MD20X • Physicians and Physician Assistants 2020

Table of Contents

MD20X • Physicians and Physician Assistants 2020

How to Receive Credit

NetCE 3 Hour Course #95150 • Responsible and Effective Opioid Prescribing

95150 • Responsible and Effective Opioid Prescribing

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

8. MANAGEMENT OF OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #94130 • Neck Pain in Adults

94130 • Neck Pain in Adults

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOPHYSIOLOGY

4. ASSESSMENT AND DIAGNOSIS

5. TREATMENT OF NECK PAIN

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #90781 • Colorectal Cancer

90781 • Colorectal Cancer

1. INTRODUCTION

2. EPIDEMIOLOGY

3. COLORECTAL CANCER RISK FACTORS

4. COLORECTAL CANCER SCREENING

5. PATHOPHYSIOLOGY

6. DIAGNOSIS AND STAGING OF COLON AND RECTAL CANCER

7. PROGNOSTIC FACTORS

8. TREATMENT OF COLON AND RECTAL CANCER

9. CONCLUSION

10. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

MD20X • Physicians and Physician Assistants 2020

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

MD20X • Physicians and Physician Assistants 2020

Expiration Date: 04/30/2021

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.

95150 • Responsible and Effective Opioid Prescribing

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2017 NetCE, All rights reserved.

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Table of Contents

95150 • Responsible and Effective Opioid Prescribing

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. SCOPE OF THE PROBLEM

3. PAIN MANAGEMENT APPROACHES

ACUTE PAIN

CHRONIC PAIN

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

RISK ASSESSMENT TOOLS

PERIODIC REVIEW AND MONITORING

CONCURRENT USE OF BENZODIAZEPINES

CONSULTATION AND REFERRAL

MEDICAL RECORDS

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

DISCONTINUING OPIOID THERAPY

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

CONTROLLED SUBSTANCES LAWS/RULES

STATE-SPECIFIC LAWS AND RULES

8. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

STIGMA OF ADDICTION

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

95150 • Responsible and Effective Opioid Prescribing

Education Category. Pharmacology

Release Date. 05/01/2017

Review Date. 09/15/2019

Expiration Date. 04/30/2021

Course Overview

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat pain patients with opioids. By implementing these tools, clinicians can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Audience

This course is designed for all physicians, osteopaths, physician assistants, and nurses who may alter prescribing practices or intervene to prevent drug diversion and inappropriate opioid use.

Course Objective

The purpose of this course is to provide clinicians who prescribe or distribute opioids with an appreciation for the complexities of opioid prescribing and the dual risks of litigation due to inadequate pain control and drug diversion or misuse in order to provide the best possible patient care and to prevent a growing social problem.

Learning Objectives

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

1. Apply epidemiologic trends in opioid use and misuse to current practice so at-risk patient populations can be more easily identified, assessed, and treated.

2. Create comprehensive treatment plans for patients with pain that address patient needs as well as drug diversion prevention.

3. Evaluate behaviors that may indicate drug seeking or diverting as well as approaches for patients suspected of misusing opioids.

4. Identify state and federal laws governing the proper prescription and monitoring of controlled substances.

5. Describe the available treatment modalities for opioid use disorder.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

Ronald Runciman, MD

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

Division Planners Disclosure

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Pain is the leading reason for seeking medical care, and pain management is a large part of many healthcare professionals' practice. Opioid analgesics are approved by the U.S. Food and Drug Administration (FDA) for moderate and severe pain and are broadly accepted in acute pain, cancer pain, and end-of-life care, but are controversial in chronic noncancer pain. In response to the long-standing neglect of severe pain, indications for opioid analgesic prescribing were expanded in the 1990s, followed by inappropriate prescribing and increasing abuse, addiction, diversion, and overdose through the 2000s. In tandem with the continued under-treatment of pain, these practice patterns led to needless suffering from uncontrolled pain, opioid analgesic addiction, and overdose. Opioid analgesic prescribing and associated overdose peaked in 2011 with both now in multi-year decline.

Patients show substantial opioid response variations in analgesia and tolerability and may exhibit a range of psychologic, emotional, and behavioral responses that reflect inadequate pain control, an emerging opioid use problem, or both. Clinician delivery of best possible care to patients with pain requires appreciation of the complexities of opioid prescribing and the dual risks of inadequate pain control and inappropriate use, drug diversion, or overdose. A foundation for appropriate opioid prescribing is the understanding of factual data that clarify the prevalence, causality, and prevention of serious safety concerns with opioid prescribing.

2. SCOPE OF THE PROBLEM

Inappropriate opioid analgesic prescribing for pain is defined as the non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of ineffectiveness of opioids [1]. Appropriate opioid prescribing is essential to achieve pain control; to minimize patient risk of abuse, addiction, and fatal toxicity; and to minimize societal harms from diversion. The foundation of appropriate opioid prescribing is thorough patient assessment, treatment planning, and follow-up and monitoring. Essential for proper patient assessment and treatment planning is comprehension of the clinical concepts of opioid abuse and addiction, their behavioral manifestations in pain patients, and how these potentially problematic behavioral responses to opioids both resemble and differ from physical dependence and pseudo-dependence. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [2].

The current extent of opioid analgesic use in the United States is unprecedented in the country's history and unparalleled anywhere in the world. Before 1990, physicians in the United States were skeptical of prescribing opioids for chronic noncancer pain. But as of 2017, 1 of 25 adults is prescribed an opioid such as oxycodone and hydrocodone for chronic pain, and sales of opioid analgesics now total more than $9 billion each year [3].

Worldwide consumption of opioid analgesics has increased dramatically in the past few decades, with the United States driving a substantial proportion of this increase. For example, the 1990 global consumption of hydrocodone was 4 tons (3,628 kg), compared with the 2009 consumption of 39 tons (35,380 kg); 99% of this was consumed in the United States. Similarly, 3 tons (2,722 kg) of oxycodone were consumed globally in 1990, versus 77 tons (69,853 kg) in 2009, of which 62 tons (56,245 kg or 81%) were consumed in the United States [3]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [4]:

- 99% of all hydrocodone

- 80% of all oxycodone

- 58% of all methadone

- 54% of all hydromorphone

- 49% of all fentanyl

- 43% of all meperidine

This disproportionate rate of opioid consumption reflects sociocultural and economic factors and standards of clinical medicine.

Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time non-medical opioid analgesic users 12 to 17 years of age increased 542% [4]. It is interesting to note that while opioid prescribing has increased precipitously among adults in the United States, the rate remained low and steady for children between 1996 and 2012 [5]. To assist in monitoring the public health problem associated with prescribed opioids, numerous governmental, non-profit, and private sector agencies and organizations are involved in collecting, reporting, and analyzing data on the abuse, addiction, fatal overdose, and treatment admissions related to opioid analgesics.

Before it was halted in 2011, the Drug Abuse Warning Network (DAWN) provided estimates of the health consequences of nonmedical use of individual drugs, including opioid medications [6]. DAWN indicates that opioid abuse is a growing problem in the United States. In 2005 and 2011, hydrocodone and its combinations accounted for 51,225 and 97,183 emergency department visits, respectively. Oxycodone and its combinations resulted in 42,810 visits to the emergency department in 2005; this number increased to 175,229 visits in 2011 [7,8]. Visits for nonmedical use of all opioids increased from 217,594 to 420,040 during the six-year period.

3. PAIN MANAGEMENT APPROACHES

Healthcare professionals should know the best clinical practices in opioid prescribing, including the associated risks of opioids, approaches to the assessment of pain and function, and pain management modalities. Pharmacologic and nonpharmacologic approaches should be used on the basis of current knowledge in the evidence base or best clinical practices. Patients with moderate-to-severe chronic pain who have been assessed and treated, over a period of time, with non-opioid therapy or nonpharmacologic pain therapy without adequate pain relief, are considered to be candidates for a trial of opioid therapy [9,10]. Initial treatment should always be considered individually determined and as a trial of therapy, not a definitive course of treatment [11].

ACUTE PAIN

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [10]. However, it is important to note that this guideline is based on emergency department prescribing guidelines for non-traumatic non-surgical pain [12]. It may be necessary to prescribe for longer periods in patients with acute severe pain.

With postoperative, acute, or intermittent pain, analgesia often requires frequent titration, and the two- to four-hour analgesic duration with short-acting hydrocodone, morphine, and oxycodone is more effective than extended-release formulations. Short-acting opioids are also recommended in patients who are medically unstable or with highly variable pain intensity [13,14,15].

CHRONIC PAIN

Nonpharmacologic therapy and non-opioid pharmacologic therapy are the preferred first-line therapies for chronic pain. Several nonpharmacologic approaches are therapeutic complements to pain-relieving medication, lessening the need for higher doses and perhaps minimizing side effects. These interventions can help decrease pain or distress that may be contributing to the pain sensation. Approaches include palliative radiotherapy, complementary/alternative methods, manipulative and body-based methods, and cognitive/behavioral techniques. The choice of a specific nonpharmacologic intervention is based on the patient's preference, which, in turn, is usually based on a successful experience in the past.

Implantable intrathecal opioid infusion and/or spinal cord stimulation may be options for severe, intractable pain. Both options require that devices or ports be implanted, with associated risks. With intrathecal opioid infusion, the ability to deliver the drug directly into the spine provides pain relief with significantly smaller opioid doses, which can help to minimize side effects (e.g., drowsiness, dizziness, dry mouth, nausea, vomiting, and constipation) that can accompany systemic pain medications that might be delivered orally, transdermally, or through an IV [90]. However, use of opioid infusion has traditionally been limited to cancer pain. With spinal cord stimulation therapy, the most challenging aspect is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months [91].

If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate. Clinicians should consider opioid therapy only if expected benefits for pain and function are anticipated to outweigh risks to the patient [10].

Opioid therapy for chronic pain should be presented as a trial for a pre-defined period (e.g., ≤30 days). The goals of treatment should be established with all patients prior to the initiation of opioid therapy, including reasonable improvements in pain, function, depression, anxiety, and avoidance of unnecessary or excessive medication use [1,10]. The treatment plan should describe therapy selection, measures of progress, and other diagnostic evaluations, consultations, referrals, and therapies.

In opioid-naïve patients, start at the lowest possible dose and titrate to effect. Dosages for opioid-tolerant patients should always be individualized and titrated by efficacy and tolerability [1,10]. When starting opioid therapy for chronic pain, clinicians should prescribe short-acting instead of extended-release/long-acting opioid formulations [10].

The need for frequent progress and benefit/risk assessments during the trial should be included in patient education. Patients should also have full knowledge of the warning signs and symptoms of respiratory depression. Prescribers should carefully reassess evidence of benefits and risks when increasing the dosage to ≥50 mg morphine equivalent dose (MED) per day. Decisions to titrate dose to ≥90 mg MED/day should be avoided or carefully justified [10].

Prescribers should be knowledgeable of federal and state opioid prescribing regulations. Issues of equianalgesic dosing, close patient monitoring during all dose changes, and cross-tolerance with opioid conversion should be considered. If necessary, treatment may be augmented, with preference for nonopioid and immediate-release opioids over long-acting/extended-release opioids. Taper opioid dose when no longer needed [16].

PALLIATIVE CARE AND PAIN AT THE END OF LIFE

Unrelieved pain is the greatest fear among people with a life-limiting disease, and the need for an increased understanding of effective pain management is well-documented [27]. Although experts have noted that 75% to 90% of end-of-life pain can be managed effectively, rates of pain are high, even among people receiving palliative care [27,28,29,30,31,32,33,34,35,36].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [37]. This reluctance is related to a variety of attitudes and beliefs [27,37]:

- Fear of addiction to opioids

- Worry that if pain is treated early, there will be no options for treatment of future pain

- Anxiety about unpleasant side effects from pain medications

- Fear that increasing pain means that the disease is getting worse

- Desire to be a "good" patient

- Concern about the high cost of medications

Education and open communication are the keys to overcoming these barriers. Every member of the healthcare team should reinforce accurate information about pain management with patients and families. The clinician should initiate conversations about pain management, especially regarding the use of opioids, as few patients will raise the issue themselves or even express their concerns unless they are specifically asked [38]. It is important to acknowledge patients' fears individually and provide information to help them differentiate fact from fiction. For example, when discussing opioids with a patient who fears addiction, the clinician should explain that the risk of addiction is low [27]. It is also helpful to note the difference between addiction and physical dependence.

There are several other ways clinicians can allay patients' fears about pain medication:

- Assure patients that the availability of pain relievers cannot be exhausted; there will always be medications if pain becomes more severe.

- Acknowledge that side effects may occur but emphasize that they can be managed promptly and safely and that some side effects will abate over time.

- Explain that pain and severity of disease are not necessarily related.

Encouraging patients to be honest about pain and other symptoms is also vital. Clinicians should ensure that patients understand that pain is multidimensional and emphasize the importance of talking to a member of the healthcare team about possible causes of pain, such as emotional or spiritual distress. The healthcare team and patient should explore psychosocial and cultural factors that may affect self-reporting of pain, such as concern about the cost of medication.

Clinicians' attitudes, beliefs, and experiences also influence pain management, with addiction, tolerance, side effects, and regulations being the most important concerns [27,34,37,39,40,41]. A lack of appropriate education and training in the assessment and management of pain has been noted to be a substantial contributor to ineffective pain management [37,39,41,42]. As a result, many clinicians, especially primary care physicians, do not feel confident about their ability to manage pain in their patients [37,39].

Clinicians require a clear understanding of available medications to relieve pain, including appropriate dosing, safety profiles, and side effects. If necessary, clinicians should consult with pain specialists to develop an effective approach.

Strong opioids are used for severe pain at the end of life [30,34,43,44]. Morphine, buprenorphine, oxycodone, hydromorphone, fentanyl, and methadone are the most widely used in the United States [45]. Unlike nonopioids, opioids do not have a ceiling effect, and the dose can be titrated until pain is relieved or side effects become unmanageable. For an opioid-naïve patient or a patient who has been receiving low doses of a weak opioid, the initial dose should be low, and, if pain persists, the dose may be titrated up daily until pain is controlled.

More than one route of opioid administration will be needed by many patients during end-of-life care, but in general, opioids should be given orally, as this route is the most convenient and least expensive. The transdermal route is preferred to the parenteral route, although dosing with a transdermal patch is less flexible and so may not be appropriate for patients with unstable pain [34]. Intramuscular injections should be avoided because injections are painful, drug absorption is unreliable, and the time to peak concentration is long [34].

4. CREATING A TREATMENT PLAN AND ASSESSMENT OF ADDICTION RISK

Information obtained by patient history, physical examination, and interview, from family members, a spouse, or state prescription drug monitoring program (PDMP), and from the use of screening and assessment tools can help the clinician to stratify the patient according to level of risk for developing problematic opioid behavioral responses (Table 1). Low-risk patients receive the standard level of monitoring, vigilance, and care. Moderate-risk patients should be considered for an additional level of monitoring and provider contact, and high-risk patients are likely to require intensive and structured monitoring and follow-up contact, additional consultation with psychiatric and addiction medicine specialists, and limited supplies of short-acting opioid formulations [10,26].

Table 1: RISK STRATIFICATION FOR PATIENTS PRESCRIBED OPIOIDS

Low Risk

Definable physical pathology with objective signs and reliable symptoms

Clinical correlation with diagnostic testing, including MRI, physical examination, and interventional diagnostic techniques

With or without mild psychologic comorbidity

With or without minor medical comorbidity

No or well-defined and controlled personal or family history of alcoholism or substance abuse

Age 45 years or older

High levels of pain acceptance and active coping strategies

High motivation and willingness to participate in multimodal therapy and attempting to function at normal levels

Medium Risk

Significant pain problems with objective signs and symptoms confirmed by radiologic evaluation, physical examination, or diagnostic interventions

Moderate psychologic problems, well controlled by therapy

Moderate coexisting medical disorders that are well controlled by medical therapy and are not affected by chronic opioid therapy (e.g., central sleep apnea)

Develops mild tolerance but not hyperalgesia without physical dependence or addiction

Past history of personal or family history of alcoholism or substance abuse

Pain involving more than three regions of the body

Defined pathology with moderate levels of pain acceptance and coping strategies

Willing to participate in multimodal therapy, attempting to function in normal daily life

High Risk

Widespread pain without objective signs and symptoms

Pain involving more than three regions of the body

Aberrant drug-related behavior

History of alcoholism or drug misuse, abuse, addiction, diversion, dependency, tolerance, or hyperalgesia

Major psychologic disorders

Age younger than 45 years

HIV-related pain

High levels of pain exacerbation and low levels of coping strategies

Unwilling to participate in multimodal therapy, not functioning close to a near normal lifestyle

HIV = human immunodeficiency syndrome, MRI = magnetic resonance imaging.

Source: [17]

Evidence Based Practice Recommendation

Despite limited evidence for reliability and accuracy, screening for opioid use is recommended by the American Society of Interventional Pain Physicians, as it will identify opioid abusers and reduce opioid abuse.

https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf

Last Accessed: September 17, 2019

Level of Evidence: Limited (Evidence is insufficient to assess effects on health outcomes because of limited number or power of studies, large and unexplained inconsistency between higher-quality trials, important flaws in trial design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes.)

Before deciding to prescribe an opioid analgesic, clinicians should perform and document a detailed patient assessment that includes [1]:

- Pain indications for opioid therapy

- Nature and intensity of pain

- Past and current pain treatments and patient response

- Comorbid conditions

- Pain impact on physical and psychologic function

- Social support, housing, and employment

- Home environment (i.e., stressful or supportive)

- Pain impact on sleep, mood, work, relationships, leisure, and substance use

- Patient history of physical, emotional, or sexual abuse

If substance abuse is active, in remission, or in the patient's history, consult an addiction specialist before starting opioids [1]. In active substance abuse, do not prescribe opioids until the patient is engaged in treatment/recovery program or other arrangement made, such as addiction professional co-management and additional monitoring. When considering an opioid analgesic (particularly those that are extended-release or long-acting), one must always weigh the benefits against the risks of overdose, abuse, addiction, physical dependence and tolerance, adverse drug interactions, and accidental exposure by children [10,16].

Screening and assessment tools can help guide patient stratification according to risk level and inform the appropriate degree of structure and monitoring in the treatment plan. It should be noted that despite widespread endorsement of screening tool use to help determine patient risk level, most tools have not been extensively evaluated, validated, or compared to each other, and evidence of their reliability is poor [17].

RISK ASSESSMENT TOOLS

Opioid Risk Tool (ORT)

The Opioid Risk Tool (ORT) is a five-item assessment to help predict aberrant drug-related behavior. The ORT is also used to establish patient risk level through categorization into low, medium, or high levels of risk for aberrant drug-related behaviors based on responses to questions of previous alcohol/drug abuse, psychologic disorders, and other risk factors [18].

Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R)

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [19].

CAGE and CAGE-AID

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [20].

Diagnosis, Intractability, Risk, and Efficacy (DIRE) Tool

The Diagnosis, Intractability, Risk, and Efficacy (DIRE) risk assessment tool is a clinician-rated questionnaire that is used to predict patient compliance with long-term opioid therapy [21]. Patients scoring lower on the DIRE tool are poor candidates for long-term opioid analgesia.

Mental Health Screening Tool

The Mental Health Screening Tool is a five-item screen that asks about a patient's feelings of happiness, calmness, peacefulness, nervousness, and depression in the past month [22]. A lower score on this tool is an indicator that the patient should be referred to a specialist for pain management.

Informed Consent and Treatment Agreements

The initial opioid prescription is preceded by a written informed consent or "treatment agreement" [1]. This agreement should address potential side effects, tolerance and/or physical dependence, drug interactions, motor skill impairment, limited evidence of long-term benefit, misuse, dependence, addiction, and overdose. Informed consent documents should include information regarding the risk/benefit profile for the drug(s) being prescribed. The prescribing policies should be clearly delineated, including the number/frequency of refills, early refills, and procedures for lost or stolen medications.

The treatment agreement also outlines joint physician and patient responsibilities. The patient agrees to using medications safely, refraining from "doctor shopping," and consenting to routine urine drug testing (UDT). The prescriber's responsibility is to address unforeseen problems and prescribe scheduled refills. Reasons for opioid therapy change or discontinuation should be listed. Agreements can also include sections related to follow-up visits, monitoring, and safe storage and disposal of unused drugs.

PERIODIC REVIEW AND MONITORING

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [1]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [1,23]:

- Analgesia

- Activities of daily living

- Adverse or side effects

- Aberrant drug-related behaviors

- Affect (i.e., patient mood)

Signs and symptoms that, if present, may suggest a problematic response to the opioid and interference with the goal of functional improvement include [24]:

- Excessive sleeping or days and nights turned around

- Diminished appetite

- Short attention span or inability to concentrate

- Mood volatility, especially irritability

- Lack of involvement with others

- Impaired functioning due to drug effects

- Use of the opioid to regress instead of re-engaging in life

- Lack of attention to hygiene and appearance

The decision to continue, change, or terminate opioid therapy is based on progress toward treatment objectives and absence of adverse effects and risks of overdose or diversion [1]. Satisfactory therapy is indicated by improvements in pain, function, and quality of life. Brief assessment tools to assess pain and function may be useful, as may UDTs. Treatment plans may include periodic pill counts to confirm adherence and minimize diversion.

Involvement of Family

Family members of the patient can provide the clinician with valuable information that better informs decision making regarding continuing opioid therapy. Family members can observe whether a patient is losing control of his or her life or becoming less functional or more depressed during the course of opioid therapy. They can also provide input regarding positive or negative changes in patient function, attitude, and level of comfort. The following questions can be asked of family members or a spouse to help clarify whether the patient's response to opioid therapy is favorable or unfavorable [24]:

- Is the person's day centered around taking the opioid medication? Response can help clarify long-term risks and benefits of the medication and identify other treatment options.

- Does the person take pain medication only on occasion, perhaps three or four times per week? If yes, the likelihood of addiction is low.

- Have there been any other substance (alcohol or drug) abuse problems in the person's life? An affirmative response should be taken into consideration when prescribing.

- Does the person in pain spend most of the day resting, avoiding activity, or feeling depressed? If so, this suggests the pain medication is failing to promote rehabilitation. Daily activity is essential, and the patient may be considered for enrollment in a graduated exercise program

- Is the person in pain able to function (e.g., work, do household chores, play) with pain medication in a way that is clearly better than without? If yes, this suggests the pain medication is contributing to wellness.

Assessment Tools

VIGIL

VIGIL is the acronym for a five-step risk management strategy designed to empower clinicians to appropriately prescribe opioids for pain by reducing regulatory concerns and to give pharmacists a framework for resolving ambiguous opioid analgesic prescriptions in a manner that preserves legitimate patient need while potentially deterring diverters. The components of VIGIL are:

- Verification: Is this a responsible opioid user?

- Identification: Is the identity of this patient verifiable?

- Generalization: Do we agree on mutual responsibilities and expectations?

- Interpretation: Do I feel comfortable allowing this person to have controlled substances?

- Legalization: Am I acting legally and responsibly?

The foundation of VIGIL is a collaborative physician/pharmacist relationship [25].

Current Opioid Misuse Measure (COMM)

The Current Opioid Misuse Measure (COMM) is a 17-item patient self-report assessment designed to help clinicians identify misuse or abuse in chronic pain patients. Unlike the ORT and the SOAPP-R, the COMM identifies aberrant behaviors associated with opioid misuse in patients already receiving long-term opioid therapy [26]. Sample questions include: In the past 30 days, how often have you had to take more of your medication than prescribed? In the past 30 days, how much of your time was spent thinking about opioid medications (e.g., having enough, taking them, dosing schedule)?

Pain Assessment and Documentation Tool (PADT)

Guidelines by the CDC, the Federation of State Medical Boards (FSMB), and the Joint Commission stress the importance of documentation from both a healthcare quality and medicolegal perspective. Research has found widespread deficits in chart notes and progress documentation with chronic pain patients receiving opioid therapy, and the Pain Assessment and Documentation Tool (PADT) was designed to address these shortcomings [46]. The PADT is a clinician-directed interview, with most sections (e.g., analgesia, activities of daily living, adverse events) consisting of questions asked of the patient. However, the potential aberrant drug-related behavior section must be completed by the physician based on his or her observations of the patient.

The Brief Intervention Tool

The Brief Intervention Tool is a 26-item, "yes-no," patient-administered questionnaire used to identify early signs of opioid abuse or addiction. The items assess the extent of problems related to drug use in several areas, including drug use-related functional impairment [22].

