ABP201 • Pediatrics Offer

Table of Contents

ABP201 • Pediatrics Offer

How to Receive Credit

NetCE 5 Hour Course #96212 • Attention Deficit Hyperactivity Disorder

96212 • Attention Deficit Hyperactivity Disorder

1. INTRODUCTION

2. EPIDEMIOLOGY

3. DIAGNOSTIC CRITERIA

4. AGE AND CHANGING SYMPTOMS

5. PATHOPHYSIOLOGY

6. TREATMENT

7. COMORBIDITIES IN CHILDREN

8. COMORBIDITIES IN ADULTS

9. EDUCATING PATIENTS AND PARENTS

10. RESOURCES

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #91742 • Child, Adolescent, and Adult Immunization Schedules

91742 • Child, Adolescent, and Adult Immunization Schedules

1. INTRODUCTION

2. AN OVERVIEW OF IMMUNIZATION SCHEDULES

3. VACCINES AND RECOMMENDATIONS

4. VACCINE CONTRAINDICATIONS

5. VACCINE SAFETY

6. OVERCOMING BARRIERS FOR CHILDREN AND ADOLESCENTS

7. OVERCOMING BARRIERS FOR ADULTS

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #92343 • Childhood Leukemias and Lymphomas

92343 • 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

ABP201 • Pediatrics Offer

Paul Ballas, DO

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

ABP201 • Pediatrics Offer

Expiration Date: 09/30/2021

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.

96212 • Attention Deficit Hyperactivity Disorder

Paul Ballas, DO

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Attention deficit hyperactivity disorder (ADHD) is a debilitating psychiatric illness affecting approximately 4% to 12% of the population. Characterized by persistent problems with distractibility, impulsivity, and/or hyperactivity, ADHD has a significant effect on day-to-day functioning and quality of life. Unfortunately, ADHD often goes unrecognized. Patients may hesitate to disclose their symptoms, and physicians unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis. This course will cover the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of ADHD. It will review the first-line treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address the roles of other therapeutic options, such as behavioral therapy.

Table of Contents

96212 • Attention Deficit Hyperactivity Disorder

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

3. DIAGNOSTIC CRITERIA

MAKING THE DIAGNOSIS

4. AGE AND CHANGING SYMPTOMS

SYMPTOMS OF ADHD IN ADULTHOOD

5. PATHOPHYSIOLOGY

6. TREATMENT

EVIDENCE-BASED RECOMMENDATIONS

PHARMACOTHERAPY

BEHAVIORAL THERAPY

TRIGEMINAL NERVE STIMULATION

7. COMORBIDITIES IN CHILDREN

LEARNING DISABILITY

DEPRESSION

CONDUCT DISORDER AND OPPOSITIONAL DEFIANT DISORDER

SUBSTANCE ABUSE

ANXIETY

OTHER DISORDERS

8. COMORBIDITIES IN ADULTS

SUBSTANCE ABUSE

DEPRESSION

MEDICAL COMORBIDITIES

9. EDUCATING PATIENTS AND PARENTS

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. RESOURCES

11. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

96212 • Attention Deficit Hyperactivity Disorder

Education Category. Psychiatric / Mental Health

Release Date. 10/01/2018

Expiration Date. 09/30/2021

Course Overview

Attention deficit hyperactivity disorder (ADHD) is a debilitating psychiatric illness affecting approximately 4% to 12% of the population. Characterized by persistent problems with distractibility, impulsivity, and/or hyperactivity, ADHD has a significant effect on day-to-day functioning and quality of life. Unfortunately, ADHD often goes unrecognized. Patients may hesitate to disclose their symptoms, and physicians unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis. This course will cover the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of ADHD. It will review the first-line treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address the roles of other therapeutic options, such as behavioral therapy.

Audience

This course is designed for all physicians, nurses, and social work/counseling groups involved in the care of patients with attention deficit hyperactivity disorder.

Course Objective

Attention deficit hyperactivity disorder (ADHD) has a significant effect on day-to-day functioning and quality of life; however, it often goes unrecognized. The purpose of this course is to educate healthcare professionals about the epidemiology, diagnosis, and management of ADHD.

Learning Objectives

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

1. Review the epidemiology of attention deficit hyperactivity disorder (ADHD).

2. Outline the diagnostic criteria for ADHD for children and adults.

3. Identify ways in which ADHD symptoms change as patients approach adulthood.

4. Discuss what is known about the pathophysiology of ADHD.

5. Describe evidence-based recommendations and the use of pharmacotherapy in the treatment of ADHD.

6. Describe the use of behavioral therapy in the treatment of ADHD.

7. Discuss the treatment of children, adolescents, and adults with ADHD and medical and psychiatric comorbidities, including the importance of patient and family education and the unique needs of non-English-proficient patients.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Paul Ballas, DO, is a child psychiatrist and formerly chief medical officer at the Green Tree School, an approved private school for children with autism spectrum disorder, developmental delays, or emotional disturbances. He has authored peer reviewed articles on ADHD, sleep disorders, and psychopharmacology and has recently co-authored a book chapter on sleep disorders.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Contributing faculty, Paul Ballas, DO, 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

Attention deficit hyperactivity disorder (ADHD) is a debilitating psychiatric illness affecting approximately 4% to 12% of the population [1]. Characterized by persistent problems with distractibility, impulsivity, and/or hyperactivity, ADHD has a significant effect on day-to-day functioning and on quality of life.

Unfortunately, ADHD often goes unrecognized. Patients may hesitate to disclose their symptoms, and physicians unfamiliar with this disorder may confuse its manifestations with other psychiatric illnesses. Common comorbidities can further cloud the diagnosis.

This course will cover the epidemiology, diagnostic criteria, pathophysiology, and differential diagnosis of ADHD. It will review the first-line pharmacologic treatments, recommended duration of therapy, and options for patients who do not respond to initial therapy. Finally, it will address the roles of other therapeutic options, such as behavioral therapy.

2. EPIDEMIOLOGY

The exact prevalence of ADHD is unknown. The 2016 National Survey of Children's Health (NSCH) found that 6.1 million children in the United States have ever been diagnosed with ADHD. This includes 388,000 children 2 to 5 years of age, 2.4 million children 6 to 11 years of age, and 3.3 million adolescents 12 to 17 years of age [2]. The percent of children 4 to 17 years of age ever diagnosed with ADHD increased from 7.8% in 2003 to 11.0% in 2011–2012 [2]. Note: Because the 2016 NSCH survey used different methods, estimates are not directly comparable with estimates based on previous NSCH data. Also, due to the increased focus on ADHD in younger children, the age ranges surveyed were expanded to include children 2 to 17 years of age [2].

In children, ADHD is nearly three times as common in boys (14%) as in girls (5%) [3]. The diagnosis is less common in Hispanic children (6%) than in non-Hispanic black (9%) or white children (12%), although the reason is not clear [3]. ADHD also occurs more often in mother-only families (12%) than in two-parent families (8%) [3].

Although often thought of as a disorder of children, ADHD is seen in adults as well. Data from the National Comorbidity Survey Replication show a prevalence of 4.4% among adults 18 to 44 years of age [4,5]. A random telephone survey of adults also found that 4.4% of the 966 respondents reported a previous ADHD diagnosis [6]. Looked at more closely, 2.9% of respondents met "narrow" criteria for ADHD (symptoms often) and 16.4% met "broad" criteria (symptoms sometimes or often). Among adults, the diagnosis of ADHD is associated with being male, being white/non-Hispanic, being divorced, and being in the "other" employment category, primarily unemployed or disabled [4].

In children, ADHD can lead to educational difficulties, social difficulties, injuries and accidents, and family problems. Adults with a childhood history of ADHD are more likely to exhibit antisocial and criminal behavior, are more prone to injuries and accidents, and have more health problems than the general population [7]. They also have more employment and marital difficulties and are more likely to have children out of wedlock.

In a community sample of 500 adults with self-reported ADHD and 501 community-based controls, the adults with ADHD were significantly less likely to have graduated from high school (83% vs. 93%), less likely to have obtained a college degree (19% vs. 26%), and less likely to be currently employed (52% vs. 72%). They were more likely to have had job changes (5.4 vs. 3.4 jobs over 10 years), to have been arrested (37% vs. 18% of controls), and to have been divorced (28% vs. 15%). They were also less likely to be satisfied with their professional, family, and social lives [8].

3. DIAGNOSTIC CRITERIA

The first step in correctly diagnosing and treating ADHD is understanding the definition. ADHD is classified within the Neurodevelopmental Disorders in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [9]. Depending on the subtype, the diagnosis of ADHD involves a persistent pattern of inattention, hyperactivity, and/or impulsivity, more than would be expected for a typical person at the same level of development. Typically, several symptoms must be present before the age of 12 years. Also, there must also be clear evidence that the symptoms cause distress or interfere with functioning. These criteria are currently used for both children and adults, although the number of criteria varies.

According to the DSM-5 criteria for ADHD, one of the following groups of symptoms must be present [9]:

- Inattention: At least six (or five for persons 17 years of age and older) of the following symptoms of inattention have persisted for at least six months to a degree that is inconsistent with developmental level and that negatively impacts social and academic/occupational activities:

- Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities

- Often has difficulty sustaining attention in tasks or play activities

- Often does not seem to listen when spoken to directly

- Often does not follow through on instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)

- Often has difficulty organizing tasks and activities

- Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental effort (e.g., schoolwork, homework)

- Often loses things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, tools)

- Is often easily distracted by extraneous stimuli

- Is often forgetful in daily activities

- Hyperactivity/Impulsivity: At least six (or five for persons 17 years of age and older) of the following symptoms of hyperactivity/impulsivity have persisted for at least six months to a degree that is inconsistent with developmental level and that negatively impacts social and academic/occupational activities:

- Often fidgets with hands or feet or squirms in seat

- Often leaves seat in classroom or in other situations in which remaining seated is expected

- Often runs about or climbs excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness)

- Often unable to play or engage in leisure activities quietly

- Is often "on the go" or often acts as if "driven by a motor"

- Often talks excessively

- Often blurts out an answer before question has been completed

- Often has difficulty awaiting turn

- Often interrupts or intrudes on others (e.g., butts into conversations or games)

Impairment from the symptoms must be present in two or more settings (e.g., at school [or work] and at home). There must be clear evidence of clinically significant impairment in social, academic, or occupational functioning. For a diagnosis of ADHD, the symptoms may not occur exclusively during the course of a pervasive developmental disorder, schizophrenia, or other psychotic disorder or be better accounted for by another mental disorder (e.g., mood disorder, anxiety disorder, dissociative disorder, or personality disorder). For individuals (especially adolescents and adults) who have symptoms that no longer meet full criteria, "in partial remission" should be specified. The category unspecified ADHD is for disorders with prominent symptoms of inattention or hyperactivity-impulsivity that do not meet the full criteria for ADHD [9].

Patients with ADHD often have features that are not part of the diagnosis but are consequences of functional impairment. Examples include low frustration tolerance, temper outbursts, stubbornness, poor self-esteem, and devaluation of academic achievement. People may have the impression that children with ADHD are lazy, irresponsible, oppositional, or willful.

MAKING THE DIAGNOSIS

The diagnostic evaluation of a child or teenager suspected to have ADHD requires a thorough evaluation, including information from parents and teachers. Laboratory, radiologic, and other studies are not usually needed. However, in 2013, a device based on electroencephalogram (EEG) technology was approved to help assess ADHD in children and adolescents 6 to 17 years of age [10]. The Neuropsychiatric EEG-Based Assessment Aid System calculates the ratio of theta and beta waves, which are shown to be higher in children with ADHD. The role of this device has not yet been established, and it should not be used alone to diagnose ADHD.

Both the American Academy of Pediatrics (AAP) and the American Academy of Child and Adolescent Psychiatry (AACAP) have developed recommendations for the assessment of ADHD. The AAP guideline for the diagnosis of ADHD was revised in 2019, and this updated guideline is in line with DSM-5 criteria and provides a general guide for identifying the disorder in children 4 to 18 years of age [11]. The AACAP guideline, published in 2007, addresses ADHD in children and adolescents between 3 and 17 years of age [7].

Evidence Based Practice Recommendation

According to the American Academy of Pediatrics, clinicians should initiate an evaluation for ADHD for any child 4 through 18 years of age who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500647

Last Accessed: September 8, 2018

Level of Evidence: B (Randomized controlled trials or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies)

Mental health assessment should include screening for ADHD [7]. The AACAP guideline assumes a psychiatric primary complaint, but any child may be screened for ADHD using questions about impulsivity, hyperactivity, and inattention. If ADHD is suspected, additional evaluation can be pursued.

Full evaluation should include information from both the parent and child and should incorporate information about functioning at school or day care [7,11]. Each symptom in the diagnostic criteria should be assessed and duration, frequency, and severity determined. The possibility of comorbid disorders, including learning disability and depression, should be explored. In addition to parent and patient interviews, family history and developmental history may increase the likelihood of ADHD diagnosis or shed light on comorbid disorders or other underlying causes of symptoms. A standardized behavior rating scale should be completed by a parent and, if possible, a teacher. Report cards and homework papers may also be helpful.

Unless medical history indicates, laboratory tests and neurologic testing are not needed [7]. Some medical conditions can cause behavior similar to ADHD, but other indications of an underlying cause will usually be present. Children who are likely to have had lead exposure, such as those in inner cities or older housing, may benefit from lead testing because this exposure has been associated with ADHD. Hyperthyroidism, on the other hand, does not usually present as purely ADHD with no other symptoms. Imaging, such as magnetic resonance imaging and electroencephalography, are not part of the routine evaluation of ADHD [7]. They should be reserved for cases when a specific indication is present.

Psychologic and neuropsychologic testing are also not generally needed. However, patients who appear to have low cognitive ability and those whose math or language performance does not seem to match their ability may require this type of evaluation. Testing can help differentiate learning disorders from learning problems that are secondary to ADHD.

Special attention should be paid to the possibility of a comorbid psychiatric disorder [7]. Comorbidities are common in patients with ADHD and may require additional treatment. In addition, symptoms resembling ADHD may be due to another psychiatric problem. ADHD itself may lead to some of the symptoms of depression or mania. When patients meet full criteria for ADHD plus another disorder, both diagnoses should be made.

As in children, diagnosis in adult patients should involve a careful history and diagnostic interview. The interview should cover childhood symptoms and developmental history, as well as current symptoms and impact on the patient's life [12]. Input from a close friend, parent, or spouse may be helpful, and alternative psychiatric diagnoses and comorbidities should be considered. A physical exam should be performed; testing should be pursued as needed to evaluate for potential physical causes for symptoms, such as hearing and vision problems, anemia, and hyperthyroidism. Current medications should be discussed to help rule out the possibility that symptoms are due to medication side effects.

Behavior Rating Scales

There are several established rating scales for evaluating ADHD symptoms, some of which are available on the Internet. Some scales focus on children, teens, or adults. Many are brief and can be completed quickly either before or during an appointment. It is worth noting whether the scale is based primarily on DSM-5 criteria or on other aspects of functioning or symptoms.

Rating scales can provide a way to determine the severity of symptoms compared to developmental norms, and they can also alert clinicians to the possibility of comorbid psychiatric disorders. Additionally, they may be useful for monitoring treatment. However, rating scales should not be used to diagnose ADHD. It is also important to ensure that the scale is appropriately standardized in order to avoid gathering inaccurate information that can adversely affect treatment.

4. AGE AND CHANGING SYMPTOMS

ADHD often continues into adolescence. Some children do seem to outgrow their symptoms, but many either continue to have residual symptoms or will meet DSM-5 criteria for ADHD as adults. Symptoms tend to shift as patients age, but do not necessarily resolve.

The actual number of children with ADHD who continue to have the disorder in adulthood is unknown for several reasons. Attrition in cohort studies tends to be high, and different studies use different inclusion and exclusion criteria. The diagnostic criteria used in studies may differ from DSM-5 criteria for ADHD. DSM-5 criteria were tested on and geared toward children, and although these criteria are used for adults, they may not accurately capture all people with the disorder.

There have been several estimates of the prevalence of ADHD in adults who were diagnosed as children. Biederman and colleagues conducted a 10-year prospective case-control study with white boys 6 to 18 years of age at the study entry point [13]. At the 10-year follow-up, the mean age of participants was 22 years. Fifty-eight percent of subjects had current full or sub-threshold ADHD at follow-up, compared to only 6% of controls. "Sub-threshold" was defined as meeting fewer criteria than required for diagnosis. Biederman and colleagues subsequently published results of a controlled 10-year follow-up study conducted to examine the age-dependent persistence of ADHD in boys transitioning from adolescence to early adulthood [14]. The study included 110 boys with ADHD and 105 non-ADHD controls who were 6 to 17 years of age at the study entry point. ADHD was defined as persistent if the youth met full or sub-threshold DSM-IV diagnostic criteria, failed to attain functional remission, or were receiving treatment for ADHD. At the 10-year follow-up point, 65% of the ADHD group no longer met the full DSM-IV criteria; 78% met at least one criterion for the definition of persistence. The authors also found that persistent ADHD was associated with more psychiatric comorbidity, more familiality with mood disorders, and higher levels of educational and interpersonal impairments than controls [14].

Barkley and colleagues conducted a prospective case-control study of children diagnosed with hyperactivity [15]. These children were diagnosed between 4 and 12 years of age, then reassessed at 19 years of age or older. At follow-up, they were evaluated for ADHD using criteria from the third edition of the DSM (DSM-III-R). Based on self-report, the prevalence of DSM-III-R defined ADHD in young adulthood was 5%, not significantly different from those in the control group. Based on parent report, the prevalence of ADHD was 46% compared to 1% in controls. Using a developmental definition, prevalence by self-report was similar to controls. Control subjects in this study were slightly younger and had more education.

Manuzza and colleagues published a report on hyperactive boys followed from a mean age of 7 years to a mean age of 24 years [16]. Adult ADHD, based on DSM-III-R criteria, was present in only 4% of this population. Antisocial personality disorder and non-alcohol substance abuse were significantly higher in the hyperactive group. These results may be limited by the fact that children with high levels of aggression or conduct problems were excluded from the study.

SYMPTOMS OF ADHD IN ADULTHOOD

There are several changes in symptoms as patients approach adulthood. There appear to be fewer overt symptoms of hyperactivity (e.g., running and climbing, inability to remain seated), but these may be replaced with or confined to fidgetiness, jitteriness, or restlessness. Restlessness may lead to difficulty participating in sedentary activities and even avoiding sedentary occupations. Impulsivity may manifest as a tendency to make decisions without thinking them through [17]. Patients may start on projects without reading or listening to instructions. An adult with ADHD may also have a tendency to speed when driving.

Other typical adult ADHD symptoms include having trouble getting organized, planning ahead, or preparing for events [17]. These patients may appear inefficient, failing to do tasks in the order that makes the most sense. Inattention may manifest as failure to persist in uninteresting tasks or daydreaming instead of concentrating.

Several screening tools have been developed for adults. The World Health Organization (WHO) created a short and long version of the Adult ADHD Self-Report Scale (ASRS) [18]. The ASRS has good specificity (98.3% long version and 99.5% short version) but limited sensitivity (56.3% and 68.7%). Because this version of the ASRS was calibrated to DSM-IV criteria, which are narrower than DSM-5 criteria, researchers sought to update the ASRS for DSM-5 criteria [19]. A semistructured diagnostic interview for DSM-5 adult ADHD was administered to two general population surveys: 119 from a household survey and 218 from a managed care subscriber survey. A novel algorithm was applied to the pooled data to create a DSM-5 version of the ASRS. The accuracy of the new scale was then confirmed in independent clinical samples of patients seeking evaluation at the New York University Langone Medical Center Adult ADHD Program (NYU Langone) from 2011–2012 and in 300 primary care controls from 2015–2016. Data analysis was conducted from April to September 2016. Of the 637 total participants, 44 household survey respondents, 51 managed care respondents, and 173 NYU Langone respondents met DSM-5 criteria for adult ADHD. Of these, 123 were male, with a mean age of 33.1 years. A six-question screening scale was found to be optimal in distinguishing ADHD from non-ADHD individuals in the first two samples. The DSM-5 ASRS screening scale detected the vast majority of general population cases of ADHD with a high specificity and positive predictive value [19].

The Utah criteria are a set of diagnostic criteria developed specifically to identify adults with ADHD [20]. Although they do not match the DSM-5 definition, they may be useful in assessing adult patients. The Utah criteria include [20]:

- History of ADHD diagnosis or symptoms consistent with ADHD during childhood

- Hyperactivity and poor concentration as an adult

- At least two additional symptoms: labile mood, hot temper, stress intolerance, impulsivity, or disorganization and inability to complete tasks

These criteria have a number of limitations. Patients with the inattentive subtype of ADHD may be missed. When hyperactivity is present in childhood ADHD, it tends to decline over time or manifest in more subtle ways. The listed symptoms, particularly lability and outbursts of temper, may indicate other psychiatric disorders. Although early research suggested that "hot temper" and irritability were aspects of ADHD, it has been found that such symptoms are associated more with the social environment and that they predict different developmental outcomes [21]. Problems with temper may be associated with ADHD but are no longer considered part of the diagnostic criteria.

Barkley and colleagues have suggested diagnostic criteria based largely on patients in an adult ADHD study based at the University of Massachusetts (UMASS) Medical School [17]. This study involved comparing adults with ADHD to adults with other disorders and to a community sample (control). Patients were recruited through an adult ADHD clinic, and community controls were recruited through flyers and advertisements. When characteristics of the adults with ADHD were compared to those of the other two groups, there were clear differences. Being easily distracted by extraneous stimuli was a clear dissimilarity between adults with ADHD and community controls; in fact, this one symptom clearly divided the two groups. However, it did not necessarily separate adults with ADHD from those with other disorders. An additional set of symptoms was found to be useful in distinguishing ADHD from other psychiatric problems. Patients more likely to have ADHD were those who often [17]:

- Made decisions impulsively

- Had difficulty stopping activities or behavior when one should do so

- Started projects or tasks without reading or listening to directions carefully

- Failed to follow through on promises or commitments made to others

- Had trouble doing things in the proper order or sequence

- Tended to speed while driving (or, in patients who do not drive, difficulty engaging in leisure/fun activities quietly)

Two additional symptoms, having difficulty sustaining attention in tasks or play activities and having difficulty organizing tasks and activities, added a small increase in classification accuracy between patients with ADHD http://www.netce.com/and community controls. The proposed diagnostic criteria suggest that adults who have six of these nine symptoms, in addition to meeting certain other criteria (including onset of symptoms prior to the age of 16 years), may be considered to have ADHD. Interestingly, in this study the diagnostic criterion of having trouble staying seated when expected to do so was more likely to identify a patient with some other psychiatric disorder than an adult with ADHD.

5. PATHOPHYSIOLOGY

Although the exact etiology of ADHD is unknown, certain genetic and neurologic factors have been implicated in the development of this disorder. ADHD often occurs in multiple members of the same family. Fifteen to 25% of first-degree relatives of children with ADHD are also affected [22]. Twenty-five to 50% of cases occur in families, and close to 50% of children who have parents with ADHD also have the disorder [22].

There have been several genes associated with ADHD, including the dopamine-beta-hydroxylase gene, the dopamine transporter gene, and the dopamine receptor gene [22,23]. However, no gene has been found that reliably predicts ADHD.

Current theory focuses on dopaminergic function as the basis of ADHD. Animal models of ADHD have shown an imbalance between dopamine and norepinephrine, with increased dopaminergic activity and decreased noradrenergic activity [23,24]. In addition, the stimulant medications used to treat ADHD influence the availability of dopamine.

Neuroimaging studies suggest that multiple areas of the brain may be involved in ADHD. The frontal striatal regions are implicated in several studies [23,25]. There may also be changes in the corpus callosum and in the cerebellum [23,26]. Functional imaging studies support the possibility that fronto-subcortical-cerebellar circuits are involved [23,25].

6. TREATMENT

EVIDENCE-BASED RECOMMENDATIONS

Stimulant medications, including amphetamine and methylphenidate, are considered first-line therapy in the treatment of ADHD [23,27]. However, other medications, such as atomoxetine, may be considered. Behavior modification has a role in the overall treatment plan of ADHD, and cognitive-behavioral therapy (CBT) may be helpful for adults, although the evidence for stimulant medications is stronger.

Both the AACAP and AAP guidelines regarding ADHD include recommendations for the treatment of children and adolescents. There are no current guidelines for adult treatment from national organizations in the United States, but a Canadian group and the United Kingdom's National Institute for Health and Care Excellence (NICE) have published recommendations that may be helpful [28,29,30]. The NICE guideline contains recommendations for the diagnosis and management of ADHD in both children and adults [30].

The AAP guideline emphasizes the need to view ADHD as a chronic disease and treatment as an ongoing process [11]. It recommends collaboration among the child, parents, and teachers to set goals and evaluate progress. Systematic follow-up is needed to assess the effects of treatment, whether medication, behavior therapy, or both, and to determine whether adjustments are needed. A child who fails to respond to one stimulant may respond to another. If treatment is not having a positive effect, evaluation should include adherence, the possibility of comorbid conditions, and confirmation that ADHD is the correct diagnosis.

Guidance from the 2007 AACAP guideline includes the recommendation that the treatment plan should be comprehensive but flexible and should be reviewed regularly [7]. It should include education for both the patient and his or her parents and take advantage of school and community resources and supports. Education should focus on information about ADHD, prepare parents for developmental challenges common in affected children, and provide general advice about managing behavior and academic functioning. The NICE guideline recommends that healthcare providers have regular discussions with patients with ADHD and their families or caregivers regarding their desired level of involvement in treatment planning and decisions. Ensuring continuity of care is stressed [30]. The NICE guideline also recommends that prior to starting any treatment, healthcare providers should discuss with patients and their families: the benefits/harms of treatment, both pharmacologic and nonpharmacologic; potential adverse effects and nonresponse rates; benefits of a healthy lifestyle, including exercise; their preferences and concerns; the impact of other mental health or neurodevelopmental conditions on treatment choices; and the importance of adherence to treatment [30].

