perineural invasion or deep invasion (>6 cm beyond subcutaneous fat). Stage III may also be any size tumor in conjunction with clinical, histologic, or radiographic evidence of disease in one lymph node (3 cm or less) and no extranodal extension [94,230]. The characteristics of stage IV disease are direct or perineural tumor invasion of the skull base or axial skeleton, involvement of two or more lymph nodes, metastasis in one or more lymph nodes that is larger than 3 cm, or distant metastasis [94]. The regional lymph nodes, lung, and liver are the most common sites of metastasis [7].

TREATMENT OPTIONS

The goals of treatment of nonmelanoma are cure, preservation of function, and cosmesis. Several treatment options are available, but surgery and radiation therapy are the primary treatment modalities [84]. Among the surgical treatments are electrodessiccation and curettage, traditional surgical excision, and Mohs micrographic surgery; superficial therapies include cryotherapy, topical treatment with 5-fluorouracil or imiquimod, and photodynamic therapy (Table 6) [7,9,32,75,76,92,95,96,97,98,99].

Table 6: TREATMENT OPTIONS FOR BASAL CELL AND SQUAMOUS CELL CARCINOMAS

Treatment Option

Type of Tumors

Comments

5-Year Cure Rate

Electrodesiccation and curettage

Low-risk tumors

A commonly used technique

>92%

Surgical excision

High-risk basal cell carcinoma, standard treatment for squamous cell carcinoma

A commonly used technique; offers good histologic control

>90%

Mohs micrographic surgery

Large, ill-defined tumors, hard-to-treat locations (head, neck, hands, feet), recurrent lesions

Offers best histologic control; saves greatest amount of healthy tissue; high cost

95% to 99%

Radiation therapy

Lesions near eye, nose, ear

Used for patients who are not good candidates for surgery

>90%

Photodynamic therapy

Superficial basal cell carcinoma, large, extensive lesions, or multiple lesions

Excellent cosmetic outcome, with minimal damage to normal tissue

Not available

Topical fluorouracil (5-FU)

Superficial basal cell carcinoma, multiple lesions, difficult treatment sites

Nonvisible dermal involvement may persist; local skin reaction

Not available

Topical 5% imiquimod cream

Superficial basal cell carcinoma

Local skin reaction

Not available

Cryotherapy

Low-risk tumors

Specialized equipment and skills; long healing time

92.5%

Laser surgery

Treatment secondary to failed topical medications

Risk of scarring and pigment loss greater than with other techniques

Not available

Hedgehog pathway inhibitors

Treatment of metastatic or locally advanced basil cell carcinoma

New class of treatment; long term efficacy unknown. Should be considered in those not responding to surgery or radiation.

Not available

Source: [7,9,32,75,76,92,95,96,97,98,100,101,232]

Basal Cell Carcinoma

Although basal cell carcinomas rarely metastasize, these lesions should be removed, as they can become large, destroying healthy surrounding tissue and causing disfigurement. Appropriate treatment is essential to minimize the risk of recurrence, which is important because recurrent basal cell carcinomas are usually more aggressive than primary lesions of this type [32,232].

A systematic review of the literature has shown that surgery or radiation therapy is the most effective treatment for basal cell carcinomas, with surgery associated with the lowest rates of failure [102,232]. Guidelines developed by the National Comprehensive Cancer Network (NCCN) recommend electrodessication and curettage for low-risk lesions, defined as lesions less than 1.5 cm in diameter and of less aggressive subtypes, as well as lesions in more favorable locations [103]. However, the technique cannot be used in a hair-bearing area, as tumor that extends into follicular structures may not be adequately removed [103]. Traditional surgical excision and radiation therapy are other options [103].

Surgical excision is the recommended treatment for high-risk basal cell carcinomas, and Mohs micrographic surgery and radiation therapy are other options [103]. In all cases of surgical excision, the margins should be evaluated postoperatively; Mohs micrographic surgery or repeat excision should be done if the margins are positive. Mohs surgery is also the treatment of choice for most morpheaform (sclerosing) basal cell carcinomas, as well as for recurrent lesions, tumors in high-risk locations, lesions that are large and ill-defined, or in instances when maximal tissue conservation is critical [9,75,76].

The high cost of Mohs micrographic surgery has raised concern about whether the cost is warranted. A review of the literature involving comparisons of Mohs surgery and surgical excision demonstrated that Mohs surgery was associated with the highest initial cure rates and the lowest recurrence rates [104]. In addition, Mohs surgery was found to be cost-effective, primarily because traditional surgical excision was associated with higher costs for frozen sections, ambulatory facility costs, and the cost of repeat excision [104].

Evidence Based Practice Recommendation

According to the American College of Radiology, radiotherapy can be used for the definitive treatment of aggressive basal cell and squamous cell carcinoma. However, surgery is typically preferred for these lesions, as it can be done more quickly, and there is some evidence that it may be associated with improved tumor control rates and cosmesis compared with radiotherapy alone.

https://acsearch.acr.org/docs/3091669/Narrative

Last Accessed: February 12, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Although a surgical approach is used most often for basal cell carcinomas, radiation therapy can also be effective. This modality is helpful for patients who are not considered to be good candidates for surgery, and it is useful for lesions near the eye, nose, or ear. However, long-term cosmesis is less favorable. Radiation therapy can also be used as an adjunct to surgery for high-risk tumors. Due to the long-term risks associated with exposure to radiation, this approach should be avoided in patients younger than 60 years of age [75].

A 2006 National Institutes of Health Consensus Statement indicated that photodynamic therapy with 5-aminolevulinic acid (ALA) is a safe and effective method for treating superficial basal cell carcinoma [98]. The following year, the International Society for Photodynamic Therapy in Dermatology published evidence-based recommendations on the use of photodynamic therapy with ALA or methyl aminolevulinate (MAL) [99]. The authors of these recommendations concluded that photodynamic therapy was effective and reliable for superficial basal cell carcinoma, offering excellent cosmetic outcomes, and was beneficial for the treatment of large, extensive, and multiple lesions [99]. In addition, five-year follow-up demonstrated long-term efficacy of photodynamic therapy with MAL for the treatment of superficial or nodular basal cell carcinoma [99]. A synthesis of international guidelines for the use of photodynamic therapy published in 2019 also supported the use for superficial and certain thin nodular basal cell carcinomas [233].

Treatment with topical 5-fluorouracil can be used for superficial basal cell carcinomas, and intralesional chemotherapy (5-fluorouracil and interferon) has been found to be effective for patients with numerous lesions [9,76]. Topical treatment with an immunomodulator has shown encouraging results for the treatment of superficial and nodular basal cell carcinomas.

Cryotherapy with liquid nitrogen or nitrous oxide can be used for low-risk tumors, but the approach calls for specialized equipment and skills, and several weeks may be needed for complete healing [9,75]. The long-term efficacy of laser surgery for the treatment of infiltrative or recurrent lesions is not known. Although this modality has some advantages, its use is limited by safety hazards and inconvenience [75].

Due to advances in the understanding of pathogenesis of basal cell carcinoma, a newer class of drugs—hedgehog pathway inhibitors—was first approved by the FDA in 2012 for the treatment of metastatic or locally advanced basal cell carcinoma [103,154,234]. Hedgehog pathway inhibitors work by selectively blocking Smoothened (Smo), a key transmembrane protein involved in hedgehog signal transduction of cancerous epithelial cells [101,154]. The 2019 NCCN practice guidelines recommend consideration of a hedgehog pathway inhibitor in patients who have exhausted other surgical and radiation treatment options. It has also been found that this class of drugs may be effective in the treatment of cutaneous squamous cell cancer of the head and neck, although this use is off-label [103,154,234]. More studies are needed to determine the efficacy and long-term outcomes of this novel treatment modality.