Urine Drug Tests

UDTs may be used to monitor adherence to the prescribed treatment plan and to detect unsanctioned drug use. They should be used more often in patients receiving addiction therapy, but clinical judgment is the ultimate guide to testing frequency (Table 2) [47]. The CDC recommends clinicians should use UDT before starting opioid therapy and consider UDT at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs [10]. However, this recommendation was based on low-quality evidence that indicates little confidence in the effect estimate.

Table 2: PATIENT RISK LEVEL AND FREQUENCY OF MONITORING

Monitoring Tool

Patient Risk Level

Low

Medium

High

Urine drug test

Every 1 to 2 years

Every 6 to 12 months

Every 3 to 6 months

State prescription drug monitoring program

Twice per year

Three times per year

Four times per year

Source: [47]

Initially, testing involves the use of class-specific immunoassay drug panels [1]. If necessary, this may be followed with gas chromatography/mass spectrometry for specific drug or metabolite detection. It is important that testing identifies the specific drug rather than the drug class, and the prescribed opioid should be included in the screen. Any abnormalities should be confirmed with a laboratory toxicologist or clinical pathologist. Immunoassay may be used point-of-care for "on-the-spot" therapy changes, but the high error rate prevents its use in major clinical decisions except with liquid chromatography coupled to tandem mass spectrometry confirmation.

Urine test results suggesting opioid misuse should be discussed with the patient using a positive, supportive approach. The test results and the patient discussion should be documented.

CONCURRENT USE OF BENZODIAZEPINES

In 2015, 23% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [87]. Benzodiazepines work by raising the level of the neurotransmitter gamma-aminobutyric acid (GABA) in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers avoid prescribing benzodiazepines concurrently with opioids whenever possible [10]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. A commonly used tapering schedule is a reduction of the benzodiazepine dose by 25% every one to two weeks [10].

CONSULTATION AND REFERRAL

It is important to seek consultation or patient referral when input or care from a pain, psychiatry, addiction, or mental health specialist is necessary. Clinicians who prescribe opioids should become familiar with opioid addiction treatment options (including licensed opioid treatment programs for methadone and office-based opioid treatment for buprenorphine) if referral is needed [1].

Ideally, providers should be able to refer patients with active substance abuse who require pain treatment to an addiction professional or specialized program. In reality, these specialized resources are scarce or non-existent in many areas [1]. Therefore, each provider will need to decide whether the risks of continuing opioid treatment while a patient is using illicit drugs outweigh the benefits to the patient in terms of pain control and improved function [48].

MEDICAL RECORDS

As noted, documentation is a necessary aspect of all patient care, but it is of particular importance when opioid prescribing is involved. All clinicians should maintain accurate, complete, and up-to-date medical records, including all written or telephoned prescription orders for opioid analgesics and other controlled substances, all written instructions to the patient for medication use, and the name, telephone number, and address of the patient's pharmacy [1]. Good medical records demonstrate that a service was provided to the patient and that the service was medically necessary. Regardless of the treatment outcome, thorough medical records protect the prescriber.

PATIENT EDUCATION ON THE USE AND DISPOSAL OF OPIOIDS

Patients and caregivers should be counseled regarding the safe use and disposal of opioids. As part of its mandatory Risk Evaluation and Mitigation Strategy (REMS) for extended-release/long-acting opioids, the U.S. Food and Drug Administration (FDA) has developed a patient counseling document with information on the patient's specific medications, instructions for emergency situations and incomplete pain control, and warnings not to share medications or take them unprescribed [16]. A copy of this form may be accessed online at https://www.fda.gov/media/86281/download.

When prescribing opioids, clinicians should provide patients with the following information [16]:

- Product-specific information

- Taking the opioid as prescribed

- Importance of dosing regimen adherence, managing missed doses, and prescriber contact if pain is not controlled

- Warning and rationale to never break or chew/crush tablets or cut or tear patches prior to use

- Warning and rationale to avoid other central nervous system depressants, such as sedative-hypnotics, anxiolytics, alcohol, or illicit drugs

- Warning not to abruptly halt or reduce the opioid without physician oversight of safe tapering when discontinuing

- The potential of serious side effects or death

- Risk factors, signs, and symptoms of overdose and opioid-induced respiratory depression, gastrointestinal obstruction, and allergic reactions

- The risks of falls, using heavy machinery, and driving

- Warning and rationale to never share an opioid analgesic

- Rationale for secure opioid storage

- Warning to protect opioids from theft

- Instructions for disposal of unneeded opioids, based on product-specific disposal information

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [49]. According to the Office of National Drug Control Policy, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [50]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [50]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

The American College of Preventive Medicine has established best practices to avoid diversion of unused drugs and educate patients regarding drug disposal [49]:

- Consider writing prescriptions in smaller amounts.

- Educate patients about safe storing and disposal practices.

- Give drug-specific information to patients about the temperature at which they should store their medications. Generally, the bathroom is not the best storage place. It is damp and moist, potentially resulting in potency decrements, and accessible to many people, including children and teens, resulting in potential theft or safety issues.

- Ask patients not to advertise that they are taking these types of medications and to keep their medications secure.

- Refer patients to community "take back" services overseen by law enforcement that collect controlled substances, seal them in plastic bags, and store them in a secure location until they can be incinerated. Contact your state law enforcement agency or visit https://www.dea.gov to determine if a program is available in your area.

DISCONTINUING OPIOID THERAPY

The decision to continue or end opioid prescribing should be based on a physician-patient discussion of the anticipated benefits and risks. An opioid should be discontinued with resolution of the pain condition, intolerable side effects, inadequate analgesia, lack of improvement in quality of life despite dose titration, deteriorating function, or significant aberrant medication use [1,10].

Clinicians should provide physically dependent patients with a safely structured tapering protocol. Withdrawal is managed by the prescribing physician or referral to an addiction specialist. Patients should be reassured that opioid discontinuation is not the end of treatment; continuation of pain management will be undertaken with other modalities through direct care or referral.

As a side note, cannabis use by chronic pain patients receiving opioid therapy has traditionally been viewed as a treatment agreement violation that is grounds for termination of opioid therapy. However, some now argue against cannabis use as a rationale for termination or substantial treatment and monitoring changes, especially considering the increasing legalization of medical use at the state level [48].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. 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. Interpreters can be a valuable resource to help bridge the communication and cultural gap between 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 treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

5. IDENTIFICATION OF DRUG DIVERSION/SEEKING BEHAVIORS

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2015 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [51]. Among persons 12 years of age or older, 40.5% obtained their prescription opioids from a friend or relative for free, 34.0% got them through a prescription from one doctor (vs. 17.3% in 2009–2010), 9.4% bought them from a friend or relative, and 3.8% took them from a friend or relative without asking [51]. Less frequent sources included a drug dealer or other stranger (4.9%); multiple doctors (1.7%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.2% in 2009–2010) [51].

As discussed, UDTs can give insight into patients who are misusing opioids. A random sample of UDT results from 800 pain patients treated at a Veterans Affairs facility found that 25.2% were negative for the prescribed opioid while 19.5% were positive for an illicit drug/unreported opioid [52]. Negative UDT results for the prescribed opioid do not necessarily indicate diversion, but may indicate the patient halted his/her use due to side effects, lack of efficacy, or pain remission. The concern arises over the increasingly stringent climate surrounding clinical decision-making regarding aberrant UDT results and that a negative result for the prescribed opioid or a positive UDT may serve as the pretense to terminate a patient rather than guide him/her into addiction treatment or an alternative pain management program [53].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [48,54,55]:

- Selling medications

- Prescription forgery or alteration

- Injecting medications meant for oral use

- Obtaining medications from nonmedical sources

- Resisting medication change despite worsening function or significant negative effects

- Loss of control over alcohol use

- Using illegal drugs or non-prescribed controlled substances

- Recurrent episodes of:

- Prescription loss or theft

- Obtaining opioids from other providers in violation of a treatment agreement

- Unsanctioned dose escalation

- Running out of medication and requesting early refills

Behaviors with a lower level of evidence for their association with opioid misuse include [48,54,55]:

- Aggressive demands for more drug

- Asking for specific medications

- Stockpiling medications during times when pain is less severe

- Using pain medications to treat other symptoms

- Reluctance to decrease opioid dosing once stable

- In the earlier stages of treatment:

- Increasing medication dosing without provider permission

- Obtaining prescriptions from sources other than the pain provider

- Sharing or borrowing similar medications from friends/family

6. INTERVENTIONS FOR SUSPECTED OR KNOWN ADDICTION OR DRUG DIVERSION

There are a number of actions that prescribers and dispensers can take to prevent or intervene in cases of drug diversion. These actions can be generally categorized based on the various mechanisms of drug diversion.

Prevention is the best approach to addressing drug diversion. As noted, the most common source of nonmedical use of prescribed opioids is from a family member or friend, through sharing, buying, or stealing. To avoid drug sharing among patients, healthcare professionals should educate patients on the dangers of sharing opioids and stress that "doing prescription drugs" is the same as "using street drugs" [49]. In addition, patients should be aware of the many options available to treat chronic pain aside from opioids. To prevent theft, patients should be advised to keep medications in a private place and to refrain from telling others about the medications being used.

Communication among providers and pharmacies can help to avoid inappropriate attainment of prescription drugs through "doctor shopping." Prescribers should keep complete and up-to-date records for all controlled substance prescribing. When possible, electronic medical records should be integrated between pharmacies, hospitals, and managed care organizations [49]. If available, it is also best practice to periodically request a report from the state's prescription reporting program to evaluate the prescribing of opioids to your pahttp://www.netce.com/tients by other providers [49].

When dealing with patients suspected of drug seeking/diversion, first inquire about prescription, over-the-counter, and illicit drug use and perform a thorough examination [49,56]. Pill counting and/or UDT may be necessary to investigate possible drug misuse. Photo identification or other form of identification and social security number may be required prior to dispensing the drug, with proof of identity documented fully. If a patient is displaying suspicious behaviors, consider prescribing for limited quantities [56].

If a patient is found to be abusing prescribed opioids, this is considered a violation of the treatment agreement and the clinician must make the decision whether or not to continue the therapeutic relationship. If the relationship is terminated, it must be done ethically and legally. The most significant issue is the risk of patient abandonment, which is defined as ending a relationship with a patient without consideration of continuity of care and without providing notice to the patient. The American Medical Association Code of Ethics states that physicians have an obligation to support continuity of care for their patients. While physicians have the option of withdrawing from a case, they should notify the patient (or authorized decision maker) long enough in advance to permit the patient to secure another physician and facilitate transfer of care when appropriate [57]. Patients may also be given resources and/or recommendations to help them locate a new clinician.

Patients with chronic pain found to have an ongoing substance abuse problem or addiction should be referred to a pain specialist for continued treatment. Theft or loss of controlled substances is reported to the DEA. If drug diversion has occurred, the activity should be documented and a report to law enforcement should be made [58].

7. COMPLIANCE WITH STATE AND FEDERAL LAWS

In response to the rising incidence in prescription opioid abuse, addiction, diversion, and overdose since the late 1990s, the FDA has mandated opioid-specific REMS to reduce the potential negative patient and societal effects of prescribed opioids. Other elements of opioid risk mitigation include FDA partnering with other governmental agencies, state professional licensing boards, and societies of healthcare professionals to help improve prescriber knowledge of appropriate and safe opioid prescribing and safe home storage and disposal of unused medication [24].

Several regulations and programs at the state level have been enacted in an effort to reduce prescription opioid abuse, diversion, and overdose, including [59]:

- Physical examination required prior to prescribing

- Tamper-resistant prescription forms

- Pain clinic regulatory oversight

- Prescription limits

- Prohibition from obtaining controlled substance prescriptions from multiple providers

- Patient identification required before dispensing

- Immunity from prosecution or mitigation at sentencing for individuals seeking assistance during an overdose

CONTROLLED SUBSTANCES LAWS/RULES

The U.S. Drug Enforcement Administration (DEA) is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [60].

According to the DEA, drugs, substances, and certain chemicals used to make drugs are classified into five distinct categories or schedules depending upon the drug's acceptable medical use and the drug's abuse or dependency potential [61]. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs are considered the most dangerous class of drugs with a high potential for abuse and potentially severe psychologic and/or physical dependence.

STATE-SPECIFIC LAWS AND RULES

Most states have established laws and rules governing the prescribing and dispensing of opioid analgesics. It is each prescriber's responsibility to have knowledge of and adhere to the laws and rules of the state in which he or she prescribes.

Arkansas Laws and Rules

An excerpt from the Arkansas Code rules and regulations relating to the regulation of controlled substances is available by clicking here.

Colorado Laws and Rules

An excerpt from the Colorado Revised Statutes relating to the electronic prescription drug monitoring program, and the full Guidelines for the Safe Prescribing and Dispensing of Opioids are available by clicking here.

New Mexico Laws and Rules

An excerpt from the New Mexico Administrative Code Title 16, Chapter 10, Part 14: Management of Pain and Other Conditions with Controlled Substances is available by clicking here.

New York Laws and Rules

An excerpt from the New York Code, Rules, and Regulations relating to the regulation of controlled substances is available by clicking here.

Vermont Laws and Rules

Information on use of the Vermont Prescription Monitoring System (VPMS) is available by clicking here.

Wisconsin Laws and Rules

The Wisconsin Medical Examining Board Opioid Prescribing Guideline is available by clicking here.

Washington Laws and Rules

Laws governing the prescribing of opioids in the state of Washington are available by clicking here.

Michigan Laws and Rules

A summary of 2017 legislation enacted in Michigan to curb substance abuse and drug diversion is available by clicking here.

Nebraska Laws and Rules

An excerpt reprinted from the Nebraska Revised Statutes 71-2454 and 71-2455 is available by clicking here.

8. MANAGEMENT OF OPIOID USE DISORDER

Management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [62]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient’s body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [62].

CRISIS INTERVENTION

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [63]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [63]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. It is available in a ready-to-use 4-mg single-dose sprayer [64,65].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [66]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [66].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [67,68]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [68,69]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [62,68].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [67].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [67]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [70]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [67]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [70].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [70,71]. The first non-opioid treatment approved for the management of opioid withdrawal symptoms is lofexidine [86]. In studies, lofexidine resulted in less severe withdrawal symptoms and greater treatment retention than placebo.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [70].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [70]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [70]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [72,73].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [74]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [75].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [76]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [76]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [62].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [62]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [62]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [62]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [62].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [67]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient’s attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [67].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [77]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [77].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [67]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [67].

As of 2018, there were 1,519 treatment programs including opioid replacement therapy in the United States [78]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [67]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [79].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [62].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine’s advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [62].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [80]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [80]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [81].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [81].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [82]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [83].

STIGMA OF ADDICTION

Many terms used in discussions of opioid use and misuse may have ambiguous meanings, and the absence of consensus in the terminology and definitions of substance use, substance use disorders, and addiction has led to considerable confusion and misconceptions. These misconceptions may be harbored by clinicians, patients, family members, and the public and can negatively impact patient interaction, assessment, treatment, and outcomes. This, coupled with pervasive stereotypes about what an opioid addict “looks” like, can negatively impact willingness to receive treatment or seek help and impair the patient’s self-worth and mental health. Correction of these erroneous beliefs and attitudes is important, as is the use of nonpejorative and nonstigmatizing language when describing opioid analgesics, the patients who need them, and patients who develop aberrant behaviors or addiction involving opioids [88,89]. It is important for all healthcare professionals to remember that addiction can affect any patients, regardless of age, sex, socioeconomic status, education, ability, or race.

PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [84]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [85].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [76].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [76].

9. CONCLUSION

Opioid analgesic medications can bring substantial relief to patients suffering from pain. However, the inappropriate use, abuse, and diversion of prescription drugs in America, particularly prescription opioids, has increased dramatically in recent years and has been identified as a national public health epidemic. A set of clinical tools, guidelines, and recommendations are now available for prescribers who treat patients with opioids. By implementing these tools, the clinician can effectively address issues related to the clinical management of opioid prescribing, opioid risk management, regulations surrounding the prescribing of opioids, and problematic opioid use by patients. In doing so, healthcare professionals are more likely to achieve a balance between the benefits and risks of opioid prescribing, optimize patient attainment of therapeutic goals, and avoid the risk to patient outcome, public health, and viability of their own practice imposed by deficits in knowledge.

Works Cited

1. Federation of State Medical Boards. Guidelines for the Chronic Use of Opioid Analgesics. Washington, DC: The Federation of State Medical Boards; 2017.

2. Institute of Medicine, Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.

3. Kenen K, Mack K, Paulozzi L. Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000–2010. Open Medicine. 2012;6(2)e41.

4. Owen GT, Burton AW, Schade CM, Passik S. Urine drug testing: current recommendations and best practices. Pain Physician. 2012;15:ES119-ES133.

5. Groenewald CB, Rabbitts JA, Gebert JT, Palermo TM. Trends in opioid prescriptions among children and adolescents in the United States: a nationally representative study from 1996 to 2012. Pain. 2016;157(5):1021-1027.

6. Miller NS, Greenfeld A. Patient characteristics and risks factors for development of dependence on hydrocodone and oxycodone. Am J Ther. 2004;11:26-32.

7. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: U.S. Department of Health and Human Services; 2007.

8. Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2014.

9. Management of Opioid Therapy for Chronic Pain Working Group. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. Washington, DC: Department of Veterans Affairs, Department of Defense; 2017.

10. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR. 2016;65(1):1-49.

11. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

12. American Academy of Pain Medicine. Comments to the CDC on the Proposed 2016 Guideline for Prescribing Opioids for Chronic Pain. Available at https://painmed.org/uploads/news/cheng-letter-to-senator-wyden.pdf. Last accessed September 17, 2019.

13. Argoff CE, Silvershein DI. A comparison of long- and short-acting opioids for the treatment of chronic noncancer pain: tailoring therapy to meet patient needs. Mayo Clin Proc. 2009;84(7):602-612.

14. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8(3):181-186.

15. National Comprehensive Cancer Network. Adult Cancer Pain, 2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Last accessed September 17, 2019.

16. U.S. Food and Drug Administration. Medication Guides: Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). Available at https://www.fda.gov/media/79776/download. Last accessed September 17, 2019.

17. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116.

18. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med. 2005;6(6):432-442.

19. Butler SF, Budman SH, Fernandez KC, Fanciullo GJ, Jamison RN. Cross-validation of a Screener to Predict Opioid Misuse in Chronic Pain Patients (SOAPP-R). J Addict Med. 2009;3(2):66-73.

20. Substance Abuse and Mental Health Services Administration. CAGE-AID: Overview. Available at https://www.integration.samhsa.gov/images/res/CAGEAID.pdf. Last accessed September 17, 2019.

21. Fine PG, Finnegan T, Portenoy RK. Protect your patients, protect your practice: practical risk assessment in the structuring of opioid therapy in chronic pain. J Fam Pract. 2010;59(9 Suppl 2):S1-S16.

22. Katz NP. Opioid Prescribing Toolkit: A Workbook for Clinicians. New York, NY: Oxford University Press; 2010.

23. American Chronic Pain Association. ACPA Resource Guide to Pain Medication and Treatment: 2019 Edition. Available at https://www.theacpa.org/wp-content/uploads/2019/02/ACPA_Resource_Guide_2019.pdf. Last accessed September 17, 2019.

24. Strickland JM, Huskey A, Brushwood DB. Pharmacist-physician collaboration in pain management practice. J Opioid Manag. 2007;3:295-301.

25. Crespi-Lofton J. VIGIL: answer the question "Is it legitimate?" Pharmacy Today. 2006;12(1):1.

26. Miner J, Babitz M, Dunn A, Fondario A, Smith M. Utah Clinical Guidelines on Prescribing Opioids for Treatment of Pain. Salt Lake City, UT: Utah Department of Health; 2018.

27. American Pain Foundation. Breakthrough cancer pain: mending the break in the continuum of care. J Pain and Palliat Care Pharmacother. 2011;25(3):252-264.

28. Qaseem A, Snow V, Shekelle P, et al. Evidence-based interventions to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146.

29. Davison SN, Jhangri GS. Impact of pain and symptom burden on the health-related quality of life of hemodialysis patients. J Pain Symptom Manage. 2010;39(3):477-485.

30. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Available at https://www.nccn.org/professionals/physician_gls/default.aspx. Last accessed September 17, 2019.

31. Blinderman CD, Homel P, Billings JA, Portenoy RK, Tennstedt SL. Symptom distress and quality of life in patients with advanced congestive heart failure. J Pain Symptom Manage. 2008;35(6):594-603.

32. Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009;38(1):115-123.

33. Esther Kim J-E, Dodd MJ, Aouizerat BE, Jahan T, Miaskowski C. A review of the prevalence and impact of multiple symptoms in oncology patients. J Pain Symptom Manage. 2009;37(4):715-736.

34. Dalal S, Bruera E. Assessment and management of pain in the terminally ill. Prim Care Clin Office Pract. 2011;38:195-223.

35. Gao W, Gulliford M, Higginson IJ. Prescription patterns of analgesics in the last 3 months of life: a retrospective analysis of 10,202 lung cancer patients. Br J Cancer. 2011;104(11):1704-1710.

36. Godfrey C, Harrison MB, Medves J, Tranmer JE. The symptom of pain with heart failure: a systematic review. J Card Fail. 2006;12(4):307-313.

37. Breuer B, Fleishman SB, Cruciani RA, Portenoy RK. Medical oncologists' attitudes and practice in cancer pain management: a national survey. J Clin Oncol. 2011;29(36):4769-4775.

38. Abrahm JL. A Physician's Guide to Pain and Symptom Management in Cancer Patients. 3rd ed. Baltimore, MD: Johns Hopkins University Press; 2014.

39. D'Arcy Y. Nursing2008 pain management survey report. Nursing 2008. 2008;38(6):42-49.

40. Zerzan J, Lee CA, Haverhals LM, Nowels CT. Exploring physician decisions about end-of-life opiate prescribing: a qualitative study. J Palliat Med. 2011;14(5):567-572.

41. Fineberg IC, Wenger NS, Brown-Saltzman K. Unrestricted opiate administration for pain and suffering at the end of life: knowledge and attitudes as barriers to care. J Palliat Med. 2006;9(4):873-883.

42. Mezei L, Murinson BB, Johns Hopkins Pain Curriculum Development Team. Pain education in North American medical schools.J Pain. 2011;12(12):1199-1208.

43. Adler ED, Goldfinger JZ, Park ME, Meier DE. Palliative care in the treatment of advanced heart failure. Circulation. 2009;120:2597-2606.

44. Douglas C, Murtagh FE, Chambers EJ, Howse M, Ellershaw J. Symptom management for the adult patient dying with advanced chronic kidney disease: a review of the literature and development of evidence-based guidelines by a United Kingdom Expert Consensus Group. Palliat Med. 2009;23(2):103-110.

45. Pergolizzi JV Jr, Mercadante S, Echaburu AV, et al. The role of transdermal buprenorphine in the treatment of cancer pain: an expert panel consensus. Curr Med Res Opin. 2009;25(6):1517-1528.

46. Passik SD, Kirsh KL, Whitcomb L, et al. A new tool to assess and document pain outcomes in chronic pain patients receiving opioid therapy. Clin Ther. 2004;26:552-561.

47. Atluri SL, Akbik H, Sudarshan G. Prevention of opioid abuse in chronic non-cancer pain: an algorithmic, evidence-based approach. Pain Physician. 2012;15:ES177-ES189.

48. National Institute on Drug Abuse. Minimizing the Misuse of Prescription Opioids in Patients with Chronic Nonmalignant Pain. Available at https://www.drugabuse.gov/nidamed/centers-excellence/resources/minimizing-misuse-prescription-opioids-in-patients-chronic-nonmalignant-pain. Last accessed September 17, 2019.

49. American College of Preventive Medicine. Use, Abuse, Misuse and Disposal of Prescription Pain Medication Patient Guide. Available at https://www.acpm.org/page/UseAbuseRx_PatGuide. Last accessed September 17, 2019.

50. Office of National Drug Control Policy. Proper Disposal of Prescription Drugs. Available at https://www.ncjrs.gov/ondcppubs/publications/pdf/prescrip_disposal.pdf. Last accessed September 17, 2019.

51. Substance Abuse and Mental Health Services Administration. Prescription Drug Use and Misuse in the United States: Results from the 2015 National Survey on Drug Use and Health. Available at https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm. Last accessed September 17, 2019.

52. Sekhon R, Aminjavahery N, Davis CN Jr, et al. Compliance with opioid treatment guidelines for chronic non-cancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). Pain Med. 2013;14(10):1548-1556.

53. Meier B. Increase in Urine Testing Raises Ethical Questions. Available at https://www.nytimes.com/2013/08/02/business/increase-in-urine-testing-raises-ethical-questions.html?_r=0. Last accessed September 17, 2019.

54. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84:593-601.

55. Holliday S, Hayes C, Dunlop A. Opioid use in chronic non-cancer pain. Part 2: prescribing issues and alternatives. Australian Family Physician. 2013;42:104-111.

56. U.S. Department of Justice Office of Diversion Control. Don't Be Scammed By A Drug Abuser. Available at https://www.deadiversion.usdoj.gov/pubs/brochures/drugabuser.htm. Last accessed September 17, 2019.

57. American Medical Association. Code of Ethics: Opinion 1.1.5 Terminating the Patient-Physician Relationship. Available at https://www.ama-assn.org/sites/ama-assn.org/files/corp/media-browser/code-of-medical-ethics-chapter-1.pdf. Last accessed September 17, 2019.

58. U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services. A Prescriber's Role in Preventing the Diversion of Prescription Drugs. Available at https://www.cms.gov/Medicare-Medicaid-Coordination/Fraud-Prevention/Medicaid-Integrity-Education/Provider-Education-Toolkits/Downloads/prescriber-role-drugdiversion.pdf. Last accessed September 17, 2019.

59. Centers for Disease Control and Prevention. Risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR. 2012;61(26):493-497.

60. Hannon K. The Prescription Drug Crisis in New York State: A Comprehensive Approach. Available at https://www.scribd.com/doc/82474334/Prescription-Drug-Abuse-Crisis-in-NYS-Comprehensive-Approach-New. Last accessed September 17, 2019.

61. U.S. Drug Enforcement Administration. Drug Scheduling. Available at https://www.dea.gov/drug-scheduling. Last accessed September 17, 2019.

62. van den Brink W, Haasen C. Evidence-based treatment of opioid-dependent patients. Can J Psychiatry. 2006;51(10):635-646.

63. Cassels C. FDA Okays Handheld Autoinjector for Opioid Overdose. Available at https://www.medscape.com/viewarticle/823039. Last accessed September 17, 2019.

64. Narcan Nasal Spray (naloxone intranasal) [package insert]. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl.pdf. Last accessed September 17, 2019.

65. U.S. Food and Drug Administration. FDA Moves Quickly to Approve Easy-To-Use Nasal Spray to Treat Opioid Overdose. Available at https://wayback.archive-it.org/7993/20180125101447/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm. Last accessed September 17, 2019.

66. Darke S, Hall W. Heroin overdose: research and evidence-based intervention. J Urban Health. 2003;80(2):189-200.

67. Krantz MJ, Mehler PS. Treating opioid dependence: growing implications for primary care. Arch Intern Med. 2004;164(3):277-288.

68. Substance Abuse and Mental Health Services Administration. Federal Guidelines for Opioid Treatment Programs. HSS Publication No. (SMA) PEP15-FEDGUIDEOTP. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2015.

69. Substance Abuse and Mental Health Services Administration. SAMHSA Opioid Overdose Prevention Toolkit. HHS Publication No. (SMA) 16-4742. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2016.

70. Kaye AD, Gevirtz C, Bosscher HA, et al. Ultrarapid opiate detoxification: a review. Can J Anaesth. 2003;50(7):663-671.

71. American Society of Addiction Medicine. National practice guideline for the use of medications in the treatment of addiction involving opioid use. Available at https://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/asam-national-practice-guideline-supplement.pdf. Last accessed September 17, 2019.

72. Amato L, Minozzi S, Davoli M, Vecchi S, Ferri M, Mayet S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2008;(4):CD005031.

73. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev. 2011;9:CD005031.

74. Fiellin DA, O'Connor PG. Office-based treatment of opioid-dependent patients. N Engl J Med. 2002;347(11):817-823.

75. Nunes EV, Sullivan MA, Levin FR. Treatment of depression in patients with opiate dependence. Biol Psychiatry. 2004;56(1):793-802.

76. Wasan AD, Correll DJ, Kissin I, O'Shea S, Jamison RN. Iatrogenic addiction in patients treated for acute or subacute pain: a systematic review. J Opioid Manag. 2006;2(1):16-22.

77. Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments. Clin Infect Dis. 2006;43(Suppl 4):S173-S177.

78. Substance Abuse and Mental Health Services Administration. National Survey of Substance Abuse Treatment Services (N-SSATS): 2018. Data on Substance Abuse Treatment Facilities. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2019.

79. Kleber HD. Methadone maintenance 4 decades later: thousands of lives saved but still controversial. JAMA. 2008;300(19):2303-2305.

80. Humphreys K, Wing S, McCarty D, et al. Self-help organizations for alcohol and drug problems: toward evidence-based practice and policy. J Substance Abuse Treat. 2004;26(3):151-165.

81. Ronel N, Gueta K, Abramsohn Y, Caspi N, Adelson M. Can a 12-step program work in methadone maintenance treatment? Int J Offender Ther Comp Criminol. 2011;55(7):1135-1153.

82. Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR. Alternative reinforcer response cost impacts cocaine choice in humans. Prog Neuropsychopharmacol Biol Psychiatry. 2012;36(1):189-193.

83. Donovan DM, Ingalsbe MH, Benbow J, Daley DC. 12-step interventions and mutual support programs for substance use disorders: an overview. Soc Work Public Health. 2013;28(3-4):313-332.

84. Dixon DW. Opioid Abuse Follow-Up. Prognosis. Available at https://emedicine.medscape.com/article/287790-followup#e4. Last accessed September 17, 2019.

85. Vukmir RB. Drug seeking behavior. Am J Drug Alcohol Abuse. 2004;30:551-575.

86. U.S. Food and Drug Administration. FDA Approves the First Non-Opioid Treatment for Management of Opioid Withdrawal Symptoms in Adults. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-first-non-opioid-treatment-management-opioid-withdrawal-symptoms-adults. Last accessed September 17, 2019.

87. National Institute on Drug Abuse. Benzodiazepines and Opioids. Available at https://www.drugabuse.gov/drugs-abuse/opioids/benzodiazepines-opioids. Last accessed September 10, 2019.

88. Oliver J, Coggins C, Compton P, et al. American Society for Pain Management Nursing position statement: pain management in patients with substance use disorders. Pain Manage Nurs. 2012;13(3):169-183.

89. Wallace LS, Keenum AJ, AbdurRaqeeb O, et al. Terminology matters: patient understanding of "opioids" and "narcotics." Pain Pract. 2013;13(2):104-108.

90. New York State Department of Health. Implantable Infusion Pumps for Non-Cancer Pain. Available at https://www.health.ny.gov/health_care/medicaid/redesign/2016/medtronic_sources_dla_rev.htm. Last accessed September 17, 2019.

91. Mailis A, Taenzer P. Evidence-based guideline for neuropathic pain interventional treatments: spinal cord stimulation, intravenous infusions, epidural injections and nerve blocks. Pain Res Manage. 2012;17(3):150-158.

Evidence-Based Practice Recommendations Citations

1. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician. 2012;15(3 Suppl):S67-S116. Available at https://painphysicianjournal.com/2012/july/2012;%2015;S67-S116.pdf. Last accessed September 17, 2019.

94130 • Neck Pain in Adults

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Acute neck pain can be minor and self-limiting or develop into chronic life-limiting pain. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated. By combining the best available evidence from diverse sources, this course can greatly assist primary care clinicians in optimizing the care of patients with acute or chronic neck pain.

Table of Contents

94130 • Neck Pain in Adults

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

1. INTRODUCTION

2. EPIDEMIOLOGY

PERSONAL AND SOCIETAL IMPACT

SPECIFIC NECK PAIN CONDITIONS

CLINICAL COURSE AND PROGNOSIS

ASSOCIATED CONDITIONS

3. PATHOPHYSIOLOGY

CERVICAL SPINE STRUCTURE AND FUNCTION

CERVICAL SPINE PATHOPHYSIOLOGY

NECK PAIN PATHOPHYSIOLOGY

4. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

ASSESSMENT OF PROGNOSTIC FACTORS

PHYSICAL EXAMINATION

DIAGNOSTIC IMAGING

LABORATORY TESTING

5. TREATMENT OF NECK PAIN

PATIENT EDUCATION

PHARMACOTHERAPIES

PHYSIOTHERAPIES

MECHANICAL AND MANUAL TRACTION

IMMOBILIZATION

PASSIVE ASSISTIVE DEVICES

THERMOTHERAPY

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

PHYSICAL AND EXERCISE THERAPIES

PSYCHOSOCIAL INTERVENTIONS

ALTERNATIVE AND COMPLEMENTARY APPROACHES

INTERVENTIONAL AND SURGICAL THERAPIES

CHRONIC REFRACTORY NECK PAIN

6. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94130 • Neck Pain in Adults

Education Category. Infection Control / Internal Medicine

Release Date. 10/01/2019

Expiration Date. 09/30/2022

Course Overview

Acute neck pain can be minor and self-limiting or develop into chronic life-limiting pain. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated. By combining the best available evidence from diverse sources, this course can greatly assist primary care clinicians in optimizing the care of patients with acute or chronic neck pain.

Audience

This course is designed for all members of the interprofessional healthcare team involved in the care of patients with neck pain.

Course Objective

The purpose of this course is to provide primary care clinicians with the best available evidence on the clinical management of patients with acute or chronic neck pain.

Learning Objectives

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

1. Outline the prevalence of neck pain in the United States.

2. Review the personal and societal impact of various types of neck pain.

3. Identify risk factors for neck pain in the general public.

4. Describe the pathophysiology of various types of neck pain.

5. Evaluate key components of the assessment of patients with neck pain.

6. Analyze the role of diagnostic imaging in the evaluation of neck pain.

7. Describe the pharmacotherapeutic options for the clinical management of neck pain.

8. Discuss physiotherapies and traction approaches to the clinical management of neck pain.

9. Review the efficacy of physical and exercise therapies for neck pain.

10. Identify alternative and complementary modalities used in the management of neck pain.

11. Compare and contrast interventional modalities used in the management of neck pain.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, 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

Eli English, PT, DPT

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.

1. INTRODUCTION

Acute neck pain can be minor and self-limiting or develop into chronic pain that adversely affects quality of life. Neck pain is the fourth leading cause of disability in the United States, but its negative physical, psychologic, and socioeconomic impact on patients continues to be underappreciated [1,2].

Primary care clinicians may find neck pain practice guidelines confusing, because recommended approaches are shaped by the training and specialty of guideline authors. This reflects the broader problem of failing to recognize pain medicine as a medical specialty, which has historically fragmented research and practice guidance and made standards of care elusive [3]. With pharmacotherapy studies in neck pain lacking, the focus of neck pain guidelines is nonpharmacologic treatment [4].

A subset of patients experience significant pain relief when structural tissue pathology is identified and treated. However, cervical spine pathology (e.g., disk bulges, degenerative changes) is common in asymptomatic persons, and the longstanding treatment focus on tissue pathology has contributed to poor pain outcomes in these patients. The diverse pain mechanisms produced by specific pathologies are suggested as a treatment focus in chronic neck pain.

By combining the best available evidence from diverse sources, this course can greatly assist healthcare providers in optimizing the care of patients with acute or chronic neck pain.

2. EPIDEMIOLOGY

Neck pain is very common in the general population, with an annual incidence of 10.4% to 21.3% and lifetime prevalence of 23%. Neck pain can occur repeatedly, and 50% of neck pain seen in primary care settings is in recurrent cases. More than 50% of the middle-aged population shows clinical or radiologic signs of cervical spine disease, which is often asymptomatic [5,6,7].

Neck pain encompasses a variety of associated disorders, including whiplash pain and associated disorders (WAD) and other non-traumatic, traumatic, and work-related neck pain [8]. Neck pain and associated disorders account for 10.2 million physician and hospital outpatient visits in the United States each year [8].

Neck pain prevalence is slightly higher in women in their fifth decade of life, and a higher incidence is found in office/computer workers, manual laborers, and healthcare workers. Chronic neck pain is associated with psychologic factors (e.g., anxiety, poor coping skills, somatization), sleep disorders, smoking, sedentary lifestyle, and genetics [9,10,11]. Common neck pain comorbidities include headache, back pain, arthralgias, and depression [2,9].

Higher body mass index increases risk of chronic neck and shoulder pain. Obese persons may be predisposed to neck pain due to systemic inflammation, deleterious structural changes, increased mechanical stress, diminished muscle strength, greater number of psychosocial factors, and greater kinesiophobia-related disability [2,12].

Treatments used in low back pain are considered applicable to neck pain. The presumptive similarity is generally true, but features of cervical anatomy and physiology make some neck pain conditions distinct from those of other spinal locations. WAD and some collision-related sports injuries (e.g., related to American football, rugby) are unique risk factors for neck pain [2,9].

In one study, risk of cervical spine injury was evaluated in roller-coaster riders [13]. In 656 neck and back injuries during roller-coaster riding, 72% considered significant were cervical disk injuries. Lumbar spine injuries also included disk herniation or vertebral compression fracture. Passenger testing showed that peak g-force for vertical or axial acceleration (4.5–5.0) and lateral acceleration (1.5) both occurred within 1/10 second (100 ms). The authors concluded a minimum threshold of significant spine injury is not established. Individual susceptibility largely explains the injuries from traumatic loading [13].

PERSONAL AND SOCIETAL IMPACT

As noted, neck pain is the fourth leading cause of disability in the United States (behind low back pain, depression, and arthritic disorders), and in some industries, it accounts for as much time off work as low back pain [1,2,14]. In many patients, neck pain becomes chronic, with life-impairing symptoms that severely decrease quality of life and restrict work productivity and daily activities [8].

However, neck pain has received a fraction of the research funding and attention directed to back pain. This reflects a wider underappreciation of its negative physical and psychologic impact, and of the associated high economic burden from medical visits, physiotherapy, pharmacologic and surgical treatments, lost work days, and compensation expenditure [2,4].

SPECIFIC NECK PAIN CONDITIONS

Whiplash Injury and Whiplash-Associated Disorders

WADs result from rapid acceleration/deceleration, typically involving rear-end or side-impact motor vehicle collisions, and represent 75% of all survivable motor vehicle collision injuries [15]. WAD can also occur from falls, diving, or collisions in contact sports. The "limit of harmlessness" with rear-end collision is 5 to 10 miles per hour (MPH); many whiplash injuries involve rear-end motor vehicle collision at speeds of 14 MPH or less [16,17,18,19]. WAD is associated with significant economic costs from lost work productivity, medical care, legal services, and other disability-related expenses, mostly incurred by patients with chronic symptoms [20].

The annual rate for acute whiplash symptoms is 1 to 6 cases per 1,000 population, and an estimated 1% of adults have chronic whiplash pain. In data from nine U.S. states, 45% of patients with chronic neck pain attributed their pain to a motor vehicle collision [16,21].

Women show higher rates of WAD, possibly due to less well-developed neck muscles than men. Pre-existing cervical spine pathology predisposes to spinal cord damage in whiplash injuries [19]. Head restraints have greatly reduced whiplash injury rates following rear-end collisions, but they increase whiplash injury risk when poorly fitted [16].

Cervical Radiculopathy

Cervical radiculopathy is cervical spine nerve root dysfunction that causes radiating neck or upper extremity pain or sensory abnormalities [22]. New cases are higher in men (107.3 per 100,000) than women (63.5 per 100,000) annually. Persons 50 to 54 years of age have the highest incidence by age. Overall, the prevalence is 3.5 cases per 1,000 population [22,23,24].

Risk factors include manual labor requiring lifting of more than 25 pounds, smoking, operating vibrating equipment, and previous spinal radiculopathy. Over-exertion or trauma antecedents are reported by 15% of patients with cervical radiculopathy [24].

CLINICAL COURSE AND PROGNOSIS

Acute Nonspecific (Idiopathic) Neck Pain

Outcomes for acute idiopathic neck pain are surprisingly poor. Resolution is often incomplete, and prognosis is markedly worse than commonly believed. Statistical pooling of published outcomes showed an average pain severity score (on a 0–100 scale) of 64 at onset, decreasing to 35 at 6.5 weeks, but increasing by 12 months to 42. Disability declined from an average score (0–100) of 30 at onset to 17 by 6.5 weeks, without further improvement at 12 months [25].

After the first 6.5 weeks, no further reduction in neck pain was found. The initial decreases in pain (45%) and disability (43%) are worthwhile to some patients, but the severity of persistent pain (35–42/100 up to one year) is sufficient to interfere with functioning and quality of life. Compared with low back pain one year after onset, neck pain intensity is twice as high and disability is comparable [25,26,27].

A comparison of 2,578 patients with WAD or nonspecific neck pain found substantially greater presence of dizziness and memory impairment at initial assessment. Between-group differences in pain and disability increased significantly over 12 months; patients with WAD had an average 2 points greater pain (on a 0–10 scale) and 17% more disability than those with nonspecific neck pain [28].

Acute Whiplash-Associated Disorders

Recovery rates from WAD have been unchanged for decades, with 50% of patients experiencing ongoing pain and disability [15]. Following acute whiplash injury, recovery is slow for pain intensity outcomes, which usually require six months or longer to decrease 20%. Recovery is no better for disability outcomes, with average scores failing to reach 20% improvement by 12 months [29]. Following acute traumatic neck pain (including WAD), patients follow one of three likely trajectories for pain and disability [29]:

- Mild problems with rapid recovery (45% of patients, depending on outcome)

- Moderate problems with incomplete recovery (40%)

- Severe problems with little or no recovery (15%)

Regardless of outcome, recovery is most rapid in the first 6 to 12 post-injury weeks, with considerable slowing after that and little recovery after 12 months [30].

Prognostic Factors in Acute WAD

During acute or subacute WAD, risk factors for persistent problems include [29]:

- High pain intensity

- High self-reported disability (as determined by Neck Disability Index [NDI] score)

- High post-traumatic stress symptoms

- Strong catastrophic beliefs

- Cold hyperalgesia

A meta-review of factors associated with long-term pain and disability after whiplash injury identified post-injury pain and disability, whiplash grade, and cold hyperalgesia as the strongest prognostic factors [31].

Factors unrelated to prognosis include those related to the collision (e.g., impact direction, stationary versus moving, seating position in car). Post-injury imaging findings or motor dysfunction has very weak association with pain/disability prognosis [29,31]. Compensation and early healthcare use were weakly positive prognostic factors, but equally plausible is reverse causality, whereby poor outcome is the cause of healthcare use and compensation-seeking [31].

Patients suffering from post-motor vehicle collision WAD often litigate to gain more comprehensive medical treatment and monetary compensation for their injury. A long-standing concern of treating physicians is that patients with whiplash may have barriers to recovery—believing they must remain "injured" to collect a settlement [16]. Compensation has been associated with incidence and prognosis, but literature indicates that litigation does not correlate with persistence of pain [32,33].

Risk factors for poor recovery from whiplash injury described in the medico-legal literature include [16,34]:

- High post-injury pain (>6/10) and disability (NDI >40%)

- Number and severity of injury-related symptoms (e.g., post-injury headache, low back pain, neuropathic pain, radicular symptoms)

- Psychologic distress (e.g., post-trauma stress symptoms, pain catastrophizing)

- Cervical spine cold hyperalgesia

- Failure to wear seatbelt

- Less than college education

Cervical Radiculopathy

Many patients with cervical radiculopathy secondary to acute disk herniation have a favorable clinical course. Symptom resolution occurs over weeks to months because 40% to 76% of herniated cervical disks spontaneously resorb independent of treatment. Acute neuropathic symptoms in spinal stenosis stabilize or improve in more than 50% of patients, but anatomic derangements do not generally improve without treatment [29,35,36].

However, patients with cervical radiculopathy and more severe acute pain or symptoms show higher risk of chronic pain. Higher pain scores and radicular symptoms are associated with chronicity and poor outcomes in both neck pain and low back pain [37,38].

Assessment of Prognostic Factors

With multiple studies showing that acute-phase risk factors can predict poor pain and disability outcomes, practice guidelines recommend that clinicians assess all patients during initial and follow-up contacts. Pain, disability, post-trauma symptoms, and pain catastrophizing are measured to quantify progress and to predict prognosis for recovery (discussed later) [39].

ASSOCIATED CONDITIONS

Vertigo

Many patients experience vertigo, dizziness, unsteadiness, and other proprioceptive abnormalities following whiplash trauma. Strains to facet joint capsules, paravertebral ligaments, or cervical musculature in WAD are thought to modify proprioceptive cervical balance to produce mild but chronic vertigo [40]. Dizziness may result from injury to facet joints supplied by proprioceptive fibers; when injured, these fibers can send confused vestibular and visual inputs to the brain [41].

Temporomandibular Joint Disorder

Temporomandibular joint disorder (TMD) is associated with whiplash injury, and TMD populations show an average 35% prevalence of whiplash trauma [42]. Chronic muscle pain in TMD is classified as localized or referred. Compared with patients with localized TMD, those with TMD and whiplash histories have greater jaw pain and dysfunction severities; more severe subjective, objective, and psychologic dysfunction; and poorer treatment outcomes. Some evidence suggests TMD pain after whiplash trauma differs pathophysiologically from localized TMD pain. Whiplash trauma is a common TMD comorbidity and probably an initiating or aggravating factor. Patients with TMD and whiplash require early evaluation and multidisciplinary management [43,44,45].

3. PATHOPHYSIOLOGY

This section discusses how neck pain develops and persists by examining pathologic processes in cervical spine and pain signaling structures. Discussion of normal function is presented first to assist in the understanding of pathology.

CERVICAL SPINE STRUCTURE AND FUNCTION

The top seven vertebrae (C1 to C7) make up the cervical spine, which provides mobility and stability to the head while connecting it to the relatively immobile thoracic spine [46]. The spine transfers force between the upper and lower extremities and generates force [47].

C1 and C2 are the upper cervical spine. C1 bears the head ("the globe") and is called the atlas. The atlas connects above with the occiput (the atlanto-occipital joint), where 50% of all neck flexion extension occurs. The atlas connects below with C2, termed the axis, forming the atlanto-axial joint, where 50% of all neck rotation occurs [46]. The lower (subaxial) cervical spine consists of vertebrae C3 to C7, connected by facet joints and intervertebral disks, unlike the complex ligament structures that connect C1 and C2 [48].

Facet joints, also called zygapophysial joints (z-joints), stabilize and limit excessive cervical spine flexion, extension, side-bending, and rotation [49]. The medial branch of the dorsal nerve innervates the facet joint. The joint contains a fibrous capsule, synovial membrane, articular cartilage, and menisci [50].

The intervertebral disk is a functional unit connecting two vertebral bodies of the spine. The disk absorbs shock, accommodates movement, provides support, and separates vertebral bodies to lend height. Disk units have a nucleus pulposus middle, annular fibers (annulus fibrosus) surrounding the nucleus pulposus, and two cartilage end plates that separate each segment level between the C2–T1 vertebrae [51]. Annular fibers are vulnerable to rotational force injury, and nociceptors innervate the middle and outer third [46].

Cervical spine nerve roots exit through small vertebral ports called the foraminal space, above their same-numbered vertebral body; the first cervical spine nerve exits above C1, and the eighth between C7 and T1 [46,48].

The longitudinal ligaments keep the seven vertebrae and atlanto-occipital joint behaving as a single unit. The ligamentum flavum connects annular fibers (laminae) of adjacent vertebrae and helps the vertebral column resume upright posture after flexion [46].

Nociceptors are sensory receptors of primary neurons in cervical spinal tissue. Nociceptors respond to harmful pressure, temperature, or biomechanical stress (noxious stimuli) by transmitting signals (nociception) to the spinal cord and brain.

CERVICAL SPINE PATHOPHYSIOLOGY

Neck pain can develop from chronic overuse or strain, injury, trauma, or degenerative processes involving bony, articular (disks, facets), nerve (root, spinal cord), or soft (ligament, tendon, muscle) tissues of the cervical spine. In this section, pathologic processes are described that can result in neck pain, starting with acute-onset conditions followed by chronic, degenerative conditions.

Facet-Mediated Pain

Facet joints and capsules are richly innervated by nociceptors sensitive to local stretch or compression. These neurons are activated by abnormal loading or excessive biomechanical stress from whiplash injury or fracture, and sensitized by inflammation and locally released inflammatory promoters (e.g., substance P, phospholipase A). Facet joint pain can develop from degenerative disk or facet joint changes; inflammatory cytokines are found at high levels in facet joint tissue when a degenerative disorder is present. Facet joints are covered by hyaline cartilage and enclosed by synovial capsules, features of other joints that make facet joints vulnerable to osteoarthritis (facet joint arthropathy) [50,52].