Evidence Based Practice Recommendation

For elementary school-aged children (6 to 11 years of age), the American Academy of Pediatrics recommends prescription of an FDA-approved medication for ADHD and/or evidence-based parent- and/or teacher-administered behavior therapy as treatment for ADHD, preferably both. The evidence is particularly strong for stimulant medications and sufficient but less strong for atomoxetine, extended-release guanfacine, and extended-release clonidine (in that order).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500647

Last Accessed: September 8, 2018

Level of Evidence: A (Well-designed randomized controlled trials or diagnostic studies on relevant populations) and B (Randomized controlled trials or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies)

First-line medical therapy with agents that are approved by the U.S. Food and Drug Administration (FDA) for ADHD is also recommended [7]. If treatment with these agents fails, the diagnosis should be reconsidered and either changed or confirmed. Off-label medications should be used for ADHD only if all the approved agents have proven unsatisfactory [7]. Treatment with behavior therapy alone may be helpful in these cases. For children younger than 5 years of age, the NICE recommends parent or caregiver participation in an ADHD-focused group training program as first-line treatment [30]. Medication for ADHD for any child younger than 5 years of age is not recommended without a second specialist opinion [30].

Healthcare professionals should be alert for side effects of medications used in the treatment of ADHD and manage them as needed. Dose reduction or a change to a different medication may be necessary. In some cases, the medication that helps the most with ADHD will also have a bothersome side effect. If this medication must be continued, certain adjunctive medications to treat the side effect may be helpful.

If medication achieves a satisfactory response, then additional treatment such as behavioral therapy is not essential, although it may be offered. Parental preference should be considered in this case [7]. Psychosocial treatment may be helpful when the response to medication is sub-optimal, when family stressors are present, or when there is a comorbid disorder.

Periodic assessments should be conducted at least several times each year for children taking medication for ADHD. If symptoms are no longer present and this continues for at least one year, consideration may be given to stopping treatment. Treatment can be restarted if ADHD signs or symptoms return.

In general, the approach for adults is similar, with many experts agreeing that pharmacotherapy is an appropriate first-line option. Some also feel that many adults will benefit from psychosocial therapy to assist them in learning important coping skills or overcoming a demoralizing self-image.

The 2011 guideline from the Canadian ADHD Resource Alliance (CADDRA), a not-for-profit alliance of professionals working in the area of ADHD, includes a section on ADHD in adults [28]. CADDRA recommends the use of mixed amphetamine salts (extended-release), long-acting methylphenidate, or atomoxetine as first-line agents. Short- or intermediate-acting stimulants are recommended as second-line or adjunctive agents, for example if a patient requires additional medication in the evening, when a long-acting preparation wears off. The guideline also recommends psychologic interventions, such as ongoing education about ADHD and coping strategies. Patients' goals should be discussed and treatment structured accordingly.

The 2018 NICE guideline asserts that treatment for adults should be comprehensive and should address psychologic, behavioral, and occupational or educational needs [30]. The recommended first-line medication is lisdexamfetamine or methylphenidate, with atomoxetine or dexamphetamine as options if lisdexamfetamine or methylphenidate cannot be tolerated or does not produce an optimal response. Six weeks of lisdexamfetamine or methylphenidate is suggested as adequate trial [30].

PHARMACOTHERAPY

Stimulant Medications

Stimulant medications appear to be effective in treating ADHD, and most children with ADHD will respond to at least one of them [11]. In a review of studies in which subjects underwent a trial of both amphetamine and methylphenidate, about 85% of children responded to one or both of these medications [31]. Forty-one percent responded equally to both classes, and 44% responded preferentially to one or the other. Stimulants are also effective in adults. One systematic review and meta-analysis sought to estimate the comparative efficacy and tolerability of amphetamines (including lisdexamfetamine), methylphenidate, modafinil, atomoxetine, bupropion, clonidine, and guanfacine with each other or placebo for ADHD in children, adolescents, and adults [32]. Efficacy was defined as the change in severity of ADHD core symptoms based on teachers' and clinicians' ratings. For ADHD core symptoms rated by clinicians in children/adolescents closest to 12 weeks, all drugs included in the review were superior to placebo, whereas only methylphenidate was superior to placebo based on teachers' ratings [32]. In adults, amphetamines, methylphenidate, bupropion, and atomoxetine were superior to placebo according to clinicians' ratings. With respect to tolerability, amphetamines were inferior to placebo in all three age groups; guanfacine was inferior to placebo only in children and adolescents; and atomoxetine, methylphenidate, and modafinil were less well tolerated than placebo only in adults. In head-to-head comparisons of the drugs, differences in efficacy, not tolerability, were found (according to clinicians' ratings). Amphetamines were favored over modafinil, atomoxetine, and methylphenidate in all three age groups at 12 weeks [32].

Stimulant medications have been shown to improve the core symptoms of ADHD, those of attention, hyperactivity, and impulsivity [11]. For children, classroom and social behavior have also been shown to improve with stimulant medication use, and these treatments may also reduce emotional over-reactivity and increase the ability to follow rules [7,11].

Characteristics of Stimulant Medications

The effect of stimulants is thought to be mediated primarily though their actions on dopamine and norepinephrine transmission. Stimulants have been shown to increase the concentration of these neurotransmitters in the frontal cortex, midbrain, and brain stem, which may explain their effect of increasing attention span and the ability to concentrate [7]. Amphetamines and methylphenidate may differ in specific actions regarding dopamine release [33]. Methylphenidate is to a large extent a norepinephrine and dopamine reuptake inhibitor, while amphetamines promote dopamine and norepinephrine efflux from neurons [34].

There is an extensive list of amphetamine and methylphenidate preparations available in the United States. Available amphetamines include dextroamphetamine, amphetamine mixed salts, and lisdexamfetamine dimesylate (prodrug of dextroamphetamine). Dexmethylphenidate and D,L-methylphenidate are methylphenidate preparations.

Stimulant medications are widely used in adults as well as children. Clinicians should review the prescribing information to determine which preparations have specifically been tested and approved for adults.

Dosing Options

Amphetamine and methylphenidate preparations are available in a variety of short- and long-acting formulations that can be taken orally. A transdermal methylphenidate patch is available as well. There is no one "best" dose for these medications. In general, stimulants should be started at a low dosage then titrated up about once a week to the desired effect.

The AACAP guideline supports a schedule of increasing the dose every one to three weeks until symptoms remit, side effects prevent further increase, or the maximum dose is reached [7]. If a long-acting formulation is preferred, there is no need to start with a short-acting formulation. It is often helpful to have reports from a parent or teacher after a week on each dose and to have an office visit after the first month of treatment. Titration should continue even if some improvement is seen at a lower dose. Higher doses may lead to better effect, but if side effects become problematic or improvement levels off, the dose can be reduced.

Patients and their families often report immediate improvement with stimulant medication [35]. In children, worsening behavior is sometimes seen in the evenings, when the drug begins to wear off [7]. This is sometimes interpreted as a "rebound" effect. However, based on studies showing this phenomenon even in children taking placebo, it is unlikely that this is an effect of the medication. If behavior is worse in late afternoon and evening, a small dose of immediate-release stimulant in the evening may help alleviate symptoms during this time.

Close follow-up multiple times a year is essential in order to evaluate progress, side effects, and adherence to medications. If medication is to be stopped, careful attention should be paid for a return of ADHD signs or symptoms. AACAP recommends not attempting to stop medication during demanding times, such as the beginning of a school year. Of note, there is an FDA-issued black box warning for severe depression during withdrawal of methylphenidate [7,34].

Side Effects

Many side effects associated with stimulant use are likely to resolve with time. Side effects that are reported commonly include insomnia, reduced appetite, headaches, stomachaches, and emotional lability [35]. Anorexia often resolves after a few weeks. In children, some height delay has been observed when treatment is initiated, but research shows this growth delay levels off by the end of adolescence [36,37,38].

Some medications may cause side effects that require adjustment of the dose, schedule, or choice of drug. Some side effects, particularly insomnia, can be improved with long-acting formulations. Occasional reactions (e.g., mood disturbances, hallucinations, psychosis) occur if the dose is too high.

In some cases, if side effects persist despite improvement in the symptoms of ADHD and changing medications is not effective or not an option, side effects may be treated with an additional medication [7]. Clonidine has been used for tics. Insomnia may be treated with an antihistamine, clonidine, or trazodone. However, the risk of priapism often discourages the use of trazodone to treat insomnia in males [34,39].

Precautions

Stimulant medications are considered safe for use in most children and adults. However, there are areas of concern that should be considered prior to initiating treatment. Although the actual cardiac risk is not known, stimulant medications carry a warning against use in persons with certain cardiac abnormalities, due to sympathomimetic effects [40]. The AAP and the American Heart Association recommend that prior to starting a patient on ADHD medications, patient and family health histories should be obtained and a physical exam should be performed with a focus on cardiovascular disease risk factors [40]. This was a Class I recommendation with level of evidence C, meaning that the recommendation was strong although based primarily on expert consensus, case studies, and/or standard of care. Acquiring an electrocardiogram (ECG) prior to starting treatment was considered reasonable but not mandatory. It was also recommended that the blood pressure and heart rate of the patient be monitored, within 1 to 3 months of starting medication and every 6 to 12 months thereafter (also a IC recommendation). Later the same year, AAP released a statement supporting the use of careful history and physical exam to assess for cardiac abnormalities [41]. However, this statement noted a lack of evidence to support routine ECGs before prescribing stimulant medications. Cardiac risk should also be considered when prescribing stimulant medications for adults. This risk will be discussed in detail later in this course.

Methylphenidate has been reported to lower seizure threshold in certain children; however, stimulants may be used safely in children who have epilepsy that is well-controlled [42,43,44]. Studies suggest that low doses of methylphenidate may also be safely used in children with difficult-to-treat epilepsy; in these instances, its use positively impacts the patient's quality of life [45,46].

Stimulants carry several black box warnings. Methylphenidate may exacerbate or induce psychosis [34,47,48]. Caution is advised for patients who are emotionally unstable. Patients with histories of alcoholism or drug dependence may become tolerant and psychologically dependent on methylphenidate. During withdrawal, severe depression may occur or be unmasked [34].

Amphetamines also carry several black box warnings. They have high abuse potential and may lead to drug dependence. There is a potential for nontherapeutic use or distribution to others. Also, there is a black box warning for serious cardiovascular adverse events and sudden death reported with misuse of this medication [34].

Non-Stimulant Medications

Atomoxetine

Atomoxetine has been approved by the FDA for the treatment of ADHD in both children and adults; however, it may be less effective than stimulant medications. Atomoxetine is a noradrenergic reuptake inhibitor, and it has several important differences in comparison to stimulants [7,34]. Atomoxetine has different side effects than stimulant medication and is more likely to cause sedation and nausea. The treatment effect may be smaller than that observed with stimulant medications, and its effect may take longer to appear.

Atomoxetine should be discontinued if symptoms of hepatic disease appear. This medication also carries cardiac warnings similar to stimulants. Lastly, atomoxetine carries a black box warning for suicidal ideation in children with ADHD, especially in the first month of treatment [34].

Clonidine

Clonidine has been evaluated for the treatment for ADHD in children with co-existing conditions, especially sleep disturbance. In a double-blind, randomized, placebo-controlled study of 122 children given clonidine, methylphenidate, or both, the authors concluded that methylphenidate offered a better combination of efficacy and tolerability compared to clonidine [49]. Clonidine was efficacious but was also associated with increased sedation.

In 2010, extended-release clonidine was FDA approved for use alone or in conjunction with stimulant therapy for pediatric ADHD [50]. The recommended initial dose is 0.1 mg at bedtime for children 6 years of age or older [34]. The dose is then increased by 0.1 mg every week until the desired response is achieved, to a maximum of 0.4 mg per day. It should also be tapered down slowly upon discontinuation [34].

Guanfacine

After being used for many years off label, extended-release guanfacine was approved for the treatment of ADHD in children and adolescents in 2009, either as monotherapy or an adjunct to stimulants [34]. Guanfacine is an alpha-2A adrenergic agonist and acts by enhancing prefrontal cortical regulation of attention and impulse control [34,51]. In a multicenter, double-blind, placebo-controlled, fixed-dosage escalation study involving 345 patients 6 to 17 years of age, three dosages of guanfacine (2 mg, 3 mg, or 4 mg per day) were associated with significant improvements on hyperactivity/impulsivity and inattentiveness subscales compared to placebo [52]. Additional studies have indicated that it may be particularly useful in children with ADHD and oppositional symptoms [53].

The recommended dose of guanfacine is 1 mg once daily; the dose may be adjusted by increments no larger than 1 mg/week, as tolerated, to a maximum dose of 4 mg/day [34]. The most common adverse effects are somnolence, xerostomia, headache, fatigue, and sedation, but they are generally mild to moderate and/or transient [34,54].

Other non-stimulant drugs, including bupropion and tricyclic antidepressants, have been used to treat ADHD. However, there is limited evidence to support their use, and they have not received indications from the FDA for ADHD [34,55]. The AACAP recommends clinicians consider using behavior therapy before using these agents because the level of effect may be similar [7].

Bupropion

Although bupropion does not have FDA approval for ADHD, it is considered by many to be a second-line agent for ADHD and possibly a first-line agent for patients who have both ADHD and either a mood disorder or a substance abuse disorder [7,34,56,57]. Studies suggest that bupropion is effective and well tolerated in children and adolescents with ADHD and may have some efficacy in treating children with ADHD and conduct disorder (CD) [58,59,60,61]. Small trials have also supported the use of bupropion for ADHD in adults [62,63,64]. However, more research is needed to establish the most appropriate role for this medication in the adult population.

Tricyclic Antidepressants

Certain tricyclic antidepressants, in particular desipramine, appear to have some efficacy in treating ADHD in children and adults [65,66]. However, there were reports of four children who had sudden death while being treated with desipramine, which led to a contraindication of its use in children younger than 12 years of age [67,68]. If tricyclic antidepressants are to be tried, a baseline ECG and ongoing monitoring are needed [7]. These medications also carry warnings, including a boxed warning about suicide risk in children, adolescents, and young adults with depression. Use of desipramine for ADHD is off-label [34].

Modafinil

Modafinil is a non-stimulant alertness agent initially approved for the treatment of narcolepsy and is currently not FDA approved in children or for ADHD [34]. Concerns about serious skin rash and preliminary safety data have limited its use in children with ADHD [69].

BEHAVIORAL THERAPY

Behavioral therapy is a term commonly used to describe a type of psychosocial approach to treating childhood ADHD. One aspect of this therapy is parent training; a typical program of behavioral therapy involves 10 to 20 sessions for parents, including information about ADHD and advice on managing behavior, anticipating misconduct, using a token economy, and using a daily school report card [7]. Therapies for children may include teaching skills and adaptive behaviors, such as how to organize school materials or how to improve relationships with peers [70]. Parent training in behavior therapy (also known as behavior management training for parents, parent behavior therapy, and behavioral parent training) has been shown to strengthen the relationship between the parent and child and to decrease children's negative or problem behaviors [71].

The Multimodal Treatment Study of Children with ADHD was a 14-month trial of specific medication management, intensive behavioral therapy (group and individual sessions, teacher consults, a classroom behavioral aide for 12 weeks, and a summer program), both medication and behavioral therapy, or ordinary community care [72]. This study revealed that combination treatment did not significantly differ from medication management alone on direct comparisons.

Combined treatment was found to be superior to intensive behavioral therapy and/or community care for oppositional and/or aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement. At follow-up three and eight years after intensive study treatments had concluded, all treatment groups were similar on measures of ADHD symptoms [73,74].

A two-year trial compared the efficacy of methylphenidate alone; methylphenidate with psychosocial treatment (including parent training and counseling, social skills training, psychotherapy, and academic assistance); and methylphenidate plus a psychosocial control treatment [75]. Significant improvement was seen with all treatments; combination treatment did not provide an advantage.

A randomized clinical trial compared combined treatment (brief intensive multimodal behavior therapy and methylphenidate) to treatment with methylphenidate alone. The 45 children who participated were reassessed at adolescence in a naturalistic follow-up 4.5 to 7.5 years after treatment. A matched non-ADHD control group included 23 children. Of the adolescents who participated in the follow-up study, 50% still met the diagnostic criteria for ADHD [76]. Adolescents in the combined treatment group used significantly less medication than those in the methylphenidate-alone group. Overall, the adolescents showed a significant decline in hyperactivity/impulsivity and oppositional and CD symptoms from post-test to follow-up. Adolescents originally diagnosed with ADHD fared significantly worse than the matched controls on all outcomes except CD and substance abuse symptoms [76].

As stated, for children younger than 5 years of age, the NICE recommends parent or caregiver participation in an ADHD-focused group training program as first-line treatment [30]. The NICE guideline also recommends training for parents and caregivers of school-aged children with ADHD [30]. Parent training and group-based ADHD-focused support is recommended for parents of school-aged children who display symptoms of oppositional defiant disorder (ODD) or CD [30]. This guideline also recommends that CBT be considered in children who have benefited from medication but whose symptoms continue to cause significant impairment in social skills with peers, problem-solving, self-control, active listening skills, and dealing with and expressing feelings [30].

Evidence regarding psychosocial treatments in adults is very limited. However, there may be a role for CBT [77,78]. A few small studies support the use of CBT programs, and CBT is often used in practice. The NICE guideline recommends either elements of or a full program of CBT for adults with ADHD in whom nonpharmacologic treatment is indicated [30].

The focus of CBT for ADHD in adults includes both the patient's thought process and his or her coping behaviors. Cognitive therapy addresses beliefs that reinforce problematic behaviors, such as feelings of failure; the goal is to diminish the power of such beliefs and to help the patient cope efficiently with the symptoms that led to them. In addition, there are many specific skills and behaviors that patients can learn, such as ways to improve organization or reduce the chance of making an impulsive decision. These skills can be individualized, depending on what works best for each patient.

Other areas of patients' lives may also be affected by ADHD. For adults, couples counseling, family therapy, and education about parenting may all be of use. Some patients will also benefit from therapy to improve their interpersonal skills.

TRIGEMINAL NERVE STIMULATION

In 2019, the FDA permitted marketing of the first medical device for the treatment of ADHD [142]. The Monarch external Trigeminal Nerve Stimulation (eTNS) System is indicated for patients 7 to 12 years of age who are not currently taking prescription ADHD medication. The device consists of a cell-phone-sized device that generates a low-level electrical pulse and connects via a wire to a small patch that adheres to a patient's forehead, just above the eyebrows [142]. TNS is done at home during sleep and may take up to four weeks to produce a noticeable response. In studies, children who used TNS showed considerable improvements in severity and frequency of ADHD symptoms [142]. The most common side effects are drowsiness, increased appetite, sleep difficulties, teeth clenching, headache, and fatigue.

7. COMORBIDITIES IN CHILDREN

Evidence Based Practice Recommendation

The American Academy of Pediatrics recommends that in the evaluation of a child for ADHD, the clinician should include assessment for other conditions that might coexist with ADHD, including emotional or behavioral (e.g., anxiety, depressive, oppositional defiant, and conduct disorders), developmental (e.g., learning and language disorders or other neurodevelopmental disorders), and physical (e.g., tics, sleep apnea) conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500647

Last Accessed: September 8, 2018

Level of Evidence: B (Randomized controlled trials or diagnostic studies with minor limitations; overwhelmingly consistent evidence from observational studies)

Comorbidities are common in patients with ADHD, and many psychiatric diagnoses may be confused with ADHD in children. Often, individuals with ADHD and a comorbid psychiatric disorder require additional treatment for the comorbid illness in order to achieve optimal functioning.

Multiple studies have shown that among children who have ADHD, 54% to 84% have ODD, 15% to 19% smoke or have other substance abuse disorders, and 25% to 35% have a learning or language problem [7]. Up to one-third of children with ADHD also have an anxiety disorder or depression, and approximately 16% meet the criteria for mania [7].

Rarely, certain medical conditions may present with symptoms of ADHD, including head trauma, encephalopathies, and thyroid disorders, in particular hyperthyroidism [7]. Patients who have ADHD and medical or psychiatric comorbidities require consideration of the effects of different medications and interactions between symptoms.

LEARNING DISABILITY

Often, ADHD is confused with learning disability, but they are distinct entities. Learning disorders are classified as specific learning disorders in the DSM-5, with divisions that specify disability in reading, writing, and mathematics [9]. Specific learning disorders are listed under neurodevelopmental disorders alongside ADHD, autism spectrum disorder, communication disorders, coordination disorders, and intellectual disability [79]. An estimated 31% to 45% of children have ADHD with specific learning disorders and 5% have ADHD without specific learning disorders [80,81].

For patients with ADHD and specific learning disorders, it is important to assess whether low performance may be secondary to ADHD and/or whether inattentiveness may be due to the specific learning disorders. It is appropriate to consider treating ADHD first, as this may allow better assessment of learning problems after symptoms of ADHD improve.

In addition to deficits in learning abilities, youth with ADHD, particularly those with a family history of substance use disorder, also exhibit deficits in reward processing. One study investigated reward-based learning as a function of the severity of substance abuse risk in drug-naïve youth with ADHD [82]. The youth were asked to perform a novel anticipation, conflict, and reward task. The authors measured reaction time, accuracy, and learning rates and assessed the influence of learned predictions of reward probability and stimulus congruency on reaction times. The most significant deficits in accuracy, in learning rates, and in adjusting to task difficulty were observed in high-risk youth (i.e., those with ADHD and parental substance use disorder) [82].

DEPRESSION

In patients who have ADHD and depression, clinicians must decide whether to treat depression or ADHD first or whether to begin treatment for both at once. If the patient is experiencing a mild depression, there is a possibility that the depressive symptoms are related to demoralization resulting from the multiple functional difficulties that ADHD can cause [7,83].

There is limited evidence for the use of antidepressants in combination with ADHD medications. In a double-blind trial, children with ADHD and depression or anxiety were treated with fluoxetine or placebo for eight weeks, and then atomoxetine was added for the final five weeks of the study [84]. ADHD, depressive, and anxiety symptoms were significantly reduced in both groups. Although this may seem to suggest that both fluoxetine and atomoxetine can treat depression, lack of a placebo-only arm precludes conclusions about such an effect. The combination was well-tolerated, however.

In a small trial of sustained-release bupropion in 24 children 11 to 16 years of age with comorbid depression, clinician-rated improvement was observed in 58% of participants for both depression and ADHD, 29% for depression only, and 4% for ADHD only. Both parents' and children's ratings of depression and ADHD improved, as did parents' ratings of ADHD. Teachers' ratings for ADHD did not improve in this study [85].

CONDUCT DISORDER AND OPPOSITIONAL DEFIANT DISORDER

Children with CD or ODD are often included in trials of ADHD treatment. Fewer studies exist that specifically assess the treatment of comorbid CD/ODD and ADHD. In a four-week randomized, double-blind study of 308 children 6 to 17 years of age with ODD, 79% of whom had comorbid ADHD, treatment with mixed amphetamine salts improved ODD symptoms as measured by parent rating scales [86]. A meta-analysis of three controlled trials concluded that atomoxetine was effective for ADHD symptoms whether or not ODD was present, and that reduction in ODD symptoms was highly related to the magnitude of ADHD response [87]. In 84 children 6 to 15 years of age with and without ADHD in a five-week randomized trial, methylphenidate improved CD symptoms [88]. A prospective study of 37 children 6 to 14 years of age with ODD and ADHD found methylphenidate and atomoxetine to be effective in the treatment of ODD comorbid with ADHD of short duration [89].

Stimulant treatment for ADHD may also help with both overt and covert aggression-related behaviors, whether or not CD or ODD is present. Overt aggression involves confrontations such as assault, threats, and tantrums. Covert aggression includes lying, cheating, and stealing. A meta-analysis involving 28 studies examined the effect of stimulants on such behaviors [90]. This analysis showed statistically significant reductions in parents' and teachers' ratings of overt aggression and in overall ratings of covert aggression as well.

Clonidine may also help with aggressive behaviors, although this is not an FDA-approved indication [34]. In a randomized trial involving 67 children with ADHD and comorbid ODD or CD, clonidine added to stimulant treatment produced significantly more responders on the conduct scale of the Connors Behavior Checklist (but not on the hyperactive index) compared to placebo and a stimulant medication [91]. Clonidine was associated with transient sedation and dizziness in this study.

Additional medications have been studied in the treatment of CD or ODD in children with ADHD. In a small, three-week study involving 24 children 12 to 16 years of age, quetiapine added to a long-acting methylphenidate reduced symptoms of ADHD in children with severe aggression who did not respond to methylphenidate alone [92]. However, a Cochrane review found no evidence to support the use of quetiapine for disruptive behavior disorders in children and adolescents, but it did find limited evidence of efficacy of risperidone in reducing aggression and conduct problems in the short term in this population [93].

SUBSTANCE ABUSE

A common concern clinicians and parents have when considering stimulant medications for the treatment of ADHD is the risk of substance abuse. In patients with a history of substance use disorder, amphetamines are generally contraindicated and caution is advised with methylphenidate.