Squamous Cell Carcinoma

As with basal cell carcinomas, treatment of squamous cell carcinoma depends on a variety of factors, including tumor characteristics (i.e., size, location, and degree of histologic differentiation) and patient characteristics (e.g., age, physical condition). In general, curettage and electrodessication is recommended for localized, low-risk lesions, with surgical excision and radiation therapy as additional options. Localized, high-risk lesions (larger than 2 cm in diameter on the trunk or extremities or larger than 1 cm on the face or neck) should be treated with surgical excision or Mohs micrographic surgery [84]. Mohs micrographic surgery is preferred when the amount of tissue removed must be kept to a minimum for cosmetic reasons or to maximize function [7]. The NCCN recommends 4- to 6-mm clinical margins when excising squamous cell carcinomas [84].

As with basal cell carcinomas, radiation therapy may be used for patients who are not surgical candidates, when it is critical to preserve function or cosmesis, or as an adjunct to surgery for high-risk tumors, and should not be used for patients younger than 60 years of age [84].

Although photodynamic therapy has been effective for superficial squamous cell carcinoma in some small studies, the recurrence rate has been as high as 69% (mean: 24%), and complete response rates to treatment are estimated to be between 48% to 89% [84,105,106]. Thus, photodynamic therapy was not recommended for the treatment of squamous cell carcinoma in the International Society for Photodynamic Therapy in Dermatology guidelines [99].

Superficial therapies may yield lower cure rates than surgery and, as such, should be used only for shallow squamous cell cancers or for individuals in whom surgery or radiation is contraindicated or impractical [84].

Cryotherapy is the most common approach for actinic keratosis [84]. Other treatment options for these premalignant lesions are photodynamic therapy and topical treatment with 5-fluorouracil or imiquimod [84,92,98].

Palpable regional lymph nodes should be surgically evaluated, and lymph node dissection should be done when the findings are positive on evaluation of samples from open biopsy or fine-needle aspiration [84]. Radiation therapy should be used for individuals who have palpable lymph nodes in the head and neck region. For individuals with palpable nodes in the trunk or extremities, radiation therapy should be considered after node dissection [84].

PROGNOSIS AND FOLLOW-UP

As noted, appropriate treatment of basal cell and squamous cell carcinomas can lead to high cure rates. However, a second nonmelanoma will develop in approximately 60% of individuals within 10 years after treatment of a first skin cancer, and the risk for cutaneous melanoma is also increased [107,108,109]. An estimated 70% to 80% of recurrent cutaneous squamous cell carcinomas develop within two years after treatment [84,110]. A primary risk factor for recurrence of either basal cell or squamous cell carcinomas is size, in accordance to location, as follows [84,103]:

- 20 mm or more: Trunk, extremities

- 10 mm or more: Cheeks, forehead, scalp, neck

- Any, not dependent on size: So-called mask areas of the face

Poorly defined borders, immunosuppression, and site of previous radiation therapy are other risk factors for recurrence of both types of nonmelanomas; site of chronic inflammatory process, neurologic symptoms, rapid tumor growth, moderate or poor differentiation, and thickness increase the risk of recurrent squamous cell carcinomas [84].

The NCCN recommends a history and physical examination, including a complete skin examination, every 6 to 12 months for 5 years after treatment and then annually for basal cell carcinoma; follow-up after treatment for squamous cell carcinoma is based on the extent of disease (Table 7) [84,103]. Follow-up for all patients should include extensive education on sun protection and self-examination [84,103].

Table 7: NATIONAL COMPREHENSIVE CANCER NETWORK RECOMMENDATIONS FOR FOLLOW-UP AFTER TREATMENT OF NONMELANOMAS

Disease

Follow-up

Frequency

Basal cell carcinoma

History and physical examination, with complete skin examination

Education on sun protection and self-examination

Every 6 to 12 months for 5 years, then annually thereafter

Squamous cell carcinoma, localized

History and physical examination, with complete skin examination and evaluation of regional lymph nodes

Education on sun protection and self-examination of skin

Every 3 to 12 months for 2 years, then every 6 to 12 months for 3 years, and annually thereafter

Squamous cell carcinoma, regional

History and physical examination, with complete skin examination and evaluation of regional lymph nodes

Education on sun protection and self-examination of skin and lymph nodes

Every 1 to 3 months for 1 year, then every 2 to 4 months for 1 year, then every 4 to 6 months for 3 years, and every 6 to 12 months annually thereafter

Source: [84,103]

4. MELANOMA

RISK FACTORS

The factors associated with an increased risk of melanoma, in decreasing order of importance, include [100,235]:

- A persistently changed or changing mole

- Adulthood (compared with childhood)

- Irregular varieties of pigmented lesions, including dysplastic nevi and lentigo maligna

- A congenital mole

- White race

- A personal or family history of melanoma

- Immunosuppression

- Sun sensitivity

- Excessive sun exposure

A review of data on nearly 363,000 individuals who were screened for melanoma demonstrated five factors that independently increased the likelihood of melanoma: history of previous melanoma, age older than 50 years, lack of a regular dermatologist, presence of a changing mole, and male sex [111,235].

A model has been developed by the National Cancer Institute (NCI) to calculate the absolute risk of melanoma based on risk factors that are easily determined during a routine history and physical examination. The model is available online at https://mrisktool.cancer.gov.

DEVELOPMENT OF MELANOMA

Melanomas originate from melanocytes, epidermal dendritic cells that synthesize melanin. Undetected primary melanomas undergo two growth phases: the radial growth phase and the vertical growth phase. In the first phase, the tumor cells are confined to the epidermis or are locally invasive without evidence of potential for growth or metastasis. In the latter stage, melanoma cells expand into the dermis and subcutaneous tissue and are at risk for systemic metastasis [112].

Research has shown that melanomas develop at different anatomic sites through divergent pathways [113,114]. For example, the number of moles has been most strongly associated with melanoma of the trunk, whereas severe, painful sunburn (intense, episodic exposure) has been most strongly related to melanoma on an upper extremity [113]. The molecular basis of melanoma continues to be explored, and mutations in several oncogenes have been linked to melanoma. Many researchers believe that the development of melanoma is a complex interaction among genetic, environmental, and possibly other factors [115,235].

Several studies have been conducted on the relationship between atypical moles (dysplastic nevi) and the risk of melanoma. Most people have several moles (10 to 40), but melanoma is less likely to arise from these typical moles than from dysplastic nevi [116]. Approximately 10% of people have at least one dysplastic nevus, which is generally larger than a typical mole and has irregular or indistinct borders [116]. The development of dysplastic nevi tends to occur in families, and often, several members of a family have a large number of dysplastic nevi; the risk of melanoma is higher for these individuals than for the general population. Researchers have found that the occurrence of melanoma is 10 times greater for individuals with five or more dysplastic nevi compared to those without, and the risk of melanoma increases as the number of dysplastic nevi increases [32,116,117,118]. The lifetime risk of melanoma is more than 50% for individuals who have both dysplastic nevi and a family history of melanoma [9].

Melanomas are categorized into four main histologic subtypes: superficial spreading, nodular, lentigo maligna, and acral lentiginous. Superficial spreading melanoma is the most common subtype, accounting for 70% of all melanomas [7,32]. Nodular melanoma accounts for 10% to 15% of all melanomas, lentigo maligna for 4% to 15%, and acral lentiginous for 2% to 8% [23,32,236]. The frequency of these subtypes varies according to ethnicity, with superficial spreading melanoma occurring most frequently in the white and Hispanic populations, and acral lentiginous melanomas appearing more often in black and Asian/Pacific Islander populations than in the white population [27,28,32].