Facet joint pain accounts for 36% to 55% of neck pain and 60% of whiplash pain [50]. The C5–C6 facet joint is the most common origin of cervical, axial, and referred arm pain. Facet joints/capsules largely underlie chronic neck pain, and referred facet pain overlaps with myofascial and diskogenic pain patterns [41].

Cervicogenic Headache

Cervicogenic headache is defined as a unilateral, non-throbbing, non-lancinating head pain caused by referred cervical spine pain. Approximately 70% of cervicogenic headaches originate from the C2–C3 facet joint [53,54,55].

The lifetime prevalence of cervicogenic headache is as high as 4.1% in the general population, 17.5% in patients with severe headaches, and 53% in patients with post-whiplash headache [53]. Cervicogenic headache occurs at rates four times higher in women, and the average patient age is 43 years. Migraines often have a cervical pain component and can co-occur with cervicogenic headache [53].

Cervical Strain/Sprain

Cervical strain is injury to the muscle-tendon unit, while cervical sprain is injury to ligamentous structures. Cervical strain/sprain injuries involve flexion, extension, or rotation, with or without axial loading. Acute neck pain frequently involves injury to cervical muscle-tendon or ligamentous structures, which can expand into a range of secondary effects [47]. For instance, edema, hemorrhage, and inflammation can follow elongation and tearing of muscles or ligaments in cervical strain/sprain. Many cervical muscles do not terminate in tendons, but attach to the periosteum (membrane covering a bone surface). Muscles respond to injury by contracting, and recruit surrounding muscles to "splint" the injured muscle. This reflexive tightening (spasm) of paraspinal muscles can cause excruciating pain [56]. Chronic pain following cervical strains usually originates from facet joints, disks, or ligaments [41].

Cervical Myofascial Pain

Cervical myofascial pain also relates to overuse, injury, or trauma and originates from cervical muscles and their surrounding fascia that support the shoulders and neck [57]. Cervical myofascial pain may result as a secondary muscle tissue response to disk or facet-joint injury [41].

Myofascial pain is common in the general population, with 21% of patients in general orthopedic clinics and 85% to 93% of patients in specialty pain management centers having a myofascial pain component. Cervical myofascial pain incidence is disproportionately high in women and peaks in midlife and declines after middle age [57].

Trigger points—the hallmark feature of myofascial pain—are hyperirritable areas in palpable, taut bands of skeletal muscle fiber that elicit local or referred pain. Rapid palpation may elicit a local twitch response, a brisk contraction of muscle fibers around the taut band. Active trigger points generate spontaneous or movement-provoked pain; latent trigger points produce pain when compressed [57].

In cervical myofascial pain, other muscles in the functional unit compensate, promoting a more widespread, chronic problem. Chronicity and disability are strongly linked to pain duration. Recurrence decreases with early treatment initiation to prevent muscle compensation patterns. Migraine and muscle contraction headache frequently co-occur, and TMD can be myofascial in origin [57].

Cervical Disk Disorders

Disk disorders can develop acutely from neck injury or trauma, or through chronic degenerative processes. The C6–C7 disk is the most frequent herniation site [51]. More common cervical disk disorders include herniated nucleus pulposus, degenerative disk disease, and internal disk disruption.

Herniated Nucleus Pulposus

Herniated nucleus pulposus is localized displacement of the nucleus, cartilage, or fragmented annular tissue beyond the intervertebral disk space. Most cases of herniated nucleus pulposus involve the annulus fibrosus. The four herniated nucleus pulposus subtypes are [51]:

- Disk protrusion: The nucleus pulposus herniates through annular fibers but is confined within the annular margin.

- Disk extrusion: Nucleus pulposus herniation extends beyond the annular margin.

- Disk sequestration: A nucleus pulposus fragment separates from the extruded disk.

- Disk migration: Disk material displaces from the extrusion site.

Herniated nucleus pulposus results from repetitive cervical stress but seldom from a single traumatic incident. Increased risk may accrue with vibrational stress, heavy lifting, prolonged sedentary position, whiplash accidents, or frequent acceleration/deceleration [51]. Disk bulge, whereby disk margins extend past the margins of adjacent vertebral end plates, is not considered a true herniation [51].

Degenerative Disk Disease

Cervical degenerative disk disease involves degenerative annular tears, loss of disk height, and nucleus pulposus degradation. It is commonly age-related and affected by poor nutrition, smoking, atherosclerosis, job-related activities, and genetics. It is important to remember that degenerative disk changes seen by x-ray may reflect natural aging and not painful pathology [51].

Internal Disk Disruption

Internal disk disruption describes pathologic annular fissuring within the disk, without external disk deformation. Internal disk disruption can result from cervical trauma-related nucleus pulposus degradation, cervical flexion/rotation-induced annular injury, or whiplash [51].

Chemical Radiculitis

Herniated or degenerated nucleus pulposus releases inflammatory promoters (e.g., phospholipase A2, prostaglandin E2, proteoglycans, cytokines, tumor necrosis factors) and mediators (e.g., substance P, bradykinin, potassium, histamine). This inflammatory cascade can cause chemical radiculitis, characterized by intense chemical irritation of cervical spine nerve roots, radicular pain, and most herniated nucleus pulposus pain [24,51,58].

Cervical Radiculopathy

In cervical radiculopathy, compression or irritation of a cervical spine nerve root, typically by herniated disk material, chemical radiculitis, or stenosis, results in radiating pain, weakness, or numbness [22,23,58].

Most cervical radiculopathies involve C7 or C6 nerve root levels, but all root levels exhibit motor, sensory, and reflex abnormalities that follow specific dermatomal or myotomal distribution patterns in the neck and upper extremities (Table 1) [2,22,56].

Table 1: TYPICAL DISTRIBUTION OF SENSORY AND MOTOR WEAKNESS IN CERVICAL RADICULOPATHYa

Affected Nerve Root (Frequency)

Sensory Deficits/Pain Location

Muscle Weakness

Abnormal Reflexes

C4 (<10%)

Lower neck, cape-like distribution in upper shoulder

None

None

C5 (10%)

Lateral arm

Deltoid

Biceps

C6 (20% to 25%)

Radial forearm, radial two digits

Biceps, wrist extension

Brachioradialis

C7 (45% to 60%)

Middle finger

Triceps, wrist flexion

Triceps

C8 (10%)

Ulnar two digits

Finger flexors

Finger flexors

aPain referral patterns can vary among patients.

Source: [2,22,56]

Mechanical compression induces nerve deformation and malfunction when external pressure exceeds intraneuronal pressure. This results in conduction block, interruption of axonal flow, vascular sequelae (e.g., hypoxia), and accumulation of metabolic byproducts [22,58]. Nerve root compression alone may not be painful unless inflammation is present. Narrowing of the foraminal space (foraminal stenosis) encroaches on the exiting spinal nerve, and foraminal stenosis from disk or facet joint degeneration accounts for many cervical radiculopathy cases [51].

Cervical Spinal Stenosis

In the C3–C7 spinal canal, the normal anteroposterior diameter is 17–18 mm. The spinal cord requires 10–11 mm; an anteroposterior diameter <10 mm is absolute spinal canal stenosis, and 10–13 mm is relative stenosis [59,60].

In acquired cervical spinal stenosis, degenerative disk or facet disease pathologically narrows the canal in middle-aged and older patients. Cervical spondylosis (arthritis) may progress to stenosis, and stenosis to cervical spondylotic myelopathy, but this sequence is variable and difficult to predict. However, adults with asymptomatic stenosis show age-related increases in cervical spondylosis. Congenital cervical spinal stenosis occurs in younger, athletic patients when bony anomalies narrow the spinal canal diameter <13 mm [59,61].

Cervical Whiplash Injury

In cervical whiplash, diverse symptoms develop following a rapid sequence of injuries [16,19,62]. The first is cervical hyperextension injury. A driver/passenger is struck from behind, which throws the body forward, but the head lags to hyperextend the neck. When the head and neck reach maximum extension, the neck snaps into flexion. The head is then thrown forward, flexing the cervical spine and resulting in rapid deceleration injury. The chin truncates forward flexion, but it can remain sufficient to cause longitudinal distraction and neurologic damage. Hyperextension may occur in the subsequent recoil. Within 100 ms, the cervical spine is compressed from below; as lower segments extend with upper segments flexed, the cervical spine assumes an S-shaped curve. In a split-second, all cervical segments are forced backward into extension. Whiplash-like loads of combined shear, bending, and compression forces can injure facet joints/capsules, and facet injury is the most common source of chronic post-whiplash pain. Spinal bones, ligaments, muscles, tendons, and disks may also become injured [41,63,66].

The diverse constellation of post-whiplash symptoms, termed WAD, reflects the range of potentially injured tissue. Symptoms can include neck pain and stiffness, occipital headache, thoracic or lumbar pain, and referred pain or numbness to shoulders, arm, or scapula. Paraspinal muscle tightness and spasm, neck tenderness, and reduced range of movements are common. Patients may also experience headache, jaw pain, fatigue, dizziness, vertigo, blurred vision, or nausea. Insomnia, depression, and general anxiety or travel anxiety when in a car can follow acute whiplash. Symptoms can be severe, often without imaging abnormalities [16,19].

Degenerative Disorders of the Cervical Spine

As noted, x-rays show degenerative cervical spine abnormalities in many asymptomatic adults, making the boundary between normal aging and disease difficult to define. Even severe degenerative changes can be asymptomatic but can eventually lead to neck pain or neurologic complications [14]. Vertebral body, disk, and facet joint degeneration decreases foraminal and canal width, initiates inflammatory processes, and promotes nerve compression/irritation, chronic neck pain, and progressive radiculopathy symptoms [14,23,24,51,58,61,67,68].

Cervical Spondylosis

Cervical spondylosis is osteoarthritis, a chronic degenerative disorder that affects cervical vertebral bodies, intervertebral disks (as disk herniation and spur formation), and contents of the spinal canal (i.e., nerve roots and/or spinal cord). It may also affect the facet joints and longitudinal ligaments, but this is debated [67].

Cervical Facet Joint (Z-Joint) Arthropathy

Facet joint arthropathy describes osteoarthritis and degenerative changes in facet joints and usually follows the development of cervical degenerative disk disease. The degenerative changes resemble those of other joints, including osteophyte formation, osteosclerosis, thinning of articular cartilage, and hypertrophy (thickening) of the facet joint capsule, ligamentum flavum, and articular process. Facet joint hypertrophy distorts articular surfaces, leading to axial or referred pain [49].

Cervical Spondylotic Myelopathy

Cervical spinal cord compression causes cervical spondylotic myelopathy, the most serious degenerative disorder consequence. Reversible neurologic deficits occur with cord compression of 40% or greater [61]. Abnormal movement and cervical spondylotic myelopathy symptoms can develop from cervical spinal cord damage with traumatic compression or ischemia from arterial compression or cervical spondylosis [60,67]. In patients with cervical spondylotic myelopathy, co-occurring cervical radiculopathy is frequent and co-occurring stenosis is occasional [67].

NECK PAIN PATHOPHYSIOLOGY

In most patients with chronic neck pain, identifying and treating the pain mechanism(s), rather than spinal tissue pathology, is more effective. Pain from tissue injury or disease that resolves with tissue healing is a symptom of the tissue damage, and resolution typically occurs within three months of onset.

Pain becomes a disease entity (rather than a symptom) when it persists after healing or resolution of the original tissue insult [3]. Chronic (more than three months) neck pain can develop from acute pain of any cervical spine origin, but it is substantially more difficult to control and can be severely consequential to patients [2,69].

Normal Pain Processes

The somatosensory system enables the perception of pain, touch, pressure, temperature, position, movement, and vibration. This system begins with receptors of peripheral sensory neurons (nociceptors) in skin, muscles, joints, and fascia (peripheral tissue). In response to potentially harmful pressure, temperature, or biomechanical stress (noxious stimuli), nociceptor fibers send signals to the dorsal root ganglia (containing the cell bodies of sensory neurons), which are relayed to the dorsal horn of the spinal cord. In the dorsal horn, primary neurons synapse with second-order nociceptive neurons. The noxious stimuli signal is sent up ascending spinal pathways to the brain. The brain interprets pain signal intensity and location, assigns meaning, activates fear or anxiety, and initiates appropriate motor responses. The brain then signals back the spinal dorsal horn, via descending pathways, to inhibit or facilitate incoming nociceptive stimuli. Thus, pain transmission signals travel up the spinal cord for processing and interpretation in the brain, which responds by pain modulation signals down descending pathways to the spinal dorsal horn. This bi-directional feedback circuit balances signaling facilitation and inhibition; normal function is maintained.

Chronic Pain Pathophysiology

With normal somatosensory function, pain from tissue injury or damage resolves during or before tissue healing or resolution. In contrast, chronic pain develops as somatosensory function becomes pathologic [41,70,71,72,73]. Mechanical/inflammatory injury of peripheral sensory nerve fibers activates the function of their ion channels (e.g., sodium, calcium). This increases excitatory synaptic transmission in dorsal horn neurons and nociceptive circuits.

Intense nociceptive bombardment in the dorsal horn impacts synaptic activity, where primary neurons signal second-order neurons. The bombardment induces synaptic release of excitatory amino acids and neuropeptides (e.g., substance P, glutamate), which bind post-synaptic receptors of second-order neurons in the dorsal horn. In altered second-order spinal cord neurons, excessive N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling reflects a hyperexcitability state that amplifies sensory responses; central sensitization develops.

In this state, brainstem control of descending pain modulatory pathways becomes impaired; balance between descending inhibition and excitation is altered, and excitation dominates. Pain perception is facilitated by ascending pain pathway sensitization and disinhibited by impaired descending inhibitory. The brain now receives altered, abnormal sensory messages.

Pain Modulation

Nociceptor activation does not necessarily produce pain. Some persons with marked spinal pathology are asymptomatic, while others experience severe, chronic, disabling pain without apparent structural pathology. Patient responses to analgesic therapy also vary substantially. A key factor in this pain response variability is how the pain message is modulated in the central nervous system (CNS).

The pain signal can be augmented or diminished as it ascends from its dorsal horn entry point to the CNS and arrives in the cerebral cortex (which mediates awareness). An assumed correlation between peripheral tissue pathology and pain intensity is subject to modification and interference in the various pathways [71,74,75,76]. Without treatment, CNS pain modulation abnormalities persist and may become refractory to intervention [77,78].

Transitions in Chronic Whiplash Pain

Post-whiplash pain is the most-studied chronic neck pain condition, with cervical facet joints key pain contributors. Facet joint structure may pathologize as chronic post-whiplash pain develops [50].

Following acute tearing of the facet joint capsule or stretching beyond its limits, the joints fill with fluid and distend, causing pain and limiting cervical range of motion. In the subacute phase, inflammatory changes develop from vasodilation and invasion of inflammatory cytokines, promoting degeneration. Laxity from joint capsule hypertrophy and distention impinges a nerve root exiting the spinal canal or neuroforamen; radiating symptoms or radiculopathy develops. Chronic inflammation leads to central sensitization, with pain stimuli thresholds decreasing and pain signal firing rates increasing. Facet capsule fibrosis and osteophyte formation further restrict segmental motion.

Psychologic Factors in Chronic Neck Pain

Psychologic factors contribute to the development of chronic neck pain and disability in some patients. In the fear-avoidance model, key psychologic processes, including emotions, cognitions, attention, and behaviors, converge to form fear-avoidance beliefs and behaviors, which become drivers of pain-related disability. Fear develops in response to negative cognitions, exaggerating both the potential threat of pain and the negative interpretation of pain-related health information. Pain catastrophizing refers to this exaggerated set of pain-related cognitions, often appearing as anticipation of the worst possible outcome [79,80]. Fear focuses the attention on pain and related symptoms, leading to a hypervigilant state and avoidance of activities (e.g., occupational, social) and movements (e.g., walking, physical therapy) perceived to possibly worsen pain [81].

Evidence connects pain, stress response, and prognosis following whiplash. After whiplash injury, the presence of hyperalgesia (amplified pain sensitivity), stress-related symptoms, and pain catastrophizing is linked to higher initial pain and disability, and strongly predicts poor functional recovery [82]. Hyperalgesia is a consequence of inflammatory processes. Intense stress exposure (as with acute trauma) can release cytokines that signal infection or inflammation, and a relationship between catastrophizing and inflammation has been identified [83]. Hyperalgesia and stress-mediated responses/symptoms in whiplash-injured patients with poor prognosis suggests contribution of inflammatory processes [84,85].

Other evidence expands the understanding of how psychologic factors may influence pain. High levels of perceived injustice following whiplash injury have been associated with prolonged work disability at follow-up, suggesting a modifiable risk factor for psychologic intervention [86]. A study of whether social pain from rejection promoted social anxiety two days later identified a link between emotional and physical pain [87]. Participants rejected during an initial social situation had higher social anxiety before and during a second situation (versus those not rejected), fully mediated by initial social pain intensity. Next, all participants in a social situation were rejected, and randomized to acetaminophen or placebo before the next social situation. Acetaminophen but not placebo lowered social anxiety before and during this exposure. Roughly 50% of this effect was mediated by, and specific to, reduction in social pain and not social anxiety [87].

Attachment insecurity (i.e., anxiety and/or discomfort in close relationships) is associated with physical symptoms, medically unexplained symptoms, and painful conditions. Medically unexplained chronic pain has been associated with attachment insecurity, after adjusting for depressive and anxiety disorders [88].

New Directions in Chronic Neck Pain Practice

Fewer than half of patients with chronic pain achieve at least 50% pain reduction with any single drug or their combinations, a consequence of [72,89,90]:

- Limitations of neuropathic pain definitions and the "nociceptive-neuropathic dichotomy" of chronic pain mechanisms

- Standard practice guidelines based on clinical trials that assess analgesic efficacy in patients with specific underlying pathologies, but not pain types

- Multiple pain mechanisms in most chronic pain, but most drugs target one pain mechanism

These flaws have prompted intensive efforts to overhaul chronic pain research and practice, leading to publications that expand and clarify chronic pain mechanisms to improve pain assessment and treatment. Many findings in chronic low back pain are relevant to chronic neck pain and are summarized here. Implementation in neck pain assessment and treatment is discussed in later sections.

Neuropathic pain definitions are often over-restrictive, with pain strictly tied to a lesion or disease in nerve structures, such as peripheral nerves (e.g., post-herpetic neuralgia, diabetic neuropathy) or spinal nerve roots (e.g., radiculopathy). In this model, without evidence of nerve lesion or disease, signs or symptoms are insufficient [91,92].

Current chronic low back pain guidelines class 85% to 90% of patients as nonspecific pain and a fraction as neuropathic pain, but many patients with chronic low back pain present with symptoms of a neuropathic component that goes undetected and untreated because nerve lesion or disease is absent [93,94,95,96]. Their misclassing as nociceptive or nonspecific pain may lead to poor treatment outcomes [95,96].

Neuropathic pain can develop when nerve fibers in any segment of the somatosensory system become dysfunctional or transmit signals inappropriately—without lesion or disease [97,98]. The painDETECT questionnaire (PDQ) was developed to identify neuropathic components in patients with chronic low back pain considered nociceptive [69,89,99]. This tool characterizes "altered nociception" as a distinct pain phenotype in chronic low back pain. In these patients, neuropathic-like signs and symptoms reflect maladaptive nervous system functioning and central rather than peripheral pain mechanisms [96,100].

Other advances are improving pain mechanism assessment. Sensory profile (pain-related sensory signs and symptoms) testing in 902 patients with diverse neuropathic pain etiologies identified distinct sensory profile subgroups: sensory loss (42%), thermal hyperalgesia (33%), and mechanical hyperalgesia (24%). All sensory profile subgroups occurred across etiologies, reflecting pain-related signs and symptoms that differ in neurobiologic mechanisms and treatment response [99].

With the nociceptive-neuropathic dichotomy of chronic pain mechanisms outdated, research has led to "altered nociception" as a proposed pain mechanism descriptor when chronic pain is neither nociceptive (tissue damage) or neuropathic (nerve pathology) [90,95,96]. Maladaptive CNS neuroplasticity in chronic pain has been recognized since the early 2000s as a disease process of its own right, and translation into clinical practice is overdue [101].

4. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

Assessment of neck pain begins with a thorough history and physical exam. This information guides further diagnostics and clinical management. The top priority is to identify potentially serious underlying pathologies, termed "red flag" conditions (Table 2). While infrequently encountered, neck pain-related signs or symptoms that suggest serious disease require immediate investigation and intervention. "Red flags" should be assessed throughout the evaluation process, and imaging confirmation is necessary when clinician suspicion remains [7,102]. After obtaining basic patient demographics, a detailed history is taken [7,8,56,102,103].

Table 2: "RED FLAG" FEATURES IN NECK PAIN

Red Flag

Potential Conditions

Associated Signs and Symptoms

Trauma (fall, motor vehicle accident, whiplash injury)

Vertebral fractures, spinal cord injury/syrinx, ligamentous disruption

Loss of or alternating consciousness, cognitive deficits, traumatic brain injury, headaches, neurologic symptoms

Rheumatoid arthritis, Down syndrome, spondyloarthropathy

Atlantoaxial subluxation

Easily fatigued, gait abnormalities, limited neck mobility, torticollis, clumsiness, spasticity, sensory deficits, upper motor neuron signs

Constitutional symptoms

Metastases, infectious process, systemic rheumatologic disease

Weight loss, unexplained fevers, anorexia, family or personal history of malignant neoplasm, diffuse joint pain and stiffness, abnormal laboratory test results

Infectious symptoms

Epidural abscess, spondylodiskitis, meningitis

Fever, neck stiffness, photophobia, elevated white blood cell count

Upper motor neuron lesion

Spinal cord compression, demyelinating disease

Hoffmann sign, hyper-reflexia, Babinski sign, spasticity, incontinence, sexual dysfunction

Age younger than 20 years

Congenital abnormalities (cervical spina bifida, Scheuermann disease)

Birthmarks, overlying skin tags, patches of hair, family history, systemic disease (diabetes, epilepsy for spina bifida)

Conditions associated with substance abuse (e.g., infection)

Male sex, poor work or school performance, depression or other psychiatric morbidity

Concurrent chest pain, diaphoresis, or shortness of breath

Myocardial ischemia or infarction

Nausea, extension of pain into the left arm (especially medial upper arm)

Age older than 50 years

Metastases, vertebral fracture, carotid or vertebral artery dissection/bleeding

Family or personal history of malignant neoplasm, previous trauma

Arterial dissection: tearing sensation, headache, visual loss, or other neurologic sequelae

Source: [2]

To assess the history of the present illness, clinicians should inquire regarding:

- Pain details

- Quality

- Onset

- Duration

- Severity

- Location

- Time course

- Progression

- Modifying factors

- Rest/activity

- Changes in position

- Weight-bearing

- Time of day (e.g., at night, on awakening)

- Tolerance for neck flexion

- Associated symptoms

- Stiffness

- Numbness

- Paresthesia

- Weakness

- Urinary retention

- Constipation

- Urinary/fecal incontinence

- Primary/secondary complaints

- Primary neck pain

- Secondary arm pain

- Headaches

- Shoulder girdle complaints

- Radiating symptoms

- Presence and distribution of upper/lower extremity numbness, paresthesia, or weakness

- Percentage of axial versus peripheral pain (e.g., 90% neck versus 10% upper limb)

- Precipitated by coughing or sneezing, or alleviated by raising the affected arm over the head

- Initial treatment of present complaint

- Emergency department

- Acute care or clinic evaluation

- Imaging

- Analgesics given and symptom response

The past spinal pain history should include information regarding:

- Known neck or back disorders (e.g., osteoporosis, osteoarthritis, disk disorders, recent or remote injury)

- Specific prior treatment, including surgery

- Chronic or recurrent symptoms

- Functional limitations

- History of motor vehicle collisions (if whiplash suspected)

- Risk factors for:

- Back disorders (e.g., cancer, osteoporosis)

- Aneurysm (e.g., smoking, hypertension)

- Infection (e.g., immunosuppression, IV drug use, recent surgery, hemodialysis, penetrating trauma)

- Extra-articular features of an underlying systemic disorder (e.g., diarrhea, abdominal pain, uveitis, psoriasis)

Patients should also be assessed regarding their medical history and a general review of systems. Any history of neoplasm, gout, arthritis, hypertension, or fractures should be noted. The review of systems will include current symptoms of systemic diseases:

- Infection (e.g., fever, sweats, chills)

- Cancer (e.g., weight loss, poor appetite)

- Multifactorial spinal pain (e.g., fatigue, depressive symptoms, headaches)

- Esophageal disorders (e.g., worsening neck pain during swallowing)

- Gastrointestinal (GI) disorders (e.g., anorexia, nausea, vomiting, changes in bowel function or stool)

- Urinary tract disorders (e.g., urinary symptoms, flank pain)

- Pulmonary disorders (e.g., cough, dyspnea, worsening pain during inspiration)

Medication use, smoking history, and diabetes risk should also be assessed.