Evidence is mixed regarding whether stimulant treatment increases the risk of substance abuse, and while predictors of risk remain understudied, the presence of CD appears to predict future substance abuse [94,95,96,97,98]. Of the core ADHD symptoms, hyperactivity/impulsivity is more consistently associated with substance abuse than inattention, which is associated only with alcohol use [97]. Studies have suggested that the use of stimulant medication may protect against future substance abuse. In a 10-year follow-up study involving 140 white male children (112 reassessed at the 10-year point) who were 6 to 17 years of age at entry, there were no statistically significant associations between treatment with stimulants and drug, alcohol, or nicotine use disorders at a mean age of 22 years [95]. These results were adjusted for CD. In a five-year follow-up study comparing 94 adolescents who had been treated with stimulants to 20 who had not, no increase in the risk of substance use disorders or cigarette smoking was seen [99]. Stimulant treatment had a protective effect on development of substance use disorders and cigarette smoking, an effect that remained after controlling for CD. However, independent of treatment with stimulants, ADHD is a significant risk factor for the development of substance use disorder and cigarette smoking in both men/boys and women/girls. A 10-year follow-up study of 268 children and adolescents with and without ADHD were followed prospectively and blindly into their young adult years. Over the follow-up period, ADHD was found to be a significant predictor of any substance use disorder and cigarette smoking. Comorbid CD and ODD at baseline were also significant predictors of substance use disorder in both sexes [98].

Increasing age at initiation of treatment with stimulant medication was positively associated with the incidence of non-alcohol substance abuse disorder in one study [100]. Post hoc analysis showed that controlling for the development of antisocial personality disorder eliminated this association. A long-term follow-up study also found an association between older age at initiation of stimulant treatment and increased risk of later substance use disorder and alcohol abuse [101]. The study of 208 boys and girls with ADHD found the relative risk for substance use disorder and alcohol abuse in adulthood was 7.7 and 5.2, respectively, compared to age-matched population controls. Female sex and childhood CD were also positively associated with an increased risk of later substance and alcohol abuse [101].

Meta-analysis was conducted on six long-term studies, with a total of 674 medicated subjects and 360 unmedicated subjects [102]. Two studies had follow-up in adolescence and four in young adulthood. Subjects were followed for a minimum of four years. Compared to subjects who were not using pharmacotherapy, those who did receive medication had a 1.9-fold lower risk for substance abuse disorders. The protective effect was larger in studies that stopped at adolescence than in studies that went into adulthood. Since this review, results from multiple longitudinal studies have not found protective effects of stimulant treatment on substance use outcomes [95,100,103]. A meta-analysis of 15 longitudinal studies examined whether treatment with stimulants for ADHD predicted later substance outcomes. A total of 2,565 individuals were analyzed across five types of substance (i.e., alcohol, cocaine, marijuana, nicotine, and nonspecific drugs) for lifetime use and abuse or dependence [104]. The results indicated that substance use/abuse outcomes for children with ADHD who were treated with stimulant medication were comparable to outcomes for children with ADHD who were not treated with stimulant medication [104].

The possibility of diversion of ADHD medication, including patients sharing stimulants with friends or selling their medication, is also a concern. Experts often suggest choosing certain preparations, including the longer-acting stimulants, to help reduce the risk of both diversion and abuse.

ANXIETY

Anxiety is comorbid with ADHD in 33% of cases, an association that aggravates inattention and concentration problems [83]. Stimulant medication has been investigated in the treatment of children with ADHD and symptoms of anxiety. One study involving 45 children 8 to 14 years of age with ADHD investigated changes in depression, anxiety, obsessive-compulsive symptoms, and health-related quality of life during treatment with methylphenidate [105]. Based on self, parent, and teacher report at baseline and at the end of the first and third months of treatment, the children were evaluated for changes in inattention, hyperactivity, impulsivity, depression, anxiety, obsessive-compulsive symptoms, and quality of life. Over three months of treatment with methylphenidate, symptoms of depression, anxiety, and checking compulsion decreased while quality of life and symptoms of inattention, hyperactivity, and impulsivity improved [105]. In a double-blind placebo-controlled study involving 176 children 8 to 17 years of age, atomoxetine was found to reduce ADHD symptoms in children with comorbid anxiety [106]. Atomoxetine was also found to reduce anxiety, on both clinician- and self-rated measures.

One small study assessed the use of fluvoxamine for anxiety in combination with methylphenidate. Twenty-six children whose ADHD symptoms had responded to methylphenidate but who still had anxiety were randomized to receive fluvoxamine or placebo in addition to the stimulant [107]. While the combination was well-tolerated, fluvoxamine was not found to have a statistically significant effect on anxiety in this group.

The role of behavior therapy in the treatment of anxiety in children also diagnosed with ADHD was examined through analysis of data from the Multimodal Treatment Study [108]. Children with ADHD plus anxiety disorders (but not ODD/CD) were likely to respond equally well to behavioral and medication treatments. Children with ADHD and no comorbidities or ADHD with ODD/CD (but without anxiety disorders) responded best to medication with or without behavioral treatments. Children with ADHD, anxiety, and ODD/CD had optimal response when treatments were combined.

The application of CBT in children with ADHD and co-occurring anxiety disorder varies depending on the type of disorder (i.e., generalized, social, or separation anxiety disorder) and should emphasize cognitive restructuring processes. Children with ADHD and anxiety disorder generally benefit less from CBT than children who are solely anxious. The distractibility and hyperactivity of the child with ADHD may interfere with and decrease the effectiveness of CBT [109].

OTHER DISORDERS

One concern with using stimulant medications is the risk of triggering mania in a patient with bipolar disorder. Evidence is limited and based on small trials but supports stimulant use after mood is stabilized [110,111,112]. Also, the development of tics is a potential side effect of stimulant medications [83]. In general, however, treatment of ADHD with stimulants does not appear to increase existing tics and may even provide improvement [7,113,114,115,116].

8. COMORBIDITIES IN ADULTS

Comorbidities are also common in adults with ADHD. Based on the National Comorbidity Survey Replication, the odds ratio of an adult with ADHD having any mood disorder is 5.0, any anxiety disorder is 3.7, any substance use disorders is 3.0, and intermittent explosive disorder is 3.7 [4].

SUBSTANCE ABUSE

Studies in teens and young adults show that diversion and misuse of stimulants are common [117,118]. One study, examining more than 100 four-year colleges in the United States, found that non-medical stimulant use was as high as 25% at some schools [119]. Data from the 2009–2014 National Survey on Drug Use and Health indicate that the highest rates of past-year prescription stimulant misuse occurred among full-time college students (4.3%) and college graduates (3.9%) [120]. First use of stimulants in adolescence and adulthood may be associated with higher risk of stimulant misuse/abuse [121].

As with children, it is recommended that stimulants be used with caution if a patient has a history of substance abuse. In fact, amphetamine-based drugs are generally contraindicated in this population. If a patient has a current substance abuse problem, it is important to treat this appropriately while addressing symptoms of ADHD. When both disorders are diagnosed at once, it is often recommended that the substance use be addressed first, in part because behaviors related to substance abuse can mimic ADHD symptoms [28,122]. After the patient has stopped the substance misuse and is in recovery, he or she can be reassessed for ADHD and treated, as necessary. Evidence suggests stimulant medications may not exacerbate addiction. In a 12-week, double-blind, placebo-controlled trial involving 48 cocaine-dependent adults with ADHD, the use of methylphenidate did not lead to group differences in self-reported cocaine use or cocaine craving or in urinalysis results [123].

A double-blind, 12-week trial involving 98 methadone-maintained patients (53% of whom also had cocaine dependence/abuse) did not find evidence of medication misuse or worsening of cocaine use in a group receiving methylphenidate [124]. In this study, the reduction in ADHD symptoms was similar with methylphenidate, bupropion, and placebo, and neither treatment nor placebo appeared to offer an advantage for reducing cocaine use. In a later study with cocaine abusers, analysis of urine toxicology data suggested that methylphenidate users had less cocaine use than a placebo group during the trial [125]. A Cochrane review found that psychostimulants, including methylphenidate, appeared to increase the proportion of patients achieving sustained cocaine and heroin abstinence among methadone-maintained, dual heroin-cocaine addicts. However, retention to treatment was low [126].

There may be an advantage to using long-acting or controlled-release formulations of stimulant medications. Spencer and colleagues studied plasma d-methylphenidate levels, responses to detection/likeability questionnaires, and dopamine transporter receptor occupancies in 12 healthy adults randomly assigned to single doses of immediate-release or osmotic-release methylphenidate [127]. Subjects receiving osmotic-release methylphenidate had a longer time to maximum concentration and to maximum central nervous system dopamine transporter occupancy, and they had no detection or likeability on questionnaires. Kollins and colleagues found stimulant-like drug effects (such as increased ratings of "good effects") with immediate-release methylphenidate, while a sustained-release formulation had smaller and more transient effects [128].

There may also be an advantage in using the pro-drug lisdexamfetamine dimesylate, which was designed to limit abuse potential. Jasinski and colleagues studied "liking effects" in single IV doses of lisdexamfetamine dimesylate (25 or 50 mg) and immediate-release d-amphetamine sulfate (10 or 20 mg) compared to placebo [129]. Data was gathered in a randomized, double-blind, crossover study including 12 total subjects, all adult substance abusers. Abuse-related liking scores were higher with 20 mg of d-amphetamine than with placebo. For 50 mg lisdexamfetamine dimesylate, there was no significant difference from placebo.

DEPRESSION

Evidence is lacking to guide treatment of depression in adults who have ADHD, although selective serotonin reuptake inhibitors (SSRIs) and bupropion are common choices. Monoamine oxidase inhibitors (MAOIs) are contraindicated in patients taking stimulants or atomoxetine. With atomoxetine, caution with SSRIs that are strong cytochrome P450 2D6 (CYP2D6) inhibitors is advised as they may increase atomoxetine levels; bupropion also inhibits this enzyme [130]. With methylphenidate, caution is advised with SSRIs and tricyclic antidepressants due to the possibility of decreased metabolism of these drugs [34]. Amphetamines may enhance the activity of tricyclic antidepressants, and cardiovascular risks may be increased with this combination [131]. Caution is also advised with amphetamines in patients taking bupropion, as this is associated with an increased risk of seizures. It is also recommended that amphetamines be avoided in patients taking venlafaxine, as this combination is associated with increased weight loss [34].

MEDICAL COMORBIDITIES

Caution is advised in prescribing stimulants or atomoxetine in adults with cardiovascular concerns. A full medical history, physical exam, and additional evaluation may be needed. Sudden death, stroke, and myocardial infarction have been reported at usual doses for ADHD, but the role of the medications in these events is not known [34]. In general, it is recommended that stimulants be avoided in adults with serious cardiac structural abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious cardiac problems. Regular monitoring for changes in blood pressure and heart rate is suggested, and stimulants and atomoxetine should be used with caution if a patient has conditions that could be worsened by such changes [34]. Clinicians must be vigilant regarding cardiac symptoms that develop during treatment.

Stimulants may increase blood pressure and heart rate, but there have been few studies on the effects on this phenomenon. In an open-label trial, 13 adults with ADHD and controlled essential hypertension took extended-release mixed amphetamine salts for six weeks and then discontinued medication for two weeks [132]. The stimulant did not cause sustained blood pressure elevations, did not increase the number of single episodes of hypertension, and did not lead to a group mean increase in blood pressure or pulse.

Weisler and colleagues found that with extended-release mixed amphetamine salts used for up to 24 months, doses of 20–60 mg/day were associated with small but statistically significant changes in blood pressure and pulse [133]. At 24 months, there was a clinically insignificant increase in QT, although no subject had a QT interval greater than 480 msec. Seven subjects stopped treatment due to a cardiovascular adverse event (two for palpitations/tachycardia and five for hypertension), although none were considered serious.

Data were reanalyzed from placebo-controlled studies of five different ADHD medications (methylphenidate, amphetamine compounds, pemoline, bupropion, and desipramine) in order to evaluate the effects of these medications on blood pressure and pulse [134]. Statistically significant increases in systolic blood pressure were observed with bupropion (5.9 mm Hg) and amphetamine (5.4 mm Hg). Significant increases in diastolic blood pressure were observed with desipramine (7.1 mm Hg). Statistically significant increases in heart rate were observed for bupropion, amphetamine, and methylphenidate. The authors concluded that, in general, adults being treated for ADHD should have blood pressure and heart rate monitored during treatment.

9. EDUCATING PATIENTS AND PARENTS

Communication with patient and family is essential to ADHD care. This includes explaining risks and benefits of medications. Ongoing education, communication, and follow-up are recommended. It is often helpful if clinicians encourage questions and have patients repeat back information in their own words.

Alerting patients and/or parents to potential side effects may help with adherence by letting them know that such responses are not unexpected. It can also be helpful to let patients and/or caregivers know that some side effects resolve on their own, and if necessary, a lower dose or adjunctive medication can reduce discomfort.

Patients and their families should also know that medication is not a cure for ADHD. Signs and symptoms will return as the medication's effect tapers. In addition, while medication can be expected to reduce core manifestations, such as hyperactivity and inattention, and may also help with children's behavior, it will not necessarily address all the problems associated with ADHD. Even if formal behavior therapy is not part of treatment, advice about managing children's behavior may be helpful.

The AACAP guideline includes education and communication as essential parts of ADHD treatment [7]. Patients, and parents when the patients are children, can benefit from information about ADHD tailored to developmental age and health literacy. Healthcare professionals should have information available about school and community supports, including special accommodations for any comorbid learning disability. In some cases, ADHD itself may be considered a disability and services may be available through the public schools.

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such an important aspect of the care of patients with ADHD, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient or caregiver understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. (In many cases, the terms "interpreting" and "translating" are used interchangeably, but interpreting is specifically associated with oral communication while translating refers to written text.) Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

Depending upon the patient's language, an interpreter may be difficult to locate. Or, an organization may not have the funds to bring in an interpreter. Also, bringing in an interpreter creates a triangular relationship with a host of communication dynamics that must be negotiated [135]. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures and assisting in promoting culturally competent communication and practice [136,137]. 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 [136,137]. Consequently, an intricate, triangular relationship develops between all three parties. Another factor affecting the communication process is the fact that many interpreters are not adequately trained in the art of interpretation in mental health and general health settings, as there are many technical and unfamiliar terms. An ideal interpreter goes beyond being merely proficient in the needed language/dialect [138]. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness [139]. They are also well-versed in interpreting both the overt and latent content of information without changing any meanings and without interjecting their own biases and opinions [139]. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital [137,138].

On the patients' side, they may be wary about utilizing interpreters for a host of reasons. They may find it difficult to express themselves through an interpreter [140]. If an interpreter is from the same community as the patient, the client/patient may have concerns about sharing private information with an individual who is known in the community and the extent to which the information disclosed would remain confidential. In some cases, raising the issue of obtaining an interpreter causes the client/patient to feel insulted that their language proficiency has been questioned. Finally, if an interpreter is from a conflicting ethnic group, the patient may refuse having interpreter services [135]. The ideal situation is to have a well-trained interpreter who is familiar with health and mental health concepts.

If an interpreter is required, the practitioner must acknowledge that an interpreter is more than a body serving as a vehicle to transmit information verbatim from one party to another [140]. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise [140]. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

A briefing time between the practitioner and interpreter held prior to the meeting with the client/patient is crucial. The interpreter should understand the goal of the session, issues that will be discussed, specific terminology that may be used to allow for advance preparation, preferred translation formats, and sensitive topics that might arise [138,140,141]. It is important for the client/patient, interpreter, and practitioner to be seated in such a way that the practitioner can see both the interpreter and client/patient. Some experts recommend that the interpreter sit next to the client/patient, both parties facing the practitioner [139].

The practitioner should always address the client/patient directly. For example, the practitioner should query the client/patient, "How do you feel?" versus asking the interpreter, "How does she feel?" [139]. The practitioner should also always refer to the client/patient as "Mr./Mrs. D" rather than "he" or "she" [140]. This avoids objectifying the client/patient.

At the start of the session, the practitioner should clearly identify his/her role and the interpreter's role [140]. This will prevent the client/patient from developing a primary relationship or alliance with the interpreter, turning to the interpreter as the one who sets the intervention [138]. The practitioner should also be attuned to the age, gender, class, and/or ethnic differences between the client/patient and the interpreter [140]. For example, if the client/patient is an older Asian male immigrant and the interpreter is a young, Asian female, the practitioner must be sensitive to whether the client/patient is uncomfortable given the fact he may be more accustomed to patriarchal authority structures. At the conclusion of the session, it is advisable to have a debriefing time between the practitioner and the interpreter to review the session [138,140,141].

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.

10. RESOURCES

Some patients and families will appreciate web-based or written information. Several reliable sources are available.

American Academy of Pediatrics

https://www.aap.org

ADHD: Parents Medication Guide, from the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry

http://www.parentsmedguide.org/parentguide_english.pdf

National Institute of Mental Health ADHD Booklet

https://www.nimh.nih.gov/health/publications/attention-deficit-hyperactivity-disorder-adhd-the-basics/index.shtml

National Resource Center on ADHD, a program of Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD)

http://help4adhd.org

11. CONCLUSION

ADHD has a significant effect on the health of millions of Americans. Accurate and timely diagnosis, referral, and treatment are necessary in order to effectively manage the disease and to maintain patients' quality of life. However, ADHD can be difficult to recognize, particularly in adults and patients with comorbid psychiatric conditions. The continued stigma of the disease further complicates diagnosis and treatment.

For clinicians, a clear understanding of the epidemiology, diagnostic criteria, pathophysiology, differential diagnosis, and treatment of ADHD is necessary in order to ensure patient-centered care. The information provided in this course should assist healthcare professionals in providing the best possible care to patients with ADHD.

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89. Garg J, Arun P, Chavan BS. Comparative efficacy of methylphenidate and atomoxetine in oppositional defiant disorder comorbid with attention deficit hyperactivity disorder. Int J Appl Basic Med Res. 2015;5(2):114-118.

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92. Kronenberger WG, Giaugue AL, Lafata DE, Bohnstedt BN, Maxey LE, Dunn DW. Quetiapine addition in methylphenidate treatment-resistant adolescents with co-morbid ADHD, conduct/oppositional-defiant disorder, and aggression: a prospective, open-label study. J Child Adolesc Psychopharmacol. 2007;17(3):334-347.

93. Loy JH, Merry SN, Hetrick SE, Stasiak K. Atypical antipsychotics for disruptive behavior disorders in children and youths. Cochrane Database Syst Rev. 2017;8:CD008559.

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95. Biederman J, Monuteaux MC, Spencer T, Wilens TE, Macpherson HA, Faraone SV. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry. 2008;165(5):597-603.

96. Kollins SH. ADHD, substance use disorders, and psychostimulant treatment current literature and treatment guideline. J Atten Disord. 2008;12(2):115-125.

97. Miranda A, Colomer C, Berenguer C, Roselio R, Roselio B. Substance use in young adults with ADHD: Comorbidity and symptoms of inattention and hyperactivity/impulsivity. Int J Clin Health Psychol. 2015;16(2):157-165.

98. Wilens TE, Martelon M, Joshi G, et al. Does ADHD predict substance-use disorders? A 10-year follow-up study of young adults with ADHD. J Am Acad Child Adolesc Psychiatry. 2011;50(6):543-553.

99. Wilens TE, Adamson J, Monuteaux MC, et al. Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorders in adolescents. Arch Pediatr Adolesc Med. 2008;162(10):916-921.

100. Mannuzza S, Klein RG, Truong NL, et al. Age of methylphenidate treatment initiation in children with ADHD and later substance abuse: prospective follow-up into adulthood. Am J Psychiatry. 2008;165(5):604-609.

101. Dalsgaard S, Mortensen PB, Frydenberg M, Thomsen PH. ADHD, stimulant treatment in childhood and subsequent substance abuse in adulthood: a naturalistic long-term follow-up study. Addict Behav. 2014;39(1):325-328.

102. Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003;111(1):179-185.

103. Molina BSG, Flory K, Hinshaw SP, et al. Delinquent behavior and emerging substance use in the MTA at 36 months: prevalence, course, and treatment effects. J Am Acad Child Adolesc Psychiatry. 2007;46(8):1028-140.

104. Humphreys KL, Eng T, Lee SS. Stimulant medication and substance use outcomes: a meta-analysis. JAMA Psychiatry. 2013;70(7):740-749.

105. Gürkan K, Bilgic A, Türkoglu S, Kilic BG, Aysev A, Uslu R. Depression, anxiety and obsessive-compulsive symptoms and quality of life in children with attention-deficit hyperactivity disorder (ADHD) during three-month methylphenidate treatment.J Psychopharmacol. 2010;24(12):1810-1818.

106. Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with attention-deficit/hyperactivity disorder with co-morbid anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(9):1119-1127.

107. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with co-morbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2005;44(5):418-427.

108. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity findings from the MTA study: comparing co-morbid subgroups.J Am Acad Child Adolesc Psychiatry. 2001;40(2):147-158.

109. Halldorsdottir T, Ollendick TH. Comorbid ADHD: implications for the treatment of anxiety disorders in children and adolescents. Cog Behavior Pract. 2014;21(3):310-322.

110. Findling RL, Short EJ, McNamara NK, et al. Methylphenidate in the treatment of children and adolescents with bipolar disorder and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1445-1453.

111. Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of co-morbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry. 2005;162(1):58-64.

112. Hah M, Chang K. Atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents with bipolar disorders. J Child Adolesc Psychopharmacol. 2005;15(6):996-1004.

113. Pringsheim T, Steeves T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev. 2011;4:CD007990.

114. Cohen SC, Mulqueen JM, Ferracioli-Oda E, et al. Meta-analysis: risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry. 2015;54(9):723-736.

115. Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev. 2018;6:CD007990.

116. Gulisano M, Rizzo R, Cali PV, Curatolo B. Tourette Syndrome and comorbid ADHD: current pharmacological treatment options. Eur J Paediatric Neurol. 2013;17:421-428.

117. Bright GM. Abuse of medications employed for the treatment of ADHD: results from a large-scale community survey. Medscape J Med. 2008;10(5):111.

118. Wilens TE, Gignac M, Swezey A, et al. Characteristics of adolescents and young adults with ADHD who divert or misuse their prescription medications. J Am Acad Child Adolesc Psychiatry. 2006;45(4):408-414.

119. McCabe SE, Knight JR, Teter CJ, Wechsler H. Nonmedical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction. 2005;100(1):96-106.

120. McCabe SE, Teter CJ, Boyd CJ, Wilens TE, Schepis TS. Sources of prescription medication misuse among young adults in the United States: the role of educational status. J Clin Psychiatry. 2018;79(2).

121. McCabe SE, Teter CJ, Boyd CJ. Medical use, illicit use and diversion of prescription stimulant medication. J Psychoactive Drugs. 2006;38(1):43-56.

122. Wilens TE. ADHD with substance use disorders. In: Brown TE (ed). ADHD Comorbidities: Handbook for ADHD Complications in Children and Adults. Washington, DC: American Psychiatric Publishing; 2009.

123. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with co-morbid cocaine dependence. Exp Clin Psychopharmacol. 2002;10(3):286-294.

124. Levin FR, Evans SM, Brooks DJ, Kalbag AS, Garawi F, Nunes EV. Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend. 2006;81(2):137-148.

125. Levin FR, Evans SM, Brooks DJ, Garawi F. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend. 2007;87(1):20-29.

126. Castells X, Cunill R, Péerez-Mañá C, Vidal X, Capella D. Psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev. 2016;9:CD007380.

127. Spencer TJ, Biederman J, Ciccone PE, et al. PET study examining pharmacokinetics, detection and likeability, and dopamine transporter receptor occupancy of short- and long-acting oral methylphenidate. Am J Psychiatry. 2006;163(3):387-395.

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129. Jasinski DR, Krishnan S. Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers. J Psychopharmacol. 2009;23(4):410-418.

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132. Wilens TE, Zusman RM, Hammerness PG, et al. An open-label study of the tolerability of mixed amphetamine salts in adults with attention-deficit/hyperactivity disorder and treated primary essential hypertension. J Clin Psychiatry. 2006;67(5):696-702.

133. Weisler RH, Biederman J, Spencer TJ, Wilens TE. Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(12 Suppl 20):35-43.

134. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005;66(2):253-259.

135. Ayonrinde O. Importance of cultural sensitivity in therapeutic transactions: considerations for healthcare providers. Dis Manage Health Outcomes. 2003;11(4):233-248.

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Evidence-Based Practice Recommendations Citations

1. Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement and Management, Wolraich M, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500647. Last accessed September 8, 2018.

91742 • Child, Adolescent, and Adult Immunization Schedules

John J. Whyte, MD, MPH

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Over the past several years, there have been significant changes to the immunization schedules for children, adolescents, and adults. The approval of multiple new vaccines has increased the opportunities for preventive care for both children and adults. Yet coverage with some vaccines remains far below national goals, and outbreaks of vaccine-preventable diseases continue to occur. The introduction of new vaccines and additional changes to the immunization schedules make it increasingly more difficult for physicians to ensure that patients receive the recommended preventive care. This course will focus on the immunization schedules for children, adolescents, and adults, with an emphasis on vaccinations that are routine for most healthy persons. It will address the current recommendations, the rationale for the addition of new vaccines and for several potential new changes, contraindications, and precautions as identified by the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP), and methods to increase vaccination coverage in outpatient practice.