There are also differences in the prevalence of these subtypes with respect to the age of the patient and the anatomic location of the lesion. For superficial spreading melanoma, the mean age at the time of diagnosis is 59 years and the most common anatomic sites are areas of intermittent sun exposure, including the trunk (especially in men), the legs (especially in women), and the back (in both) [119,236]. In contrast, lentigo maligna occurs most often in individuals who are 70 to 80 years of age and typically develops in chronically sun-damaged areas (e.g., the face, neck, back of hands) [32]. Lentigo maligna may be difficult to diagnose if it develops in areas of sun-damaged skin [120]. Acral lentiginous melanoma appears on the palmar and plantar surfaces, the digits, and subungual areas [25].

DETECTION AND DIAGNOSIS

Most melanomas are detected by nonphysicians; one study found that 72% of melanomas were found by the individual or his or her family or friend [121]. Although this finding points to the importance of self-examination, the role of healthcare providers cannot be overstated, as they have typically detected thinner melanomas than those found by nonphysicians, and this earlier detection increases the likelihood of cure [122]. For example, in another study, 53% of melanomas were self-detected, but the incidental rate of melanoma detected by dermatologists was 80% [237]. Healthcare providers can also detect melanomas in anatomic areas that are outside an individual's view [122].

The history, physical examination, and biopsy are integral to diagnosing melanoma. Evaluating the clinical and pathologic features to determine the stage of disease is essential for selecting appropriate treatment.

Clinical Features

As with squamous cell carcinomas, the clinical features of melanomas vary according to subtype (Table 8) [7,9,32,33,76]. Detection and diagnosis rely on careful evaluation of the appearance and anatomic site of the lesion and signs and symptoms of metastasis.

Table 8: CLINICAL FEATURES OF MELANOMAS

Type of Melanoma

Surface

Color

Border

Common Anatomic Sites

Similar in Appearance

Premalignant Lesions

Superficial spreading

Flat or slightly raised

Dark with variegated colors. Variation in pigment pattern, color (occasionally amelanotic).

Irregular, sometimes notched

Back (men); back and lower legs (women)

—

Dysplastic nevi (papular lesions, up to 6 mm or larger; cobblestone surface with variable mixture of tan, brown, and red or pink coloration; characteristically hazy and indistinct borders)

Nodular

Dome-shaped or pedunculated

Black, brown, blue, gray, tan, red. Variation in pigment pattern, color (occasionally amelanotic).

Smooth or regular

Back (men); back and lower legs (women)

Blood blisters, hemangiomas, nevi, or polyps

Lentigo maligna

Flat, focal papular or nodular areas

Dark brown, reddish-brown, blue-black. Variation in pigment pattern, color (occasionally amelanotic).

Scalloped and convoluted

Sun-damaged, sun-exposed sites (face, neck, back of hands)

—

Acral lentiginous

Flat or nodular

Brown, black, multicolored. Variation in pigment pattern, color (occasionally amelanotic).

Irregular, sometimes notched

Palms, soles, nail beds, mucous membranes

—

Source: [7,9,32,33,76]

Appearance

With melanomas, the most important feature is a change in appearance over time. As the lesion develops by penetrating deeper into the skin, the borders become irregular and may be notched (Image 5). The color and pigment pattern vary. Occasionally, melanomas are amelanotic and may be lighter than the surrounding skin or may be red. An increase in size or a change in color is noted by the patient in approximately 70% of early lesions [123]. Subungual melanomas are usually characterized by a pigmented band on the nail (typically more than 3 mm wide), variable pigment, a rapid increase in size, and the presence of a solitary lesion [27]. Bleeding, ulceration, and pain may be present in advanced disease.

Image 5:

Superficial spreading melanoma arising from a dysplastic nevus. The 4-by-8-mm, pink-tan lesion with irregular borders at the upper left (arrow) is a dysplastic nevus. Arising from it is an invasive malignant melanoma, with its characteristic blue-black color, notched border, and distorted surface. The gray area at the lower left represents tumor regression.

Source: National Cancer Institute

As with nonmelanomas, detection focuses on distinguishing melanoma from nonmelanoma. In 1985, the ABCD rule was developed to help physicians distinguish melanomas from benign lesions (Table 9) [124]. According to this system, A represents asymmetry; B, border irregularity; C, color; and D, diameter (Image 6, Image 7, Image 8, and Image 9). "E" (evolving) was added to the rule to recognize the importance of changes in the size, shape, surface, shades of color, or symptoms (e.g., itching, tenderness), and it is considered the most important factor in diagnosing melanoma [125]. This system has a sensitivity of about 65% to 80%, primarily because some melanomas may be smaller than 6 mm, some may have a regular shape, and some may lack color variation [126].

Table 9: ABCDE RULE FOR DISTINGUISHING BENIGN TUMORS FROM MELANOMAS

Criteria

Benign Tumors

Melanoma

A: Asymmetry

Symmetric

Asymmetric

B: Border

Clear-cut, distinct border

Irregular border

C: Color

Uniform light or dark pigment

Pigment variegation

D: Diameter

<6 mm (usually)

≥6 mm

E: Evolving

No change over time

Change in size, shape, surface, shades of color, or symptoms

Source: [124,125]

Image 6: Asymmetry

A melanoma that is irregular in shape.

Source: National Cancer Institute

Image 7: Border

A melanoma with a border that is uneven, ragged, or notched.

Source: Skin Cancer Foundation

Image 8: Color

A melanoma with coloring of different shades of brown, black, or tan.

Source: Skin Cancer Foundation

Image 9: Diameter

A melanoma with a diameter that is greater than 6 mm.

Source: Skin Cancer Foundation

Dysplastic nevi, common precursors to melanoma, appear as macular or papular lesions, and they may be present in great numbers. They may be as large as 6 mm and have a cobblestone surface with hazy or indistinct borders (Image 10). The pigment pattern is highly varied; colors can include a mixture of tan, brown, and red or pink.

Image 10:

The periphery of this dysplatic nevus is macular, irregular, indistinct, and slightly pink.

Source: National Cancer Institute

Anatomic Sites

In general, melanomas primarily occur in sun-exposed areas in white and Hispanic individuals and in sun-protected areas in black, American Indian/Alaska Native, and Asian/Pacific Islander populations [2,27,28,127]. Specific anatomic sites vary among racial/ethnic groups. Among white and Hispanic individuals, the head, neck, and trunk are the most common sites for melanoma in men, and the lower part of the leg (knee to ankle) and the head and neck are the most common sites for women [113]. The trunk is the primary site for American Indian/Alaska Native individuals; the lower extremity is a common site for Hispanic, black, and Asian/Pacific Islander individuals [2,127]. The foot is a common site for black and Asian/Pacific Islander individuals, and mucosal and subungual sites are also common in these populations [2,127,128,129]. Uveal melanomas are rare but are the most common intraocular malignant lesions in adults [130].

Signs and Symptoms of Metastasis

Information from the history and physical examination can help in determining whether the melanoma has metastasized. Signs and symptoms such as general malaise, weight loss, headaches, visual difficulty, or bone pain are indicative of metastasis. If metastasis is suspected, imaging of the liver, lung, bone, and brain should be done, as these are the most common sites of metastasis [94].

BIOPSY

When melanoma is suspected, full-thickness excision should be done when possible [25,76]. An excisional biopsy allows for the determination of the thickness of the melanoma, an important clinical and prognostic factor [131,132].

A full-thickness incisional biopsy or punch biopsy can be done on very large lesions or lesions in such anatomic areas as the palm or sole, a digit, the face, or an ear; in these cases, the biopsy should be done through the clinically thickest portion of the lesion [132]. A shave biopsy should be done only when the suspicion of melanoma is low, as this type of biopsy may compromise pathologic assessment [132]. All biopsy specimens should be evaluated by a pathologist experienced in pigmented lesions [132].