ASSESSMENT OF PROGNOSTIC FACTORS

Clinicians should perform functional assessments during initial contact and all follow-ups and a psychosocial ("yellow flag") assessment during initial or follow-up visit to obtain important information about baseline status, trajectory, and prognosis of recovery. Both assessments are easily conducted using validated self-report questionnaires.

Functional Assessment

The Visual Analog Scale (VAS), the Numerical Pain Rating Scale (NRS), the NDI, the Pain Catastrophizing Scale (PCS), and the Impact of Events Scale-Revised (IES-R) measure clinical variables with significant prognostic value in acute neck pain; all may be used for the initial assessment and follow-up. Patients with high initial scores are at much greater risk of persistent pain and disability and may require treatment of greater intensity or focus. Clinical factors and cutoff scores for prognosis [22,29,39,104]:

- Pain severity: High pain intensity (NRS or VAS score ≥6 on a 1–10 scale)

- Interference with daily activities: Evaluates pain impact on personal care, lifting, reading, concentration, work, driving, sleeping and recreation; pain intensity, and headaches. High self-reported disability is defined as an NDI score of ≥30%.

- Pain catastrophizing: Belief that pain is to be feared or may be severely disabling. High pain catastrophizing is defined as a PCS score of ≥20.

- Acute post-traumatic stress symptoms: The IES-R evaluates post-traumatic stress symptoms, not post-traumatic stress disorder (PTSD). High acute post-traumatic stress symptoms is defined as an IES-R score of ≥33.

"Yellow Flag" Assessment

The Tampa Scale of Kinesiophobia (TSK), the Fear Avoidance of Pain Scale (FAPS), the Patient Health Questionnaire-9 (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS) measure "yellow flags," psychosocial conditions that may predispose the patient to a more complex clinical course, chronicity, or disability [8,19,103]. The following psychologic factors should be identified and measured using the associated tools:

- Pain catastrophizing: PCS

- Kinesiophobia, or avoiding activities due to fear of pain (fear-avoidance behavior): TSK or FAPS

- Passive coping: PCS

- Depressed mood or feelings of depression about pain: PHQ-9 or HADS

- Anxiety or fear about pain: TSK or FAPS

- Pessimism and poor recovery expectation: Ask the patient: Do you think that your injury will…

- Get better soon

- Get better slowly

- Never get better

- Don't know

- High levels of frustration or anger about pain. Ask the patient to quantify (on a 0–10 scale) how frustrated (angry) he or she feels about the pain.

- Obtain during history:

- Past/current social or financial problems

- Past/current multiple medical diagnoses, unresolved musculoskeletal conditions

- Past/current history of physical abuse, emotional abuse, chronic pain

- Past/current active substance abuse

Sleep Assessment

Sleep quality and pain are intimately linked, making sleep important to assess. For every 1-point decrease in sleep quality (on a 0–3-point scale), pain intensity increased 2.08 points (on a 0–10-point scale) among 1,246 patients with acute low back pain [105]. This large effect of poor sleep on subsequent pain intensity was unrelated to depression or other common factors.

Among 1,016 patients with chronic low back pain or neck pain, 42.22% experienced sleep deprivation (less than six hours per night) and 19.88% experienced serious sleep impairment (less than four hours per night), even when using analgesics. Severity of sleep impairment strongly correlated with pain intensity score and pain chronification grade, but did not differ between low back pain and neck pain [106].

PHYSICAL EXAMINATION

The physical exam supports patient history findings, screens for serious pathology, informs further diagnostic work-up, and guides treatment selection. Neck pain origin is important to identify (when possible) and document, but underlying pathology of neck pain is seldom curable, and its treatment targeting has led to inadequate outcomes. Specific pathologies can generate different pain types, and the importance of pain type assessment and treatment is now stressed.

Characterizing neuropathic pain and identifying neuropathic components in chronic nociceptive neck pain are essential tasks during the physical exam. Sensory, motor, and reflex testing during the physical exam, assessment, and provocative tests assist in this task [2,19,29,41,96,103,107].

General Visual Inspection

Observe patient to identify nonverbal facial or behavioral pain expressions. Gait abnormalities can reflect spinal cord (myelopathy) or brain injury. Note traumatic or developmental abnormalities. Assess gait, posture, stance, rapid walking, balance, and visible deformities.

Palpation

Palpate the spine, facets, and paravertebral muscles for tenderness, muscle spasm, myofascial tightness, and trigger points. Painful facets can reflect osteoarthritis or post-traumatic irritation of the joint capsule.

Thoracic Spine and Shoulder

Examine shoulder for range of motion impingement and rotator cuff function.

Motor and Sensory Examination

Evaluate upper muscle groups with specific nerve root focus; assess sensation to light touch, pin prick, temperature, position, and vibration. A >2 cm difference in circumference of two upper extremities may indicate muscle atrophy; motor and sensory differences may implicate a specific nerve root.

Reflex Testing

Asymmetry of deep tendon reflexes may indicate pathology. Inverted reflexes (e.g., arm flexion or triceps tap) may indicate nerve root or spinal cord pathology at the tested level. Pathologic reflex tests include wrist clonus, grasp reflex, and Hoffman sign. In patients with suspected malingering or who report severe pain in the absence of pain-related behaviors, reflexes may be the only objective exam tool.

Cervical Range of Motion

During rotation, flexion, and extension, assess quality of motion and for presence of muscle spasm. Motion evaluation of specific joints may be indicated. Do not assess in acute trauma cases until fracture and instability are ruled out.

Cervical range of motion is often limited in all patients with neck pain, but aggravating and alleviating factors and specific exacerbating movements may provide clues to the pain origin and inform decisions to concerning further work-up. Pain-exacerbating movements and suggested pain origin include [2,14]:

- Turning or bending head ipsilateral to source: Radicular or facet pain

- Contralateral turning of head: Myofascial origin

- Arm pain aggravated by neck extension: Spinal stenosis

- Arm pain aggravated by neck flexion toward affected side: Foraminal stenosis and/or radiculopathy

- Forward flexion: Diskogenic origin

- Morning stiffness: Facet joint pain due to arthritis

- Severe unrelenting pain unaffected by rest or position changes: Assess for "red flags" (e.g., malignancy, primary neurologic disorder, infection)

Neuropathic Neck Pain

Cervical radiculopathy is the most common neuropathic neck pain. Distribution of abnormal sensations or pain can follow patterns specific to the innervated skin (dermatome) of the involved nerve root, and less commonly, other innervated structures that include muscles (myotome), joints, or ligaments (sclerotome) [22]. Symptom distribution with mechanical stimulation of nerve roots (dynatome) differs from dermatomal patterns. Cervical disk herniation may induce thermal distributions (thermatome). Radiculopathy can occur without pain, and distribution patterns vary among patients [51].

Cervical radiculopathy can result from nerve root irritation (chemical radiculopathy) or compression (e.g., disk herniation, foraminal stenosis, cord compression in myelopathy) [2,29,51].

The origins of radiating neck pain/sensory disturbance are [7,107]:

- Cervical radiculopathy: Sensory, motor, and reflex abnormalities, with pain/sensory distribution from the affected nerve, weakness/tenderness of muscles innervated by the nerve, and hypoactive deep tendon reflexes of the same muscle.

- Radicular pain: Sharp, shooting, burning, or aching pain that radiates along the course of a nerve root—without neurologic abnormalities. Neck, upper trapezoid, or scapula tenderness is common.

- Referred pain: Pain radiates into the neck, head, upper trapezoid, scapula, or upper arm, but does not involve spinal nerve roots and is non-neuropathic (sensory, motor, reflex changes).

The Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) pain scale can help differentiate neuropathic from nociceptive pain [2,93,108].

Neuropathic Components in Neck Pain

Chronic non-radiculopathic neck pain may have a neuropathic component without apparent nerve root or spinal cord pathology, reflecting CNS alteration [96]. Assessment of a neuropathic component is performed by the physical exam and the PDQ tool [69,71,72,73]. The cardinal features are spontaneous pain (arising without stimuli), abnormal pain response to normally non-painful stimuli such as light touch or moderate heat/cold (allodynia), and exaggerated response to mildly painful stimuli (hyperalgesia). The spontaneous pain may be paroxysmal (e.g., shooting, stabbing, electric shock-like), dysesthetic (e.g., unpleasant abnormal sensations of touch, for example prickling, pins and needles, or crawling), or abnormal thermal sensations (e.g., burning, ice cold). These signs and symptoms can co-occur with loss of afferent sensation.

The PDQ is extensively used worldwide in research and clinical practice to identify neuropathic components in chronic spinal pain. A PDQ score greater than 18 indicates a significant neuropathic pain component, regardless of radiculopathy presence [96].

Provocative Tests in Neck Pain Assessment

Evidence Based Practice Recommendation

According to the Royal Dutch Society for Physical Therapy, the Spurling test and the traction/distraction test are considered to be valid as specific tests for ruling in cervical radiculopathy.

http://stoverpt.com/uploads/3/4/8/2/34823947/neeck_pain_guidelines.pdf

Last Accessed: September 17, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Some specialist and primary care practice guidelines recommend provocative tests (Table 3). They can be helpful adjuncts to history and physical exam findings in identifying potential neuropathic pain origins. These tests are not diagnostic alone, and clinicians should look for patterns in patient-reported, physical exam, and provocative test findings to rule in or rule out specific painful pathologies [29].

Table 3: PROVOCATIVE TESTS: DESCRIPTION AND DIAGNOSTIC USE

Test

Description

Cervical radiculopathy

Spurling

Radicular pain reproduced by lateral flexion and rotation to affected side with axial compression of the head

Shoulder abduction

Ipsilateral cervical radicular symptoms relieved by placing symptomatic arm on head (abduction)

Neck distraction test

Radicular symptom relief when examiner grasps patient's head under occiput and chin and applies 10–15 kg of axial traction force

Valsalva maneuver

Radicular pain reproduced by forced expiratory effort with mouth and nose closed

Upper limb tension test

Radicular pain reproduced with scapular depression; shoulder abduction; forearm supination, wrist and finger extension; shoulder external rotation; elbow extension; contralateral followed by ipsilateral cervical lateral flexion

Cervical myelopathy

Lhermitte sign

Electrical-like sensations down spine or arms with passive flexion of neck

Hoffmann sign (also for spinal stenosis)

Reflex contraction of thumb and index finger from nipping of the middle finger

Babinski sign

Stimulation of the foot sole elicits dorsiflexion of hallux, or dorsiflexion and abduction of other toes

Hyper-reflexia

Over-reactive deep tendon reflexes

Clonus

More than two repetitive beats during wrist or ankle dorsiflexion movements

Jackson compression

Downward pressure on head with lateral flexion

Facet joint pain

Paraspinal tenderness

Paraspinal > midline pain with palpation. The only test that identifies facet pain, distinguishes from diskogenic pain, and predicts treatment response.

Source: [2,29,49,51,56]

DIAGNOSTIC IMAGING

Diagnostic imaging has an essential role in some neck pain presentations. However, imaging findings of bulging disks or degenerative changes are common in asymptomatic persons and increase with age [14,103]. In some patients, the imaged abnormality is causing their neck pain. In most patients with acute neck pain, imaging fails to identify a pathologic cause or pathologic findings have uncertain relevance or do not change the course of treatment [29].

Imaging can produce false positive (abnormalities are inert) or false negative (pathology undetected) results. Clinicians should correlate imaging results with history and physical exam findings before deciding its relevance to patient symptoms [102].

Imaging results should be presented with patient education on prevalence, treatment, and prognosis. Patients may intensely want a clear-cut diagnosis of their neck pain. Neglecting this education increases the risk of patient fixation on the imaging abnormality (which may be inert), subsequent pursuit of "cure" for the assumed diagnosis, and with failed expectations, initiation into a chronic cycle that may have been prevented [102,103].

For these reasons, clinical practice guidelines state that patients with acute cervical spine injury, suspected "red flag" conditions, or suspected radiculopathy (and a few select presentations) should receive initial imaging, with imaging considered in other patients remaining symptomatic three to six weeks later [102,103].

Diagnostic Imaging Modalities

Imaging tests differ in accuracy for various pathologies, and no imaging test alone assures correct diagnosis. Information from patient history and physical exam should correlate with imaging results [103].

The indications in the following sections pertain to patients remaining symptomatic after four to six weeks of conservative therapy or with new onset or progression of neurologic symptoms at any follow-up time.

Plain Radiography

Evidence Based Practice Recommendation

According to the American College of Radiology (ACR), in absence of red flag symptoms, imaging may not be required at the time of initial presentation of the patient with neck pain, and the results rarely alter therapy. However, radiographs are widely accessible and useful to diagnose spondylosis, degenerative disk disease, malalignment, or spinal canal stenosis. As such, the ACR states that cervical spine x-ray is usually appropriate for initial imaging of patients with new or increasing nontraumatic cervical or neck pain with no red flags.

https://acsearch.acr.org/docs/69426/Narrative

Last Accessed: September 17, 2019

Level of Evidence: Expert Opinion/Consensus Statement

X-ray images are taken from different anatomic views to identify the following abnormalities [51]:

- Anteroposterior: Tumors, osteophytes, fractures

- Lateral: Stability, spondylosis (spurring, disk space narrowing)

- Odontoid: C1–C2 stability, odontoid process (bony projection of C2, prone to fracture)

- Bilateral oblique: Degenerative disk disease, foraminal encroachment by osteophytes

- Flexion-extension: Subluxations, cervical spine instability

A standard cervical spine x-ray series captures anteroposterior, lateral, and odontoid views [19]. All five views are used to evaluate the intervertebral foramen [41]. Radiographs of the lateral cervical spine may show straightening or reversal of the normal lordotic curve, which can represent spasm, guarding, or splinting of muscles that stabilize the neck [41].

Cervical spine x-ray is indicated for any significant trauma, pain, or cervical spine-related dysfunction; to rule out fracture; or screen for stenosis in symptomatic patients [16,41,59].

Magnetic Resonance Imaging

MRI is the imaging study of choice for most cervical spinal abnormalities. MRI can add important information about soft tissue injuries related to bony injuries seen on x-ray or CT or disk or ligamentous injuries suggested by x-ray, CT, or clinical findings [109]. It can also distinguish hematoma from edema. MRI is highly accurate in identifying disk injury and ligament injuries [19,110]. It is able to detect ligament disruption and subtle vertebral fracture, but is unreliable in depicting sources of cervical diskogenic pain because significant annular tears can escape MRI detection [16,41].

Indications for cervical spine MRI at four to six week follow-up include [22,41,47]:

- Persistent arm pain, neurologic deficits, or clinical signs of nerve root compression

- Cervical radiculopathy signs and symptoms

- Cervical disk injuries with any neurologic decline

- Failure of axial neck pain to resolve as expected

Patients with progressive neurologic deficit should receive MRI without delay.

MRI is contraindicated in patients with certain implanted devices, but MRI scanners compatible with pacemakers are now available. Some patients have panic reactions during MRI from claustrophobia and require mild sedation [103].

Computed Tomography

MRI is superior at imaging soft tissue abnormalities and potential neurologic compromise, while CT better delineates bony pathology by producing multiple 2- and 3-dimensional images of spinal segments [7]. CT alone has limited value in assessing cervical radiculopathy but is useful for visualizing degenerative spine and facet changes, spinal alignment, fractures, herniated disks, spinal and foraminal stenosis, and osteophyte formation, especially when not clearly shown on x-ray [23,24,50,58,103]. It is important to avoid unnecessary CT scanning to limit patient radiation exposure and associated carcinogenic risk [103].

CT Myelography

Myelogram followed by CT scan evaluates the spinal canal, its relationship to the spinal cord, and nerve root impingement from disk, spur, or foraminal encroachment. CT myelography is superior to MRI in detecting encroachment but is reserved for complex cases due to greater expense and morbidity or when MRI is unavailable, intolerable to the patient, or contraindicated [19,51].

Provocative Cervical Diskography

Provocative cervical diskography is the only procedure that can identify a disk as the pain generator. In this test, contrast dye is injected into the nucleus pulposus to visualize disk architecture and provoke a pain response. Discomfort and invasiveness make this procedure less desirable than cervical MRI, which provides much of the anatomic information. Possible complications include diskitis, epidural abscess, quadriplegia, stroke, pneumothorax, and nerve and spinal cord injury [51].

MRI often misses significant tears, which diskography can reveal as diskogenic source of cervical pain. As noted, while MRI can identify most painful disks, it has relatively high error rates [41].

Electrodiagnostic Tests

Electromyography and nerve conduction studies are the standard for evaluating cervical spine neurologic function and have advantages of limited cost and morbidity [51]. With persistent radicular symptoms, electromyography can help identify injuries to cervical nerve roots, brachial plexus, or peripheral nerves [16]. It may show nerve injury missed by imaging studies that only show structural injury [41].

Electromyography shows abnormalities with high specificity in cervical radiculopathy, diagnosed when two muscles innervated from the same nerve root are abnormal. Multiple muscles should be examined, including the paraspinals [11,12,22]. Nerve conduction studies are useful when extremity pain rather than cervical pain is more severe [7].

Initial Imaging

Initial imaging is recommended for some patients when they first present for medical attention with neck pain or symptom complaints.

Acute Cervical Spine Injury

The Canadian C-spine Rule identifies patient risk of cervical spine injury and appropriate diagnostic imaging. "Dangerous mechanism of injury" is defined as falling from a height greater than 3 feet or axial load to the head from diving, high-speed or rollover motor vehicle accident, ejection from a motor vehicle, accident involving motorized recreational vehicles or horse riding, or bicycle collision [111]. The Canadian C-spine Rule assesses high, low, or no patient risk of cervical spine injury (Table 4). Importantly, neck movement is unsafe to assess in high-risk patients [109,111].

Table 4: ASSESSMENT OF RISK LEVEL FOR CERVICAL SPINE INJURY

High Risk

One or more of the following factors:

Dangerous mechanism of injury

Age 65 years or older

Paresthesia in upper or lower limbs

Low Risk

Patients unable to rotate their neck 45° left and right and one or more of the following factors:

Involved in a minor rear-end motor vehicle accident

Comfortable in a sitting position

Ambulatory at any time since the injury

No midline cervical spine tenderness

Delayed onset of neck pain

No Risk

Patient has one low-risk factor and can rotate his/her neck 45° left and right.

Source: [111]

Cervical spine x-rays are indicated for all high-risk and low-risk patients [19,109,111]. CT and/or MRI is recommended for patients with one or more high risk factors, or one or more low-risk factors and inability to rotate neck 45° left and right. The Congress of Neurological Surgeons recommends CT and MRI for cervical spinal injury in patients with cervical spondylitis, even after minor trauma [112,113]. No-risk patients do not need imaging. Other indications for cervical spine MRI include [103,111]:

- Suspicion of cord compression

- Neurologic signs or symptoms, even if x-ray is negative

- Ligament or disk injuries suggested by x-ray, CT or clinical findings

- Suspected nerve root compression, disk herniation or cord contusion following neck injury

- Assessment of red-flag conditions

LABORATORY TESTING

Unless red flag conditions are suspected, laboratory tests are seldom needed in the evaluation of neck pain [103].

5. TREATMENT OF NECK PAIN

Practice guidelines for primary care are consistent in recommended management of acute neck pain [7,102,103,107]. After red flag causes and radiculopathy are ruled out, the neck pain condition is given a nonspecific diagnosis. Patients should then be instructed to take over-the-counter analgesics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) if needed and to avoid bed rest and maintain activity. Patients should also be reassured their neck pain is benign, time-limited, and has an excellent prognosis. If pain worsens at any time, clinicians should consider specialist referral. If pain persists three to six weeks later, a brief psychosocial assessment is performed to assess "yellow flags," and patients are referred to physical therapy.

This standard guidance has merits of simplicity for clinicians, the benefits of remaining active, and the spontaneous resolution of acute neck pain in some patients. However, some assumptions may be inaccurate, such as the benign, self-limiting nature of most neck pain and patient access to, or availability of, specialist pain providers. Several systemic barriers interfere with patient access to pain therapy, including [114,115]:

- The acute nationwide shortage of pain specialist physicians

- The limited availability in some areas of trained physical, psychologic, or occupational therapy providers

- Insurance non-coverage of nonpharmacologic pain therapies, restrictive coverage that fragments and delays therapy continuity, and/or deductibles that are unaffordable

Poorly controlled acute pain can have negative consequences that include delayed recovery, disrupted sleep, and impaired physical and social functioning that diminishes the quality of life. Regardless of origin, poorly managed acute pain can transition to chronic pain [116]. Pain should be treated at once if it impairs functioning, and treatment options should be discussed clearly with the patient to prevent unrealistic expectations and possible disappointment [73].

The adverse impact of chronic pain on mortality captures the gravity of this state and importance to control. A study followed 1,528 patients with severe chronic pain over 12 years after they completed a multidisciplinary pain program. Among patients who died during follow-up (16%), the average age at death was 14 years younger than life expectancy. One year after the multidisciplinary pain program, pain and health-related quality of life scores were statistically and clinically worse among patients who died but significantly improved among patients who remained alive at last follow-up. These findings of significant premature mortality in patients with uncontrolled chronic pain raise questions of whether some deaths were preventable [117].

PATIENT EDUCATION

Evidence Based Practice Recommendation

For patients with acute neck pain with movement coordination impairments (including WAD), the American Physical Therapy Association recommends clinicians provide education to the patient to return to normal, non-provocative pre-accident activities as soon as possible; to minimize use of a cervical collar; and to perform postural and mobility exercises to decrease pain and increase range of motion. Patients should be reassured that recovery is expected to occur within the first two to three months.

https://www.jospt.org/doi/full/10.2519/jospt.2017.0302

Last Accessed: September 17, 2019

Strength of recommendation/Level of Evidence: B (Moderate recommendation based on one or more level II systematic reviews or a preponderance of level III systematic reviews or studies support the recommendation, providing evidence for a mild to moderate magnitude of effect)

As noted, acute neck pain guidelines recommend that clinicians educate and reassure patients of the typically benign nature and self-limited course of nonspecific neck pain and the importance of maintaining activity and movement. Education and counseling may also include spine anatomy and proper postures, pain perception neuroscience, pain coping strategies, and resumption of normal activities. Education interventions may add small benefits to physiotherapy but should not be used alone due to ineffectiveness [8,118].

For patients who are not proficient in English, it is important that information regarding the etiology of their pain and pain management resources be provided in their native language, if possible. 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. Interpreters can be a valuable resource to help bridge the communication and cultural gap between 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 treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

PHARMACOTHERAPIES

Standard practice guidelines recommend the following analgesic options for acute/subacute neck pain [7,102,103,107]:

- Acetaminophen

- NSAIDs

- Muscle relaxants

- Opioid analgesics

Chronic neck pain management is more difficult and complex, but pharmacotherapy guidelines for chronic neck pain are non-existent, and general guidelines for the management of chronic pain may be unhelpful.

Practice guidelines recommend drug and non-drug therapies based on randomized controlled trials, considered the best study design to detect efficacy. Analgesic randomized controlled trials are usually placebo-controlled. Systematic reviews examine treatment efficacy by pooling the results of randomized controlled trials to measure differences in average response to treatment versus comparator/placebo [119].

Systematic reviews of guideline-recommended analgesics for neck pain have found acetaminophen ineffective and NSAIDs minimally effective, compared with placebo. Systematic reviews have also found minimal benefit in other analgesics considered effective. These results may reflect true ineffectiveness or possible limitations with randomized controlled trial evaluation of analgesics, including [120,121]:

- Rigid protocols that disallow dose adjustments when ineffective or intolerable

- Strict enrollment criteria, with outcomes of research subjects dissimilar to typical patients

- Increasing placebo-response rates that require larger studies to show relevant differences from placebo

In some cases, it is not the study design but the paradigm itself that limits usefulness. Randomized controlled trials have evaluated analgesic efficacy in patients with specific pathologies (e.g., disk herniation, degenerative processes). The efficacy of oral analgesics is mostly unrelated to underlying tissue pathology, which can produce diverse pain mechanisms. Pain mechanism targeting is now emphasized [71,72].