Table of Contents

91742 • Child, Adolescent, and Adult Immunization Schedules

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. AN OVERVIEW OF IMMUNIZATION SCHEDULES

THE CHILD AND ADOLESCENT IMMUNIZATION SCHEDULE

THE ADULT IMMUNIZATION SCHEDULE

3. VACCINES AND RECOMMENDATIONS

SEASONAL INFLUENZA

TETANUS/DIPHTHERIA/PERTUSSIS

HUMAN PAPILLOMAVIRUS

MENINGOCOCCAL DISEASE

HEPATITIS A

HERPES ZOSTER

PNEUMOCOCCAL VACCINES

4. VACCINE CONTRAINDICATIONS

GENERAL INFORMATION

ALLERGY/HYPERSENSITIVITY

IMMUNODEFICIENCY

PREGNANCY

TUBERCULOSIS

HISTORY OF GUILLAIN-BARRÉ SYNDROME

OTHER ISSUES

5. VACCINE SAFETY

MMR AND AUTISM

THIMEROSAL AND AUTISM

MULTIPLE VACCINES AND THE IMMUNE SYSTEM

ROTAVIRUS VACCINES AND INTUSSUSCEPTION

INFLUENZA VACCINE AND GUILLAIN-BARRÉ SYNDROME

MCV AND GUILLAIN-BARRÉ SYNDROME

HPV VACCINE AND ADVERSE EVENTS

6. OVERCOMING BARRIERS FOR CHILDREN AND ADOLESCENTS

EDUCATING PARENTS ABOUT VACCINES AND VACCINE SAFETY

REDUCING THE NUMBER OF INJECTIONS

ADDRESSING CONCERNS ABOUT VACCINE COSTS

INSTITUTING REMINDER SYSTEMS

7. OVERCOMING BARRIERS FOR ADULTS

REDUCING "MISSED OPPORTUNITIES" FOR ADULTS

REMINDER SYSTEMS FOR ADULT PATIENTS

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

91742 • Child, Adolescent, and Adult Immunization Schedules

Education Category. Community Health

Release Date. 03/01/2019

Expiration Date. 02/28/2022

Course Overview

Over the past several years, there have been significant changes to the immunization schedules for children, adolescents, and adults. The approval of multiple new vaccines has increased the opportunities for preventive care for both children and adults. Yet coverage with some vaccines remains far below national goals, and outbreaks of vaccine-preventable diseases continue to occur. The introduction of new vaccines and additional changes to the immunization schedules make it increasingly more difficult for physicians to ensure that patients receive the recommended preventive care. This course will focus on the immunization schedules for children, adolescents, and adults, with an emphasis on vaccinations that are routine for most healthy persons. It will address the current recommendations, the rationale for the addition of new vaccines and for several potential new changes, contraindications, and precautions as identified by the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP), and methods to increase vaccination coverage in outpatient practice.

Audience

This course is designed for healthcare professionals working in all practice settings who may encourage patients to receive appropriate vaccinations and improve the overall vaccination rates.

Course Objective

There have been significant changes to the immunization schedules for children, adolescents, and adults, and the approval of multiple new vaccines has increased the opportunities for preventive care for both children and adults. However, coverage with some vaccines remains far below national goals, and outbreaks of vaccine-preventable diseases continue to occur. The purpose of this course is to provide healthcare professionals with the information necessary to identify patients who should be vaccinated and methods to increase vaccination coverage in outpatient practice.

Learning Objectives

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

1. Discuss the regulation of vaccines and identify the child, adolescent, and adult immunization schedules.

2. Explain the rationale behind the addition of new vaccines and changes to existing recommendations, and differences between current vaccines and newer options in development.

3. State contraindications to the administration of specific vaccines.

4. Explain recent safety data regarding vaccines.

5. Identify barriers to timely vaccination.

6. Describe methods for maximizing vaccination coverage.

Faculty

John J. Whyte, MD, MPH, is currently the Chief Medical Officer at WebMD. In this role, he leads efforts to develop and expand strategic partnerships that create meaningful change around important and timely public health issues. Previously, Dr. Whyte was the Director of Professional Affairs and Stakeholder Engagement at the FDA’s Center for Drug Evaluation and Research and the Chief Medical Expert and Vice President, Health and Medical Education at Discovery Channel, part of the media conglomerate Discovery Communications.
Prior to this, Dr. Whyte was in the Immediate Office of the Director at the Agency for Healthcare Research Quality. He served as Medical Advisor/Director of the Council on Private Sector Initiatives to Improve the Safety, Security, and Quality of Healthcare. Prior to this assignment, Dr. Whyte was the Acting Director, Division of Medical Items and Devices in the Coverage and Analysis Group in the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency responsible for administering the Medicare and Medicaid programs. In his role at CMS, Dr.Whyte made recommendations as to whether or not the Medicare program should pay for certain procedures, equipment, or services. His division was responsible for durable medical equipment, orthotics/prosthetics, drugs/biologics/therapeutics, medical items, laboratory tests, and non-implantable devices. As Division Director as well as Medical Officer/Senior Advisor, Dr. Whyte was responsible for more national coverage decisions than any other CMS staff.
Dr. Whyte is a board-certified internist. He completed an internal medicine residency at Duke University Medical Center as well as earned a Master’s of Public Health (MPH) in Health Policy and Management at Harvard University School of Public Health. Prior to arriving in Washington, Dr. Whyte was a health services research fellow at Stanford and attending physician in the Department of Medicine. He has written extensively in the medical and lay press on health policy issues.

Faculty Disclosure

Contributing faculty, John J. Whyte, MD, MPH, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, 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

Since the mid-1990s, a childhood vaccination schedule approved by the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics, and the American Academy of Family Physicians has been published annually by the Centers for Disease Control and Prevention (CDC). A standardized adult immunization schedule has been published each year since 2002.

Over the years, there have been significant changes to the immunization schedules for children, adolescents, and adults. The approval of multiple new vaccines has increased the opportunities for preventive care for both children and adults. Yet, coverage with some vaccines remains far below national goals, and outbreaks of vaccine-preventable diseases continue to occur. The introduction of new vaccines, plus additional changes to the immunization schedules, makes it increasingly difficult for healthcare professionals to ensure that patients receive the recommended preventive care.

Changes in disease incidence illustrate the successes of widespread vaccination. Between 2000 and 2013, the incidence of acute hepatitis B declined in all age groups, with rates plateauing in 2011. Between 2013 and 2016, the rate increased slightly. In 2016, the rate was highest among persons 30 to 39 years of age and lowest among adolescents and children 19 years of age and younger [1]. Five years after the introduction of the heptavalent pneumococcal conjugate vaccine (PCV), the incidence of invasive pneumococcal disease (IPD) decreased by 82% among children 1 year of age and by 77% in children younger than 5 years of age [2]. The introduction of this vaccine in children appears to have reduced the incidence of IPD caused by covered strains in older adults as well [3].

However, for vaccines against communicable diseases to have the greatest impact, large proportions of the population should be covered. For childhood vaccines, the Healthy People 2020 goal is 90% coverage within five years of a new vaccine being added to the immunization schedule. On a national scale, more than 90% of children have received age-appropriate doses of inactivated polio vaccine (IPV), measles/mumps/rubella (MMR), Haemophilus influenzae type b (Hib), hepatitis B (HepB), and varicella (VAR) vaccines by 19 to 35 months of age [4]. However, certain vaccines remain significantly underutilized. For children 19 to 35 months of age, completion of four doses of the heptavalent PCV, added to the immunization schedule in 2001, has been increasing but had reached only 82.4% in 2017, with no significant improvements since 2010 [4]. In 2017, full coverage with the hepatitis A vaccine (HepA) for all young children was approximately 59.7%. Coverage with vaccines against rotavirus was approximately 73.2% [4]. In 2017, 49% of adolescents were up to date on the human papillomavirus (HPV) vaccine [114]. This vaccine is considered too new to expect coverage to have met the national goal of 90% by 2020, and ongoing effort is needed to ensure that goals are reached.

Undervaccination remains a concern among children even when national data show broad coverage. Coverage varies geographically and among different socioeconomic groups. Not all children receive their vaccinations on time, leaving them unnecessarily vulnerable [5]. Some parents opt out of vaccination entirely because of concerns about adverse effects or because they assume that the vaccine-preventable diseases are no longer a threat. There is also considerable misinformation about vaccine safety. However, recent measles outbreaks confirm that vaccination is still an important public health measure [4,6].

In the adult population, vaccines are significantly underutilized (Table 1). For many years, the 23-valent pneumococcal polysaccharide vaccine (PPSV) has been recommended as a routine vaccination for adults 65 years of age and older, and multiple studies confirm that it can reduce the risk of IPD in this population. Yet according to estimates from the 2015 National Health Interview Survey, only 62.8% of adults in this age group have been vaccinated [7]. Similarly, only about 47.6% of adults 50 to 64 years of age and about 71.4% of adults 65 years of age and older recalled receiving an influenza vaccination within the previous 12 months [7]. Even more than in the pediatric population, special effort may be needed to ensure that adults are aware of and have access to newer vaccines. In the first year after the herpes zoster vaccine was approved, only 2% of adults 60 years of age and older were vaccinated [8]. Attention to disparities is also needed. For example, Hispanics and non-Hispanic blacks are substantially less likely than whites to receive the influenza vaccine.

Table 1: U.S. ADULT IMMUNIZATION RATES, 2015

Vaccine

Subgroup

Percent Vaccinated

Influenza

50 to 64 years of age

48.7%

65 years of age and older

73.5%

Pneumococcal disease

19 to 64 years of age, high risk

23.0%

65 years of age and older

63.6%

Human papillomavirus

Women 19 to 26 years of age

41.6%

Men 19 to 26 years of age

10.1%

Herpes zoster (shingles)

60 years of age and older

30.6%

Tdap

19 years of age and older

61.6%

Hepatitis A

19 to 49 years of age

12.3%

Hepatitis B

19 to 49 years of age

32.0%

Tdap = diphtheria and tetanus toxoids and pertussis.

Source: [9]

The following course will focus on the immunization schedules for children, adolescents, and adults, with an emphasis on vaccinations that are routine for most healthy persons. It will address the recommendations as of 2019, the rationale for the addition of new vaccines and for several potential new changes, contraindications and precautions as identified by the CDC and the ACIP, and methods to increase vaccination coverage in outpatient practice. The full schedules, including recommendations for patients with specific risk factors and catch-up schedules for patients who have missed doses, are available from the CDC.

Of note, the decision to vaccinate any individual patient should be based on a careful review of the patient's history and of current recommendations regarding each specific vaccine. The recommendation to vaccinate "all" children or adults with a given vaccine should not be interpreted to include those with contraindications or those for whom risks would outweigh benefits.

2. AN OVERVIEW OF IMMUNIZATION SCHEDULES

It is helpful to understand how vaccines are approved and then recommended as part of a schedule. The U.S. Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines in the United States. Vaccine clinical development follows the same general pathway as drugs and other biologics. A sponsor who wishes to begin clinical trials with a vaccine must submit an investigational new drug application (IND) to the FDA. The IND describes the vaccine, its method of manufacture, and the types of quality control testing done prior to administering the vaccine to humans. Also included is information about the vaccine's safety and ability to elicit an immune response in animal testing. In addition, the IND contains the proposed clinical protocol.

If the clinical trials are considered successful, a manufacturer will then submit a biologics license application. To be considered, the license application must provide the multidisciplinary FDA reviewer team with the efficacy and safety information necessary to make a risk/benefit assessment and to recommend or oppose the approval of a vaccine. In some cases, the FDA may present their findings to the Vaccines and Related Biological Products Advisory Committee. This non-FDA expert committee (consisting of scientists, physicians, biostatisticians, and a consumer representative) provides advice to the FDA regarding the safety and efficacy of the vaccine for the proposed indication. The FDA makes the final decision for/against approval but relies heavily upon the recommendation of its advisory committees.

It is also important to note that vaccine approval requires the provision of adequate product labeling to allow healthcare providers to understand the vaccine's proper use, including its potential benefits and risks. This information allows healthcare providers to communicate with patients and parents and to safely deliver the vaccine to the public.

FDA approval, however, does not guarantee that a vaccine will be considered routine. Rather, the CDC plays a critical role in determining the schedule. The ACIP consists of 15 experts in fields associated with immunization who have been selected by the Secretary of the U.S. Department of Health and Human Services to provide advice and guidance on the control of vaccine-preventable diseases. The Committee develops written recommendations for the routine administration of vaccines to children and adults in the civilian population; recommendations include age for vaccine administration, number of doses and dosing interval, and precautions and contraindications. The ACIP is the only entity in the federal government that makes such recommendations. These recommendations create the immunization schedules.

THE CHILD AND ADOLESCENT IMMUNIZATION SCHEDULE

In 1995, the first year that a harmonized childhood immunization schedule was published, there were only five items on the childhood immunization schedule, incorporating protection against nine diseases. Even then, a comment in the journal Pediatrics noted that the schedule's complexity could be confusing for both physician and patient [10]. The recommended shots were [11]:

- HepB

- Diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP), diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP), or tetanus and diphtheria toxoids vaccine (Td), depending on age

- Hib

- Oral polio vaccine (OPV)

- MMR

To achieve full coverage, children required a total of 15 shots and four oral doses spread out over at least six visits. DTaP has since replaced DTP and IPV replaced OPV without any changes in the necessary visits.

However, with the many new changes that have occurred, parents may be taken by surprise by the number of doses and visits their youngest children need. In 2013, the child and adolescent schedules were combined for the first time, resulting in one schedule for persons 0 to 18 years of age, a format that continues today (Table 2). This combined schedule contains vaccines against up to 16 infectious agents. Expansion of flu vaccine recommendations means annual visits. Other vaccines require multiple visits in the first year of life and at 11 or 12 years of age. Depending on the specific options used, full coverage can involve more than three dozen shots. A "catch-up" schedule for children and adolescents who fall behind on immunizations has also been established (Table 3).

Table 2: RECOMMENDED IMMUNIZATION SCHEDULE FOR PERSONS 0 THROUGH 18 YEARS OF AGE, 2019

Source : [12]

Table 3: CATCH-UP IMMUNIZATION SCHEDULE FOR PERSONS AGED 4 MONTHS THROUGH 18 YEARS WHO START LATE OR WHO ARE MORE THAN 1 MONTH BEHIND, 2019

Vaccine

Minimum Age for Dose 1

Minimum Interval Between Doses

Dose 1 to 2

Dose 2 to 3

Dose 3 to 4

Dose 4 to 5

Children 4 months through 6 years of age

Hepatitis B

Birth

4 weeks

8 weeks and at least 16 weeks after first dose. Minimum age for final dose: 24 weeks.

––

––

Rotavirus

6 weeks Maximum age for first dose: 14 weeks, 6 days

4 weeks

4 weeks

Maximum age for final dose: 8 months, 0 days

––

––

Diphtheria, tetanus, pertussis

6 weeks

4 weeks

4 weeks

6 mos.

6 mos.

Haemophilius influenzae type b

6 weeks

4 weeks (if dose before 1st birthday) OR 8 weeks (as final dose) if first dose at 12 to 14 mos. If first dose at ≥15 mos., no further doses needed.

4 weeks (if current age <12 mos. and first dose administered at <7 mos. and at least one previous dose was PRP-T or unknown) OR 8 weeks and age 12 mos. through 59 mos. (as final dose) if current age is <12 mos. and first dose administered between 7 and 11 mos.; if current age is 12 through 59 mos. and first dose administered before 1st birthday and second dose

If previous dose at ≥15 mos., no further doses needed.

8 weeks (as final dose), only for children age 12 through 59 mos. who received 3 doses before 1st birthday.

––

Pneumococcal

6 weeks

4 weeks (if first dose before 1st birthday) OR 8 weeks (as final dose for healthy children) if first dose at ≥12 mos. No further doses needed for healthy children if first dose at ≥24 mos.

4 weeks (if current age <12 mos. and previous dose given at <7 mos.) OR 8 weeks (as final dose for healthy children if current age ≥12 mos. and previous dose given at 7-11 mos.). No further doses needed for healthy children if previous dose at ≥24 mos.

8 weeks (as final dose), only for

children 12

through 59 mos. who received

3 doses before 12 mos. or for children at high risk who received

3 doses at any age.

––

Inactivated poliovirus

6 weeks

4 weeks

4 weeks if current age <4 yrs. OR 6 mos. (as final dose) if current age>4 yrs.

6 mos. (Minimum age for final dose: 4 years)

––

Meningococcal

2 months for MenACWY-CRM, 9 months for MenACWY-D

8 weeksa

a

a

––

Measles, mumps, rubella

12 mos.

4 weeks

––

––

––

Varicella

12 mos.

3 mos.

––

––

––

Hepatitis A

12 mos.

6 mos.

––

––

––

Persons 7 through 18 years of age

Tetanus, diphtheria; tetanus, diphtheria, pertussis

7 years

4 weeks

4 weeks (if first dose DTaP/DT before 1st birthday) OR

6 mos. (as final dose) if first dose of DTaP/DT or Tdap/Td at ≥12 mos.

6 mos. if first dose DTaP/DT before 1st birthday

––

Human papillomavirus

9 years

Routine dosing intervals are recommended.b

Hepatitis A

––

6 mos.

––

––

––

Hepatitis B

––

4 weeks

8 weeks and at least 16 weeks after first dose

Inactivated poliovirus

––

4 weeks

6 mos.

A fourth dose indicated only if all previous doses administered <4 yrs. OR if third dose administered <6 mos. after second dose

––

Meningococcal

––

8 weeks

––

––

––

Measles, mumps, rubella

––

4 weeks

––

––

––

Varicella

––

3 mos. if age <13 years OR 4 weeks if age ≥13 years

––

––

––

a Administer MenACWY vaccine at age 13 through 18 years if not previously vaccinated. If the first dose is administered at age 13 through 15 years, a booster dose should be administered at age 16 through 18 years with a minimum interval of at least 8 weeks between doses. If the first dose is administered at age 16 years or older, a booster dose is not needed.

b Administer the second dose 4 weeks after the first dose and the third dose 12 weeks after the second dose.

Source: [12]

Major changes to the annually published childhood schedule in the last decade have included [11]:

- 2003: Influenza vaccination was to be "encouraged" for all children 6 to 23 months of age.

- 2004: Influenza vaccination was recommended for all children 6 to 23 months of age and close contacts of children 0 to 23 months of age.

- 2006: Tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine replaced Td for adolescents, meningococcal conjugate vaccine (MCV) was recommended for certain age groups, and HepA was expanded to include all children, not just those in selected areas.

- 2007: Rotavirus and HPV vaccines were added. Influenza vaccination was expanded to all children 6 to 59 months of age. A second VAR dose was recommended for all children.

- 2008: The recommendation for MCV was expanded to include immunization of all children 11 years of age and older at the earliest opportunity.

- 2009: The recommendation for influenza vaccination was expanded to include children 6 months to 18 years of age (beginning with the 2008–2009 season).

- 2012: HPV vaccination recommendation extended to include boys 11 or 12 years of age.

- 2016: Meningococcal B vaccine added for high-risk children and adolescents 10 years of age and older.

Other changes to the childhood schedule have added to the potential for confusion. For example, there are two different rotavirus vaccines, with different numbers of doses. Understanding the differences is essential to these vaccines' safe and effective use.

Until 2009, a shortage of Hib had led to many children missing their 12 to 15 month booster dose; however, a new vaccine to cover that dose was approved during 2009 and has led to a recommendation that children 12 months to 4 years of age receive a catch-up dose at the earliest opportunity [13]. In mid-2009, the ACIP also made some changes and clarifications to the recommendations for IPV, including extending the minimum interval between doses 3 and 4 from four weeks to six months and noting that the final dose in the IPV series should be given when the patient is 4 years of age or older, regardless of the number of previous doses [14]. This updated recommendation also includes clarifications regarding the use of combination vaccines.

THE ADULT IMMUNIZATION SCHEDULE

As noted, the adult immunization schedule was created in 2002 to bring together the recommendations for routine vaccination of adults and to help healthcare professionals recall the specific needs of patients in certain chronic disease groups. The intention was to provide an up-to-date tool for providers to use in assessing patients' vaccination needs, creating standing orders and reminder systems, and otherwise reducing missed opportunities for vaccination [15].

The original adult schedule had a relatively short list of routine vaccinations for healthy persons, including [11]:

- Td every 10 years

- Annual influenza vaccine for adults 50 years of age and older

- PPSV for adults 65 years of age and older, with 1 booster for certain patients

- MMR (up to age 49 years) and varicella for those who are susceptible

Since that time, several changes have been made (Table 4 and Table 5). The recommendation for routine vaccination against influenza was temporarily changed to age 65 years and older due to a vaccine shortage, but it has now returned to include all patients 6 months of age and older. Tdap is now recommended in lieu of one Td dose for adults up to 64 years of age. HPV vaccine is recommended for women and men up to 26 years of age, and the herpes zoster vaccine is routine for adults 60 years of age and older.

Table 4: RECOMMENDED ADULT IMMUNIZATION SCHEDULE BY VACCINE AND AGE GROUP, 2019

Vaccine

19–21 years

22–26 years

27–49 years

50–64 years

65 years and older

Influenza (IIV, RIV, or LAIV)

1 dose (IIV, RIV, or LAIV) annuallya

1 dose (IIV or RIV) annuallya

Tetanus, diphtheria, pertussis (Td or Tdap)

One dose of Tdap, then boost with Td every 10 years

Varicella

2 doses (if born in 1980 or later)a

—

Human papillomavirus (female)

2 or 3 dosesa

—

—

—

Human papillomavirus (male)

2 or 3 dosesa

2 or 3 dosesb

—

—

—

Zoster

—

—

—

2 doses RZV (preferred) or 1 dose ZVLa

Measles, mumps, rubella

1 or 2 doses (if born 1957 or later)a

—

Pneumococcal 13-valent conjugate (PCV13)

1 doseb

1 dosea

Pneumococcal polysaccharide (PPSV23)

1 or 2 dosesb

1 dosea

Hepatitis A

2 or 3 dosesb

Hepatitis B

2 or 3 dosesb

Meningococcal ACWY

1 or 2 doses, then booster every 5 yearsb

Meningococcal B (MenB)

2 or 3 dosesb

Haemophilus influenzae type b (Hib)

1 or 3 dosesb

aFor all patients in this category who lack evidence of immunity.

bRecommended if other risk factor is present.

Source: [19]

VACCINES THAT MIGHT BE INDICATED FOR ADULTS BASED ON MEDICAL AND OTHER INDICATIONS, UNITED STATES, 2019

Vaccine

Pregnancy

Immunocompromised (excluding HIV)

HIV infection

Men who have sex with men (MSM)

CD4+ <200 cells/mcL

CD4+ ≥200 cells/mcL

Tetanus, diphtheria, pertussis (Td or Tdap)

1 dose Tdap each pregnancy

1 dose Tdap, then boost with Td every 10 yearsa

Human papillomavirus (female)

Delay

3 doses through 26 years of agea

—

Human papillomavirus (male)

—

3 doses through 26 years of agea

2 or 3 doses through 26 years of agea

Varicella

Contraindicated

2 dosesa

Zoster

Delay RZV

ZVL contraindicated

ZVL contraindicated

—

2 doses RZV or 1 dose ZVLa

Measles, mumps, rubella

Contraindicated

1 or 2 dosesa

Influenza

1 dose annuallya (LAIV contraindicated)

1 dose annuallya

Pneumococcal polysaccharide (PPSV23)

1, 2, or 3 dosesb

1, 2, or 3 dosesa

1, 2, or 3 dosesb

Pneumococcal 13-valent conjugate (PCV13)

—

1 dosea

1 doseb

Hepatitis A

2 or 3 dosesb

2 or 3 dosesa

Hepatitis B

3 dosesb

3 dosesa

Meningococcal ACWY

1 or 2 doses, then booster every 5 yearsb

1 or 2 doses, then booster every 5 yearsa

1 or 2 doses, then booster every 5 yearsb

Meningococcal B (MenB)

Exercise precaution

2 or 3 dosesb

Haemophilus influenzae type b (Hib)

—

3 doses post-stem cell transplant recipients onlya

1 doseb

Table 5: VACCINES THAT MIGHT BE INDICATED FOR ADULTS BASED ON MEDICAL AND OTHER INDICATIONS, UNITED STATES, 2019 (Continued)

Vaccine

Heart disease, lung disease, chronic alcoholism

Asplenia, complement deficiencies

Chronic liver disease

Diabetes, end-stage renal disease, hemodialysis

Healthcare personnel

Tetanus, diphtheria, pertussis (Td/Tdap)

1 dose Tdap, then boost with Td every 10 yearsa

Human papillomavirus (female)

2 or 3 doses through 26 years of agea

Human papillomavirus (male)

2 or 3 doses through 21 years of agea

Varicella

2 dosesa

Zoster

2 doses RZV (≥50 yrs) or 1 dose ZVL (≥60 yrs)a

—

2 doses RZV (≥50 yrs) or 1 dose ZVL (≥60 yrs)a

Measles, mumps, rubella

1 or 2 dosesa

Influenza

1 dose annually (exercise precaution with LAIV)a

1 dose annually (LAIV contraindicated)a

1 dose annually (exercise precaution with LAIV)a

1 dose annuallya

Pneumococcal polysaccharide (PPSV23)

1, 2, or 3 dosesa

1, 2, or 3 dosesb

Pneumococcal 13-valent conjugate (PCV13)

1 doseb

1 dosea

1 doseb

1 dosea (for diabetesb)

1 doseb

Hepatitis A

2 or 3 dosesb

2 or 3 dosesa

2 or 3 dosesb

Hepatitis B

3 dosesb

3 dosesa

Meningococcal 4-valent conjugate (MenACWY)

1 or 2 doses, then booster every 5 yearsb

1 or 2 doses, then booster every 5 yearsa

1 or 2 doses, then booster every 5 yearsb

Meningococcal B (MenB)

2 or 3 dosesb

2 or 3 dosesa

2 or 3 dosesb

Haemophilus influenzae type b (Hib)

1 doseb

1 dosea

1 doseb

aFor all patients in this category who lack evidence of immunity.

bRecommended if other risk factor is present.