STAGING

As with nonmelanomas, melanoma is staged according to the AJCC TNM classification (Table 10) [94]. Two primary factors considered in staging the melanoma are thickness (Breslow thickness) and ulceration [94]. In 2017, the AJCC TNM classification was updated and the requirement of mitotic rate for defining T1 tumors was removed, the Breslow stratification was lowered to 0.8 mm, and new staging subdivisions were added [94,231].

Table 10: AMERICAN JOINT COMMISSION ON CANCER TNM CLASSIFICATION FOR MELANOMA

Tumor (T)

Tis

Melanoma in situ

T1

≤1.0 mm

Unknown or unspecified

a: without ulceration <0.8 mm

b: with ulceration <0.8 mm OR 0.8–1.0 mm with or without ulceration

T2

1.0–2.0 mm

Unknown or unspecified

a: without ulceration

b: with ulceration

T3

2.0–4.0 mm

Unknown or unspecified

a: without ulceration

b: with ulceration

T4

>4.0 mm

Unknown or unspecified

a: without ulceration

b: with ulceration

Regional Lymph Nodes (N)

N0

No regional metastases detected

N1

1 lymph node

a: clinically occult (i.e., detected by SLN biopsy)

b: clinically detected

c: in-transit metastasis/satellite(s) without regional lymph node disease

N2

2 or 3 lymph nodes

a: clinically occult

b: at least one clinically detected

c: in-transit metastasis/satellite(s) with one lymph node clinically occult or clinically detected

N3

4 or more metastatic lymph nodes, matted lymph nodes, or combinations of in-transit metastasis/satellite(s) and metastatic lymph nodes

a: clinically occult

b: at least one clinically detected or presence of any matted nodes

c: in-transit metastasis/satellite(s) with two or more clinically occult or clinically detected and/or presence of any matted nodes

Metastasis (M)

M0

No detectable evidence of distant metastasis

Normal LDH

M1a

Distant skin, subcutaneous, or lymph node metastasis

Not recorded or unspecified

(0): Normal LDH

(1): Elevated LDH

M1b

Lung metastasis with or without M1a sites of disease

Not recorded or unspecified

(0): Normal LDH

(1): Elevated LDH

M1c

Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease

Not recorded or unspecified

(0): Normal LDH

(1): Elevated LDH

M1d

Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease

Not recorded or unspecified

(0): Normal LDH

(1): Elevated LDH

CNS = central nervous system; LDH = serum lactate dehydrogenase; SLN = sentinel node biopsy.

Source: [94]

Tumor thickness is the most important prognostic factor for early stage melanoma, with highly significant decreases in 5-year and 10-year survival as thickness increases [32,94,133]. Ulceration is the next most important prognostic factor. The Clark level of invasion is no longer used in staging melanoma; this factor had been used in staging melanomas since 1969, but other factors have now been found to be more strongly correlated with survival rates [94].

Staging of regional lymph nodes is determined primarily by the number of involved nodes and tumor burden (micrometastasis or macrometastasis). Overall, the disease status of the lymph nodes is the most important prognostic factor for melanoma [94,135]. The M classification is defined by the site of metastasis and the serum lactate dehydrogenase (LDH) level [94]. Although it is uncommon to include a laboratory value in a staging system, the serum LDH level has been found to be a highly significant predictor of outcome for patients who have advanced stage disease [94].

After the TNM factors have been determined, a melanoma is assigned a stage based on defined groupings, from stage 0 (melanoma in situ) to stage IV (distant metastasis) [94]. Stage I melanoma is localized (no involved lymph nodes) and is subcategorized as stage IA (0.8 mm thick or less with or without ulceration (T1a) or 0.8–1.0 mm with or without ulceration (T1b) or stage IB (1.0–2.0 mm thick without ulceration).

Stage II melanoma is also localized; stage IIA lesions are 1–2.0 mm thick with ulceration or 2.0–4.0 mm thick with no ulceration; stage IIB lesions are 2.0–4.0 mm thick with ulceration or more than 4.0 mm thick with no ulceration; stage IIC lesions are more than 4.0 mm thick with ulceration [94].

Regional lymph nodes are involved with stage III melanoma. When lymph nodes are evaluated clinically only, there are no subclassifications of stage III disease. However, when lymph nodes are evaluated pathologically, this stage is subclassified into [94]:

- Stage IIIA: T1a/b–T2a with one to three clinically occult nodes

- Stage IIIB:

- T1a/b–T2a with one to three nodes clinically detected or one node with in-transit metastasis/satellite(s) without regional lymph node disease; or

- T2b–T3a with clinically occult or clinically detected in one to three nodes or one node with in-transit metastasis/satellite(s) without regional lymph node disease)

- Stage IIIC:

- T1a–T3a with at least one lymph node clinically occult or clinically detected or in-transit metastasis/satellite(s) and/or presence of any matted nodes in two or more nodes, or

- T3b/T4a with any lymph node involvement, or

- T4b with one to three lymph nodes clinically occult or clinically detected, with or without in-transit metastasis/satellite(s), or

- T0 with at least two nodes involved and one node clinically detected or at least one node with in-transit metastasis/satellite(s) with clinically or occult or clinically detected nodes with or without the presence of matted nodes)

Evidence Based Practice Recommendation

Sentinel lymph node biopsy is recommended by the American Society of Clinical Oncology and the Society of Surgical Oncology for patients with intermediate thickness cutaneous melanomas (Breslow thickness: 1–4 mm) of any anatomic site.

http://ascopubs.org/doi/10.1200/JCO.2017.75.7724

Last Accessed: February 12, 2019

Level of Evidence/Strength of Recommendation: Intermediate/moderate

Sentinel lymph node biopsy is considered by many to be a standard-of-care procedure for obtaining information on involvement of lymph nodes for staging melanoma, although fine-needle aspiration or core biopsy is also used [136,137]. The AJCC Cancer Staging Manual notes that if either of these methods are performed in the absence of complete nodal dissection, the N category of the TNM classification should be noted with a suffix of (sn) for sentinel node biopsy or (fn) for fine-needle aspiration or core biopsy [94].

Approximately 84% of individuals with melanoma have localized disease at the time of diagnosis [132]. Regional disease is present at the time of diagnosis in approximately 9% of individuals and distant metastasis in approximately 4% [132]. However, these rates vary significantly across racial/ethnic populations, with much higher rates of more advanced disease among minority populations and lower five-year survival rates [1,47,204]. In a study of 1,690 melanoma cases in Miami-Dade County (Florida), melanoma was diagnosed at later stages in black and Hispanic populations than in white populations. Regional disease was evident at the time of diagnosis in 21% of black individuals, compared with 11% of Hispanic individuals and 7% of white individuals; the corresponding rates for distant disease were 31%, 16%, and 9% [24]. Other studies have confirmed these disparities [127,204]. In addition, the rate of thinner melanomas was reported to be lower among Asian/Pacific Islander individuals than among white individuals (49% vs. 66%) [127].

TREATMENT OPTIONS

The goal of treatment of newly diagnosed melanoma is to remove all malignant tissue and to minimize the risk of local recurrence. Melanomas in children should be treated as aggressively as those in adults [138]. Surgical excision should be done for all local and regional disease, with adequate clinical margins. A systematic review published in 2016 indicated that for melanomas less than 2 mm, a 1-cm margin appears to be wide enough, and for melanomas greater than 2 mm, a 2-cm margin is recommended [238]. However, there is still much debate and insufficient evidence on the optimal excision margins for melanoma. It is unclear if a margin wider than 2 cm would result in better outcomes [139,238]. In its guidelines for care of primary cutaneous melanoma, the American Academy of Dermatology and the NCCN recommend margins according to the thickness of the lesion (Table 11) [93,132].