Central sensitization is recognized to underlie many chronic neck pain cases and is very difficult to treat. Optimized pain reduction can require combining medications that target peripheral inputs in the dorsal horn (bottom-up) and descending pain modulation pathways (top-down) with tapentadol (opioid and norepinephrine reuptake inhibitor) or opioids plus NSAIDs, norepinephrine reuptake inhibitors, or anticonvulsants. Adding topical analgesics can help decrease peripheral nociceptive input [71,98,122,123]. A 2017 practice guideline recommended combining analgesics in chronic pain treatment [124].

Assessment of Analgesic Response

Assessing treatment response to neck pain pharmacotherapy is very important. This requires the patient reaching and maintaining adherence to a target dose at which therapeutic effect is expected for at least two weeks. The most common errors are underdosing and insufficient treatment duration [73].

Assess treatment response using a 0–10 scale, and use the results to help guide treatment planning [73]. With a pain reduction to <3, continue monotherapy and consider indication for combination therapy, when appropriate. For a pain reduction by ≥30% but a pain intensity ≥4, combine the existing therapy with an additional first-line drug. If pain is reduced by <30% and the pain intensity ≥4, the drug should be considered ineffective and the patient should be switched to another first-line agent.

It is also important to check for side effects [73]. If intolerable side effects prevent effective dosing, switch to another drug. If the patient is taking a clinically effective dose but intolerable side effects continue, lower the dose before switching analgesics. Depending on the therapeutic and side effects after this is done, try switching the drug or starting combination therapy with a low dose of the original drug. If the pain relief remains inadequate, consult a pain specialist or refer the patient to a pain center.

Acetaminophen

Acetaminophen (paracetamol) is a nonsalicylate antipyretic analgesic recommended as first-line therapy in mild-to-moderate acute or chronic low back, spinal, and musculoskeletal pain [125,126,127]. Enduring assumptions of its efficacy and safety were first challenged by a randomized controlled trial of 1,649 patients with acute low back pain. Following 28 days of acetaminophen or placebo taken as regular dosing (three times per day) or as needed for pain, acetaminophen did not differ from placebo on any pain outcome, average time to recovery, or tablets consumed per day [126].

Reviews of placebo-controlled trials concluded that acetaminophen was ineffective in reducing pain and disability in low back pain and showed little evidence of efficacy in diverse chronic pain conditions. Even 4,000 mg/day for 1 to 12 weeks had no effect beyond placebo on pain, quality of life, function, or sleep quality in acute low back pain, and any effect in chronic low back pain was uncertain [125,127,128]. A caveat is that very few studies have evaluated acetaminophen in neck pain.

Acetaminophen shows a significant dose-response effect for increased risks of cardiovascular, renal, and GI adverse effects, suggesting considerable toxicity risk, especially at the upper end of standard analgesic dosing [129]. Acetaminophen may cause liver failure in acute overdose or chronic excessive exposure [130]. The universal endorsement and routine use of acetaminophen as first-choice analgesic in acute and chronic neck pain is questioned [125,126,127].

Muscle Relaxants

Appropriate for muscle spasm with pain, there is strong evidence that muscle relaxants can provide short-term pain relief in acute low back pain (and by extension, neck pain due to spasm). Clinicians should consider the side effects of drowsiness or dizziness. Carisoprodol is not recommended because its active metabolite, meprobamate, is a drug with abuse potential [103].

NSAIDs

NSAIDs are endorsed universally as first-line therapy for acute mild-to-moderate pain of any origin and broadly as first-line therapy for diverse chronic pain conditions, including neck pain. NSAIDs have similar pharmacology but diverse molecular structure. Patient response to specific NSAIDs varies, and several trials of different NSAIDs may be needed to identify an effective agent [103].

A meta-analysis evaluated 35 randomized controlled trials for NSAID efficacy in low back, neck, and sciatica pain. Pain and disability outcomes of NSAIDs or placebo were pooled and averaged, and differences were compared using a 0–10 scale. No study reported outcomes beyond 12 weeks. Only two neck pain studies were found, and the outcomes of these studies were for less than four weeks [131].

NSAIDs surpassed placebo in neck pain reduction by 1.6, a minimally important difference to patients in pain. NSAIDs surpassed placebo by 1.2 in disability reduction. Average differences between NSAIDs and placebo in low back pain/sciatica were lower than neck pain. In aggregate, six participants required treatment with NSAIDs, instead of placebo, for one additional participant to achieve clinically important pain reduction [131].

Another review of NSAIDs in spine pain found two neck pain studies. One involved intravenous NSAIDs, but the other study found greater pain reduction with indomethacin and piroxicam over placebo, and no difference between NSAIDs [47].

NSAIDs inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes that convert arachidonic acid to pro-inflammatory prostanoids. COX-2 inhibition reduces inflammation and pain. Prostanoids also play key roles in maintaining normal physiologic processes; their inhibition accounts for the adverse effects of NSAIDs [132,133].

COX-1 inhibition suppresses prostaglandins that protect the gastric mucosa and thromboxanes that promote platelet aggregation. COX-2 inhibition suppresses prostacyclins in vascular endothelium that inhibit platelet aggregation [134]. Thus, serious or fatal GI, cardiovascular, or renal adverse effects can result from NSAIDs use [133].

In 1997, 16,500 deaths from upper GI bleeding/perforation were linked to NSAIDs [135,136]. This prompted introduction of COX-2-selective NSAIDs to reduce GI risks, which became linked to cardiovascular adverse effects. The view emerged that COX-2 selective NSAIDs had greater risk of cardiovascular toxicity and lower risk of GI toxicity than traditional NSAIDs. Greater accrual of patient outcomes demonstrated all NSAIDs carry GI and cardiovascular risks [132,137,138,139].

Celecoxib has the least GI toxicity but high, dose-related cardiovascular risk. Naproxen has the best cardiovascular safety, but greatest GI toxicity [139]. Concurrent NSAID and selective serotonin reuptake inhibitor (SSRI) use increases upper GI bleeding risks [140,141]. Adding a proton pump inhibitor or switching NSAIDs to celecoxib is recommended to mitigate upper GI risks [142]. Despite greater awareness, NSAIDs cause 7,000 to 10,000 GI hemorrhage fatalities annually [143].

All NSAIDs increase risks of fatal and non-fatal cardiovascular and cerebrovascular events and renal failure, especially in elderly patients. Serious adverse effects can occur within one month of regular therapy. Long-term NSAID use is not recommended, and NSAIDs should be used at the lowest effective dose for the shortest duration possible [103,134,144]. Given the risk profile, clinicians should reconsider using NSAIDs for pain and limit their use to pain with inflammation [145].

Antidepressants

Noradrenergic projections form a key component of descending pain inhibition pathways. Impaired descending pain inhibition can facilitate and maintain chronic pain. Drugs that inhibit norepinephrine reuptake can enhance spinal noradrenergic efficiency to reduce chronic pain, including some antidepressants and the opioids tramadol and tapentadol [71,123].

Tricyclic antidepressants (TCAs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) are recommended first-line options in chronic neuropathic pain disorders and in chronic pain with a neuropathic component [69,71,73].

Tricyclic Antidepressants

The first antidepressants used in pain treatment, TCAs may also produce analgesia by blocking NMDA-induced hyperalgesia, voltage-gated sodium channels, and delta-opioid receptor interaction [146,147,148]. Amitriptyline is the most studied, endorsed, and prescribed TCA in chronic pain, and some evidence suggests it may be the most effective analgesic antidepressant [70,72,73,81]. Other TCAs (e.g., nortriptyline, desipramine) are better tolerated but lack the evidence base of amitriptyline. Analgesic effects are independent of antidepressant effect, and analgesic dosing is 20% to 33% of antidepressant doses [148].

SNRIs

Duloxetine and venlafaxine are the most-studied SNRIs in chronic pain, with duloxetine the most widely endorsed agent [81]. SNRIs inhibit reuptake of serotonin and norepinephrine, but norepinephrine activity accounts for analgesic effects. In contrast, SSRI antidepressants have negligible norepinephrine activity and minimal analgesic efficacy.

Unlike TCAs, SNRIs require antidepressant doses for analgesia, especially venlafaxine, which only inhibits serotonin reuptake at lower doses (<175 mg/day) [148]. Duloxetine 60–120 mg/day is used for pain, with doses <60 mg/day ineffective [73].

Several placebo-controlled trials have evaluated duloxetine in chronic low back pain without radiculopathy or stenosis. Outcomes from four of these studies were pooled; 12 to 14 weeks of duloxetine led to pain reduction ≥30% in 60% (versus 48% with placebo) and ≥50% in 49% (versus 35% with placebo). Analgesic response to duloxetine surpassed placebo by 13% on both pain outcomes [149].

Another study of different doses found duloxetine 20 mg, 60 mg, and 120 mg no different from placebo at week 13, and noted a 24% dropout rate from side effects with duloxetine 120 mg [150].

With duloxetine in chronic pain, analgesic effects accounted for 91% of pain reduction in patients screened for depression, which shifted over time to antidepressant effects in patients with comorbid depression. The authors noted the mutually reinforcing relationship between pain and depression makes it plausible that alleviating depression can reduce pain symptoms [151].

Duloxetine was less effective in isolated chronic low back pain than in patients with two or more painful sites. Multiple pain sites may better reflect CNS alterations that amplify pain perception, and suggest duloxetine is more effective in centralized chronic pain [149].

Milnacipran, another SNRI, after six weeks was no different from placebo in pain reduction in chronic low back pain with a neuropathic component [152].

Antidepressant Adverse Effects

TCA side effects are intolerable for some patients, and low-dose (10 mg/day) initiation with gradual increase to 75 mg/day is suggested [73]. TCAs should be used cautiously in elderly patients due to greater risks of postural hypotension, impaired cognition, and falls and should be avoided in patients with a history of cardiovascular disease [70,148].

In placebo-controlled pain studies, desipramine and venlafaxine had the highest overall rates of adverse effects. Desipramine, milnacipran, venlafaxine, and duloxetine had highest dropout from side effects, suggesting greater severity and unpleasant perception. Adverse effects associated with duloxetine (e.g., nausea, constipation, dry mouth, hyperhidrosis) differed somewhat from amitriptyline (e.g., dry mouth, thirst, constipation, headache, weight gain, blurred vision, palpitations) [153].

Antiepileptic Drugs

Antiepileptic drugs are diverse, but pregabalin and gabapentin are the only widely studied agents in chronic low back pain. As with antidepressants, few neck pain studies are available and chronic low back pain outcomes are used to inform decisions.

Pregabalin and gabapentin are widely recommended first-line agents in neuropathic pain disorders, such as painful diabetic neuropathies and postherpetic neuralgia [72]. Analgesic, anxiolytic, and anticonvulsant effects arise from binding to alpha-2/delta-1 subunits of calcium channels, highly expressed in brainstem structures where descending pain modulatory pathways originate and a likely key analgesic target of pregabalin/gabapentin [70].

Pregabalin has greater binding affinity and greater analgesic potency in neuropathic pain than gabapentin. Pregabalin also has more rapid absorption, greater bioavailability, and a linear dose-response [70].

The dosage of pregabalin in pain treatment is 300–600 mg/day in divided doses. Gabapentin is used at 1,200–3,600 mg/day in three divided doses. Both can be initiated at 10% the maximum dose, increased every three to four days [73]. Pregabalin 600 mg/day has greater efficacy than 300 mg/day [72].

Pregabalin/gabapentin is generally well tolerated. The adverse effects most common with pregabalin are dizziness, somnolence, dry mouth, edema, and blurred vision; with gabapentin, common adverse effects include dizziness and somnolence (>20% of patients), confusion, and peripheral edema [70].

Adverse effects increase with pregabalin dose but do not appear to be age-related. In patients 65 years of age and older, titration to the lowest effective dose may help minimize adverse effects. Absence of known drug interactions with pregabalin/gabapentin increases safety in patients requiring polypharmacy [154].

Gabapentinoid efficacy in chronic spine-related pain is inconsistent. An uncontrolled study compared pregabalin monotherapy, pregabalin add-on therapy, and non-pregabalin therapy under "real-world" primary care conditions in 1,351 patients with chronic painful cervical (13%) or lumbosacral (87%) radiculopathy [155]. Pregabalin groups received 190 mg/day (mean). At 12 weeks, pain intensity reduction ≥50% was attained by 63%, 56%, and 33% of patients in pregabalin, pregabalin add-on, and non-pregabalin groups, respectively. Differences in pain reduction were significant by week 4. Improvements in sleep disturbances, depression, anxiety, and quality of life showed large effect sizes in pregabalin groups and moderate effect sizes in the non-pregabalin group [155]. The authors noted non-pregabalin patients received NSAIDs (67%) or acetaminophen (37%) rather than tramadol (19%), gabapentin (13%), or amitriptyline (5%), indicating inappropriate treatment with NSAIDs and acetaminophen, which are ineffective in chronic pain with a neuropathic component [155].

In contrast to these uncontrolled results, a review of pregabalin/gabapentin studies in nonspecific chronic low back pain found minimal pain improvement with gabapentin compared with placebo, and pregabalin inferior to active-drug control groups (with buprenorphine, tapentadol, or celecoxib). Studies comparing pregabalin to placebo were not found [156].

In a small trial, patients with chronic cervical or lumbar radicular pain had greater pain reduction with placebo than pregabalin after three weeks [157]. Pregabalin plus tapentadol did not improve tapentadol efficacy in severe chronic low back pain with a neuropathic component and significantly increased dizziness and somnolence [158].

An uncontrolled trial of pregabalin in cervical spondylosis pain found significant pain reduction after eight weeks, but intolerable somnolence and dropout by 27 of 50 patients. The authors suggest greater sensitivity to this side effect in the Asian study population [159].

Importantly, drug users who combine heroin (and possibly some patients receiving opioid therapy) with gabapentin or pregabalin potentially increase their risk of acute overdose death by reversing opioid tolerance or through additive effects on respiratory depression [160].

Opioid Analgesics

When severe pain requires powerful analgesic control, few options are as effective and widely available as opioids [161]. Non-opioid analgesics were examined for chronic pain efficacy in 271 randomized controlled trials. Many showed statistically significant effect sizes, but pain reduction sizes were usually not clinically relevant [162]. However, the current regulatory environment and concern regarding misuse inhibits opioid prescribing, placing clinicians with patients in severe pain in a double-bind [163].

Opioid prescribing is a complex issue that should be approached by balancing control (to prevent inappropriate use) with access (for appropriate patients). With focus on either, and neglect of the other, consequences follow [164]. Overemphasis on access has led to increased opioid prescriptions and related addiction, diversion, and overdose deaths. Opioid prescribing and related overdose deaths (16,917) appear to have peaked in 2011 [165,166,167].

Until improved analgesics are developed, opioids remain the only option for severe pain in many patients [161]. Clear evidence demonstrates that screening for substance use disorder before initiating opioid therapy in patients with chronic pain minimizes its development [98,168,169,170]. In addition, most fatalities involving prescription opioid analgesics occur with co-ingested benzodiazepines, alcohol, and other CNS/respiratory depressants. Prevention involves patient education and cautious or avoidance of co-prescribing CNS depressants [171,172,173].

In controlling severe acute neck pain, oxycodone, morphine, and hydromorphone are similarly effective. For chronic moderate-to-severe neck pain, the suggested options shift to several more recent opioid preparations with lower abuse potential, greater tolerability, and/or alternate drug delivery that increase safety in long-term use.

Opioid-induced constipation is a class-wide opioid adverse effect perceived by patients as the most distressing side effect [174]. A study of chronic pain patients with opioid-induced constipation from prior opioids found patient fear of constipation led to a number taking little or no study medication and inadequate pain control, despite the study drug being designed to reduce opioid-induced constipation [175].

Unlike other opioid side effects, opioid-induced constipation does not typically resolve with continued use, becoming chronic in 40% to 45% of patients on long-term opioids and adversely affecting patient quality of life and pain control [98,174]. Opioid-induced constipation should be anticipated and managed prophylactically. Several medications are approved by the U.S. Food and Drug Administration (FDA) for opioid-induced constipation, including naloxegol, methylnaltrexone, lubiprostone, and naldemedine.

Abuse-Deterrent Formulations

All extended-release oral opioids are available in abuse-deterrent formulations, designed to make nontherapeutic use more difficult, less attractive, or less rewarding. Abuse-deterrent formulations use physical barriers that resist crushing; chemical barriers that form into a viscous gel if mixed with liquid; and/or opioid antagonist sequestration that product tampering activates to neutralize the agonist. Some abuse-deterrent formulations use multiple deterrence mechanisms. While abuse-deterrent formulations can deter extended-release opioid tampering to defeat the slow-release mechanism for a rapid-onset, high-dose opioid effect, they cannot prevent abuse of intact pills. Abuse-deterrent formulations are one of several approaches to minimize prescription opioid abuse, but insurance non-coverage is common, due to higher costs than standard opioid formulations [98,176,177].

Oxycodone/Naloxone

To reduce opioid-induced constipation during long-term therapy, the opioid antagonist naloxone was combined with oxycodone extended-release in a fixed-dose 2:1 ratio. Unlike short-acting naloxone, the extended-release formulation limits systemic exposure and does not block or reverse oxycodone analgesia [178]. Combination oxycodone/naloxone (Targin) was FDA-approved in 2014 [174]. Oxycodone/naloxone and oxycodone extended-release show similar efficacy in chronic pain. Oxycodone/naloxone reduces but does not eliminate constipation and seems more effective in new patients with opioid-induced constipation than in preventing constipation during treatment [178].

Buprenorphine

Buprenorphine differs from standard opioids as a partial mu-opioid receptor agonist. This produces a respiratory depression ceiling effect, making buprenorphine safer in overdose, and a euphoria ceiling effect that lowers drug "liking." Buprenorphine is a kappa-opioid receptor antagonist, producing an anti-hyperalgesic effect relevant to neuropathic pain that often contributes to chronic spine-related pain [179,180,181]. Transdermal buprenorphine is the primary form used in chronic pain treatment. The transdermal patch is effective for seven days, after which it is replaced [182]. A buccal formulation was FDA-approved in 2016 based on studies demonstrating efficacy in patients with moderate-to-severe chronic low back pain [183].

The lower abuse potential of transdermal buprenorphine also reflects its slow onset rate and difficulty extracting buprenorphine from the patch. Compared with fentanyl patches, extended-release opioids, and extended-release tramadol, transdermal buprenorphine has shown the lowest rates of abuse and diversion. Common side effects are constipation, dry mouth, nausea, vomiting, headache, dizziness, somnolence, and application site skin irritations [179,180,182].

In a study of transdermal buprenorphine therapy of 465 patients (median age: 67 years) with diverse chronic pain conditions, transdermal buprenorphine pain relief was rated effective/very effective by 69% after 3 months and 91% after at least 36 months [180]. Patient satisfaction with transdermal buprenorphine showed the same temporal pattern. Non-prescribed dose escalation (3%) was low, but patient motive (e.g., pain control, euphoria) was not analyzed. Dropout from ineffectiveness (4%) or adverse effects (12%, mostly skin irritation) exceeding similar trials [180].

Tramadol

Tramadol is a weak opioid that also inhibits serotonin and noradrenaline reuptake, and it is an established option in chronic low back pain. Opioid and non-opioid mechanisms both act to produce analgesia, and account for its low "likeability" by drug misusers, with lower abuse potential than other opioids. It may also have anti-inflammatory activity. Tramadol use with other serotonergic medications (e.g., most antidepressants) may result in serotonin syndrome and should be avoided [73,98,158].

Tapentadol

Tapentadol is a mu-opioid receptor agonist and norepinephrine reuptake inhibitor combined in a single molecule. Tapentadol extended-release was extensively investigated in Europe, with the finding that the formulation is effective in diverse chronic pain, with or without neuropathic pain component, in evaluations up to two years [184,185]. Researchers found function, health status, and quality of life improved during long-term treatment. The drug has a good safety profile, with GI tolerability more favorable than other opioids and a low risk of withdrawal after cessation. To date, analgesic tolerance has not been found in long-term data.

In studies, tapentadol was as effective as oxycodone in nociceptive and neuropathic chronic low back pain, with better GI tolerability and treatment adherence [73,186,187,188]. Earlier gains in function, health status, and quality of life maintained over one year in 1,154 patients receiving open-label tapentadol extended-release after completing randomized controlled trials, including average pain scores (3.9 start, 3.7 end) [189].

As noted, few studies have evaluated opioid therapy, and pharmacotherapy in general, in chronic neck pain. However, an uncontrolled trial evaluated tapentadol extended-release in 54 patients with moderate-to-severe chronic neck pain over 12 weeks [4]. Participants' reported pain-intensity scores (on 0–10 scale) were 1.7 resting (versus 6.8 at baseline) and 2.9 with movement (versus 8.8 at baseline). Approximately 89% of patients experienced ≥30% reduction in pain intensity on movement; 68% reported a ≥50% reduction. In addition, the average NDI score decreased from 55.6 at baseline to 19.7 after 12 weeks. Quality of sleep improved ≥30% in 79% of patients. Cervical range of motion was evaluated on flexion, extension, right and left lateral flexion, and rotation. Compared with baseline, patients with normal range of motion on flexion increased 13%; the other five measures increased 23% to 35% [4].

No patient dropped out from side effects, despite 90% being opioid-naïve on study entry. The average final dose was 204 mg/day, and tapentadol extended-release was well-tolerated in patients requiring 400 mg/day. Common side effects at 12 weeks were constipation and dizziness [4].

With further subject accrual, a second paper from this study compared tapentadol extended-release response in 94 patients with or without a neuropathic neck pain component. Both groups showed comparable reductions in neck pain intensity ≥30% (69% versus 70%) and in average pain scores from baseline (4.4 versus 4.8) at 4 weeks, and reduction in NDI scores from baseline to 12 weeks (46 to 13 versus 58 to 18) [190].

Despite the limitations of uncontrolled trials, this data, together with studies in chronic low back pain, suggest tapentadol extended-release may be effective and tolerable for patients with chronic moderate-to-severe neck pain.

The mu-opioid receptor binding affinity of tapentadol is 18-fold lower than morphine, suggesting lower abuse potential than standard opioids (confirmed by several studies) [98,191]. In 113,914 individuals assessed for substance abuse treatment, tapentadol abuse was lowest overall and significantly lower than other prescribed oral opioids. Adjusted for nationwide prescription volume, tapentadol abuse liability was the second lowest, after only tramadol [192]. Among 1.9 million messages posted by recreational drug users on online forums, the proportion of discussions and endorsements for abuse were substantially lower for tapentadol than comparator drugs [193].

Data from drug diversion databases and investigators and anonymous street drug pricing websites indicate illicit sales and use of tapentadol extended-release was rare. In the few cases of illicit sales, tapentadol extended-release was 10% the price of standard opioids [194].

Cebranopadol and NKTR-181

Two novel opioid analgesics designed to improve safety over standard opioids are in pre-approval evaluation. Cebranopadol is a mu-opioid receptor agonist and nociceptin/orphanin FQ peptide receptor agonist that may improve respiratory depression safety. A 14-week study in chronic low back pain found cebranopadol comparable to tapentadol in analgesic efficacy and sleep and functional improvements [195].

NKTR-181 is a long-acting mu-opioid receptor agonist with structural properties that alter its brain-entry kinetics and may limit abuse potential [176]. Initial studies involving patients with chronic low back pain have found improvements in pain score and sleep compared with placebo [196].

Topical Analgesics

Transdermal analgesic formulations are used for systemic drug delivery, absorption, and distribution. In contrast, topical analgesics are used for drug delivery to local tissue while avoiding systemic exposure.

Topical analgesics have evolved to gain acceptance as analgesic options and have the potential to reduce pain in some conditions while avoiding the side effects of systemic analgesics. Topical analgesics include FDA-approved and compounded formulations.

FDA-Approved Topical Analgesics

FDA-approved topical analgesics include NSAID gel or cream, 5% lidocaine patch or plaster, and 8% capsaicin patch [197].

Topical NSAIDs are increasingly favored in musculoskeletal conditions to avoid the systemic adverse effects of oral NSAIDs, with diclofenac and ketoprofen the most-studied topical NSAIDs. In acute pain, benefit in sprains or strains has good evidence, but the formulation used is critically important; this same consideration may also apply to chronic conditions. Use in chronic musculoskeletal conditions assessed over 6 to 12 weeks showed good pain relief beyond inert carrier in a minority of patients with knee osteoarthritis, limited benefit in hand osteoarthritis, and no evidence in other chronic painful conditions [198,199].