Source: [19]

Since 2009, annual vaccination has been recommended for all persons 6 months of age and older. The 2019–2020 influenza vaccine contained an H1N1-like antigen as well as H3N2 and two B antigens [20].

3. VACCINES AND RECOMMENDATIONS

Given the large number of vaccines now recommended, both parents and adult patients often have concerns about whether all the doses are needed. The following review of the rationale behind the changes to the child, adolescent, and adult immunization schedules is intended to help clinicians improve their own understanding and explain the rationale to patients.

SEASONAL INFLUENZA

Evidence Based Practice Recommendation

According to the Advisory Committee on Immunization Practices (ACIP), routine annual influenza vaccination is recommended for all children 6 months through 18 years of age.

https://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf

Last Accessed: February 15, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Recommendation for Children: Influenza vaccine is recommended annually for children 6 months through 18 years of age. Two doses, separated by at least four weeks, should be given to children if they are receiving influenza vaccine for the first time. Also give two doses if the child was vaccinated for the first time the prior season but received only one dose. For the 2019–2020 season, use of live attenuated influenza vaccine (LAIV) may be considered.

Recommendation for Adults: Vaccination is recommended annually for all adults without a contraindication with inactivated influenza vaccine (IIV) or recombinant influenza vaccine (RIV). Other options include high-dose or adjuvanted IIV for adults 65 years of age or older or intradermal IIV for adults 18 to 64 years of age. IIV or RIV should be used for age-appropriate persons with severe egg allergy (i.e., involving symptoms other than hives). Women who are or may become pregnant should not receive LAIV.

The expansion of the recommended ages for the vaccination of children and adults against influenza is one of the most significant changes to the schedule in recent years. It requires an annual visit to a healthcare provider, including among older children and young adults who typically have low rates of physician visits.

The ACIP considered multiple factors in making this recommendation. First, according to accumulated evidence, the influenza vaccine appears to be both safe and effective, with the benefits of vaccination outweighing the small risk of adverse effects [21]. Widespread vaccination is also intended to lower the social and economic impact of influenza. The number of missed days of school for children and missed days of work for parents is substantial. Physician visits for the flu may lead to a prescription for antibiotics—treatment that is unnecessary and potentially dangerous.

The recommendation is also intended to simplify the decision to advise vaccination for children [21]. In previous years, vaccination was recommended for a number of groups with specific risk factors. These included older children with certain medical conditions and children who were close contacts of people who should be immunized. Making vaccination routine for all children is expected to lead to a 50% increase in coverage for those children who have a specific risk-based or contact-based indication.

Another change, for both children and adults, was the development of LAIV, a nasal-spray vaccine that can be easier for some patients to accept than an injection [22]. Data from the 2015–2016 flu season found an only 3% efficacy rate with LAIV (compared with 63% with IIV), and LAIV was not recommended between 2015 and 2018 season [19,20]. However, the 2018–2019 influenza guideline reintroduced LAIV as an option for persons 2 to 49 years of age for whom it is appropriate, and it remained an option in the 2019–2020 guideline [20]. This excludes women who are pregnancy and those with HIV, immunocompromise, asplenia, and/or complement deficiencies.

TETANUS/DIPHTHERIA/PERTUSSIS

Recommendation for Children: DTaP is recommended at 2, 4, 6, and 15 to 18 months of age (or as early as 12 months, if 6 months have passed since the last dose) and at 4 to 6 years of age. Tdap is recommended at 11 to 12 years for children who have completed the recommended childhood DTP/DTaP vaccination series and have not received a Td booster dose and for older children who have not received a dose. If a child has already received Td, a five-year interval before Tdap is encouraged unless pertussis protection is specifically needed.

Recommendation for Adults: Td booster every 10 years. Tdap replaces one Td dose for adults who have not already received Tdap. (See immunization schedule for special situations, including adults who have not received primary childhood vaccination and pregnant women.)

The inclusion of Tdap on the adult immunization schedules may create confusion because it replaces a dose of Td that was previously routine and patients may be uncertain about which vaccine they received. However, Tdap also has the potential to make an important impact on the public's health [23]. In the past, vaccination against pertussis was given only during young childhood. However, immunity against pertussis declines within about 5 to 10 years [23]. Reported cases of pertussis increased steadily from the 1980s to a peak in 2014. In 2017, 18,975 cases were reported—a decrease of more than 42% since 2014—but many more go undiagnosed and unreported [24]. Infants younger than 1 year of age are at highest risk and continue to have the highest reported rate of pertussis; nearly half require hospitalization. Adolescents 11 to 19 years of age and adults 20 years of age and older accounted for approximately 47.1% of reported cases in 2017; cases among children 7 to 10 years of age accounted for approximately 13.7% of reported cases [24]. Adults may also have complications including pneumonia, rib fracture, and loss of consciousness ("cough syncope") [25]. The true risks are somewhat unclear, however, because cases without a classic presentation are less likely to be diagnosed and reported.

The primary objective of the ACIP in recommending Tdap for adolescents is to protect individual adolescents against pertussis while continuing the standard protection against tetanus and diphtheria [23]. An important secondary goal is to reduce the reservoir of pertussis within the population as a whole. This may be particularly important for infants. The recommendation for adults was put in place primarily to protect individual adults against pertussis and also to reduce the reservoir of pertussis [25]. Widespread immunization of adults may also reduce the impact of pertussis on healthcare facilities and other institutional settings.

The recommended timing of Tdap vaccination takes into account recommendations for the administration of other tetanus and/or diphtheria toxoid-containing vaccines, including MenACWY, because of an association between frequent doses of such vaccines and a risk of increased local and systemic reactogenicity [23].

HUMAN PAPILLOMAVIRUS

Recommendation for Adolescents: HPV vaccine is recommended for girls and boys 11 to 12 years of age and for older adolescents who have not yet been vaccinated. Children 9 to 10 years of age may also be vaccinated.

Recommendation for Adults: HPV vaccine is recommended for adult women up to 26 years of age who have not completed the vaccine series. HPV vaccine is also recommended for men up to 21 years of age and older men (up to 26 years of age) if desired or if a risk factor is present.

When it was first added, there was significant public controversy over the inclusion of the HPV vaccine on the adolescent immunization schedule. Some parents remain concerned about the vaccine's safety or about the possibility of promoting sexual activity among young teens. Meanwhile, in some places this vaccine is now required for school attendance, although exemptions are generally allowed [27].

Statistics regarding HPV infection and cervical cancer illustrate the rationale behind the vaccine itself. About 13,170 cases of cervical cancer will be diagnosed in the United States in 2019, and more than 4,250 will die from the disease [28]. The CDC estimates that 43,371 new cancers attributable to HPV occurred in 2015 [16].

There are three licensed HPV vaccines available in the United States: Cervarix, Gardasil, and Gardasil 9. Cervarix is a bivalent vaccine covering HPV types 16 and 18; however, this vaccine is no longer used in the United States [12]. Gardasil and Gardasil 9 are recommended for girls 11 and 12 years of age, women 13 to 26 years of age not previously vaccinated, and boys and men 9 to 26 years of age [29,108]. Gardasil is a quadrivalent vaccine covering types 6, 11, 16, and 18 [30,31]. In 2014, a 9-valent HPV recombinant vaccine (Gardasil 9) was approved that adds protection to HPV types 31, 33, 45, 52, and 58 in addition to those types covered by the original Gardasil [108]. In 2018, the FDA approved expanded use of Gardasil 9 to include women and men up to 45 years of age [113]. Three-fourths of cervical cancers are squamous cell tumors, and HPV 16 and 18 account for about 68% of these [32]. The rest are adenocarcinomas, and HPV types 16 and 18 account for about 83% of these tumors [32]. The increased coverage of the 9-valent vaccine has the potential to prevent up to 90% of cervical, vulvar, vaginal, and anal cancers [108].

Epidemiologic data on HPV incidence and age of sexual debut suggest that the pre-teen years are an appropriate time to begin HPV protection [32]. Genital HPV is the most common sexually transmitted infection in the United States, with 14 million new infections among people 15 to 59 years of age each year. Teens and young adults are particularly at risk; 49% percent of those infections occur in individuals 15 to 24 years of age. One multisite, clinic-based study of sexually active females found the highest prevalence of HPV in girls 14 to 19 years of age. In another study, using a representative, population-based sample, HPV prevalence was 26.9% among sexually active women 18 to 25 years of age [33]. The prevalence of types 16 or 18 was 7.8%. Another study, also intended to be representative of the general population, found that the prevalence of HPV was 26.8% for women 14 to 59 years of age and nearly 45% among women 20 to 24 years of age [34]. In the overall study population, the prevalence of type 16 was 1.5%, and type 18 was 0.8%.

An important consideration in protecting girls who are not yet sexually active is that HPV infection is common within the first few years after sexual debut [32]. In addition, studies have shown high antibody titers with vaccination at age 11 to 12 years. The projected impact of vaccinating girls at 12 years of age is a 20% to 66% reduction in lifetime cervical cancer risk, depending on the effectiveness of the vaccine and the duration of protection. Vaccination could also lead to a 21% reduction in low-grade abnormalities on Pap tests over the life of a cohort of vaccinated females. A comparison of HPV prevalence data from the vaccine era (2009–2012) and the prevaccine era (2003–2006) found that the prevalence of the HPV types included in the quadrivalent vaccine decreased by 64% (from 11.5% to 4.3%) among girls 14 to 19 years of age [17]. Considering the modest uptake of this vaccine, the potential impact is significant.

The recommendation to vaccinate young adult women takes into account the fact that many will already be sexually active and may have been exposed to one or more types of HPV. Young women who are not yet sexually active can receive the full benefit of vaccination. In addition, it is likely that many women who are infected have not yet encountered each of the vaccine-covered types, so they can receive at least partial benefit [35,36]. The recommendation to vaccinate adults to the age of 26 years, but not after, reflects the safety and efficacy testing on which the vaccines' approvals were based [30,31,37]. Use in older women is being studied, and as noted, the FDA has approved use up to 45 years of age.

ROTAVIRUS

Recommendation for Children: Rotavirus vaccine is recommended for infants 6 weeks to 14 weeks of age (maximum age for first dose: 14 weeks 6 days). The last dose should be given by age 8 months, 0 days.

A rotavirus vaccine was first added to the immunization schedule in 1999 but was quickly taken off the market due to concerns about intussusception. The two available vaccines have each been tested in hundreds of thousands of infants [38,39]. A large-scale study completed in 2014 found a slight increase in risk with RV5 (1.5 excess cases of intussusception per 100,000 recipients of the first dose) and some evidence of an elevated risk with RV1 [38]. However, these data should be considered in light of the benefits of vaccination. In an effort to maximize safety, these vaccines have a narrow age range for administration, reflecting the ages of the children in the large safety studies.

In adding rotavirus vaccination to the routine immunization schedule, the ACIP observed that rates of illness are similar in industrialized and less developed countries, suggesting that public health measures such as clean water supplies and good hygiene are not enough to control rotavirus disease [40]. Further, there is a high level of morbidity due to rotavirus in the United States in spite of available medical care. In the years before vaccination was available, rotavirus was responsible for approximately 20 to 60 deaths each year, 55,000 to 70,000 hospitalizations, more than 200,000 emergency department visits, 400,000 physician visits, and direct and indirect costs of approximately $1 billion [40,41].

The vaccines are designed to mimic the effect of a first bout of rotavirus, which is usually the most serious [40]. Subsequent bouts of symptomatic infection can occur after a first natural infection, but they tend to be milder. As such, vaccination is not expected to prevent disease entirely but to reduce the severity of symptoms, the need for medical care, and the risk of serious sequelae, including hospitalization and death.

In 2009, the age parameters for vaccine administration were adjusted to harmonize the schedules of the two approved rotavirus vaccines [40]. One is a pentavalent reassortant vaccine based on a bovine rotavirus, often abbreviated as RV5. The other is a live, attenuated human rotavirus vaccine, often abbreviated as RV1. RV5 has a three-dose schedule, while RV1 requires two doses [41]. The maximum ages for these vaccines are somewhat different, according to their prescribing information, but an ACIP workgroup has concluded that safety and efficacy are unlikely to be affected if the same age limits are used for both [40].

MENINGOCOCCAL DISEASE

Recommendation for Children: MCV is recommended routinely for children 11 to 18 years of age, for older children who have not yet been vaccinated, and for children 6 weeks to 10 years of age in certain risk groups. MenB vaccination is recommended for children 10 to 18 years of age in certain risk groups. In addition, young adults 16 to 23 years of age (preferred age range: 16 to 18 years) may be vaccinated to provide short-term protection against most strains of serogroup B meningococcal disease.

Recommendation for Adults: MenACWY vaccine is recommended for adults 19 years of age and older with increased risk for meningococcal disease, including military recruits, freshmen college students living in dormitories, persons without a spleen or with a damaged spleen, those with terminal complement deficiency, and persons traveling to or residing in countries in which the disease is common. Revaccination with MenACWY every five years is recommended for adults previously vaccinated who remain at increased risk of infection. MenB vaccine is recommended for adults with certain risk factors, including all adults with anatomical or functional asplenia or persistent complement component deficiencies.

Historically, before widespread vaccination, there were about 1,400 to 2,800 cases of meningococcal disease in the United States each year [42]. Although not a common illness, meningococcal disease has a rapid course and a high degree of mortality, with a case-fatality ratio of about 10% to 14%. Among survivors, 11% to 19% will experience serious sequelae, such as neurologic deficit, deafness, or loss of a limb [43]. The degree of severity means that, in addition to putting the patient's life at risk, each case requires a substantial public health effort to identify additional cases quickly and prevent the disease from spreading [44].

There are two main types of serogroup A, C, W, and Y meningococcal vaccine: MenACWY and MPSV. However, MPSV is no longer available in the United States. The three available vaccines are Hib-MenCY (6 weeks to 55 years), MenACWY-D (9 months to 55 years), and MenACWY-CRM (2 months to 55 years) [19]. Needs for expanded coverage include a vaccine to cover serotype B [42]. While the Hib-MenCY vaccine, approved in 2012, is an option for infants, it provides coverage of only serotypes C and Y [107]. The serogroup most common in infants, serogroup B, is not covered by any currently licensed vaccine [43]. MenACWY covers serogroups C, Y, A, and W-135 [44]. In the United States, serogroups C, Y, and B have each been responsible for about one-third of cases overall.

In 2010, the novel quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, was licensed by the FDA as a single dose for use in patients 11 to 55 years of age. The ACIP also recommends vaccination with MenACWY-CRM for persons 2 months of age and older who are at increased risk for meningococcal disease [45].

Incidence of meningococcal disease also increases during adolescence, and this group is the main focus of the recommendations for vaccination with MenACWY. Among people 11 years of age and older, 75% of cases are caused by group C, Y, or W-135, which are all covered by the vaccine [42]. The original recommendation for the use of MenACWY focused on certain age groups: children 11 to 12 years of age, children entering high school, and college freshmen who would be living in dorms. These specifications were created because of concerns about there being a short supply of vaccine during the first few years of production [47]. Now that supply is expected to be adequate, the recommendation is to vaccinate all children 11 years of age and older who have not previously received vaccination against meningococcus, with a booster at 16 years of age. This broader recommendation is intended to simplify decisions about vaccinating and improve overall coverage. The child and adolescent immunization schedules provide details about revaccinating children who have received MPSV in the past.

Creating a vaccine against serogroup B was particularly challenging because of its immunochemical structure. However, the first vaccine to protect against invasive meningococcal disease caused by Neisseria meningitidis serogroup B was approved by the FDA in 2014 [46]. There are now two MenB vaccines available: MenB-FHbp and MenB-4C [18]. The MenB vaccines are approved for use in persons 10 to 25 years of age; however, because there is no theoretical difference in safety for persons older than 25 years of age compared to those in the approved age-group, MenB vaccine is recommended for routine use in persons older than 10 years of age who are at increased risk for serogroup B meningococcal disease [19]. MenB vaccine should either be administered as a three-dose series of MenB-FHbp or a two-dose series of MenB-4C. The two vaccines are not interchangeable; the same vaccine product must be used for all doses [18]. MenB vaccine may be administered concomitantly with MenACWY vaccine but at a different anatomic site, if feasible [19].

HEPATITIS A

Recommendation for Children: HepA is recommended for all children 12 to 23 months of age and for unvaccinated children 24 months and older if immunity is desired.

Recommendation for Adults: HepA is recommended for certain risk groups.

Hepatitis A can be a serious disease. According to U.S. surveillance data, an estimated 11% to 22% of people who contract hepatitis A are hospitalized [48]. Adults who are hospitalized lose an estimated 33 days of work, and those who do not require hospitalization lose about 15 days [48]. In the pre-vaccine era, infection was especially common among children. Although young children often had asymptomatic or unrecognized infection, they were an important source of disease transmission.

Evidence Based Practice Recommendation

The ACIP recommends immunizing adults for hepatitis A who travel to or work in countries that have high or intermediate endemicity of hepatitis A, who are users of injection or noninjection illicit drugs, and men who have sex with men.

https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf

Last Accessed: February 15, 2019

Level of Evidence: Expert Opinion/Consensus Statement

The ACIP has been pursuing an incremental strategy to increase immunization, with the goal of potentially eliminating indigenous hepatitis A virus transmission entirely [48]. At first, routine vaccination for healthy children was recommended only for areas with high rates of disease. Implementation of vaccination in such regions led to a decline in local disease rates to the lowest levels ever recorded. This left the highest rates in places where routine vaccination was not yet recommended. The next step was the current recommendation to vaccinate all children at 1 year of age [12]. (Some local programs also incorporate vaccination of older children.)

The range to begin routine vaccination, 12 to 23 months of age, was chosen in part because well-child visits are more frequent before 2 years of age. Vaccination is also recommended for older children and adults in certain high-risk groups. Younger children (6 to 12 months of age) may be vaccinated if they will be travelling internationally [12].

HERPES ZOSTER

Recommendation for Adults: Zoster vaccine is recommended for individuals 50 years of age and older.

There are an estimated 1 million cases of herpes zoster each year, and incidence increases with age [49]. Without vaccination, about one-third of Americans will experience shingles at some point in their lives [49]. In addition to discomfort and inconvenience for the patient, there is also a risk of viral transmission leading to primary varicella in at-risk contacts. Postherpetic neuralgia (PHN) is an unfortunate but fairly common complication. A community-based study in Minnesota looked at the incidence of PHN as defined by various durations of pain [50]. Eighteen percent of patients experienced PHN-type pain for at least 30 days, 13% for at least 60 days, and 10% for at least 90 days [50]. The ACIP added the zoster vaccine to the adult immunization schedule to take advantage of the opportunity to decrease both the burden of disease and the risk of complications. In 2018, the recombinant zoster vaccine (RZV) was added as the preferred vaccine for adults 50 years of age and older [19]. This newer vaccine has better proven efficacy in preventing herpes zoster, and breakthrough cases are associated with less severe herpes zoster-related pain and less interference on activities of daily living [56].

Although treatment for herpes zoster is available, it does not always fully alleviate symptoms [63]. In addition, the potential effectiveness of treatment initiated more than 72 hours after rash onset has not been established. When PHN occurs, treatments often have limited effectiveness, and tolerance in older patients may be poor.

In a large clinical trial comparing the ZVL vaccine to placebo, the incidence of herpes zoster was reduced by 51.3% in vaccinated patients, and pain associated with shingles was substantially reduced [51]. The incidence of PHN (defined as persistent pain for 90 days) was reduced by 66.5%.

Of note, the zoster vaccine is recommended whether or not the patient has had a prior episode of shingles [19,63]. The zoster vaccine is not recommended for patients who have received the varicella vaccine.

PNEUMOCOCCAL VACCINES

Recommendation for Children: PCV13 is recommended at 2, 4, 6, and 12 to 15 months of age. (PPSV23 is also recommended for certain risk groups at 2 years of age or older, with a single revaccination after 2 years).

Recommendation for Adults: PPSV is recommended for individuals 65 years of age and older and for younger adults in certain risk groups. One-time revaccination recommended after five years for people in certain risk groups and for those 65 years and older who were first vaccinated before 65 years of age. PCV13 is recommended for adults 65 years of age or older or 19 years of age and older with certain risk factors.

The pneumococcal conjugate vaccine recommended for routine use in healthy children, PCV13, covers 13 serotypes of Streptococcus pneumoniae. The use of this vaccine has led to a significant decline in IPD, from 98.7 cases per 100,000 children younger than 5 years of age in 1997–1999, to less than one case per 100,000 by 2007 and continuing to 2015 [2,52]. Rates of all-cause pneumonia in children younger than 2 years of age have also declined, by about 35% between 1997 and 2006 with use of a vaccine covering seven serotypes [53]. Most of this decline occurred shortly after the vaccine became available.

However, the rates of non-PCV type IPD had been rising, and overall rates of IPD plateaued between 2002 and 2005 [52]. This prompted the development of the 13-valent pneumococcal conjugate vaccine, licensed in 2010. PCV13 includes coverage for six additional serotypes, which are responsible for a large proportion of remaining IPD [54]. Invasive pneumococcal disease caused by the 13 serotypes covered by PCV13 decreased from 91 cases per 100,000 people in 1998 to 2 cases per 100,000 people in 2015 [26].

Of note, PPSV, the 23-valent vaccine included on the adult immunization schedule, protects against 12 of the 13 serotypes in PCV13. PPSV can also be used in children and is recommended for certain risk groups, but it is not immunogenic in infants and very young children and is indicated for use only in people 2 years of age and older.

4. VACCINE CONTRAINDICATIONS

GENERAL INFORMATION

Confusion about contraindications can lead to undervaccination or, occasionally, to serious adverse events if contraindicated vaccines are given. There are a few general safety considerations that apply to all vaccines. There are also several situations in which healthcare professionals may hesitate to administer vaccines, when in fact most could be given with a high degree of safety.

As a general rule, a serious allergic reaction to a prior dose or a severe allergy to any vaccine component is a contraindication to the use of any vaccine [55]. In most cases, vaccination should be deferred in the setting of moderate or severe acute illness.

On the other hand, vaccination is generally not contraindicated in the following situations [55]:

- Mild acute illness, with or without low-grade fever, or recovering from illness

- Lack of previous physical examination in well-appearing person

- Current use of antimicrobial therapy (except certain antivirals with VAR and zoster)

- Premature birth (except HepB in certain circumstances)

- Recent exposure to infectious disease

- History of non-vaccine allergy

- Current use of allergen extract immunotherapy

- History of Guillain-Barré syndrome (GBS)

The prescribing information for VAR does note a small possibility of transmission of vaccine virus to healthy susceptible contacts (including pregnant women if they are susceptible to varicella) and recommends weighing this small risk against the risk of acquiring and transmitting natural varicella virus [57]. The prescribing information for the live zoster vaccine contains a similar caution, recommending that patients be informed of the possibility of transmission [58].

The following details about specific contraindications and cautions are based primarily on recommendations from the CDC. The CDC reports and current prescribing information should always be consulted.

ALLERGY/HYPERSENSITIVITY

The ingredients, contraindications, and precautions for any vaccine should be reviewed before administering it to a patient with known allergies or a history of a severe reaction to a previous dose or to any vaccine ingredient. However, clinicians can be well served by recalling many of the potential hypersensitivities. Table 6 is based on a list of contraindications and cautions as recommended by the CDC, which provides recommendations when anaphylactic allergy is present [55]. (A fully definitive list is beyond the scope of this course.)

Table 6: HYPERSENSITIVIES AND VACCINE RECOMMENDATIONS

Hypersensitivity

Vaccine

CDC Recommendation

Yeast

HPV

Do not use

Eggs

Influenza (LAIV)

Do not usea

Latex

Rotavirus (RV1), MenB

Check packaging to see if latex is used and for guidance

Gelatin

MMR

Varicella

Use extreme caution if administering

Zoster

Do not use

Neomycin

IPV

MMR

Varicella

Zoster

HepA

Some influenza vaccines

Do not use

Streptomycin

IPV

Do not use

Polymyxin B

IPV

Some influenza vaccines

Do not use

Thimerosal

Some brands/formulations, including certain DTaP, influenza (IIV), Td, DT

Check package insert

aProtocols have been devised for administering IIV to patients with egg allergies.

Source: [20,29]

IMMUNODEFICIENCY

Immunodeficiency creates a potentially confusing situation regarding vaccination, because there are different degrees and causes of immune suppression. In general, the CDC recommends that MMR, varicella, and LAIV, which contain live virus, should not be used [55]. The prescribing information for LAIV notes that administration to immunocompromised patients requires careful weighing of benefits and risks [22]. If the patient is healthy but there is a close contact who is severely immunosuppressed and requires care in a protective environment, IIV is preferred over LAIV [55].

VAR also contains live virus. According to the CDC, it is contraindicated in patients with cellular immunodeficiencies but may be used in patients with impaired humoral immunity [55]. The prescribing information, however, includes hypogammaglobulinemic and dysgammaglobulinemic states as contraindications [57]. If a first-degree relative has congenital or hereditary immunodeficiency, VAR should not be given unless the patient's own immune competence has been verified [57,59]. For such patients, the prescribing information for MMR notes that it, too, should also be deferred until immune competence is confirmed [60]. According to the prescribing information for VAR, because there may be rare transmission of the vaccine virus between recipients and susceptible contacts, recipients should try to avoid contact with susceptible, high-risk contacts for up to six weeks [57]. This includes immunocompromised persons and pregnant women if they are susceptible to chickenpox. (If contact is unavoidable, vaccination risk should be weighed against the risk of acquiring and transmitting natural varicella virus.)