Table 11: RECOMMENDATIONS FOR SURGICAL MARGINS WITH EXCISION OF MELANOMA

Thickness of Lesion

Margin

Melanoma in situ

0.5–1.0 cm

≤1 mm

1 cm

>1–2 mm

1–2 cm

>2.0–4 mm

2 cm

>4 mm

2 cm

Source: [132]

A review of the literature has shown no benefit to adjuvant therapy for stage II or III melanoma [140]. However, interferon alfa-2b has provided some benefit for patients with stage III disease, including significant improvement in recurrence-and disease-free survival and in overall survival, although results of a 20-year study published in 2016 show no improvement or benefit in patients with minimal stage III melanoma, defined as melanoma in only one lymph node [141,142,143,239]. Interferon is associated with severe toxicity in almost half of patients treated with the high-dose protocol approved by the U.S. Food and Drug Administration (FDA). Factors to consider are the goal of treatment, the quality of life, and the cost [144,145]. Studies are focusing on ways to optimize immunotherapy and on gaining a better understanding of melanoma biology and tumor immunology [141,146,147,239].

Hyperthermic isolated limb perfusion is an option for patients with stage III unresectable in-transit metastasis [132]. This approach involves melphalan and tumor necrosis factor, and some studies have indicated a high response rate [148]. Radiation therapy is another option for this stage of disease.

There is no curative treatment for metastatic melanoma (stage IV), and the prognosis is poor for most patients with distant disease, regardless of treatment [149]. Biochemotherapy (a combination of chemotherapy and biologic agents) has been shown in phase II–III clinical trials to have a response rate of 21% to 64% and a complete response rate of 7.5% to 21% in patients with metastatic melanoma [132]. If disease is limited (resectable), surgical resection is the preferred option, and nivolumab, pembrolizumab, or high-dose ipilimumab may be used after excision [132]. Immunotherapy with either interferon alfa-2b or interleukin-2 (IL-2) has led to response rates of 10% to 20% in appropriately selected patients, and complete responses achieved with immunotherapy seem to be more durable than those obtained with chemotherapy [132,148]. However, the toxicity associated with immunotherapy can be severe.

The NCCN recommendations for first-line treatment include checkpoint immunotherapy (anti-PD-1 monotherapy with pembrolizumab or nivolumab or nivolumab/ipilimumab); for BRAF-mutated disease, the recommendation is for BRAF-targeted therapy (BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib, or single-agent BRAF inhibitor therapy with vemurafenib or dabrafenib) [132]. For second-line therapy, the NCCN recommends nivolumab, pembrolizumab, nivolumab/ipilimumab, dabrafenib, vemurafenib, dabrafenib/trametinib, vemurafenib/cobimetinib, dacarbazine, temozolomidepaclitaxel, albumin-bound paclitaxel, and carboplatin/paclitaxel [132].

Since 2011, the FDA has approved several new treatment options for melanoma, including ipilimumab, a chemotherapeutic agent for the treatment of nonresectable or metastatic melanoma [152]. In clinical trials, ipilimumab improved survival rates in patients with advanced disease compared to the use of tumor vaccine [152,153]. It is the first in the monoclonal antibody group of medications to target an antigen on the surface of T cells. The approved dosage is 3 mg/kg administered intravenously every three weeks for four doses [154]. The most common side effects are fatigue, diarrhea, pruritus, and rash. It should be noted that the NCCN no longer recommends single-agent ipilimumab monotherapy, as anti-PD-1 therapy or nivolumab/ipilimumab has been shown to improve outcomes in comparison [132].

Vemurafenib is a BRAF kinase inhibitor and is approved for the treatment of advanced melanoma in patients with the BRAFV600E mutation, as detected by an FDA-approved test [155]. A clinical trial involving 675 patients with previously untreated, metastatic melanoma with this mutation found that overall survival was significantly better with vemurafenib (84%) than with dacarbazine (64%) [156]. Compared with dacarbazine, vemurafenib was associated with a 74% reduction in the risk of either death or disease progression. The recommended dose is 960 mg twice daily orally, until disease progression or unacceptable toxicity [154]. In cases of intolerable toxicity, the treatment should be interrupted and then restarted at a lesser dose (not less than 480 mg twice daily).

In 2013 and 2014, three additional drugs (dabrafenib, trametinib, and pembrolizumab) were approved for the treatment of patients with advanced or unresectable melanoma who are not responding to other medications [157]. These agents have different mechanisms of action and therefore present new options for patients with refractory melanoma. In 2018, the FDA approved two new combination drugs for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation as detected by an FDA-approved test: trametinib/dabrafenib and encorafenib/binimetinib [150,151]. Pembrolizumab, the first PD-1 blocking drug approved by the FDA, inhibits negative immune regulation [154,157]. Systemic chemotherapy is preferred for disseminated (unresectable) disease. Palliative resection or radiation therapy should be considered for individuals with brain metastases [132]. Systemic therapy is also an option for these individuals [132].

SENTINEL LYMPH NODE BIOPSY AND LYMPH NODE DISSECTION

At one time, lymph node dissection was done routinely with excision, because of the significant association between the disease status of the nodes and survival. However, the rate of metastasis to regional nodes is low for early stage melanoma; nodes are involved in approximately 1% of melanomas that are 0.75 mm or less thick, in approximately 15% of melanomas that are 1.0–2.0 mm thick, and in approximately 15% to 20% of lesions of so-called intermediate thickness (1.2–3.5 mm) [159,160,161]. To avoid the morbidity associated with potentially unnecessary lymph node dissection, the procedure is no longer done routinely and its indications have been debated.

The most definitive trial to date on the role of sentinel lymph node biopsy is the Multicenter Selective Lymphadenectomy Trial I (MSLT-I), in which 1,269 patients with melanomas of intermediate thickness were randomly assigned to either excision with sentinel node biopsy and lymph node dissection if metastasis was found or to excision and observation, with dissection done only when disease became clinically evident in a node [161]. Several important findings of the study have been noted [136,137,161]:

- Presence of metastases in the sentinel node was the most important prognostic factor, with a five-year survival rate of 90% for patients with no metastasis in the sentinel node and 72% for patients with metastasis in the sentinel node.

- The five-year survival rate was significantly higher for patients who had immediate dissection after sentinel node biopsy compared with patients who had delayed dissection (72% vs. 52%), although five-year melanoma-specific survival rates were similar (approximately 87%).

- The similarity in the incidence of node metastases in patients who had excision and observation and the total incidence of metastasis detected by sentinel node biopsy suggests that micrometastatic disease will become clinically detectable disease if the node is not removed.

- Sentinel node biopsy detected micro-metastases a median of 16 months earlier than metastasis can be detected in the nodes clinically.

Further research led to the publication of a guideline, jointly developed by the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO), on the use of sentinel lymph node biopsy [162,163]. The following are the guideline recommendations [163,240]:

- Sentinel lymph node biopsy is recommended for patients with cutaneous melanomas with Breslow thickness of 1–4 mm (intermediate thickness) at any anatomic site.

- Sentinel lymph node biopsy may be recommended for staging purposes and to facilitate regional disease control for patients with melanomas that are T4 or >4 mm in Breslow thickness (thick).

- There is insufficient evidence to support routine sentinel lymph node biopsy for patients with melanomas that are T1 or <0.8 mm (thin), although it may be considered for selected high-risk patients.

- Complete lymph node dissection is recommended for all patients with a positive sentinel lymph node biopsy.