Emerging data suggest the capsaicin 8% patch and lidocaine 5% patch or medicated plaster may both be effective in the treatment of chronic low back pain (and by extension, chronic neck pain) with a neuropathic component [73]. Sodium channels expressed on nerve fibers become altered in neuropathic pain to enhance excitatory neurotransmission [71]. Lidocaine prevents the generation of pathologic nerve excitation by blocking sodium channels. Topical lidocaine may be beneficial when neuropathic pain is localized, because the maximum penetration depth is 8–10 mm. Lidocaine patches are applied to the painful area for 12 hours, followed by a patch-free interval of 12 hours [70].

An uncontrolled study evaluated 5% lidocaine plaster in 23 patients with cervical or lumbar disk herniation and peripheral neuropathic pain (radiculopathy). Compared with baseline, mean pain intensity scores following average treatment duration of eight months decreased from 8.3 to 3.1. Treatment was well-tolerated [200].

In neuropathic pain, transient receptor potential (TRP) channels induce and maintain spontaneous pain and thermal hyperalgesia. The TRPV1 agonist capsaicin activates TRP channels, and desensitization that follows can reduce neuropathic pain [72,73]. Capsaicin 8% patch was effective in painful radiculopathy when placed on involved spinal nerve dermatomes. Fifty patients with cervical or lumbar radiculopathy were evaluated 12 weeks after a single treatment. Among patients with pain duration 3 months, 24 months, or >24 months, 50%, 71%, and 39% achieved ≥30% pain reduction, respectively. Four patients experienced application site pain or pruritus [201].

Compounded Analgesic Formulations

Analgesic medications compounded for topical use are gaining popularity in chronic pain management. Compounded analgesic formulations have the potential advantages of FDA-approved topical analgesics, but with a broader range of options, including ketamine, clonidine, gabapentin, baclofen, and phenytoin [197]. Compounded analgesic formulations typically combine three or more analgesic drugs to achieve multiple complementary effects at lower doses of each drug [202].

Some evidence suggests greater pain reduction with compounded versus FDA-approved topical analgesics. In an uncontrolled study, 2,177 patients with chronic pain received one of three treatments [203]:

- Cream I: Flurbiprofen (20%), tramadol (5%), clonidine (0.2%), cyclobenzaprine (4%), and bupivacaine (3%)

- Cream II: Flurbiprofen (20%), baclofen (2%), clonidine (0.2%), gabapentin (10%), and lidocaine (5%)

- Voltaren gel: 1% diclofenac sodium (an FDA-approved NSAID formulation)

Pre-treatment chronic extremity, joint, musculoskeletal, or neuropathic pain intensity (0–10 scale) in all groups was severe (range: 7.9–8.4). Post-treatment pain intensity scores decreased 37% with cream I, 35% with cream II, and 19% with Voltaren gel. The compounded analgesic formulations did not differ in efficacy, and both were superior to Voltaren [203].

Many small uncontrolled trials show compounded analgesic formulations' efficacy, but this approach must balance local penetration against systemic exposure and potential toxicity. Compounding is not FDA-regulated; vehicle formulation and active drug concentration should be standardized for greater confidence in compounded analgesic formulations safety and efficacy [204].

Cannabinoids

Cannabinoids, which include plant Cannabis, cannabidiol extracts, and pharmaceutically synthesized molecular constituents of Cannabis, are increasingly available to patients with pain through state-level enactment of medical access. Cannabinoids are seldom considered first-choice therapeutic options but are used instead in patients for whom standard therapies are ineffective or intolerable, either as sole therapy or more typically as an add-on to the current regimen [205]. Cannabis has been safely co-administered with a wide range of other drug agents and acts synergistically with opioids to enhance analgesia and allow opioid dose reduction. Chronic pain treatment often requires multiple drug agents that target different pain mechanisms, and the novel mechanism and superior safety profile of cannabis versus opioids suggests that it can be a valuable addition to therapeutic options for chronic pain [206,207].

PHYSIOTHERAPIES

Physiotherapies broadly encompass passive interventions (i.e., without patient exertion or effort), such as massage and manipulation, and active interventions (i.e., requires patient exertion and effort), such as physical and exercise therapy. They are delivered by trained and licensed allied healthcare professionals manually to affected soft tissue or joints, or through instruction and supervision with active interventions. Physiotherapies may also include mechanical devices that patients with positive results can purchase for continued use at home but must be prescribed by their physician [41].

Soft Tissue Therapies

Massage

Massage therapy involves manual manipulation of soft tissue structures. Clinical (therapeutic) massage aims to accomplish specific goals, such as releasing muscle spasms. An example is myofascial trigger point therapy. Relaxation massage aims to relax muscles, move body fluids, and promote wellness [8].

Indications for massage include edema, muscle spasm, adhesions, and the need to improve peripheral circulation and range of motion or to increase muscle relaxation and flexibility prior to exercise. Massage can produce immediate pain reduction, and a frequency of one to two times per week for six to eight weeks is suggested [103]. Massage therapy (once-weekly for 10 weeks) can provide short-term relief for chronic cervical myofascial pain and reduce pain-related impairments [57].

A practice guideline concluded therapeutic massage can decrease pain and tenderness and improve range of motion in patients with subacute or chronic neck pain. Massage interventions are effective for relieving neck pain symptoms at post-treatment, but data on long-term effects are insufficient [208].

Soft Tissue Mobilization

Mobilization of soft tissue applies muscle energy, strain/counter strain, myofascial release, manual trigger point release, and other manual therapy techniques to improve or normalize movement patterns by reducing soft tissue pain and restrictions [103]. Mobilization applies gentle pressure within or at the limits of normal motion with the goal of increasing cervical range of motion [67].

Indications include muscle spasm around a joint, trigger points, adhesions, and neural compression. Mobilization should be accompanied by active therapy. The usual course of treatment is up to three times per week for four to six weeks [103].

Myofascial Release Therapy

In myofascial release therapy, after myofascial tissue with pain-generating trigger points is identified, focused manual pressure and stretching is applied to loosen restricted muscle and joint movements and reduce pain.

Pressure pain threshold is a validated measure of mechanical hyperalgesia and accurately discriminates chronic neck pain with neuropathic features from that without. Using an algometer (hand-held device), tissue pressure is increased until pain is evoked (the pressure pain threshold) [209].

Myofascial release therapy was compared with physical therapy for efficacy in reducing pressure pain threshold and neck pain in 41 patients randomized to myofascial release therapy (5 sessions) or multimodal physical therapy (10 sessions of ultrasound therapy, transcutaneous electrical nerve stimulation [TENS], and massage) over two weeks. At one-month follow-up, significant mean differences were found in pain scores and pressure pain threshold (trapezius, suboccipital) favoring myofascial release therapy. Better short-term improvement in neck pain with myofascial release therapy over physical therapy is suggested [209].

Joint-Directed Therapies

Joint-directed therapies include manipulation and joint mobilization. Spinal manipulation and mobilization may restore normal range of motion and decrease pain. The therapeutic mechanisms remain unknown, but facet joint adjustment may normalize afferent signaling from mechanoreceptors to the CNS, which may improve muscle tone, decrease muscle guarding, promote effective local tissue metabolism, and lead to pain and range of motion improvements [51].

Manipulation

Manipulative treatment applies manually guided force to reduce pain and improve physiologic function [103]. Manipulation is a broad term that includes high-velocity, low-amplitude thrusts to the cervical spine, and modalities such as myofascial release, counterstrain, and/or indirect or direct muscle energy techniques. Non-high-velocity, low-amplitude techniques may also be referred to as mobilization [16].

The most common chiropractic spinal manipulation is high-velocity, low-amplitude thrust to spinal segments, applied at or near the end of a joint's passive range of motion to increase articular mobility or realign the spine. Manual manipulation is also performed by osteopathic physicians trained in manipulative medicine [210].

Some evidence supports chiropractic treatment of WAD [16]. A 2015 Cochrane review of multiple manipulation treatment sessions in neck pain concluded combining laser therapy with manipulation may be superior to manipulation or laser alone for acute and chronic neck pain [211]. For acute and subacute neck pain, manipulation was more effective than muscle relaxants, NSAIDs, and acetaminophen in improving pain and function at immediate (same day) and long-term (around one year) follow-up, and function at intermediate (around six months) follow-up. For patients with acute neck pain, manipulation may be more effective in improving pain and function at short (three months) or intermediate (six months) follow-up. Manipulation may be more effective than massage in improving pain and function in patients with chronic cervical headache at short/intermediate follow-up, and may be favored over TENS for pain reduction at short-term.

The recommended frequency of manipulation therapy is one to two times per week for the first two weeks, and one treatment per week for the next six to eight weeks. At week 8, patients should be re-evaluated [103].

Contraindications include myelopathy, severe degenerative changes, fracture or dislocation, infection, malignancy, ligamentous instability, and vertebrobasilar insufficiency [67]. Relative contraindications include stenosis, spondylosis, and disk herniation [103].

Vertebral artery dissection caused by high-velocity, low-amplitude thrusting is a rare but recognized outcome. Vascular accidents following extension and rotation of the neck beyond the physiologic range lead to a cascade of events including thrombosis, stroke, and death [212]. More than 400 cases following cervical manipulation have described arterial dissection, brain stem injury, cerebellar injury, spinal cord injury, thrombosis, locked-in syndrome, joint dislocation, and death. Risk of these rare but catastrophic events can be minimized by avoiding extension-based high-velocity, low-amplitude thrust [16].

Joint Mobilization

Joint mobilization techniques incorporate a low-velocity and small- or large-amplitude oscillatory movement, within a joint's passive range of motion [8]. A mobilization treatment consists of passive movement involving oscillatory motions to the vertebral segment(s). The passive mobility is performed in a graded manner (I, II, III, IV, or V), which depicts the speed and depth of joint motion during the maneuver. Mobilization may include skilled manual joint tissue stretching [103]. Other modalities include myofascial releases, counterstrain, and indirect or direct muscle energy techniques [16]. Indications include the need to improve joint play, segmental alignment, or intracapsular arthrokinematics or to reduce pain associated with tissue impingement. Mobilization should be accompanied by active therapy [103].

A 2015 Cochrane review of mobilization therapy in neck pain noted anterior-posterior mobilization may favor pain reduction over rotatory or transverse mobilizations at immediate follow-up in patients with acute and subacute neck pain [211]. For those with subacute and chronic neck pain, cervical mobilization alone may not be different from ultrasound, TENS, acupuncture, and massage in improving pain, function, quality of life, and participant satisfaction at immediate and intermediate follow-up. Multiple sessions of TMD manual therapy may be more effective than cervical mobilization in improving pain/function at immediate and intermediate follow-up for patients with chronic cervical headache and TMD.

For grade V mobilization, contraindications include joint instability, fracture, severe osteoporosis, infection, metastatic cancer, active inflammatory arthritides, and signs of progressive neurologic deficits, myelopathy, vertebrobasilar insufficiency, or carotid artery disease. Relative contraindications include stenosis, spondylosis, and disk herniation [103].

Manipulation and Joint Mobilization Co-Therapy

Manipulation and mobilization show similar results on most outcomes. In acute and chronic neck pain, manipulation and cervical mobilization produced similar changes in pain, function, quality of life, global perceived effect, and patient satisfaction at immediate-, short-, and intermediate-term follow-up [211].

Outcomes with gentle mobilization were superior to physical therapy and comparable to high-velocity, low-amplitude thrust [211]. For mechanical neck disorders, manipulation or mobilization were more beneficial combined with exercise than as monotherapy [16]. Short-term improvement is documented in acute whiplash pain, cervicogenic headache, and radiculopathy secondary to disk herniation, but others conclude that mobilization or manipulation in patients with radicular findings has insufficient evidential support [16,51]. No evidence exists that manipulation confers long-term benefit, improves chronic conditions, or alters the natural course of a neck pain disorder [16].

MECHANICAL AND MANUAL TRACTION

Manual or mechanically assisted traction applies an intermittent or continuous distractive force to the cervical spine. Distraction refers to gentle pulling of the head upward to relieve pressure and compression of joints or nerve roots in the cervical spine [8].

Traction is initiated manually by a physiotherapist or as a component of manipulation or mobilization treatment. The usual course of treatment is two to three times per week for four weeks. Patients who benefit from manual traction should continue with a home cervical traction unit [103].

Traction regimens may be heavy weight-intermittent or light weight-continuous. The neck is flexed 15–20 degrees (i.e., not extended) during traction. In the cervical spine, 10 pounds of force is necessary to counter gravity and 25 pounds of force is needed to achieve separation of posterior vertebral segments. Light weight-continuous home traction is cost-effective and provides greater autonomy to the patient. Pneumatic traction devices afford greater patient comfort, which can increase treatment adherence [51].

Traction is popular among patients with cervical radiculopathy, but it is contraindicated with tumor, infection, fracture, or dislocation [103]. Mechanical traction is widely used to promote cervical immobilization and widen the foraminal openings. Cervical traction may relieve radicular pain from nerve root compression, but it does not improve pain from soft-tissue injury. Hot packs, massage, or electrical stimulation should be applied before traction to relieve pain and relax muscles [67].

IMMOBILIZATION

Immobilization limits neck motion to reduce nerve or soft tissue irritation, and soft cervical collars are the most widely used device. For acute soft-tissue neck injuries, cervical collar use should not exceed three to four consecutive days to avoid risks of losing cervical range of motion and neck strength from muscle disuse and atrophy [51].

In radiculopathy caused by foraminal stenosis, the wide part of the collar is placed posteriorly, with the thin part placed anteriorly to promote neck flexion, discourage extension, and open the intervertebral foramina. Cervical collars can be worn during sleep or distance-driving [51].

In severe cervical spondylosis with evidence of myelopathy, cervical spine immobilization is the mainstay of conservative treatment. Soft cervical collars do not sufficiently limit cervical spine motion and should only be used in daytime. More rigid orthoses adequately immobilize the cervical spine; isometric cervical exercises may help limit loss of muscle tone [67].

PASSIVE ASSISTIVE DEVICES

Passive assistive devices inhibit or prevent movement [8]. Molded cervical pillows can better align the spine during sleep and provide symptom relief for some patients [67].

THERMOTHERAPY

Thermotherapy applies heat or cold to superficial or deep tissue. Superficial thermotherapy applies heat or cold to raise or lower skin tissue temperatures. This approach is indicated for reducing acute pain, edema, muscle spasm, and inflammation, or for promoting stretching/flexibility. Heat packs or hydrotherapy can apply heat, while cold packs or vapocoolant spray can apply cold. Cold and heat packs can be used at home [8,103].

Deep tissue thermotherapy is applied to affect structures beneath the skin surface and includes low-level laser, electrical muscle stimulation, pulsed electromagnetic therapy, and ultrasonic heat [8]. Electrical muscle stimulation is indicated for muscle spasm or atrophy with varying frequencies, from twice daily to once weekly. A home unit should be purchased, if effective. Short-wave diathermy applies an electromagnetic field to soft tissues to reduce muscle guarding, inflammation, or edema, typically two to three times per week for three to five weeks [103].

TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Evidence Based Practice Recommendation

For patients with chronic neck pain with movement coordination impairments (including WAD), the American Physical Therapy Association asserts that appropriate treatment options are education, TENS, and cervical mobilization plus individualized progressive exercise.

https://www.jospt.org/doi/full/10.2519/jospt.2017.0302

Last Accessed: September 17, 2019

Strength of recommendation/Level of Evidence: C (Weak recommendation based on one or more level III systematic reviews or a preponderance of level IV evidence supports the recommendation, providing minimal evidence of effect)

Indications for TENS therapy in patients with neck pain include muscle spasm, atrophy, and decreased circulation and pain control. Minimal TENS unit parameters should include pulse rate, pulse width, and amplitude modulation. In patients with pain relief using TENS, also consider functional improvement before prescribing for purchase of a home unit [103].

PHYSICAL AND EXERCISE THERAPIES

Functional Restoration Programs

Functional restoration programs assist patients disabled by chronic cervical pain to overcome obstacles to recovery, such as deconditioning, secondary gain, poor motivation, and psychopathology. Patients should receive education on cervical anatomy, biomechanics, pathology, and ergonomics, and develop preventive strategies that protect against further injury during daily activities. These medically directed interdisciplinary programs have been successful in helping workers' compensation patients return to work and in reducing recurrent injury, new surgeries, and healthcare use in patients with chronic cervical pain who successfully complete a program [51].

The McKenzie Approach

For most cervical disk disorders, studies support conservative treatment, such as the McKenzie approach or cervicothoracic stabilization programs combined with aerobic conditioning. The McKenzie system identifies three mechanical syndromes that cause pain and compromise function [51]:

- The postural syndrome: Provokes pain when normal soft tissues are loaded statically at end-range of motion. Treatment aims to correct posture.

- The dysfunction syndrome: Produces pain when the patient attempting full movement mechanically deforms contracted scarred soft tissue. Therapy involves stretching and remodeling of such contracted tissue.

- The derangement syndrome: Produces intermittent pain with certain movements or postures from activity-dependent displacement of intradiskal material. Therapy attempts to correct derangement by promoting activity that centralizes pain.

The McKenzie theory recognizes that patients may demonstrate similar signs and symptoms, but one movement (i.e., cervical extension) may help some patients and aggravate symptoms in others. In McKenzie therapy, treatment individualization plays a key role [51].

Cervicothoracic Stabilization Programs

Cervicothoracic stabilization programs reduce pain, maximize function, and prevent further injury through cervical spine flexibility, postural training, and strengthening [51,103]. Flexibility restoration prevents further repetitive microtrauma resulting from poor movement patterning. Soft tissue or joint restriction that inhibits range of motion is treated, and range of motion is restored through spine and soft-tissue mobilization, passive range of motion, self-stretching, and correct posturing.

Postural training in spinal stabilization uses mirrors and therapist feedback to maintain neutral spine and correct posture during daily activities. Patients learn whole-body movements while maintaining a stabilized spine, and progress to controlled movement of the spine that approximates normal biomechanical motions without creating undue vertebral stress.

Cervicothoracic stabilization requires strengthening and coordination of neck, shoulder, and scapular muscles, as well as training of the lumbar spine and lower extremities to provide a foundation for the cervicothoracic spine. Stabilization exercises proceed systematically from simple to complex. Isometric and isotonic resistive exercises employ elastic bands, weight machines, and free weights. Such conditioning distributes forces away from the cervical spine. Exercise repetition ultimately encodes an engram that commands immediate, automatic cervicothoracic stabilization during everyday activity. Proprioceptive skills are used during strengthening exercises to facilitate stable, safe, and pain-free cervical posture during strenuous activity.

Neuromuscular Re-Education

Neuromuscular re-education and movement training involves stabilizing and mobilizing muscles, proper sequencing, and optimal biomechanical motion patterns for daily tasks and activities. Tasks are broken down into their component single-joint movement patterns and perfected with proper alignment, breathing, and muscle stabilization in non-weight-bearing postures using manual or mechanical assistance. After single-joint patterns are mastered without symptoms, the training complexity increases, with multi-joint movement, non-linear motion (circular or diagonal), weight-bearing postures, proprioceptive challenges (e.g., eyes closed, unstable surfaces), progressive resistance, and/or variable speeds and durations. The end goal is to transition the patient from movement incompetence to a state of automatic movement competence [213]. Directional exercises are used in pain-generators that show "directional preference" to apply beneficial mechanical loads that correct the abnormality and avoid loading in the direction of vulnerability [213].

In cervical myofascial pain, the goal of physical therapy is to restore balance between muscles working as a functional unit, accomplished using cervical stretch and stabilization, myofascial release techniques, massage, and postural retraining [57].

Strengthening Exercise

General exercise is defined as purposeful physical activity involving repetitive exercises that incorporate multiple muscle groups [214]. In contrast, therapeutic exercise programs should be specific to the injury and address general functional deficits as identified in the diagnosis and clinical assessment. Common specific approaches include strengthening, stretching/range of motion, and flexibility training [8].

Many patients with spine-related symptoms and functional deficits lose strength in specific muscles or muscle groups from neurologic compromise, disuse, and deconditioning. Strength training rehabilitation is used for restoring muscle loss and reversing changes, and for easing recurrent spine-related symptoms in patients with pre-episode deficits. This process can take many months of effort. In the early phases, most gains are in learning and neuromuscular adaptation, which lead to better efficiency and economy of movement [213].

Strengthening is initiated under trained supervision and is later self-directed. Strength training is performed two to five days per week, with any number of movement patterns performed 8 to 20 times over two to four sets. The loads, intensity, volume, and duration used for desired outcomes vary greatly. Equipment that can assist in strengthening includes barbells and dumbbells, exercise machines, medicine balls, and elastic cords [213].

Stretching

Lack of flexibility in certain muscle groups is linked to spine-related symptoms. A causal relationship is not established, but improving the flexibility of muscle, tendon, and connective tissue elements may enhance recovery and reduce focal areas of tension and stress. Stretching involves techniques ranging from static, passive, low-load, long-duration strategies applied by a therapist, to contract-relax tactics that enhance muscle reception to stretching [213].

Patients should continue exercise and stretching therapies at home as an extension of the treatment process to maintain improvement levels. Follow-up visits to reinforce and monitor progress and proper technique are recommended. Home exercise can include exercise with or without mechanical assistance or resistance and functional activities with assistive devices [103].

Evidence of Efficacy

Strengthening tailored to individual patients with neck pain is superior to generalized strengthening [213]. A 2016 practice guideline stated that supervised qigong, Iyengar yoga, and programs that combined strengthening, range of motion, and flexibility were effective in persistent neck pain; exercise alone had minimal benefit [215].

Exercise combined with any blend of manipulation, mobilization, muscle energy, and stretching is more effective in reducing neck pain and disability than any single approach used alone [103]. A systematic review of exercise efficacy in neck pain disorders concluded that use of strengthening and endurance exercises for the cervico-scapulothoracic region and shoulder may be beneficial in reducing pain and improving function; and that stretching exercises alone are not beneficial [216]. In acute radiculopathy, cervical stretch, strengthening, and stabilization exercises show a small benefit in pain reduction. For chronic neck pain, the authors identified five modalities with some evidence of efficacy for neck pain [216]:

- Cervico-scapulothoracic and upper extremity strength training: Moderate to large improvements in pain at short-term follow-up

- Scapulothoracic and upper extremity endurance training: Smaller beneficial effect on pain at short-term follow-up

- Combined cervical, shoulder, and scapulothoracic strengthening and stretching exercises: Smaller to large-magnitude benefit on pain from post-treatment to long-term follow-up, and a medium magnitude of effect on improved function at short-term follow-up

- Cervico-scapulothoracic strengthening/stabilization exercises: Improved pain and function at intermediate-term follow-up

- Mindfulness exercises and qigong: Minimally improved function at short term

The study also determined that weak evidence suggested minimal-to-no short-term benefit on pain or function with breathing exercises, general fitness training, stretching alone, and feedback exercises with pattern synchronization. Very weak evidence suggests neuromuscular eye-neck coordination and proprioceptive exercises may improve pain and function short-term [216].

In patients with chronic cervicogenic headache, static-dynamic cervico-scapulothoracic strengthening/endurance exercises (including pressure biofeedback) were found to improve pain, function, and global perceived effect at post-treatment and probably at long-term follow-up [216]. Low-grade evidence supports sustained natural apophyseal glide exercises in this patient population.

Two randomized controlled trials compared the outcomes of patients with chronic nonspecific neck pain after four weeks of stabilization exercises alone or combined with a manual therapy. In the first trial, patients receiving cervical and scapulothoracic stabilization exercises plus manual therapy showed significantly greater improvements in pressure pain threshold, disability, pain intensity at night, cervical rotation motion, and quality of life than patients receiving exercises alone [217].

The second trial compared cervical and scapulothoracic stabilization exercises alone or plus connective tissue massage. Both decreased pain intensity and anxiety levels, but combination therapy led to significantly greater improvements in pain intensity at night, pressure pain threshold, state anxiety, and mental health than exercises alone [218]. At six-month follow-up, patients with chronic nonspecific neck pain showed significantly greater reductions in pain and disability from global postural re-education than manual therapy (nine 1-hour sessions for both) [219].

The Alexander technique is an educational approach to modify dysfunctional posture, movement, and thinking patterns associated with musculoskeletal disorders. In patients with chronic nonspecific neck pain, the Alexander technique did not differ from local heat application in pain reduction after both were delivered weekly for five weeks [220].

Consensus indicates that exercise therapy is beneficial for chronic pain, but the lack of endogenous analgesia in some chronic pain disorders should not be ignored and clinicians should account for this when treating patients with chronic pain [221]. General exercise is frequently recommended for WADs. In contrast to other musculoskeletal pain conditions, a review of high-quality studies concluded general exercise does not reduce pain or disability in patients with WAD [214].