The zoster vaccine, another live-virus vaccine, is also contraindicated in many forms of immunodeficiency. According to CDC recommendations, it may be administered to people with impaired humoral immunity such as hypogammaglobulinemia, although in the prescribing information, a history of primary or acquired immunodeficiency is listed as a contraindication [55,58]. As with VAR, it is noted that transmission of the vaccine virus to susceptible contacts may rarely occur.

The safety and efficacy of the rotavirus vaccines have not been established in patients who are immunosuppressed. In such patients, the ACIP recommendation is to consult with an infectious disease specialist or immunologist before giving the vaccine [40]. In phase 3 studies of RV5, viral shedding was observed as long as 15 days after a dose, raising concerns about use in patients with immunosuppressed contacts [61]. However, the actual risk of transmission is unknown. RV1 can also be shed after a dose, with shedding tending to peak at about seven days [62]. Again, the risk of transmission is not known.

Many vaccines may be less immunogenic in patients who are immunosuppressed. Potential effectiveness, as well as timing in patients taking immunosuppressive therapy, should be considered.

PREGNANCY

A few of the routine vaccines for healthy persons are contraindicated in pregnancy. MMR and VAR should not be used, and the CDC recommends against the use of LAIV [55]. The zoster vaccine should also be avoided, although with the current age indication it is unlikely a patient would be pregnant. For many other vaccines, safety during pregnancy is unknown. For example, there is little safety data on MCV and HPV vaccines when used in pregnant women, although caution is indicated with HPV [32,42,48,55]. If Td or Tdap is to be given, administration during the second or third trimester is preferred. For many vaccines without good pregnancy data, providers are encouraged to report any exposure to the vaccine in a pregnant woman to the manufacturer's pregnancy registry; details are provided in the prescribing information.

In general, prescribing information should be consulted for recommendations regarding individual vaccines and pregnancy, and risks and benefits reviewed with the patient as necessary.

TUBERCULOSIS

While a positive purified protein derivative (PPD) test on its own is not generally a contraindication to vaccination, some vaccines should not be used in the presence of active, untreated tuberculosis. In such cases, MMR should not be given, due to a theoretical risk of exacerbating the disease [55]. The zoster vaccine should also be deferred in patients with untreated, active tuberculosis.

HISTORY OF GUILLAIN-BARRÉ SYNDROME

Some vaccines have been associated with Guillain-Barré syndrome (GBS), although it is often unclear whether the vaccines actually cause this syndrome [55]. This section will summarize contraindications of routine vaccines for healthy children and adults with a history of GBS; more information about certain vaccines and GBS is included in the section on vaccine safety.

DTaP, Tdap, and Td all require caution if GBS occurred in a patient within six weeks after a previous dose of a vaccine containing tetanus toxoid [21,23,64,65]. Similarly, IIV/RIV requires caution if GBS occurred within six weeks of a prior influenza vaccination, and the CDC suggests considering not vaccinating such patients if they are not at high risk of influenza complications [21,64]. The prescribing information for LAIV recommends caution in any patient with a history of GBS, and the ACIP has identified history of GBS after an influenza vaccination as a contraindication [21,22]. The actual risks with these or other vaccines are not known, and providers should weigh the potential risk of vaccinating against the patient's risk of serious illness.

OTHER ISSUES

There are several other concerns or cautions with specific vaccines. Although it is not possible to list every issue here, a few of the specific contraindications will be discussed.

Rotavirus Vaccine and Gastrointestinal Disease

Some studies have suggested a small increase in the risk of intussusception following rotavirus vaccination [38,66]. In patients with a history of intussusception, benefits and risks should be weighed on an individual basis.

DTaP, Tdap, and Neurologic Events

Both DTaP and Tdap are contraindicated if encephalopathy occurred within seven days of a prior dose of a vaccine with pertussis components [23,25,55]. This is based on a possible link between DTP and encephalopathy and evidence suggesting an association between acellular pertussis vaccines and encephalopathy in Japan (about one attributable case per 10 million doses). Canadian surveillance data from 1993 to 2002, on the other hand, did not find a link between whole-cell or acellular pertussis vaccines and acute encephalopathy cases. Contraindications and precautions listed in the prescribing information for vaccines with pertussis components also include the presence of unstable or evolving neurologic disorders, and package inserts and the ACIP recommendations should be reviewed for details [67,68,69,70,71,72]. The CDC recommends that decisions about DTaP in children with proven or suspected neurologic conditions be decided on an individual basis [55].

With DTaP, caution should also be observed if reactions after a prior dose included events such as high fever, collapse or shock-like state, or persistent/inconsolable crying lasting three hours or more within two days of prior dose, or seizure within three days [23,25,55]. However, according to the ACIP recommendations, such reactions following DTP or DTaP should not be considered contraindications to use of Tdap or Td in adolescents and adults.

Of note, the prescribing information for some, but not all, tetanus toxoid-containing vaccines does caution against use in patients who have had neurologic reactions following a previous dose of Td or of tetanus toxoid.

DTaP, Tdap, Td, and Arthus Reactions

History of an Arthus reaction is another consideration with tetanus toxoid-containing or diphtheria toxoid-containing vaccines [23,25,55]. An Arthus reaction is a local vasculitis that is associated with an immune reaction. Although it is an uncommonly reported event after vaccination, it can occur with vaccines containing tetanus or diphtheria toxoid. Signs include swelling, induration, edema, and hemorrhage, and there may be local necrosis. Pain is severe. The CDC recommends that, in a patient who experienced an Arthus reaction after a prior dose of tetanus toxoid- or diphtheria toxoid-containing vaccine, providers should consider deferring doses of DTaP, Tdap, or Td for at least 10 years [55]. If the reaction was to a vaccine with diphtheria toxoid but not tetanus toxoid, and more than 10 years have elapsed since tetanus vaccination, the patient can be evaluated for serum antitetanus level to determine if tetanus protection is needed before vaccination is considered.

Vaccines Containing Diphtheria or Tetanus Components

Certain vaccines contain diphtheria or tetanus components, although they are indicated for prevention of other diseases. For example, MCV and PCV contain a diphtheria component (but no tetanus toxoid) and therefore should be avoided in patients with hypersensitivity to diphtheria toxoid [73,74]. In MCV, Neisseria meningitides capsular proteins are conjugated to diphtheria toxoid protein. In PCV, capsular antigens of Streptococcus pneumoniae are conjugated to diphtheria CRM197 protein. Certain Hib vaccines contain a Haemophilus influenzae capsular polysaccharide bound to a tetanus toxoid [75]. As always, vaccine components should be reviewed in patients who have known hypersensitivities or have had serious reactions to prior vaccinations.

Influenza (LAIV) and Acute or Chronic Illness

The ACIP recommends that LAIV not be used in patients with asthma or other conditions predisposing to flu complications [12,21]. In most cases, IIV can be used instead. LAIV should also be avoided in children and adolescents who are receiving aspirin or salicylate therapy. Acute respiratory illness with nasal congestion, which could interfere with delivery of the vaccine, is a reason to consider delaying the use of this vaccine until the congestion has decreased. Children younger than 5 years of age who have recent or recurrent wheezing should not receive LAIV [12,21].

PPSV Considerations

According to the prescribing information, PPSV should be deferred in patients with febrile respiratory illness or other active infection, unless the benefit of vaccinating at that time outweighs the risk [76]. Some providers revaccinate with PPSV every five years. However, revaccination is not recommended in most healthy patients [77]. Most adults will need one lifetime dose. A second dose should be given to patients who are 65 years of age and older if they were previously vaccinated with PPSV prior to 65 years of age and if more than five years have passed [19]. Children and adults at very high risk of serious pneumococcal disease or who are likely to have a rapid decline in antibody levels (such as those with anatomic or functional asplenia or who are immunocompromised) should also receive a second dose at least five years after the first [19].

5. VACCINE SAFETY

Vaccine safety is initially established through clinical trials, and benefits must be shown to outweigh any risks before a new vaccine can be approved. However, the trial populations are not necessarily large enough to ensure that all possible adverse events are observed. Postmarketing surveillance provides additional safety information.

In the United States, vaccine safety is monitored through three major systems. The Vaccine Adverse Event Reporting System (VAERS) invites voluntary reporting [80]. VAERS receives approximately 30,000 reports annually, with most reports coming from vaccine manufacturers and healthcare providers. About 85% to 90% of the reports describe mild side effects such as fever, arm soreness, and crying or mild irritability. Reporting forms are available at the VAERS website, https://vaers.hhs.gov. This type of surveillance is a useful way to collect information about possible adverse events, particularly uncommon events. However, with no control group, it is often difficult to be certain whether reported events are truly related to vaccination. Researchers often compare reported events to background rates of disease, but because reporting is voluntary (referred to as passive reporting), it is not possible to know the true number of events. VAERS therefore serves primarily as an "early warning system," alerting the CDC to potential problems that require further investigation.

The Vaccine Safety Datalink (VSD) is a collaborative project, partnering the CDC with nine large managed-care organizations [81]. Each managed-care organization tracks and reports data about vaccinations given, medical outcomes, and patient demographics. The VSD project is designed to allow planned safety studies and rapid investigations of concerns raised by patterns in VAERS data or other sources.

The Clinical Immunization Safety Assessment (CISA) Project is a network of vaccine safety experts from the CDC's Immunization Safety Office, seven medical research centers, and other partners [82]. Researchers at these centers evaluate and investigate questions about health risks that may be associated with immunization.

Safety information about several specific vaccines is discussed below, with an emphasis on issues that have been in the news and may thus be on patients' or parents' minds.

MMR AND AUTISM

Although measles was considered effectively eliminated in the United States in 2000, resurgence in the disease and regional outbreaks have resulted from suboptimal vaccination rates. In 2014, there were 667 cases of measles in the United States, more than 10 times the number of cases in 2000; another spike (372 cases) occurred in 2018 [95]. A large outbreak in 2014–2015 was linked to unvaccinated children visiting Disneyland, the source patient probably being infected overseas (likely the Philippines) [6,95]. The decrease in vaccine coverage is in part attributed to the false belief that the MMR vaccine may cause autism. Based on multiple studies, experts generally agree that there is no evidence for a link between the MMR vaccine and autism, and it is important that clinicians address these misconceptions with patients. In 2004, the Institute of Medicine (IOM) reported that "the body of epidemiological evidence favors rejection of a causal relationship between the MMR vaccine and autism" [83]. The American Academy of Pediatrics has also concluded that the evidence does not support such a connection. In addition, autism is not thought to be immune-mediated, and there is no clear mechanism by which MMR would cause this disorder [84].

Research on the topic includes a Canadian study involving 27,749 children born between 1987 and 1998 [85]. This study found no association between rates of pervasive developmental disorder and either one or two doses of the MMR vaccine. In a 2015 retrospective cohort study of 95,727 children, MMR vaccine receipt was not found to predict autism diagnosis, even among children with older siblings with an autism spectrum disorder [78]. A study of 657,461 children born in Denmark between 1999 and 2010 found no increased risk of autism in those who received the MMR vaccine, including in special subgroups (e.g., autism risk factors, other childhood vaccinations) [115].

Some of the concern about MMR and autism is based on a study in the late 1990s that found measles virus ribonucleic acid (RNA) in the gastrointestinal tissue of children with gastrointestinal problems and autism. However, a case-control study designed to explore this issue further found no association between autism and persistent measles virus RNA in the gastrointestinal tract, or between autism and MMR exposure [86].

Another study used polymerase chain reaction to detect measles virus nucleic acids in the peripheral blood mononuclear cells of children with autism spectrum disorder [87]. This study found no evidence of measles virus persistence in affected children.

THIMEROSAL AND AUTISM

Some of the concerns about autism involve the use of thimerosal, a mercury-containing preservative. The IOM has concluded that, as with concerns about MMR, the evidence favors rejecting the idea of a causal relationship between thimerosal-containing vaccines and autism [83]. In addition, the same study that looked at MMR and autism in a large cohort of Canadian children also looked for any relationship between ethylmercury exposure and autism and failed to find a connection [85]. Exposure levels were comparable to levels in the United States during the 1990s. Another study, which examined the incidence of autism in California children before and after thimerosal was removed from childhood vaccines, found no decrease in autism following the change [88].

Most vaccines for children 6 years of age or younger that had contained thimerosal either no longer contain this preservative or contain only trace amounts—small enough that the FDA considers them "preservative free" [89]. IIV is an exception. Thimerosal-free preparations of IIV are available, however, in limited quantities.

MULTIPLE VACCINES AND THE IMMUNE SYSTEM

Some parents worry that receiving multiple vaccines at a single visit is hard on a child's immune system or that it will weaken the child's immune defenses. However, there is no evidence that giving multiple vaccinations at a single visit weakens the immune system [84]. In addition, although more childhood vaccines are given than in the past, the immunologic load has actually decreased due to advances in vaccine technology [84].

ROTAVIRUS VACCINES AND INTUSSUSCEPTION

Parents and physicians who remember the withdrawal of the original rotavirus vaccine may worry about a risk of intussusception. Each of the current rotavirus vaccines has been tested in large safety studies.

Safety testing for RV5 included the Rotavirus Efficacy and Safety Trial, involving more than 68,000 infants [90]. However, postlicensure data from the Mini-Sentinel program for 2004–2011 indicate a slightly increased risk of intussusception after the first dose (but not after subsequent doses) [38]. A 2010 FDA update continues to support the safety of the vaccine [91]. Prelicensure clinical trials did raise the possibility of Kawasaki disease as an uncommon adverse event, with five cases seen in infants who received the vaccine and one case in a child who received placebo (a non-significant difference) [40]. There have been a few cases reported since licensure, but these are not thought to exceed the background rate [92].

Original studies with RV1 involved more than 63,000 infants [39]. Again, no association with intussusception was observed. Since then, a major study in the United States did note a possibly increased risk of intussusception [38]. Composite safety data have shown numerically higher cases of Kawasaki disease with the vaccine than with placebo, but again this was not a statistically significant difference [62].

INFLUENZA VACCINE AND GUILLAIN-BARRÉ SYNDROME

GBS was associated with a swine flu vaccine in 1976, with an estimated 1 case per 100,000 people vaccinated [21]. Some observational studies since then have found a small increase in GBS cases associated with influenza vaccination, while others have found no link. Whether there is an association between current influenza vaccines and GBS is not known. According to the CDC, based on studies in prior seasons, if an association does exist the risk would likely be low (i.e., one case per 1 million people vaccinated). The IOM conducted a thorough scientific review of this issue in 2003 and concluded that people who received the 1976 swine influenza vaccine had an increased risk for developing GBS. Scientists have multiple theories regarding why this increased risk may have occurred, but the exact reason for this association remains unknown [93].

MCV AND GUILLAIN-BARRÉ SYNDROME

As of early 2008, there had been 26 confirmed case reports of GBS within six weeks of vaccination with MCV [94]. This is likely similar to the background rate, and causality has not been established. However, the CDC and the FDA have noted that the timing in relation to vaccination is reason to pursue the question further and to gather more information. Providers are asked to report any cases of GBS that may be vaccine-related to VAERS. Providers are also asked to report all GBS cases to their state health departments, in accordance with local guidelines. More complete data collection will help to clarify whether GBS is a concern with this vaccine.

HPV VACCINE AND ADVERSE EVENTS

Clinical trials and the post-licensure monitoring data of both Cervarix and Gardasil show that both vaccines are safe [29]. Since the licensure of the HPV vaccines, both the CDC and the FDA have monitored HPV vaccine safety through VAERS, VSD, and CISA systems. A 2009 CDC/FDA report found that the most common adverse events reported to VAERS following vaccination with Gardasil were fainting, swelling at the injection site, headache, and nausea. Seven percent were considered serious. However, no common pattern for serious events has emerged, making it difficult to form theories about causality. GBS was reported but did not appear to occur at a rate above background levels. Blood clots were reported in a small number of patients, most of whom had pre-existing risk factors (e.g., smoking, obesity, use of oral contraceptives). VSD surveillance examined adverse events associated with administration of Gardasil (e.g., GBS, stroke, venous thromboembolism) and found no statistically significant increased risk for any of these adverse events [79]. Ongoing safety studies for HPV include review of serious individual reports to VAERS; VAERS data reviews by the FDA; review of two years of safety data on Gardasil used in boys and men; research on venous thromboembolism following HPV vaccination; and continued consultation with CISA [29].

Because of postmarketing reports, the prescribing information for the HPV vaccines includes a warning that syncope, sometimes associated with seizure-like activity, has been reported following vaccination [29]. Patients should be observed for 15 minutes following injection.

6. OVERCOMING BARRIERS FOR CHILDREN AND ADOLESCENTS

Barriers to on-time vaccination among children and adolescents can be traced to many different issues, including parental concerns, the need for multiple visits, cultural differences, and financial constraints. Some parents are uncomfortable with the idea of multiple shots given at a single visit, and some have safety concerns that lead them to forgo certain vaccinations for their children or refuse immunization entirely. In some cases, parents are simply unaware of their children's preventive care needs.

EDUCATING PARENTS ABOUT VACCINES AND VACCINE SAFETY

In the last several years, news reports have increased parents' concerns about vaccine safety and have led some parents to reconsider the value of immunization. Although certain vaccinations are required for school attendance, parents can usually opt out for religious reasons. Some states allow "philosophical" objections as well, creating room for parents who feel uneasy about childhood vaccinations to avoid them. In places where requirements are stricter, some parents are choosing to home school their children rather than accept vaccination [96].

Healthcare providers can have an influence when parents are concerned or confused about vaccines. For example, in one survey, 28% of parents had some level of uncertainly about vaccines [97]. For those who ultimately decided to allow timely vaccination, assurances or information provided by a healthcare provider were important reasons for the decision.

When explaining vaccine recommendations or vaccine safety, the provider should take into account the parents' level of health literacy, any language or reading literacy barriers, and social and cultural expectations. For example, for some parents, written material may not be sufficient due either to a low level of literacy or to a desire to discuss the information with the physician directly.

Because patient education is such a vital aspect of vaccine promotion, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.

REDUCING THE NUMBER OF INJECTIONS

Many parents are upset by the idea of multiple shots on a single visit, feeling that their children will be too frightened or upset. Some parents request that certain shots be delayed, and some providers have devised alternative immunization schedules that spread injections out over time. However, there is evidence that delaying vaccinations to reduce the number of injections can lead to undervaccination. When doses are deferred, immunization coverage at both 1 and 2 years of age declines [98]. Future visits may be missed or delayed, and children may be left vulnerable to vaccine-preventable illnesses.

One way to help reduce the number of injections is to make use of combination formulations, which allow for multiple vaccines in one shot [99]. In addition to the familiar MMR and DTaP, Tdap, and Td vaccines, available combination products include [99]:

- HepB and HepA

- DTaP and IPV

- DTaP, IPV, and HepB

- DTaP, IPV, and Hib

- MMR and varicella

Some of these products include premixed components, while others involve components that must be combined by the healthcare provider according to instructions. Except for products that are designed to be used in this manner, individual vaccines should not be combined in a single syringe.

In their 2017 General Recommendations on Immunization, the ACIP recommended the use of combination vaccines whenever possible to reduce the number of injections and improve coverage [100]. The 2019 immunization schedule includes these formulations as an option when any component of the combination is indicated, other components are not contraindicated, and the combination vaccine is FDA approved for that dose of the series [12].

ADDRESSING CONCERNS ABOUT VACCINE COSTS

The Vaccines for Children (VFC) program is designed to help overcome cost as a barrier to childhood vaccination. All of the ACIP-recommended vaccines are available for children enrolled in Medicaid, with VFC covering children through 18 years of age, and Medicaid funding covering young adults 19 and 20 years of age [101]. Children who have no health insurance coverage, children who are underinsured, and children who are American Indian or Alaska Native are also eligible for vaccines through VFC.

"Underinsured" children are those who have private health insurance coverage that does not include vaccines, that covers only certain vaccines, or that has a cap on the amount to be paid for vaccinations [101]. In each case, VFC will cover vaccines that the insurance does not. These children must visit a Federally Qualified Health Center (FQHC) or Rural Health Clinic (RHC) to receive the covered vaccines. An FHQC is a center with a special government designation to provide care to an underserved population. A typical FQHC would be a community health center in an underserved area. An RHC is a specially certified clinic in an underserved area or one where there is a recognized shortage of healthcare professionals.

Although the vaccines are free and patients cannot be charged for them, providers participating in VFC may charge an administrative fee to cover other costs [101]. These fees are established by the states. Healthcare providers can learn more about VFC, including how to become a VFC provider, at the Vaccines for Children Program website, https://www.cdc.gov/vaccines/programs/vfc/index.html.

INSTITUTING REMINDER SYSTEMS

Reminding parents to bring their children in for vaccinations is a proven way to increase coverage and is recommended in standards developed by the National Vaccine Advisory Committee and supported by other organizations [102,103]. Reminders need not take up extensive staff time. Mailed reminders have been shown to increase child vaccination rates and so have telephone calls, which may be computer-generated to save work by the office staff [104,105,106]. Outreach should be more intensive for families at high risk of missing appointments [102].

Setting up a system of reminders for the physician who is responsible for prescribing the vaccinations can also be helpful. Charts can be flagged, or a computerized database can be used. The National Vaccine Advisory Committee also recommends conducting chart audits to review how well the practice is meeting immunization needs and to look for areas for improvement [102].

7. OVERCOMING BARRIERS FOR ADULTS

Barriers to adult vaccination are similar to those impacting children and adolescents. These include: cultural differences, lack of information about what vaccinations are needed and when, lack of physician recommendation, unawareness that the protection they received as children for some diseases decreases over time, unawareness of vaccines received in childhood, lack of insurance, and mismanagement of time/priorities during office visits.

Lack of awareness is a primary reason that adults miss recommended vaccinations. It is common for adults to report that no healthcare provider had recommended a given vaccination, and so they did not know it was needed. There may also be cultural differences in how adults approach vaccination or in how services are provided. According to 2015 surveillance data, racial/ethnic disparities exist for all seven vaccines the CDC is tracking [9]. The gap is most marked for black adults, whose vaccination rate averaged 27% lower than their white counterparts with respect to seasonal influenza, tetanus (with pertussis), and hepatitis B [9].

"Missed opportunities," visits during which a patient was eligible for a vaccination but did not receive it, are common for adults. Reasons include constraints on time during office visits, a focus on acute care needs instead of prevention, and a lack of standing orders or an office reminder system that could prompt staff to offer the recommended vaccines [109,110].

REDUCING "MISSED OPPORTUNITIES" FOR ADULTS

There is evidence that when physicians recommend preventive services, patients are interested in receiving them. For example, 95.1% of patients in a national survey stated that they would accept the herpes zoster vaccination if their doctor recommended it [111]. Standards provided by the National Vaccine Advisory Committee, in cooperation with more than 60 organizations, offer evidence-based methods to help reduce missed opportunities for adults [110]. Providers should assess the vaccination status of all new patients and review vaccination status annually. Pneumococcal vaccination status should be reviewed when patients present for influenza vaccination.

Standing orders for vaccination should be used, based on evidence that they improve adult vaccination coverage in many different settings [110]. Reminder systems for staff can also improve vaccination rates. In one review of studies, use of physician reminder systems, such as chart notations, stickers, and patient lists, improved coverage by a median of 22% [112]. Assessing a practice's success at vaccinating patients who are eligible and reporting the results to staff can also help to improve coverage [110].

REMINDER SYSTEMS FOR ADULT PATIENTS

Telephone calls, mailed reminders, and texts/electronic reminders can help raise vaccination coverage among adults as well as among children [110]. Reminders can specify that patients are due or overdue for vaccinations, or they can invite patients to contact the provider's office to see which vaccinations they need. As with children, adults who are likely to miss appointments or fail to comply with recommendations may need particularly intensive follow-up.

8. CONCLUSION

Staying up-to-date, working with patients to maximize vaccination coverage, and monitoring and improving day-to-day practice can all help to improve vaccination rates. However, keeping up with changes to the child, adolescent, and adult immunization schedules can be challenging. Annual schedules often change from year to year and include both major changes and subtle ones. Mid-year announcements from the CDC and the ACIP require clinicians to be alert to new information and to make adjustments to practice. To help clinicians check for updates, verify information about vaccines, and locate answers to common clinical questions, the CDC provides a Vaccines and Immunizations website, as does the Immunization Action Coalition. Healthcare professionals should consider every healthcare visit as an opportunity to assess vaccination status and administer vaccines when needed. This will improve rates across the life spectrum, from infancy to elderly.

9. RESOURCES

Centers for Disease Control and Prevention Vaccines and Immunizations

https://www.cdc.gov/vaccines

Immunization Action Coalition

http://www.immunize.org

Vaccine Adverse Event Reporting System (VAERS)

https://vaers.hhs.gov

Vaccines for Children Program (VFC)

https://www.cdc.gov/vaccines/programs/vfc/index.html

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113. U.S. Food and Drug Administration. FDA Approves Expanded Use of Gardasil 9 to Include Individuals 27 through 45 Years Old. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622715.htm. Last accessed February 7, 2019.

114. Centers for Disease Control and Prevention. HPV Vaccination Coverage Data. Available at https://www.cdc.gov/hpv/hcp/ vacc-coverage/index.html. Last accessed February 6, 2019.

115. Hviid A, Hansen JV, Frisch M, Melbye M. Measles, mumps, rubella vaccination and autism: a nationwide cohort study. Ann Intern Med. 2019; [Epub ahead of print].

Evidence-Based Practice Recommendations Citations

1. Advisory Committee on Immunization Practices. Recommended immunization schedules for persons aged 18 years and younger—United States, 2019. MMWR. 2019;68(5):112-114. Available at https://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf. Last accessed February 15, 2019.