The recommendations in the 2019 version of the NCCN guidelines differ slightly from those in the ASCO/SSO guidelines. The NCCN expert panel agrees that routine sentinel lymph node biopsy is not recommended for thin melanomas (<0.8 mm), but notes only that a discussion of sentinel lymph node biopsy should be considered for melanomas that are 0.8–1.0 mm thick [132,240]. The NCCN states that other factors (such as ulceration) should be considered when deciding on sentinel lymph node biopsy [132]. Complete lymph node dissection is recommended when the sentinel node is positive and also when disease is clinically evident in one or more nodes [132].

Despite its value as a staging tool and the available guidelines, sentinel lymph node biopsy has been underused, especially for patients older than 65 years of age, minority populations, patients with melanomas on the trunk and head and neck, and patients in some geographic areas [164,165]. Even when sentinel lymph node biopsy is done, appropriate dissection does not always follow. A 2008 study of practice patterns showed that complete dissection was done in approximately half of patients in whom disease was found in the sentinel node [166].

PROGNOSIS AND FOLLOW-UP

The prognosis for melanomas is related to the stage of disease at the time of diagnosis, the anatomic site, the sex of the patient, and other tumor characteristics. A poorer prognosis has been associated with melanomas diagnosed at a later stage; with those located on the head, neck, and trunk; and for those in men [25]. For metastatic disease, the prognosis is better for patients with metastasis to soft tissues or lymph nodes than for those with metastasis to the brain or liver. The five-year survival rate ranges from 97% for stage IA melanoma to 15% to 20% for stage IV disease (Table 12) [167]. As stated, survival rates are lower for racial/ethnic minority populations [27,47,127].

Table 12: SURVIVAL ACCORDING TO STAGE OF MELANOMA

Stage

Survival Rate

5 Years

10 Years

IA

97%

95%

IB

92%

86%

IIA

81%

67%

IIB

70%

57%

IIC

53%

40%

IIIA

78%

68%

IIIB

59%

43%

IIIC

40%

24%

IV

15% to 20%

10% to 15%

Source: [167]

Follow-up, including the search for second primary melanomas, is crucial after treatment for melanoma, and the intervals depend on several factors, including thickness of the lesion and patient risk factors. The American Academy of Dermatology suggests follow-up one to four times per year for two years and one to two times per year thereafter [93]. The NCCN offers guidelines for follow-up based on stage of disease (Table 13) [132]. Follow-up should include emphasis on self-examination of the skin and lymph nodes [93,132]. Family members of patients with melanoma should be screened yearly.

Table 13: NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN) RECOMMENDATIONS FOR FOLLOW-UP AFTER TREATMENT FOR MELANOMA

Clinical/Pathologic Stage

Follow-Up

Stage 0 (in situ)

Skin examination at least annually for life

Stage IA–IIA

History and physical exam (with emphasis on lymph nodes and skin) every 6 to 12 months for five years, then annually as clinically indicated. Routine laboratory testing or imaging studies to screen for asymptomatic recurrent or metastatic disease is not recommended.

Stage IIB–IV

History and physical exam (with emphasis on lymph nodes and skin) every 3 to 6 months for two years, then every 3 to 12 months for three years, then annually as clinically indicated. Chest x-ray and other imaging studies may be considered to screen for recurrent/metastatic disease every 3 to 12 months. Routine laboratory testing or imaging studies to screen for asymptomatic recurrent or metastatic disease is not recommended after three to five years.

Source: [132]

5. SKIN CANCER SCREENING

Skin cancer screening practices vary considerably, and screening rates are generally low, even among individuals at high risk for skin cancer. The reported rates for full body skin examinations done during routine physician care have ranged from 15% to 60% [81,122]. Of 32,000 adults who participated in the 2000 or 2005 National Health Interview Survey (HINTS) cancer control supplements, 8% said they had had a skin examination within the past 12 months, although 70% had seen a physician during that time; 15% of the respondents reported ever having a skin cancer examination [168]. The rate of skin cancer screening was lower for individuals who had high-risk occupations (i.e., increased exposure to UV rays) than for individuals who had low-risk occupations [168]. An analysis of NHIS cancer control supplement data from 2010 showed that screening rates were higher among the elderly, the fair-skinned, those reporting sunburn(s), and those with a family history of skin cancer [169]. Of the estimated 104.7 million (51.1%) U.S. adults at high risk for developing melanoma, only 24% reported at least one total body skin examination by a physician [169].

Several factors have been reported to be barriers to physician skin examinations [122]. Lack of time is the number-one barrier, cited by 42% of dermatologists and 70% of primary care providers [122]. Involving other practice staff, such as nurse practitioners and physician assistants, can help ease this burden. Other barriers included poor or no training and lack of confidence [122]. In a study of medical students, 69% said that there was insufficient attention to skin cancer examinations in their medical training. Of the respondents, 23% had never observed a skin cancer examination and 27% had never been trained to perform such an examination [40]. As a result, only 28% rated themselves as somewhat or very skilled in the procedure. Education to enhance the knowledge and diagnostic skills of medical students as well as primary care providers has led to increased confidence and diagnostic accuracy [122]. More initiatives such as these can help further improve early detection.

Another barrier to screening is the lack of scientific evidence to support the practice [122]. In general, there is insufficient evidence to recommend periodic screening for melanoma in the general adult population. This was the conclusion of the U.S. Preventive Services Task Force (USPSTF) when it updated its statement in 2016 [170,171]. The Task Force noted that there was "fair" evidence that screening by clinicians was "moderately accurate" in detecting melanoma, but that there was insufficient evidence to determine that screening reduces the morbidity or mortality rates associated with skin cancer [170]. Potential harms of detection and early treatment were noted to be misdiagnosis, overdiagnosis, and harm related to biopsy and treatment [170]. This same conclusion has been drawn by many other organizations, including the American Academy of Family Physicians and the NCI [172,173]. The HINTS study indicates that routine screening through total-body skin exam for melanomas and nonmelanomas is also not recommended, as there is inadequate evidence to suggest that population-wide screening would be effective [241].

Other professional organizations have set forth recommendations that primarily target individuals at high risk for melanoma. The American College of Preventive Medicine recommends total body skin examinations, especially for individuals at high risk for malignant melanoma, and a National Institutes of Health Consensus Panel recommended screening for melanoma as part of routine primary care [174,175]. Similarly, the American College of Obstetricians and Gynecologists recommends skin examination for female individuals beginning at 13 years if they have increased exposure to sunlight, a family or personal history of skin cancer, or clinical evidence of precursor lesions [176]. The American Academy of Dermatology suggests an annual skin examination by a dermatologist, especially for adults who have known risk factors, such as a history of substantial sun exposure or a family history of skin cancer [177]. The Academy also offers the Melanoma/Skin Cancer Screening Program, which provides free skin examinations by volunteer dermatologists [177]. The American Cancer Society has set forth definitive screening recommendations: skin examination by a physician as part of a cancer check-up every three years for individuals 20 to 39 years of age and annually beginning at 40 years of age [178]. The American Cancer Society, American Academy of Dermatology, and the NCI recommend that individuals perform self-examinations, usually at four-to eight-week intervals [172,177,178].

Since the USPSTF issued its update, studies have shown that both physician examination and self-examination can lead to earlier detection, when cure is more likely. In a study of 126 asymptomatic individuals with melanomas, skin examinations by dermatologists were associated with significantly thinner melanomas (less than 1.0 mm) and an increasing likelihood of the lesion being in situ [179]. In a case-control study, skin cancer screening was associated with a 38% higher likelihood of being diagnosed with a thin melanoma (0.75 mm or less) [180]. An increased rate of detection of melanomas when they are thinner would seem to support an association with better outcomes, given that tumor thickness is an important prognostic factor. There has been a call for a national plan to enhance prevention and detection by providing screening as a health benefit, expanding outreach and education, and advocating for legislation to support screening and education [181].

6. PREVENTION

Evidence Based Practice Recommendation

The U.S. Preventive Services Task Force recommends counseling young adults, adolescents, children, and parents of young children about minimizing exposure to UV radiation for persons 6 months to 24 years of age with fair skin types to reduce their risk of skin cancer.

https://jamanetwork.com/journals/jama/fullarticle/2675556

Last Accessed: February 12, 2019

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Patient education is the cornerstone of efforts to prevent skin cancer. In a 2018 update to its report on counseling to prevent skin cancer, the USPSTF recommended counseling for children, adolescents, young adults, and parents of young children to minimize UV exposure among those 6 to 24 years of age, thereby reducing the risk of skin cancer [182]. The USPSTF found insufficient evidence to assess the balance of benefits and harms of such counseling for adults older than 24 years of age, but recommends selective counseling based on presence of risk factors for skin cancer [182]. Talking to patients about ways to protect themselves from UV rays should be carried out, with several points of emphasis (Table 14). Every summer, the consumer media is inundated with information on reducing the risks of sun exposure, and physicians should reinforce this information. Healthcare providers should work toward attaining the goal set by Healthy People 2020 to increase from 70% to 80.1% the proportion of adults who usually or always apply sunscreen with a sun protection factor (SPF) of 15 or higher, wear protective clothing, or seek shade; as of 2015, 70.8% of adults reported usually or always using sun-protection methods [183].

Table 14: POINTS OF EMPHASIS FOR PATIENT EDUCATION ON PREVENTION OF SKIN CANCERS

Use of Sunscreen

All individuals, regardless of skin color, should use sunscreen. Children require extra protection, as sun damage begins early and progresses over time.

Choose a sunscreen that has a sun protection factor (SPF) of 15. (Higher SPFs impart only slightly more protection.)

Select a sunscreen that protects against both UV-A and UV-B rays. Look for labels with "broad spectrum" or "multispectrum" or ingredients such as avobenzone (Parsol 1789), titanium dioxide, zinc oxide, or oxybenzone.

Expand the use of sunscreen beyond the summer; snow reflects up to 80% of the sun's rays.

Apply sunscreen at least 30 minutes before going out in the sun.

Use sunscreen even if wearing make-up that has SPF. (Apply sunscreen underneath make-up.)

Apply sunscreen liberally (at least a shot glass full per application for adults) and reapply at least every two hours (sooner if swimming or sweating).

Make sure to use sunscreen on often-forgotten areas, such as ears, scalp (if bald), and back of the neck.

Check the expiration date on the bottle of sunscreen; expired products are not effective.

Other Protection from UV Rays

Use lip balm (SPF 30); petroleum jelly does not provide protection against the sun.

Wear protective clothing.

Wear a broad-brimmed hat.

Wear sunglasses that protect against UV rays.

Avoid the sun during its highest intensity (10 a.m. to 4 p.m.).

Avoid tanning beds and tanning salons; warn parents of the danger of this practice among teenagers.

Self-Examination

Learn how to:

- Perform self-examination of the skin

- Recognize moles and dysplastic nevi

- Use the ABCDE criteria

- Perform self-examinations at least monthly and examine other family members, including children

Other

Early detection of skin cancers provides the best opportunity for cure.

Family history has an important role in the development of skin cancers; greater precautions are needed for children of parents with skin cancers.

Educational materials vary in quality; choose high-quality print and online resources.

Source: Compiled by Author

Efforts to educate patients should emphasize three key points: protection from UV rays, the importance of self-examinations and examination of family members, and the need to monitor existing moles for changes.

PROTECTION FROM UV RAYS

Given the high association between sun exposure and increased risk for skin cancer, many skin cancers could be prevented through enhanced protection from UV rays. Skin cancer prevention campaigns have emphasized several behaviors to protect against UV rays [184,185]:

- Use sunscreen

- Seek shade

- Wear a wide-brimmed hat

- Wear protective clothing (long-sleeved shirt and/or long pants)

- Avoid the sun between 10 a.m. and 4 p.m.

The rates of these regular sun-safety practices are low, despite the clear link between UV protection and lower rates of skin cancer, as well as the substantial number of initiatives to heighten awareness about the importance of UV protection [5,186,187]. In the 2017 National Cancer Institute's Cancer Trends Progress Report, approximately 65% of respondents reported not regularly using sunscreen, and approximately 60% did not wear protective clothing or seek shade (Figure 4) [183].

Figure 4: SUN-SAFETY PRACTICE IN THE U.S. POPULATION

Source: [183]

Many individuals remember to use sunscreen when they intend to be exposed to the sun, but they do not use sunscreen routinely [5]. The low rate of sunscreen use and other sun protections is reflected in the rates of sunburn in the United States. Data from 2000–2015 were examined and showed that 55.8% of high school students and 35.3% of all adult respondents had at least one sunburn during the preceding year [188]. In adults, the rates were highest among non-Hispanic white individuals (46.3%), followed by Hispanic (22.4%), and black individuals (9.9%) [188]. Sunburns were found to be equally common in men (35.5%) and women (35.2%), but higher in younger individuals (18 to 24 years of age) and in individuals more prone to sunburn [188,189].

Some have claimed that the use of sunscreen actually increases the risk for melanoma, but this finding was not supported by an analysis of 18 case-controlled studies [190]. There is also debate regarding the effectiveness of sunscreen in reducing skin cancer, and no study has shown that the use of sunscreen reduces the risk of basal cell carcinoma. A few studies have shown that sunscreen reduces the incidence of squamous cell carcinoma and melanoma, but large-scale reliable information is lacking and these studies are contradicted in other literature [158,171,191,192].

It has been postulated that sunscreen use has not reduced the rates of skin cancer because individuals who use sunscreen may remain in the sun longer because they feel protected. To test this, researchers provided vacationers with free sunscreen that was labeled as high protection or basic protection; the high protection sunscreen had a sun protection factor (SPF) of either 12 or 40, while the basic protection had an SPF of 12. The researchers found that the higher SPF did not influence the amount of time in the sun [193]. A more plausible reason for continued high rates of skin cancer is the widespread inappropriate use of sunscreens. In one study, 73% of individuals who used sunscreen still sunburned [194].

Protection behaviors are especially crucial for individuals with risk factors for skin cancers related to UV exposure, such as fair complexion, light-colored eyes, blond or red hair, and tendency to burn or freckle with exposure to the sun. Individuals with these characteristics have been shown to be more likely to use sun protection than other individuals and may be receptive to educational interventions on prevention [187]. Protection from the sun is also crucial for children, as they are at highest risk for sunburn and because they may receive as much as two to three times the sun exposure as adults [195]. Special attention should be given to children with a family history of skin cancer. One study found that frequent sunburns, suboptimal use of sunscreen, and high rates of tanning salon use were evident among children of mothers with a personal or family history of skin cancer [196]. Reinforcing sun protection habits in young children can enhance the likelihood that the habits will be continued through adolescence and adulthood [197]. The appropriate use of sunscreen in childhood may reduce the lifetime risk for nonmelanoma skin cancer by up to 78% [198].

Fact sheets on prevention targeted to different grade levels are part of the Centers for Disease Control and Prevention (CDC) Sun Safety Resource Toolkit, which is available on the CDC website.