2. Advisory Committee on Immunization Practices. Recommended immunization schedule for adults aged 19 years and older—United States, 2019. MMWR. 2019;68(5):115-118. Available at https://www.cdc.gov/vaccines/schedules/downloads/adult/adult-combined-schedule.pdf. Last accessed February 15, 2019.

92343 • Childhood Leukemias and Lymphomas

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2021 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

92343 • Childhood Leukemias and Lymphomas

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

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

92343 • Childhood Leukemias and Lymphomas

Education Category. Pediatrics

Release Date. 09/01/2021

Expiration Date. 08/31/2024

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.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs 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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

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 2021, cancer will be diagnosed in an estimated 15,590 children/adolescents 0 to 19 years of age and will be the cause of 1,780 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 fifth leading cause for older children, representing approximately 5.5% of all deaths among individuals 10 to 24 years of age [11]. Hematologic cancers are among the most common childhood cancers in children 0 to 14 years of age; brain and central nervous system tumors and 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, now in its fourth (revised) edition [12,13]. 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. The revision clarifies the diagnosis and management of lesions at very early stages and refines the diagnostic criteria for some entities [13].

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 83% of all leukemias [1].

Acute leukemia is the leading type of childhood cancer, representing 24.3% of all new childhood cancer cases [14]. Lymphoid leukemia is more common in both children and adolescents, with acute lymphocytic leukemia (ALL) accounting for 8.3% of leukemias in children and adolescents, compared with acute myeloid leukemia (AML), which accounts for 3.6% of leukemias in children and adolescents [14]. 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 [15]. 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, 3,318 children and adolescents were diagnosed with lymphoma between 2009 and 2018 [1]. Hodgkin lymphoma is the most prevalent cancer among adolescents and young adults 15 to 19 years of age, representing 6.7% of all childhood cancers in this age group; non-Hodgkin lymphoma accounts for 4.3% [1]. Among children 14 years of age and younger, non-Hodgkin lymphoma is the more prevalent lymphoma, accounting for 9% of cancers, with Hodgkin lymphoma representing less than 6% [1].

The incidence of pediatric ALL and AML increased significantly between 1975 and 2018. The incidence of non-Hodgkin lymphoma showed no measurable increase, 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 [16,17,18,19]. Increased risk is associated with several other genetic syndromes as well (Table 1) [17,18,19].

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: [17,18,19]

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 [20,21,22]. 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 [23,24,25,26]. 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 [27]. Infection in early childhood may reduce the risk of Hodgkin lymphoma, as the incidence is lower for children with many siblings or many playmates [28,29]. 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 [23,30]

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 [31]. 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 [31]. 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 [32].

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 [33]. 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 [34]. A meta-analysis found that maternal smoking during pregnancy was associated with a modest increase in risk for non-Hodgkin lymphoma [35].

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 [36]. 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 [36].

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 [37]. 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 5,470 children and adolescents each year, with most cases occurring in children 1 to 4 years of age. The median age at diagnosis is 6 years of age [1,14]. The incidence is higher for male than female children/adolescents for all races/ethnicities (5.3 per 100,000 vs. 4.3 per 100,000, respectively) [14]. Among racial/ethnic populations of children/adolescents, the incidence of leukemia (all types) is highest for the Asian/Pacific Islander population and lowest for the non-Hispanic black population (Table 2) [1,14].

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)

55

35

65

69

Acute lymphoblastic leukemia

40

23

51

44

Acute myeloid leukemia

6

8

7

14

Hodgkin lymphoma

7

6

5

7

Non-Hodgkin lymphoma

9

10

10

12

Source: [14]

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 [38]. Research has demonstrated that childhood ALL is initiated in utero, with another event required for full malignant transformation [39,40]. 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 72% of leukemias in children and adolescents [1]. The incidence of ALL varies according to sex, age, and race/ethnicity. ALL is more common among male children/adolescents (45 per million) than among female children/adolescents (39 per million) [1]. ALL typically develops in children between 1 and 9 years old, with a sharp peak in the incidence for children 1 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 2000–2018 (Table 3) [1]. The observed long-term survival for ALL is 88% at 5 years, with an 82% probability of 10-year survival for children/adolescents who have 5-year survival (Table 4) [1,14].

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

2000–2018

Acute lymphocytic leukemia

41%

88%

Acute myeloid leukemia

6%

75%

Hodgkin lymphoma

72%

98%

Non-Hodgkin lymphoma

47%

90%

Source: [14]

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

Cancer Type

5-Year Survival

Acute lymphoblastic leukemia

89%

Acute myeloid leukemia

68%

Hodgkin lymphoma

98%

Non-Hodgkin lymphoma

90%

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 [41]. AML involves the malignant transformation of stem cells or progenitor cells in the bone marrow.

As noted, AML accounts for 3.6% of leukemias in children and 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 (8 vs. 7 per million, respectively) [14]. The incidence is highest in the Hispanic and White populations, but the range across race/ethnicities is narrow [1,14].

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 46% in 2000 to 63% in 2013 [14]. The observed long-term survival is 68% at five years [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 [42]. 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 [24]. 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 2,420 children and adolescents, and the incidence increases with age, with significant peaks in adolescence [1]. Hodgkin lymphoma accounts for 30% of lymphomas in children and 70% of lymphomas in adolescents, while non-Hodgkin lymphoma accounts for 46% of lymphomas in children and 65% of lymphomas in adolescents [1]. The disease is more common among male children/adolescents (18 per million) than among female children/adolescents (8 per million) [14]. 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 [1,14].

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 [24]. 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 [24]. 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 [43,44]. 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 more common among male children/adolescents (8 per million) than female children/adolescents (4 per million) [14]. With regard to race/ethnicity, the incidence of Hodgkin lymphoma is highest in the non-Hispanic white and Asian/Pacific Islander populations and lowest in the Hispanic population [14]. Hodgkin lymphoma is the most curable childhood cancer, with a five-year survival rate of nearly 97% in 2011–2017, 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 [45]. 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 [1,46]. Non-Hodgkin lymphoma develops nearly twice as often in male than female children/adolescents across all age-groups (15 vs. 6 per million) [14]. The incidence is fairly similar across races/ethnicities, with the highest incidence in the Hispanic and Black populations and the lowest incidence in the non-Hispanic White population [14].

The five-year survival rate for non-Hodgkin lymphoma improved from approximately 74% in 1975–1979 to 90% in 2000–2018 [14].

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 14% of pediatric non-Hodgkin lymphoma in the United States [1]. It most commonly develops in boys 10 to 14 years of age [46]. It is more common in non-Hispanic whites than in Hispanic whites [46]. This type of lymphoma was first noted by Denis Burkitt, who was studying children in Africa [45]. Burkitt lymphoma is endemic in Africa, where it occurs at a very high rate [46,47].

There are clinicopathologic differences between the endemic and sporadic forms of the disease [45]. 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 [47].

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is the second most common non-Hodgkin lymphoma, representing 10% to 20% of pediatric non-Hodgkin lymphoma. It occurs most frequently in adolescents 15 to 19 years of age [46]. 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 [48]. The gene expression profile of this type of non-Hodgkin lymphoma is distinct and suggests a close association with Hodgkin lymphoma [49,50].

Lymphoblastic Lymphoma

Lymphoblastic lymphoma represents approximately 20% of pediatric non-Hodgkin lymphoma [46]. It develops most often in boys, especially in the 10 to 14 year age group [46]. 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 [51].

Anaplastic Large-Cell Lymphoma

Anaplastic large-cell lymphoma accounts for approximately 10% of pediatric non-Hodgkin lymphoma, occurring most often among male adolescents [1,46]. 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 [52]. 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 [53]. 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 [54]. 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 [53].

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 [55].

Cytogenetic testing identifies chromosomal abnormalities with respect to either number or structure [56]. 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 [57,58].

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 [38]. On average, symptoms are present for four to six weeks before diagnosis and are associated primarily with leukemia-related pancytopenia [19,38]. The clinical manifestations of ALL and AML are similar, although there are some distinctions (Table 5) [19,38,59]

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: [19,38,59]

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 [38]. 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 [38].

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 [19,38]. 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 [59]. 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 [38].

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 [19,38].

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 [19,38]. Signs of CNS involvement include headache, seizures, vomiting, asthenia, blurred vision, slurred speech, imbalance, cranial nerve palsy, and poor performance in school [19,38].

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 [59]. 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 [60]. When all three of these factors were present, the sensitivity of a diagnosis of ALL was 100% and the specificity was 85% [60].

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 [61]. 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) [61].

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 [62]. 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 [63]. 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 [19].

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: [19,62]

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 [56]. Hyperploidy (more than 50 chromosomes in a tumor cell) is evident in approximately 25% of pediatric ALL but is extremely rare in AML [56]. The most frequent numerical abnormalities in AML are trisomy 8 (three copies of chromosome 8) and acquired trisomy 21 [56].

In infant leukemia (both ALL and AML), abnormality of the mixed-lineage leukemia (MLL) gene at 11q23 is found in nearly 80% of cases [31]. 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 [64]. Several other common abnormalities occur frequently in ALL (Table 7) [56].

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: [56,64,65]

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 [56,65]. Other common abnormalities associated with AML are aberrations of 11q23 and inv(16) [56].

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 [38]. However, studies have been inconsistent in identifying factors present at or shortly after the time of diagnosis of AML that are predictive of outcome [19,66,67,68,69,70,71]. The greatest prognostic factor is the response to treatment [72].

Acute Lymphoblastic Leukemia (ALL)

The following factors have been found to have prognostic significance for children with ALL [72,73]:

- 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 [74,75]. 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 [76,77,78,79]. In addition, the risk of treatment failure is high for infants with ALL, especially infants younger than 3 months of age [80,81,82].

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 [79]. 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 [83,84,85]. With respect to the sex of the patient, the prognosis has been slightly better for girls than for boys [86,87,88]. Although testicular relapse is one reason for this difference, relapse in bone marrow and CNS is also more frequent among boys [86,87,88]. Male sex has not been a risk factor in studies in which the event-free survival rate is more than 80% [89,90]. Studies that have examined sex differential for etiologic clues have identified several sex-specific genetic markers for childhood ALL risk [91,92,93,94] .

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 [95]. 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 [82,96]. Social, biologic, and pharmacokinetic factors should be explored in an effort to better understand racial/ethnic variations in outcome [97]. Clinical and public health strategies can help improve access to health care, clinical trial enrollment, treatment, and survivorship care for children with ALL [98].

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 [76,77,99,100,101,102]. 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) [72,100]. Extreme hypoploidy and presence of the Philadelphia chromosome has been an indicator of very poor prognosis in B-cell ALL [103].

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 [64,77,104]. 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 [56,105]. 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 [106,107,108].

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 [67,68]. 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 [68]. Adolescent patients are at higher risk for treatment-related mortality compared with younger children [109].

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 [67]. In addition, a higher platelet count (more than 20,000/mcL) and absence of hepatomegaly were independent prognostic factors of better overall survival [67].

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 [19]. Although sex has not been used as a prognostic factor, several studies have suggested that the outcome is more favorable for girls than boys [19,67].

The ability of cytogenetic findings to predict outcome has varied, but they appear to be the best prognostic factors in AML [66,110,111]. 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 [78]. 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) [19,66]. Aberrations of chromosome 16q have also been shown to be a prognostic indicator of complete remission and better overall survival [65,67]. For children with monosomy 7, AML progresses rapidly and the response to treatment is poor [56]. In contrast to the situation in ALL, children with Down syndrome and AML have a good response to treatment [67,110]. 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 [112].

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) [113]. 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 [113]. On physical examination, the most common finding is a persistent, painless adenopathy, usually in the supraclavicular or cervical area [59,113]. 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: [113,114,115,116]

Involvement of only lymph nodes and/or the spleen is present in most patients [113]. 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 [113]. 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 [117,118]. 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 [113].

The mediastinum is involved in about two-thirds of patients [113]. 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 [24,113]. 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 [113].

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 [24,113]. Lymphopenia and normochromic normocytic anemia are indicators of extensive disease [119,120]. 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 [59]. An elevated level of alkaline phosphatase may indicate metastatic bone disease, and further testing should be done to determine if there is skeletal involvement [113].

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 [24]. 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 [113].

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 [113]. However, the least invasive procedure should be used [121,122]. 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 [24]. Mixed cellularity Hodgkin lymphoma accounts for approximately 25% of pediatric Hodgkin lymphoma, most frequently developing in children younger than 10 years of age [24]. 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 (also referred to as the Lugano classification system), which categorizes the disease as stage I through IV according to the extent of lymph node involvement (Table 9) [123]. The system is based on the premise that Hodgkin lymphoma progresses along contiguous lymph nodes [124]. Within this classification system there are additional designations that are applied to further define symptoms and disease [124].

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: [123,125]

Prognostic Variables

Evidence Based Practice Recommendation

According to the National Comprehensive Cancer Network, there is no uniform risk stratification for pediatric Hodgkin lymphoma. However, several factors are considered to confer poor prognosis, including B symptoms, extranodal disease, Ann Arbor stage, gender, and response to initial chemotherapy.

https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf

Last Accessed: August 5, 2021

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 [117,126,127]. Studies in which prognostic factors were evaluated in multivariate analysis have demonstrated the following factors to be of import [126,128]:

- 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 [126,128,129]. 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 [126,129,130]. 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 [123,131].

Several laboratory studies, including the WBC count, hemoglobin, erythrocyte sedimentation rate, and serum ferritin level, have also been correlated with a poor prognosis [123,126,132]. 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 [126].

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 [126]. 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 [133].

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 [127,134].

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 [114,115,116]. Most children/adolescents will have advanced disease at the time of presentation [46,115].

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 [135,136]. The most common site of B-cell lymphoma is the abdomen, and involvement of peripheral lymph nodes is relatively uncommon [46,114]. 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 [114]. 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 [59,114]. 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 [46]. The mass forms in the anterior mediastinum. Dyspnea is often the first symptom [115]. 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 [46]. 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 [115].

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 [115].

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 [137,138]. 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 [46,116,138].

Soft tissue and skin are the most frequent sites of extranodal involvement [46,116,138,139,140]. Cutaneous manifestations may be single or multiple nodules, multiple or disseminated red-yellow papillomatous lesions, or large ulcerated lesions [116]. 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 [115]. 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 [116]. A CSF sample should be examined, and evaluation of biopsy specimens should include histopathologic analysis, immunophenotyping, and cytogenetic and molecular analysis [114,115,116,138].

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 [114]. 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 [114,141]. Skeletal scintigraphy is useful for detecting bone involvement, such as with anaplastic large-cell lymphoma [138]. Positron emission tomography (PET)/CT scanning has largely supplanted scintigraphy and is highly recommended for patients with suspected non-Hodgkin lymphoma [142,143,144]. 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 [114,141]. If advanced disease is suspected, MRI or CT of the brain should be done [141].

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 [145,146]. These stages are [46,145,146]:

- 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 [114]. 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 [114]. The tumor burden is high for patients with extensive bone marrow involvement (more than 25%) [114]. 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 [48,147,148].

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 [114]. 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 [135]. Again, the universal applicability of these findings is not established.

In an analysis of p12ooled 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 [114,140,148,149,150,151]:

- 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 [46].

In a comprehensive analysis of potential prognostic factors for outcome in lymphoblastic lymphoma, no factor was found to be associated with outcome [152].

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 [153]. 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 [154,155,156].

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 2019, approximately 67.8 million Americans (22% of the population) speak a language other than English in the home, with more than 3.4 million of them (1.1% of the population) reporting that they speak English less than "very well" [157]. 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 [158]. 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 [159].

The national standards on Culturally and Linguistically Appropriate Services (CLAS) include four standards related to communication and language access services that are mandated for health care organizations [160]. 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 [160]. 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 [161,162,163]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [164]. 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 [165]. According to one study, this practice has only modestly improved since 2004 [166]. 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 [167].

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 [168]. 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 [169]. 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 [156,170]. Predictors of limited health literacy are poor self-rated reading ability, low level of education, male sex, and nonwhite race [170,171].

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) [156]. REALM takes 3 minutes to administer, whereas S-TOFHLA takes 7 to 12 minutes to administer [156]. 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 [156,170]. 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?" [156].

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 [154]. The AAP Task Force on the Family noted that "nonjudgmental, culturally sensitive, family-oriented care" should be provided by all pediatricians [172]. The task force further noted that providing such care requires that the "family's history, interactions, and preferred solutions are considered, used, and supported" [172]. 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: [173]

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 [174]. 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 [164]. These beliefs may underlie the degree or quality of the parents' involvement in the child's care or noncompliance with treatment or recommendations [174].

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 [175]. 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 [176,177,178]. 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 [179]. 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 [179]. Studies have also shown that satisfaction with treatment choices is increased when communication in the diagnosis phase has been effective [176].

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 [176]. 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 [176]. Eliciting and validating emotional reactions at this time will help parents and patients better understand and comply with further diagnostic testing [176].

Guidelines are available to help clinicians deliver bad news in the childhood cancer setting with sensitivity (Table 11) [179,180,181]. 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 [180]. After relating bad news, clinicians can build a partnership by allowing parents to express their feelings and opinions [182]. 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: [179,180,181]

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 [183]. However, studies have shown that children often recognize the seriousness of their illness and prefer open communication about their disease and prognosis [183,184,185]. 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 [183,185]. 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 [186]. 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 [186].

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 [183]. 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 [178]. 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 [187].

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 [57,58]. 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" [57,58].

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 [188]. 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 [70,129,188]. These differences are thought to be related to the substantial differences between adult and pediatric protocols [188].

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 [189,190]. Virtually all children with leukemia or lymphoma are eligible for treatment in a clinical trial, yet 40% to 60% do not participate [189,191]. 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 [189]. 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 [189]. The rate of participation among adolescents is substantially lower, ranging from 10% to 15%, and this low rate is of special concern [188].

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) [192]. 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 [192]. 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 [193]. 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 [194].

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 [195]. 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 [183,196,197]. 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 [196,197]. 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 [197,198,199]. 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 [197]. Studies involving focus groups of healthy adolescents have shown that research concepts such as placebo and randomization are difficult to understand even for teenagers [200]. 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 [199,201].

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 [202]. 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 [202]. 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 [197]. 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 [197].

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 [191]. 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 [176]. 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 [191].

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 [197,199]. Respectful assent also involves responding to dissent [197,199]. The child's participation in a trial should be monitored, and persistent expressions of distress about continued participation should be addressed [197].

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 [203]. Parents also suggested that clinicians should [203]:

- 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 [203].

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 [204]. 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 [183,202,204].

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: [203,205]

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 [205]. 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 [205]. 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 [206]. Multimedia approaches to describe research procedures have been shown to enhance overall understanding of both parents and children/adolescents [207].

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 [197].

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 [208,209].

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 [210,211,212]. 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

Asparaginase (Erwinia asparaginase [recombinant])

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 [213]:

- 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) [147,214].

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 [215]. Imatinib (an oral drug that has been successful in adults) received FDA approval in 2013 for treatment of pediatric Philadelphia chromosome-positive (Ph+) ALL [216].

Acute Lymphoblastic Leukemia (ALL)

Risk-adapted treatment protocols developed in the 1990s have achieved a cure rate of 80% [96,217]. 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 [216,218].

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 [38]. All children with ALL receive CNS prophylaxis, primarily with intrathecal chemotherapy [70,213]. 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 [70,213].

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 [38]. This phase of treatment typically lasts four weeks [213]. The rate of complete remission after induction therapy is high, ranging from 96% to 99% [70,213]. 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 [89,152,213,219,220]. 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) [213]. 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 [213]. Patients treated by three other study groups receive an induction regimen with four or more drugs regardless of presenting features [213]. 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 [221]. 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 [221]. A randomized trial comparing doxorubicin and daunorubicin given during induction found no difference in efficacy between the agents in early response measures [222]. In June 2021, the U.S. Food and Drug Administration (FDA) approved Rylaze (Erwinia asparaginase [recombinant]) as a component of the multi-agent chemotherapy regimen to treat ALL (and lymphoblastic lymphoma) in adult and pediatric patients (one month and older) who have developed hypersensitivity to Escheria coli-derived asparaginase products [223]. Rylaze was found to maintain a clinically meaningful level of asparaginase activity throughout the entire duration of treatment [223].

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 [224]. 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, 9 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 [225].

Consolidation/Intensification Therapy

Consolidation/intensification therapy begins after normal hematopoiesis has been restored. The most commonly used intensification regimen was first introduced by the Berlin-Frankfurt-Munster (BFM) clinical trials group and usually includes 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). Maintenance typically includes 6-MP, weekly low-dose methotrexate, and sometimes administration of vincristine and a corticosteroid, as well as continued intrathecal therapy [70,213]. This regimen, with variations (e.g., intensification for higher-risk patients, use of escalating doses of methotrexate without leucovorin rescue, elimination or truncation of some phases for lower-risk patients), has been adopted by COG and has been associated with favorable outcomes in children with standard-risk ALL [226,227].

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%) [228]. 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 [229].

In a landmark multicenter COG study of 92 children (1 to 21 years of age) with Ph+ ALL, investigators evaluated whether imatinib (340 mg/m^2 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 [230]. 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 [231].

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 [232]. 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% [232].

Continuation (Maintenance) Therapy

Continuation therapy usually consists of weekly methotrexate and daily 6-MP for a period of 2 to 2.5 years [70,213]. 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 [233,234].

CNS Prophylaxis

Before the routine use of CNS prophylaxis, relapse involving the CNS occurred in approximately 80% of all patients with complete remission [235]. 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% [19,96]. 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 [70,208]. As such, the use of intrathecal chemotherapy, usually methotrexate or cytarabine, is now used in most cases [213]. 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 [152,213,236].

Treatment for Relapsed or Refractory Disease

Relapse occurs in approximately 25% of patients with ALL [237]. The most common sites of relapse in ALL are bone marrow, the CNS, and the testicles [237]. 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 [237]. Treatment of CNS relapse usually involves intensive systemic therapy, with cranial or craniospinal radiation delayed for six months [238].

In 2017, the FDA approved the first gene therapy for the treatment of B-cell precursor ALL in children and young adults [239]. 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% [239]. However, tisagenlecleucel is associated with potentially severe side effects, including cytokine release syndrome, neurologic events, serious infections, acute kidney injury, and hypoxia [240].

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 [213]. 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 [241]. 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 [213].

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 [242,243]. Allogeneic HSCT is recommended for children who [243]:

- 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 [243]. In general, HSCT approaches benefit only children at high risk for relapse with standard chemotherapy approaches [244].

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 [245].

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 [246]. 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) [247].

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 bone mineral density

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: [247]

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 [41,248]. Optimal treatment of AML requires control of bone marrow and systemic disease [249]. 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 [19,41,249]. 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) [19].

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, 45% to 55% for event-free survival, and 55% to 65% for overall survival [41,249].

Induction Therapy

The most effective chemotherapy regimen for induction in AML has been an anthracycline, cytarabine, and etoposide [41,249]. 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 [41,249].

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 [19,250]. High-dose cytarabine, usually given with mitoxantrone, has led to improved outcomes for children with high-risk disease [249].

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 [19,249]. Cytarabine, methotrexate, or both, along with hydrocortisone, are the preferred agents for prophylaxis [249]. The rate of isolated CNS relapse is reported to be 2% [41]. Cranial radiation is not used for prophylaxis [41,249].

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%) [251]. 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 [41,249]. Anthracyclines are effective, but the increased risk for cardiotoxicity limits their use in the relapse setting if they have been used for primary treatment [251]. Liposomal daunorubicin has been added to fludarabine plus cytarabine in an attempt to limit cardiotoxicity [41]. However, cure is unlikely with chemotherapy alone for relapsed AML [41]. In 2020, the FDA extended the indication for gemtuzumab ozogamicin to include newly diagnosed CD33-positive AML in pediatric patients 1 month of age and older [252]. The drug was previously approved for children 2 years of age and older with relapsed or refractory AML [249,253]. Efficacy and safety information for the extended indication was supported by data from a multicenter randomized study of 1,063 patients, 0 to 29 years of age, with newly-diagnosed AML. The estimated percentage of patients free of induction failure, relapse, or death at five years was 48% in the gemtuzumab ozogamicin plus chemotherapy arm versus 40% in the chemotherapy alone arm. No difference in overall survival was found between treatment arms. The most common adverse events included cardiotoxicity, hepatotoxicity, infection, fatigue, and fever [253]. 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 [254]. HSCT is thought to be the only curative treatment for relapse [41,249,250,251,255].

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 [256]. 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 [257]. 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 [258]. Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission [249]. 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 [257,259,260,261].

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 [61]:

- 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 [61]. 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 [262].

TREATMENT OF LYMPHOMA

Hodgkin Lymphoma

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends that treatment of patients with favorable-risk pediatric Hodgkin lymphoma typically involve participation in an ongoing clinical trial.

https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf

Last Accessed: August 5, 2021

Level of Evidence: Expert Opinion/Consensus Statement

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 [113,263]. The German Hodgkin Study Group found that adult treatment protocols were safe and effective treatment options for adolescents with Hodgkin lymphoma [264].

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 [265]. 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) [113]. Stages III and IV typically represent high-risk disease.

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 [265,266]. 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 [265]. 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 IIIB Hodgkin lymphoma with bulk disease or stage IV disease [267]. When followed by guideline-directed consolidation therapy, the treatment led to overall survival of 97% and five-year event-free survival of 94% [267]. 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 [265,268].

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 [113]. 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 [113]. 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 [269].

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 [117,270]. Researchers continue to debate the issue of adding low-dose radiation to chemotherapy because of the toxicity associated with each modality [271,272,273]. 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 [265].

Treatment for Relapsed/Refractory Disease

Relapse will occur after first-line treatment in approximately 10% to 20% of children with advanced-stage Hodgkin lymphoma [263]. Relapse occurs most often within four years, but late relapse is not rare [265]. 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 [263]. Nonmyeloablative stem cell transplantation has been used in selected patients with high-risk disease [263]. 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% [274]. The COG has evaluated ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) and its derivatives across all risk groups [275,276,277]. 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 [278,279,280].

COG investigated treatment of relapsed/refractory disease with brentuximab vedotin and gemcitabine in 46 children and young adults [281]. Twenty-four of 42 patients treated at the recommended phase II dose of 1.8 mg/kg experienced a complete response within the first four cycles. Four of 13 patients (31%) with partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle four. By modern response criteria, these are also complete responses, increasing the complete response rate to 28 of 42 patients. There were no treatment-related deaths. The most common adverse events among all patients treated were neutropenia, rash, transaminitis, and pruritus [281]. Trials are ongoing to determine the efficacy and toxicity of combining brentuximab vedotin with chemotherapy. Additionally, phase I/II trials of immune checkpoint inhibitor therapy (with nivolumab and pembrolizumab) for use in childhood refractory/relapsed disease are ongoing [282,283].

Stem Cell Transplantation

HSCT is usually limited to patients who have relapse or in whom disease is refractory to primary conventional therapy [113,127,284].

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 [285].

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 [46,135,286]. 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 [287]. However, another study found that age was not a factor in increased risk of treatment failure [148]. 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 [148]. Response to treatment also is an important prognostic indicator. With the exception of anaplastic large-cell lymphoma, pediatric non-Hodgkin lymphoma that is refractory to first-line therapy has a very poor prognosis, regardless of histology [288,289,290].

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 [291]. 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 [46]. 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 [114]. 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 [114]. 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 [46,291,292]. The combination of vincristine, cyclophosphamide, doxorubicin, and prednisone has been highly effective in this setting [214]. A single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma [293]. 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 [294,295]. For higher risk disease, the addition of two or three courses of chemotherapy, high-dose methotrexate, and high-dose cytarabine was also effective [214,296,297].

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 [51,298]. This approach was superior to short, intensive pulsed chemotherapy regimens [299,300,301]. 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) [46]. 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 [302]. 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 [302]. 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% [303].

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 [46,115]. In such cases, low doses of radiation are used. Cranial radiation may be reserved for patients with CNS involvement at the time of diagnosis [301].

Several treatment strategies have been used for anaplastic large-cell lymphoma, and the outcomes have been comparable [46,116,140]. Treatment has been adapted to risk in some cases, usually according to stage of disease [140]. 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) [139,140]. 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 [304]. CNS involvement in anaplastic large-cell lymphoma is rare at diagnosis [46].

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 [305]. It has been demonstrated that CNS prophylaxis can be omitted in lymphoblastic lymphoma [301,306]. 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 [140,296]. 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 [307].

Treatment for Recurrent or Refractory Disease

Relapse occurs in approximately 12% of children/adolescents with non-Hodgkin lymphoma [286]. 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 [114,308,309,310,311]. 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% [274].

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 [46,312]. 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 [312]. 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 [312].

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 [313].

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 [19,314]. 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 [314,315]. Most infections that occur in children during or after treatment for leukemia or lymphoma are the same as those found in healthy children [315].

Evidence Based Practice Recommendation

According to the Advisory Committee on Immunization Practices, the measles, mumps, rubella, and varicella vaccine is contraindicated in children with severe immunocompromise (including as a result of leukemia or lymphoma).

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

Last Accessed: August 5, 2021

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 [314]. In addition, it is important to protect the integrity of the skin and mucosal surfaces, as they serve as barriers to infectious pathogens [315]. 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 [314]. Unless the child is at high risk for fever and neutropenia, routine prophylaxis against viral, bacterial, and fungal agents is not recommended [315,316,317]. One exception is prophylaxis for Pneumocystis jiroveci, which occurs in 15% to 20% of children treated for ALL [315,318,319]. Prophylactic treatment consists of trimethoprim-sulfamethoxazole (TMP-SMZ), given either daily or on three consecutive days per week [253,319,320]. Treatment with TMP-SMZ on two consecutive days per week has also been shown to be effective [321].

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 [322]. 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 [322].

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) [314]. Laboratory testing should include a CBC, blood cultures, urinalysis, and urine culture [314]. The absolute neutrophil count (ANC) should be determined, as neutropenia is the most significant predisposing factor for infection [314,323]. Approximately 70% to 80% of bacterial infections occur in children who have moderate neutropenia [323]. The presence of fever and neutropenia requires hospitalization for empiric treatment with intravenous administration of broad-spectrum antibiotics [324]. 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 [325]. 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 [325].

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://childrensoncologygroup.org/downloads/COG_SC_FN_Guideline_Document.pdf

Last Accessed: August 5, 2021

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 [326,327]. Care of external catheters requires strict adherence to aseptic technique, daily flushing of the catheter, and frequent changes of the sterile dressing [315]. 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 [328]. However, if signs of septicemia develop and bacteremia persists 48 hours after the start of antibiotic administration, the catheter should be removed [314]. 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 [329].

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 [314]. 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 [326,330,331]. 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 [332]. However, other studies, including a meta-analysis, have indicated that CSFs have no significant effect on the incidence of infection [330,333]. 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 [334]. 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 [331]. Secondary prophylaxis with CSFs should be limited to children at high risk [331]. The risk of AML has also led to the recommendation to avoid the routine use of CSFs after induction therapy [326,331]. Pegfilgrastim, a recombinant G-CSF used to prevent neutropenia in adults, has been shown to be safe and effective for children [335].

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 [317]. 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[317].

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: [317]

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 10^9/L for clinically stable pediatric patients receiving chemotherapy for leukemia.

https://www.c17.ca/application/files/2916/2006/0821/C17_Platelet_Guideline_English_Summary_2011.pdf

Last Accessed: August 5, 2021

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 [326]. 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 [314,326]. 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 [336].

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 [326]. 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) [326]. 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 [314].

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 [323,337]. Collectively, these abnormalities comprise tumor lysis syndrome, which is most commonly associated with high tumor burden [114,115]. 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 [114,115,323,337].

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 [338]. 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 [338]. Repeated complications, primarily occlusions, should prompt investigation for thrombosis [314,338]. Treatment consists of a thrombolytic agent, such as tissue plasminogen activator [314,339]. 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 [340].

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 [173,341,342,343,344,345,346]:

- 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 [344,347]. 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" [346].

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 [173]. As much as possible and appropriate, the child should be allowed to participate in discussions about the direction of care [344,348]. 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 [349,350,351,352].

ASSESSING AND MANAGING SYMPTOMS

The assessment and management of symptoms represent the cornerstone of palliative care [173,353]. Symptom management is crucial not only to relieve physical and psychologic suffering but also to avoid feelings of mistrust and fear [348]. In general, studies have shown that pain, fatigue, and nausea/vomiting are the most common physical symptoms in children being treated for cancer [173,348,354,355,356]. 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 [357]. 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 [358].

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 [356]. Symptom management should be timely and include both pharmacologic and nonpharmacologic strategies [173,341,348]. 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 [53,348]. 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 imp23aired children (Table 16) [53,359,360,361,362,363,364,365,366,367,368]. 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 [369,370,371,372].

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: [53,359,360,361,362,363,364,365,366,367,368]

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 [359,360,361,362,363].

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 [373,374,375]. 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 [373].

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 [173]. 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 [173,348].

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: [53,348]

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 [376]. Clinicians and parents should also be alert to breakthrough pain, which occurred in 57% of children with cancer in one study [377]. 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 [376].

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 [53].

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 [342,348,356]. 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 [378,379]. 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 [380]. 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 [380]. Results of another study indicate that cancer-related fatigue results in a low health-related quality of life for pediatric patients [381].

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 [173,348]. 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 [113,173,348,382]. Anticipatory nausea may be alleviated by benzodiazepines and the use of relaxation techniques [323,348]. Use of a hydration fluid may be necessary to prevent dehydration in a child who is vomiting excessively [348]. Taking medications after meals, when possible; eating small, frequent meals; and avoiding strong smells may also help ease nausea [173].

Constipation is also common among children/adolescents with cancer and is usually related to medications, particularly opioids and vincristine [348]. This symptom is often under-recognized or undertreated by clinicians [173]. 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 [53].

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 [323,337]. 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 [337]. Small studies have shown that chlorhexidine is beneficial for alleviating mucositis in children, but the results must be confirmed by larger trials [383]. One literature review focused on randomized clinical trials to evaluate the effectiveness of chlorhexidine mouthwash in alleviating mucositis in children receiving chemotherapy [384]. 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 [384]. 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 [323,337].

Pruritus

Pruritus usually occurs as a side effect of medications, especially morphine and other opiates, and may also be associated with progressive lymphoma [53]. Physical manifestations of pruritus include excoriation, erythema, and lichenification; rubbing of the eyes, nose, or skin may also indicate pruritus [248]. 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 [248].

PSYCHOSOCIAL AND SPIRITUAL ISSUES

Anxiety, worry, and sadness are among the most frequently occurring psychologic symptoms for children/adolescents with cancer [173,348,357]. 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 [173]. 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 [173]. This process can help foster the patient's sense of control and independence and enhance self-esteem [173]. 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 [348]. 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 [345].

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 [385]. 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 [386,387]. Still, hospice care is used by only 5% to 25% of eligible children in the United States and Canada [388].

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 [389,390]. 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" [391,392,393]. 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 [394].

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 [394]. 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 [394]. 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 [394]. 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 [395,396,397,398].

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 [399]. 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 [400]. 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 [343,353,358].

Several barriers to pediatric end-of-life care have been identified (Table 18) [173,343,348,401,402]. 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 [401,402,403,404]. 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 [402]. 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 [346]. 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 [394].

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: [173,343,346,348,394,398,401,402,404,405,406]

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" [348,407]. 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 [408]. Family denial was another commonly reported barrier, noted by 36% of respondents [408]. Paradoxically, the high rates of cure and long-term survival associated with most pediatric leukemias and lymphomas foster parents' hope for cure [343,407]. 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%) [401]. 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 [401]. 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 [398].

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 [409]. At this point, it is helpful to emphasize the importance of alleviating pain and other symptoms and making the child comfortable [173]. In addition, the family should understand that the primary oncologist and/or primary care provider will remain involved in the child's care [173]. 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 [173,341].

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 [353]. Pain, nausea, drowsiness, and energy loss have been reported by more than half of children/adolescents (6 to 17 years old) with advanced cancer [353,410]. Other common symptoms include dyspnea, weight loss and anorexia, vomiting, and constipation [353]. Bone marrow failure may occur as a result of progressive disease, leading to infection, fatigue, and bleeding [353]. 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%) [353]. 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 [353]. 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) [411].

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: [411]

Dyspnea is particularly present near the end of life, occurring in approximately 30% of children with leukemia and lymphoma [353,400]. 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 [348]. The use of oxygen, opiates, and/or benzodiazepines can provide symptomatic relief [173,348]. Nonpharmacologic interventions include relaxation techniques and the use of fans to blow air across the child's bed [173].

The need for spiritual support is heightened during the end of life as children and family prepare for dying [348]. Faith and the involvement of clergy play a critical role in decision making about end-of-life care [345]. A survey of pastoral care workers indicated that more than half of patients and 60% to 80% of parents had spiritual needs [412]. Because the illness experience, primary fears, and concept of death range according to the child's developmental age, appropriate spiritual interventions vary (Table 20) [173,341,348]. Patients grieve because of the isolation and loss associated with the disease, and the palliative care team should provide support for this process [413]. 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 [173,343]. 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 [413]. 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 [414]. 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 [414]. Parents should be encouraged to talk to their spiritual or religious advisor for guidance in how to talk with their child [173]. 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 [415].

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: [173,341,348]

Bereavement and Grieving

Bereavement and grieving support are other essential components in end-of-life care [173,346,413]. Bereavement care may best address grief by providing family members with outlets to communicate feelings and memories about a dying or deceased child [416,417]. It is important to provide support for siblings, who report often feeling left out and abandoned [346,413]. Despite a growing body of literature substantiating the needs of siblings, they continue to be unmet [418,419,420,421]. Siblings also may experience post-traumatic stress symptoms, poor quality of life, and a sense of aloneness [422]. Healthcare providers can address the needs of siblings by [422,423,424,425]:

- 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 [173]. 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 [426]. 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 [427]. 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 [428,429]. The maintenance of the connection through conversation appears to aid in healing for grieving parents [429].

Grieving is relieved by the continued involvement and support of the palliative care team and the primary care provider after a child's death [430]. Attendance at a memorial service and handwritten notes of sympathy from the clinician and medical team are valued highly by grieving families [423,431]. 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 [346]. 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

Evidence Based Practice Recommendation

The Psychosocial Standards of Care Project for Childhood Cancer recommends that youth with cancer and their family members should routinely receive systematic assessments of their psychosocial health care needs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397048

Last Accessed: August 5, 2021

Strength of Recommendation/Level of Evidence: Strong/High

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.

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 [432]. 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 [433]. Based on thematic analyses conducted with data from 31 semi-structured interviews of parents, the authors identified three themes and one overall expectation [433]:

- "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 [433].

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 [172]. 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 [172]. Clinicians may be able to provide the auxiliary emotional support and guidance the child and his or her family needs [433,434]. 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" [435]. The two main types of coping are problem-focused and emotion-focused [435]. 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 [354]. These control strategies are used commonly by children and their parents when coping with cancer [355,356]. 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 [436].

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 [437,438]. However, subgroups of these patients are at special risk for poor psychologic outcomes [439,440,441].

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 [442,443]. 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 [444,445].

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 [446].

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 [447].

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 [447].

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 [448]. Regardless of the cancer stressors experienced, patients with a high sense of humor have better psychosocial adjustment and fewer infections [449].

Potential long-term effects: Experiencing leukemia can interfere with the proper development of an early school-age child's social and academic skills [450,451,452,453]. 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 [454]. 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 [455].

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 [454]. Role-play discussions should be performed to assist in understanding how to best tell an individual child distressing news [180]. 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 [451]. Animal therapy programs may reduce a young child's emotional distress and promote socialization [456].

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 [457]. By 9 years of age, children understand that death is irreversible; however, their concept of the future is still very limited [458]. 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 [185,454].

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 [457].

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 [451]. 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 [459,460,461]. 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 [451].

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 [357,457,462]. 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 [447].

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 [462,463,464]. One study found that better problem-solving skills were associated with lower adolescent distress [465]. A systematic review analyzed how childhood cancer patients and survivors communicate about their cancer with family and peers [466]. 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 [466]. 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 [463]. 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 [467]. Diagnosis at adolescence has been linked to an increased risk for the development of post-traumatic stress disorder [440]. However, one study found that personality factors, such as adaptive style, were a stronger determinant of post-traumatic stress than health history [468]. 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 [469].

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 [9,462,470]. 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 [471]. 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 [472,473]. 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 [449,474]. Healthy psychosocial adjustment was strongly correlated to humor coping [449].

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 [475,476,477]. 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 [477]. Hospitalizations, poor physical health/appearance, academic difficulties, and poor parental coping skills can also limit the patient's development of relationships with peers [451,478].

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 [314]. 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 [187,479].

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 [480]:

- 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 [480].

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 [481]. 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 [482].

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 [451,472,479,483,484,485,486,487].

- 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 [488]. 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 [489]. Most siblings who experience these emotional and physical responses do not suffer long-term problematic outcomes; however, a subset of siblings does experience difficulties [490].

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 [491]. 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 [492]. In addition, the incidence of poor psychologic outcomes in response to guilt and heightened fear of death increases if the sibling with cancer dies [493]. 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 [492,494].

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 [495,496]. 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 [497]. 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 [497].

Factors that promote healthy psychologic outcomes in cancer-free siblings are related to support and functioning of the entire family. Specifically, these factors include [498,499,500]:

- 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 [501]. 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 [501].

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 [502]. 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 [489]. 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 [503]. 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 [489]. 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 [501].

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%) [489]. 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 [503].

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 [504,505,506]. Still, approximately 25% to 33% of parents face long-term psychologic issues [359,504,506,507]. Healthcare professionals' attention to the specific needs of the family can enhance the family's resilience [508,509,510,511]. Post-traumatic stress disorder is the most common psychologic disturbance for parents of childhood cancer survivors [507,512].

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 [513]. 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 [514].

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 [481,515,516]. Of interventions that have been studied in randomized trials, two have been shown to offer significant benefit [481]. 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 [515]. 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 [516]. 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 [517]. 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 [517]. 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 [518]. The improvements represented increases of 5% to 25% over the baseline values and were sustained over a period of one year. One study surveyed children's pain and distress levels immediately before and after a one-hour Kids Kicking Cancer in-person class [519]. Eligible participants were enrolled in standard classes, diagnosed with a chronic health condition (e.g., cancer), or the sibling of a child diagnosed with a chronic health condition, and between 5 to 17 years of age. Pain and distress were reported using Likert-style scales. Friedman test was used to test for overall changes in pain and distress, and within subgroups. A total of 59 youth (19 cancer patients, 17 non-cancer patients, 23 siblings) completed the study. Overall, pain and emotional distress were significantly reduced following a one-hour class, with 50% and 89% of youth reporting a reduction in pain and distress, respectively. The reduction in pain was most pronounced with cancer and non-cancer patients, whereas, the reduction in distress was most pronounced among healthy siblings. Reductions in pain and distress did not significantly differ among subgroups [519].

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 [520]. Among adolescents 15 to 19 years of age who were diagnosed with cancer from 2008 to 2014 and followed through 2017, 73% had a five-year relative survival rate if diagnosed with leukemia, 89% if diagnosed with non-Hodgkin lymphoma, and 97% if diagnosed with Hodgkin lymphoma [521]. 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 [522]. 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 [523]. Pediatricians, family practitioners, and nurses have an important role in the follow-up care for children with cancer [313,314,520,524]. Children with cancer should have regularly scheduled visits for routine preventive care, such as immunizations and the monitoring of growth and development [314]. 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 [313]. 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 [525,526]. The guidelines were developed by an expert panel within COG and are available online [526]. 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 [527]. 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 [52]. 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 [528]. 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 [528]. 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) [3,4,529].

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: [3,4,529]

Among the most common late effects are [3,4,209,266,313,520,526,529]:

- 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: [3,4,209,266,313,520,526,529,530,531,532,533,534,535]

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

Radiation

Baseline fasting lipid profile every two years

Testicular hormonal dysfunction/impaired spermatogenesis; ovarian hormone deficiencies/reduced ovarian follicular pool

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, radiation

Yearly assessment of hearing difficulties and otoscopic examination

Complete audiologic evaluation by audiologist, yearly, for patients age ≤5 years

Pure tone audiometry testing at 1,000–8,000 Hz every 2 years for patients 6 to 12 years of age, then every 5 years beginning at 13 years of age

Hepatic dysfunction

Antimetabolites, methotrexate

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 (high-dose IV), neurosurgery (brain)

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), hematopoietic cell transplant, thoracic surgery

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), hematopoietic cell transplant, nephrectomy

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), thyroidectomy, systemic radiation

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 30 years of age, whichever occurs last

Lung cancer

Radiation

Yearly pulmonary examination

Discuss the benefits and risks/harms of spiral CT scanning for patients at highest risk (e.g., smokers)

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: [526]

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 [3,266,520,536,537,538,539,540]. 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 [7,535].

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 [534]. 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 [532].

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 [541]. Second cancers among childhood cancer survivors call for vigilant screening and surveillance according to individual risk [526,542]. 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%) [535].

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 [210,211,520,533,543]. 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 [526]. Examples of nonanthracycline agents used in pediatric populations that have been associated with cardiotoxicity include cyclophosphamide, cytarabine, cisplatin, and ifosfamide [544].

A wide range of cardiac abnormalities have been noted in survivors [3,4,209,313,520]. 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/m^2 [545,546,547,548]. 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/m^2 [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% [209,520]. 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 [210,549,550].

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 [209,520,533]. The use of lower doses of radiation for children with lymphoma has decreased the occurrence of radiation-related cardiac toxicity [209].

The COG guidelines suggest yearly history and physical examination for survivors at risk for cardiac abnormality related to either chemotherapy or radiation [526]. 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 [266,551,552,553]. 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 [266,313,526]. Other factors, such as age younger than 4 years, female sex, obesity, concomitant use of corticosteroids, and radiation dose, contribute to risk [266,526,551].

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 [551,552]. 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 [520,551,552,553]. However, maintenance therapy with methotrexate and 6-MP may prevent catch-up growth [554]. Catch-up growth does not occur with radiation-induced impairment [552].

Radiation therapy to the head and neck or cerebral cortex can cause hypothyroidism, leading to short stature and poor growth [266,555]. This risk has been somewhat decreased by the use of lower cumulative doses of radiation therapy in treatment protocols for childhood lymphoma [209]. Bone marrow transplantation is also associated with a high risk for severe growth impairment, especially when the conditioning regimen involves total body radiation [266].

Survivors should have regular growth assessment consisting of measurement of height on standardized growth charts [526]. Growth hormone therapy may be beneficial if growth hormone deficiency is found to be the cause of impaired growth [313,520,526]. 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 [266,313].

Obesity

Obesity is another well-recognized long-term complication in survivors of ALL, occurring in as many as half of long-term survivors [266,313,520]. 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 [266,520,526].

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 [556]. 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 [557]. 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 [557]. Data from a longitudinal analysis of a multiethnic cohort of pediatric ALL survivors suggest that weight gain within the first year after diagnosis is more strongly associated with long-term increased BMI than early (within 30 days) weight gain [558].

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 [313,520,526].

Gonadal Dysfunction

Gonadal dysfunction can occur in both boys and girls as a result of alkylating agents or radiation therapy [266,520,526]. 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 [209,266,313,520,526]. The risk is dose-dependent and is increased when an alkylating agent is used in combination with radiation or an anthracycline [209,526]. 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 [559]. 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 [266]. The risk of infertility is low and is directly related to gonadal exposure to radiation and age at the time of treatment [560,561]. The possibility of maintaining gonadal function in the presence of higher cumulative doses of alkylating agents is greater in girls than for boys [526].

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 [526]. 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 [526].

Neurocognitive Impairment

Neurocognitive impairment is among the most common and distressing late effect of pediatric cancer treatment [4,313,451,520,562,563,564]. 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 [526]. 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 [526]. The intensity of treatment and the time since treatment are also factors [526]. 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 [562,563,564].

A variety of impairments have been reported, and the most common deficits are related to [52,313,465,526,563]:

- 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 [526].

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) [564]. 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 [564]. Survivors of leukemia and non-Hodgkin lymphoma were among those who were least likely to finish high school [564]. 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%) [451]. Leukemia survivors were among the subgroups that were more likely to have educational problems. While there is longstanding recognition that these effects span the whole illness trajectory and continue beyond treatment completion, further clarity is needed on the specific barriers and facilitators to education during cancer treatment and beyond, as well as on the experiences of children and adolescents across the full range of education settings (e.g., hospital, home, virtual, original school of enrollment), in order to determine which interventions are successful in improving access and experience from their perspective [565].

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 [526]. 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 [52]. 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 [209,266,313,520]. 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 [266]. Dental caries and periodontal disease are also associated with bone marrow transplantation with chronic graft-versus-host disease [526].

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 [566]. 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 [526].

Psychosocial Disorders

Psychosocial disorders are thought to be related to physical function, well-being, and anxiety related to future health needs [438]. 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 [454].

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 [438]. Following that study, the CCSS reported on the psychologic outcomes for survivors of pediatric leukemia and lymphoma [439]. 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 [439,567].

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 [529]. 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 [529]. This rationale supports the finding of post-traumatic stress disorder symptoms in approximately 20% of adolescent survivors [568].

Age and time since diagnosis may be factors in reported levels of post-traumatic stress disorder [569]. 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 [569].

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 [570].

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 [439,529]. One systematic review assessed unemployment in adult childhood cancer survivors compared with the general population, and its predictors [571]. 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 [571]. 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 [526]. 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 [572]. 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 [572]. 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 [573]. 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 [573].

HEALTH PROMOTION AND EDUCATION

Surveys of childhood cancer survivors have shown knowledge deficits regarding the late effects of cancer and cancer treatment [574,575]. 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 [575]. 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 [575].

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 [576,577]. Among the basic elements of a survivorship care plan are [577]:

- 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 [578]. 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 [578].

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 [579].

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 [525,526]:

- 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 [52,524]. 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 [580]. In one study, 40% of survivors reported eating a nutritious diet, 64% said they practiced sun protection, and 94% said they did not smoke [581]. 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 [580]. 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 [580].

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 [582]. 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 [582]. A report from the Childhood Cancer Survivor Study found that poor physical activity during adolescence, parents with less than a college education, previous treatment with cranial radiation, limitations of activity due to health or mobility restriction, and low self-esteem were associated with level of psychosocial functioning among childhood and young adult cancer survivors [583].

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 [524,542,561,576]. 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 [584]. 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 [585]. 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 [586].

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 [587]. 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 [520]. 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 [52,314,520,576,588]. 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 [589].

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 [588]. 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 [520].

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 [489]. 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 [498,499,500]. 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 [503]. The use of a professional interpreter helps to make Mr. and Mrs. P more comfortable and provides for better comprehension [163]. 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 [515]. 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

https://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://ulmanfoundation.org

SURVIVORSHIP

Cancervive

https://cancervive.ca

Children's Oncology Group

http://www.survivorshipguidelines.org

Stupid Cancer

https://stupidcancer.org

National Coalition for Cancer Survivorship

https://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/camp/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

https://specialove.org/event/camp-fantastic

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Evidence-Based Practice Recommendations Citations

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