Healthcare professionals should also talk to their patients about the hazard of indoor tanning facilities, targeting those patients who are most likely to use such facilities. According to the 2015 HINTS, 85% of individuals indicated that their physician had not talked them about reducing rates of exposure to the sun or indoor tanning devices [199]. As noted, rates of indoor tanning have been decreasing since the early 2000s, but in 2015, 3.5% of adults and 7.3% of adolescents still used indoor tanning [67,68,69]. The highest rate of indoor tanning is among white women 18 to 21 years of age (20.4%) 69]. The danger of indoor tanning for youths has led at least 44 states to establish legislation restricting youth's access to such facilities. In addition, 19 states and the District of Columbia have passed legislation banning the use of tanning beds for all children younger than 18 years of age [71]. Most tanning facilities require parental consent for minors (younger than 18 years of age), and healthcare providers should encourage parents to decline giving consent. The FDA continues to review the growing body of literature linking UV radiation exposure from tanning devices and skin cancer in consideration of stricter regulations overall. In 2014, the FDA changed labeling requirements for sunlamp products and ultraviolet or UV lamps used in indoor tanning salons from low-risk to moderate-risk devices. The agency has also required the products to carry a black box warning. The warning must be visible to consumers and must state that the product should not be used for people younger than 18 years of age [206].

SELF-EXAMINATION AND MONITORING MOLES

Self-examination has been estimated to reduce melanoma-related mortality by 63%, and healthcare providers should encourage their patients, especially those at high risk for skin cancer, to perform self-examination regularly [207]. Knowledge of skin cancer risk and of the importance of early detection have been associated with increased likelihood of performing self-examination, and a diagnosis of skin cancer within the previous three years is a strong predictor [122]. Instructional videos, sample photographs, and hand mirrors have been shown to enhance performance of self-examination [208]. Healthcare providers should talk to their patients about the importance of monitoring moles or skin lesions over time and about the indicators of melanoma, describing the ABCDE criteria. Determining the A, B, C, and E criteria from the ABCDE rule may be difficult for some individuals, but training can enhance skills [209].

Problems with eyesight and physical mobility may make it difficult for some individuals, especially older persons, to carry out self-examination. Healthcare providers should engage other family members in discussions about self-examination and encourage spouses and partners to help with skin examinations. Educational programs directed at the individual as well as a partner (a person living with the individual) have been found to be more effective than programs directed solely at the individual [210].

ADDRESSING PATIENTS' EDUCATIONAL NEEDS

Because of differences in culture, literacy, and learning preferences, individual needs for educational resources vary. All these needs should be addressed to effectively convey the importance of strategies to prevent skin cancer.

Culture and Literacy

Culture, reading literacy, and health literacy (i.e., the ability to understand health information and make informed health decisions) are all factors to consider when talking to patients about skin cancer and its prevention. The disparities in survival attributable to advanced stage at the time of diagnosis call for enhanced awareness in minority populations about their risk for skin cancers and about how the site of skin cancers may differ from traditional sites (i.e., areas of the body not exposed to sun). The rates of sunburn reported for minority populations also suggest that more education is needed about the importance of sun protection.

Compounding the issue of educating individuals about skin cancers and prevention are the lower rates of health literacy among populations at high risk [211]. The National Assessment of Adult Literacy estimated that only 12% of adults have "proficient" health literacy and 14% have "below basic" health literacy, and rates of health literacy are especially low among ethnic minority populations and individuals older than 60 years of age [211,212]. In addition, according to U.S. Census Bureau data from 2017, more than 64 million Americans speak a language other than English in the home, with approximately 25.6 million of them (8.5% of the population) speaking English less than "very well" [213].

Healthcare professionals should assess their patients' literacy level and understanding and talk with them in a manner that increases the likelihood of understanding. For example, clinicians should use plain language in their discussions with patients who have low literacy or limited English proficiency. They should ask patients to repeat pertinent information in their own words to confirm understanding [214]. Reinforcement with the use of low-literacy or translated educational materials is helpful.

It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" (if the healthcare professional is English-speaking) [215]. In addition, physicians should ask what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [215].

"Ad hoc" interpreters (i.e., family members, friends, bilingual staff members) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. Physicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [216]. Even when allowed by law, the use of a patient's family member or friend as an interpreter should be avoided, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [216]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [216]. Individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [217].

Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [218]. A systematic review of the literature showed that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [219,220].

A professional interpreter is more than a neutral party who communicates information between two parties. An interpreter is an active agent, negotiating between two cultures and assisting in promoting culturally competent communication and practice [221]. In this more active role, the interpreter's behavior is also influenced by a host of cultural variables such as gender, class, religion, educational differences, and power/authority perceptions of the patient [221].

Learning Preferences and Types of Resources

Healthcare providers should have educational resources available in a variety of formats and media, as learning styles differ among adults. Depending on the individual, learning may be optimal with printed materials, illustrations, videos, interactive tutorials, online resources, or a combination of resources. Asking an individual how he or she prefers to learn can help healthcare providers select the best resources. A variety of government agencies and professional organizations have developed educational materials about skin cancers. These resources, available in print and online, are often available in languages other than English (Table 15).

The Internet has become a primary source of health information; approximately 80.2% of respondents to the 2015 HINTS said they used the Internet in the past 12 months to search for health or medical information [199]. However, in a study of 74 websites offering information on melanoma, researchers found that most websites had incomplete information and 14% contained inaccuracies [223]. The sites were likely to lack complete basic information, such as that related to risk factors, diagnosis, treatment, prevention, and prognosis. Clinicians can help ensure that their patients gain accurate information from online sources by guiding patients to authoritative websites.

7. CONCLUSION

Basal cell carcinoma, squamous cell carcinoma, and melanoma comprise the majority of skin cancers. Advances in treatment have led to lower mortality rates associated with melanoma, but the prevalence of all three types continues to escalate. The higher prevalence is thought to be related to increased exposure to the sun, making it essential to educate patients about sun-safety practices. The risk for skin cancers varies among several populations, with the highest rates found for white men older than 50 years of age, and lower rates among the black, American Indian, Hispanic, and Asian populations than for white individuals. Also increasing risk are immunosuppression, characteristics that predispose the skin to sunburn (e.g., light complexion, light-colored eyes and hair), and a personal or family history of skin cancer.

Early treatment of nonmelanomas and melanoma is integral to cure, making it essential for patients to know how to detect suspicious lesions and to understand the importance of seeking medical attention for such lesions. In turn, primary care providers should enhance their abilities to detect skin cancer, especially given that formal education and training has not been strong in this area. The primary challenges in diagnosing skin cancers are to distinguish between benign and malignant lesions and to identify lesions with malignant potential. The clinical characteristics and use of the ABCDE method are key to diagnosis. Several treatment options are available for nonmelanomas, and the type of treatment is selected on the basis of several factors, such as tumor characteristics, patient age, medical status, and patient preference. Guidelines are available for both nonmelanomas and melanoma. For melanoma, the goal of treatment is to remove all malignant tissue and minimize local recurrence. Sentinel lymph node biopsy, an underused procedure, can help identify individuals who will benefit from lymph node dissection and those who can avoid the procedure (and its morbidity) without compromising survival.

Although the USPSTF has determined that there is insufficient evidence to recommend periodic screening for melanoma in adults, annual examinations by a healthcare provider, along with monthly self-examinations, is prudent. The combination of patient education, particularly about the harmful effects of UV radiation from natural and artificial UV radiation and about early detection and treatment, can substantially reduce the morbidity and mortality associated with skin cancers.

8. RESOURCES

Centers for Disease Control and Prevention

Sun Safety Resource Toolkit

https://www.cdc.gov/cancer/skin/toolkit

National Cancer Institute Melanoma Risk Assessment Tool

https://mrisktool.cancer.gov

Skin Cancer Foundation

https://www.skincancer.org

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Evidence-Based Practice Recommendations Citations

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