Exercise-induced hypoalgesia describes the desired effect of reduced pain sensitivity following exercise. The effect of acute exercise on pain sensitivity in chronic pain conditions is controversial, because hypoalgesia, unchanged pain sensitivity, and hyperalgesia (impaired exercise-induced hypoalgesia) have all been reported. Evidence suggests impaired exercise-induced hypoalgesia is evident in WAD following aerobic exercise [222].

In patients with chronic WAD, exercise-induced hypoalgesia responses to isometric (3 minute wall squat) or aerobic (30 minute bicycling) exercise were compared by recording neck and leg pressure pain thresholds before and after exercises. Pressure pain threshold increases were found at both areas after isometric, but not aerobic, exercise. Isometric exercises directed at non-painful muscles may reduce local and remote pain sensitivity in patients with chronic WAD and mild-to-moderate neck pain and disability [223].

In patients with chronic neck pain, exercise-induced hypoalgesia after isometric exercises seems less dependent on exercise intensity than aerobic exercises, which may increase adherence. Isometric exercise has potential as a rehabilitation component to target central mechanisms of pain [222].

PSYCHOSOCIAL INTERVENTIONS

People with chronic pain are not passive; they actively attempt to change the causes of pain and their behavior in response to pain. For many patients, such change without therapeutic help is unachievable, and repeated misdirected efforts to resolve their pain problem can drive a cycle of pain, depression, and disability. Psychologic interventions are designed to promote adaptive pain management and reduce the consequences [224]. As such, psychosocial interventions are used in select patients with acute or chronic pain. Examples include cognitive-behavioral therapy (CBT), relaxation training, mindfulness training, and sleep hygiene training.

Cognitive-Behavioral Therapy

CBT is widely used in the treatment of pain-related functional impairments and disabilities. In general, CBT is a skills-training intervention that emphasizes identifying and changing maladaptive cognitions, emotions, and behaviors, and can be delivered in individual or group-based sessions [81].

In fear-avoidance, CBT targets pain catastrophizing and avoidant beliefs (maladaptive cognitions), fear (a maladaptive emotion), and avoidant (maladaptive) behaviors by helping the patient develop and apply coping strategies that enhance problem-solving for successfully confronting and self-managing health-related threats posed by pain. Core elements of this approach are [81,225]:

- Graded homework assignments

- Cognitive restructuring (i.e., learning how to challenge maladaptive cognitions)

- Relaxation training (e.g., diaphragmatic breathing, progressive muscle relaxation, imagery)

- Time-based activity pacing (paced by time and not task completion)

- Extinguishing pain behaviors (i.e., verbal and nonverbal expressions of pain)

Other strategies taught to patients include distraction (diverting attention away from pain), reinterpretation (changing thoughts about pain), dissociation (separating pain from other sensations), coping self-statements (affirming self-messages), and emotional disclosure (expressive writing) [225].

CBT is widely endorsed for patients with subacute or chronic spinal pain and comorbid psychosocial conditions. CBT can lead to long-term improvements in pain intensity, disability, quality of life, pain-related coping, depressed mood, and health care-seeking behaviors. The favorable effects of CBT on pain outcomes are supported by functional imaging studies [81,226].

Two systematic reviews found inconsistent evidence of pain reduction with CBT. In chronic neck pain, changes in pain and disability were only found when CBT was compared with no treatment, and no effects on kinesiophobia were found. In subacute neck pain, CBT showed benefit in pain relief but not disability compared with other interventions, but the size of these effects was not clinically meaningful. These conclusions were stated as based on low-quality evidence, which might change with new data [227].

A broader review of psychologic interventions evaluated recent-onset and persistent neck pain separately [228]. In persistent (three to six months) neck pain with or without radiculopathy, researchers found no clear evidence supporting CBT or relaxation training for reducing pain intensity or disability; however, they did find that Jyoti (candle or light) meditation may help reduce neck pain intensity and bothersomeness. In persistent post-whiplash pain, evidence to support the efficacy of biofeedback or relaxation training was not found, and evidence for using CBT was conflicting. Adding progressive goal attainment to functional restoration physiotherapy may benefit these patients.

In recent-onset (less than three months) neck or post-whiplash pain, there was no evidence for or against using psychologic interventions. The limited evidence support for psychologic interventions may reflect interventions that are ineffective or poorly conceptualized or implemented [228].

In another study, a physiotherapist-led cognitive-behavioral intervention was effective in modifying cognitive risk factors in patients with chronic neck pain. These patients showed larger increases in functional self-efficacy, greater reductions in pain intensity and pain-related fear, and a greater proportion attained clinically meaningful reductions in pain and disability compared with patients randomized to a progressive neck exercise program. Both were delivered in group format [229].

ALTERNATIVE AND COMPLEMENTARY APPROACHES

Acupuncture

Acupuncture therapy is one of most popular complementary approaches and has become a widely accepted treatment for diverse pain-related conditions [230]. Acupuncture therapy involves insertion of needles into the skin and underlying tissues at specific sites, known as acupoints, to reduce pain or induce anesthesia. Needles may be manipulated manually or through electrical stimulation [2,8].

The persistence of therapeutic effects following a course of acupuncture was evaluated in a meta-analysis of 29 randomized controlled trials of diverse chronic pain. Depending on the control group (no-acupuncture versus sham acupuncture), 50% to 90% of acupuncture benefit was sustained 12 months after treatment and did not seem to decrease importantly in chronic pain [231]. Patients can generally be reassured that treatment effects persist. Questions of acupuncture cost-effectiveness can take these findings into account.

Acupuncture is not without risks. Deaths and serious nonfatal complications of acupuncture are reported, with pneumothorax the most frequent fatal and non-fatal cause. All deaths were avoidable with proper acupuncture technique and sufficient anatomic knowledge. Most reports originated in East Asia, but some came from the United States and Western Europe [212].

Yoga, Qigong, and Tai Chi

Iyengar yoga involves a range of classical yoga poses adapted to patients with neck pain with the use of supportive props. Emphasis is placed on muscle strengthening, stretching, joint mobility, and proper posture [8]. A systematic review found evidence for significant short-term benefits in neck pain intensity, neck pain-related disability, quality of life, and mood, suggesting that yoga might be a good treatment option in chronic nonspecific neck pain [232].

With origins in traditional Chinese medicine, qigong and tai chi are gentle, focused exercises for the mind and body that aim to increase and restore the flow of qi energy and encourage healing [8]. In one study, patients with chronic nonspecific neck pain were randomized to 12 weeks of group tai chi, sessions of conventional neck exercises, or to a wait-list control group. Tai chi and exercise intervention did not differ, and both significantly improved pain on movement, functional disability, and quality of life compared with the wait-list group [233].

Of 89 patients with chronic neck pain randomized to 8 weeks of jyoti meditation or self-care exercise program, meditation training significantly reduced pain and pain-related bothersomeness compared with the exercise group. Researchers suggest that mediation may support patients with chronic pain in pain reduction and pain coping [234].

INTERVENTIONAL AND SURGICAL THERAPIES

Interventional modalities involve injection or ablation approaches in the treatment of spinal pain. They are considered minimally invasive, in contrast to spinal surgery, which is invasive. Cervical epidural, spinal nerve root, facet joint, and sympathetic injections serve diagnostic and therapeutic roles. These procedures can be instrumental in identifying the anatomic pain generator (e.g., nerve root, facet joint) and providing aggressive treatment [51].

Cervical Epidural Injections

For cervical radiculopathy, epidural steroid injections place a corticosteroid and anesthetic (lidocaine or bupivacaine) into the epidural space (interlaminar) or along the nerve root (transforaminal) under radiographic guidance. Epidural steroid injections are thought to reduce pain by interrupting the inflammatory cascade, blocking C-fiber transmission, increasing microcirculation around ischemic areas, and/or modulating pain transmission in the dorsal horn [235,236].

Rare but catastrophic neurovascular complications following cervical transforaminal steroid injections have resulted from particulate matter in corticosteroid preparations. Only the nonparticulate steroid dexamethasone should be used in cervical transforaminal injections. All epidural steroid injections should be performed under radiographic guidance to avoid serious CNS injuries [237].

Epidural steroid injections can induce dose-dependent suppression of the hypothalamic-pituitary-adrenal axis lasting one to three months. Steroids provide no additional benefit to local anesthetic (bupivacaine) alone in pain, function, or disability. Considering local and systemic risks versus negligible benefit, adding a corticosteroid to local anesthetic is not recommended. Aside from cervical radiculopathy, epidural injections are not indicated for other neck pain conditions [2,238,239].

Cervical Facet Joint Interventions

Facet joint interventions identify and treat facet-mediated pain. To identify facet joints as the pain source, inter-articular injections of local anesthetic are placed into facet joints or along their innervating nerve fibers (sensory medial branch). A separate comparative block is performed on a different date to confirm the level of involvement and reduce placebo response. Pain relief from both medial branch nerve blocks confirms facet origin, and radiofrequency ablation is indicated for extended pain control [50,240].

Radiofrequency neurotomy applies a radiofrequency current with heat sufficient to ablate the afferent nerve supply of the facet joint. Denervating these joints is effective in relieving pain and restoring function in these patients. Nerve regeneration occurs 9 to 12 months post-radiofrequency neurotomy, but repeat radiofrequency neurotomy is usually successful and longer-lasting [103,241]. Continuous radiofrequency neurotomy is the preferred method; pulsed radiofrequency neurotomy should not be used, as it may result in incomplete denervation [50]. Precise positioning of the radiofrequency probe with fluoroscopic guidance is required [103].

A systematic review of cervical medial branch thermal radiofrequency neurotomy found most patients were pain-free at six months and more than 33% reported being free of pain at one year [242]. The evidence of effectiveness was rated as high quality. Side effects were reported in 12 studies; most were minor and temporary. Adhering to International Spine Intervention Society guidelines on fluoroscopic-guided cervical medial branch thermal radiofrequency neurotomy was stressed; when performed as described, cervical medial branch thermal radiofrequency neurotomy is effective for resolving chronic facet joint pain and carries only minor risks [242]. Repeat procedures may lead to atrophy of supportive spinal musculature from denervation of sensory and motor nerve inputs. Focused physical therapy may mitigate this risk [103].

Trigger Point Injections

Trigger point injection with a local anesthetic (with or without corticosteroid) is widely used in treating myofascial pain. With trigger point injection, the trigger point in the taut muscle band is palpated, slightly stretched to prevent it from moving, and injected. The needle is redirected in the area to ensure injectate distribution. The fast-in/fast-out method is the most successful in eliciting a local twitch response (which helps confirm diagnosis) and reducing myofascial pain [57]. Sedation is not needed for trigger point injection [103]. The efficacy of this approach is enhanced when immediately followed by a myofascial intervention [57,103].

There are two main approaches to trigger point injection. The first is the stretch and spray technique, in which areas around the trigger point and referred pain are stretched using parallel strokes in the same direction, and a vapocoolant spray is applied. A variant involves spraying first, then stretching, and repeating the spraying. The second is ischemic compression (myotherapy). With this approach, the affected muscle is placed in a fully stretched position and sustained pressure by thumb press is applied on the trigger point, with pressure gradually increased as the pain lessens. Specific soft tissue mobilization or physical modalities may be used with either approach.

Rare trigger point injection complications include infection, pneumothorax, anaphylaxis, neurapraxia, and neuropathy. Corticosteroid injection carries a risk of local myopathy. Severe pain on trigger point injection suggests an intraneural injection, and the needle should be immediately repositioned [103].

Intradiskal Interventions

A variety of different approaches have been used to address diskogenic pain. In the treatment of cervical diskogenic pain, thermal annuloplasty applies heat along the annulus fibrosus to denervate the annulus and/or reconfigure the collagen structure of the disk [243]. Coblation nucleoplasty applies bipolar radiofrequency current to decrease the volume of disk tissue. Intradiskal electrothermal therapy places an electrode or catheter into the annulus of the disk and applies electrothermal energy to denervate the annulus. Percutaneous intradiskal radiofrequency places an electrode or catheter into a disk to apply alternating radiofrequency current.

Diskography is used for identifying the disk as the axial pain source by placing contrast dye into the intervertebral disk under fluoroscopy before CT imaging. The validity of diskography remains controversial, and there is concern that the procedure may accelerate disk degeneration [244].

Disk Decompression

In treating radicular pain secondary to intervertebral disk herniation, percutaneous disk decompression is used to remove a portion of disk material in order to reduce intradiskal pressure and decompress the involved nerve [245].

Vertebroplasty consists of injecting polymethyl methacrylate cement into the vertebral body. Kyphoplasty involves inflating a balloon within the vertebral body before polymethyl methacrylate is injected. The proposed mechanism is the combination of thermal necrosis and chemotoxicity of intraosseous pain receptors [246]. Vertebroplasty did not show benefit over sham or placebo interventions in two large randomized trials [247].

Botulinum Toxin A Injections

Botulinum toxin A reduces muscular contractions and spasm by inhibiting acetylcholine release into the neuromuscular junction. Compared with placebo, trigger point injections of botulinum toxin A into painful muscles significantly improved pain scores, reduced headaches per week, and improved general activity and sleep after 12 weeks in patients with severe shoulder girdle and chronic cervical myofascial pain [248]. Trigger point injections with botulinum toxin A for chronic cervical myofascial pain are now considered supported by the available evidence [64,249]. Side effects with cervical botulinum toxin A injection include transient dysphagia, neck weakness, dry mouth, and vocal hoarseness [103].

Botulinum toxin A may also be effective in relieving primary headache disorders, trigeminal neuralgia, chronic neuropathic pain, and nociceptive and osteoarticular pain. The favorable side effect profile and long-lasting pain relief after a single injection, when effective, makes botulinum toxin A an attractive treatment option. As neck pain therapy, optimal dosing and patient selection need clarification [65].

Cervical Spine Surgery

Cervical spine surgery is indicated when natural history and prognosis with surgical treatment is better than with non-operative treatment. Indications include progressive neurologic deficits, compression of the cervical nerve root and/or spinal cord, or intractable pain. Cervical spine surgical outcomes are most favorable for radicular pain, spinal instability, progressive myelopathy, or upper extremity weakness [51,67,103]. Detailed discussion of cervical spine surgeries is beyond the scope of this course.

CHRONIC REFRACTORY NECK PAIN

In patients with chronic neck pain refractory to standard therapies, established therapeutic options include stimulation of spinal dorsal horn columns to block spinal pain transmission, or intrathecal drug delivery systems to deliver opioids, with or without other medications, to maximize effectiveness and reduce systemic side effects [244].

6. CONCLUSION

A significant proportion of acute neck pain resolves with conservative management. However, chronic neck pain is substantially more difficult to treat and can develop from an acute neck injury or insidiously over time. Long-term changes in the CNS maintain chronic pain. Anatomic, biochemical, and functional abnormalities develop in the brain and spinal cord that amplify pain perception and perpetuate pain.

Pharmacologic and nonpharmacologic therapies have shown disappointing long-term outcomes in chronic pain. Pharmacotherapy focusing on tissue pathology has contributed to inadequate pain reduction. As such, pain mechanism identification and targeting is increasingly stressed, and combining pharmacotherapies that target different pain mechanisms is also emphasized. A substantial volume of new research is changing chronic pain assessment and treatment, and its uptake into clinical practice brings optimism for improving pain and functioning of patients with chronic neck pain in the near future.

Works Cited

1. Murray CJ, Atkinson C, Bhalla K, et al. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591-608.

2. Cohen SP. Epidemiology, diagnosis, and treatment of neck pain. Mayo Clin Proc. 2015;90(2):284-299.

3. Webster LR. Pills, policies, and predicaments: the unintended consequences of a health care system's policy towards opioids. Pain Med. 2013;14(10):1439-1440.

4. Billeci D, Coluzzi F. Tapentadol extended release for the management of chronic neck pain. J Pain Res. 2017;10:495-505.

5. Hoy DG, Protani M, De R, Buchbinder R. The epidemiology of neck pain. Best Pract Res Clin Rheumatol. 2010;24(6):783-792.

6. Hill J, Lewis M, Papageorgiou AC, Dziedzic K, Croft P. Predicting persistent neck pain: a 1-year follow-up of a population cohort. Spine. 2004;29(15):1648-1654.

7. Teichtahl AJ, McColl G. An approach to neck pain for the family physician. Aust Fam Physician. 2013;42(11):774-777.

8. Côté P, Wong JJ, Sutton D, et al. Management of neck pain and associated disorders: a clinical practice guideline from the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J. 2016;25(7):2000-2022.

9. Côté P, van der Velde G, Cassidy JD, et al. The burden and determinants of neck pain in workers: results of the bone and joint decade 2000–2010 task force on neck pain and its associated disorders. Spine. 2008;33(4):S60-74.

10. Nilsen TI, Holtermann A, Mork PJ. Physical exercise, body mass index, and risk of chronic pain in the low back and neck/shoulders: longitudinal date from the Nord-Trondelag health study. Am J Epidemiol. 2011;174(3):267-273.

11. Kääriä S, Laaksonen M, Rahkonen O, Lahelma E, Leino-Arjas P. Risk factors of chronic neck pain: a prospective study among middle-aged employees. Eur J Pain. 2012;16(6):911-920.

12. Vincent HK, Adams MC, Vincent KR, Hurley RW. Musculoskeletal pain, fear avoidance behaviors, and functional decline in obesity: potential interventions to manage pain and maintain function. Reg Anesth Pain Med. 2013;38(6):481-491.

13. Freeman MD, Croft AC, Nicodemus CN, Centeno CJ, Elkins WL. Significant spinal injury resulting from low-level accelerations: a case series of roller coaster injuries. Arch Phys Med Rehabil. 2005;86(11):2126-2130.

14. Binder AI. Cervical spondylosis and neck pain. BMJ. 2007;334(7592):527-531.

15. Ritchie C, Ehrlich C, Sterling M. Living with ongoing whiplash associated disorders: a qualitative study of individual perceptions and experiences. BMC Musculoskelet Disord. 2017;18(1):531.

16. American Academy of Physical Medicine and Rehabilitation. Cervical Whiplash. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-whiplash. Last accessed September 16, 2019.

17. Castro WH, Schilgen M, Meyer S, Weber M, Peuker C, Wortler K. Do "whiplash injuries" occur in low-speed rear impacts?Eur Spine J. 1997;6(6):366-375.

18. Bunketorp OB, Elisson LK. Cervical status after neck sprains in frontal and rear-end car impacts. Injury. 2012;43(4):423-430.

19. Patient Platform Limited. Whiplash and Cervical Spine Injury. Available at https://patient.info/doctor/whiplash-and-cervical-spine-injury. Last accessed September 16, 2019.

20. Teasell RW, McClure JA, Walton D, et al. A research synthesis of therapeutic interventions for whiplash-associated disorder (WAD): part 2—interventions for acute WAD. Pain Res Manag. 2010;15(5):295-304.

21. Freeman MD, Croft AC, Rossignol AM, Centeno CJ, Elkins WL. Chronic neck pain and whiplash: a case-control study of the relationship between acute whiplash injuries and chronic neck pain. Pain Res Manag. 2006;11(2):79-83.

22. American Academy of Physical Medicine and Rehabilitation. Cervical Radiculopathy. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-radiculopathy. Last accessed September 16, 2019.

23. Polston DW. Cervical radiculopathy. Neurol Clin. 2007;25(2):373-385.

24. Carette S, Phil M, Fehlings MG. Cervical radiculopathy. N Engl J Med. 2005;353:392-399.

25. Hush JM, Lin CC, Michaleff ZA, Verhagen A, Refshauge KM. Prognosis of acute idiopathic neck pain is poor: a systematic review and meta-analysis. Arch Phys Med Rehabil. 2011;92(5):824-829.

26. Pengel LH, Herbert RD, Maher CG, Refshauge KM. Acute low back pain: systematic review of its prognosis. BMJ. 2003;327(7410):323.

27. Henschke N, Maher CG, Refshauge KM, et al. Prognosis in patients with recent onset low back pain in Australian primary care: inception cohort study. BMJ. 2008;337:a171.

28. Anstey R, Kongsted A, Kamper S, Hancock MJ. Are people with whiplash-associated neck pain different from people with nonspecific neck pain? J Orthrop Sports Phys Ther. 2016;46(10):894-901.

29. Blanpied PR, Gross AR, Elliott JM, et al. Neck pain: revision 2017. J Orthop Sports Phys Ther. 2017;47(7):A1-A83.

30. Sterling M, Hendrikz J, Kenardy J. Compensation claim lodgement and health outcome developmental trajectories following whiplash injury: a prospective study. Pain. 2010;150(1):22-28.

31. Sarrami P, Armstrong E, Naylor JM, Harris IA. Factors predicting outcome in whiplash injury: a systematic meta-review of prognostic factors. J Orthop Traumatol. 2017;18(1):9-16.

32. McLean SA, Ulirsch JC, Slade GD, et al. Incidence and predictors of neck and widespread pain after motor vehicle collision among US litigants and nonlitigants. Pain. 2014;155(2):309-321.

33. Spearing NM, Connelly LB, Nghiem HS, Pobereskin L. Research on injury compensation and health outcomes: ignoring the problem of reverse causality led to a biased conclusion. J Clin Epidemiol. 2012;65(11):1219-1226.

34. Worsfold C. When range of motion is not enough: towards an evidence-based approach to medico-legal reporting in whiplash injury. J Forensic Leg Med. 2014;25:95-99.

35. Minamide A, Yoshida M, Maio K. The natural clinical course of lumbar spinal stenosis: a longitudinal cohort study over a minimum of 10 years. J Orthop Sci. 2013;18(5):693-698.

36. Micankova Adamova B, Vohanka S, Dusek L, Jarkovsky J, Bednarik J. Prediction of long-term clinical outcome in patients with lumbar spinal stenosis. Eur Spine J. 2012;21(12):2611-2619.

37. Hsu E, Atanelov L, Plunkett AR, Chai N, Chen Y, Cohen SP. Epidural lysis of adhesions for failed back surgery and spinal stenosis: factors associated with treatment outcome. Anesth Analg. 2014;118(1):215-224.

38. Costa Lda C, Maher CG, McAuley JH, et al. Prognosis for patients with chronic low back pain: inception cohort study. BMJ. 2009;339:b3829.

39. Chiarotto A, Fortunato S, Falla D. Predictors of outcome following a short multimodal rehabilitation program for patients with whiplash associated disorders. Eur J Phys Rehabil Med. 2015;51(2):133-141.

40. Li Y, Peng B. Pathogenesis, diagnosis, and treatment of cervical vertigo. Pain Physician. 2015;18(4):E583-E595.

41. Freeman MD. Cervical Sprain and Strain. Available at https://emedicine.medscape.com/article/306176-overview. Last accessed September 16, 2019.

42. Abboud WA, Hassin-Baer S, Joachim M, Givol N, Yahalom R. Localized myofascial pain responds better than referring myofascial pain to botulinum toxin injections. Int J Oral Maxillofac Surg. 2017;46(11):1417-1423.

43. Häggman-Henrikson B, Rezvani M, List T. Prevalence of whiplash trauma in TMD patients: a systematic review. J Oral Rehabil. 2014;41(1):59-68.

44. Häggman-Henrikson B, List T, Westergren HT, Axelsson SH. Temporomandibular disorder pain after whiplash trauma: a systematic review. J Orofac Pain. 2013;27(3):217-226.

45. Landzberg G, El-Rabbany M, Klasser GD, Epstein JB. Temporomandibular disorders and whiplash injury: a narrative review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(2):e37-e46.

46. Windsor RE. Cervical Spine Anatomy. Available at https://emedicine.medscape.com/article/1948797-overview. Last accessed September 16, 2019.

47. Wong JJ, Côté P, Ameis A, et al. Are non-steroidal anti-inflammatory drugs effective for the management of neck pain and associated disorders, whiplash-associated disorders, or non-specific low back pain? A systematic review of systematic reviews by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Eur Spine J. 2016;25(1):34-61.

48. Bokshan SL, DePasse JM, Eltorai AE, Paxton SE, Green A, Daniels AH. An evidence-based approach to differentiating the cause of shoulder and cervical spine pain. Am J Med. 2016;129(9):913-918.

49. Everett C, Bauernfeind M, Essaff D. Cervical and Thoracic Zygapophyseal Joint Arthropathy. Available at https://now.aapmr.org/cervical-and-thoracic-zygapophsial-joint-arthropathy. Last accessed September 16, 2019.

50. Nance PW, Adcock EM. Facet Mediated Pain. Available at https://now.aapmr.org/facet-mediated-pain. Last accessed September 16, 2019.

51. Furman MB. Cervical Disc Disease. Available at https://emedicine.medscape.com/article/305720-overview. Last accessed September 16, 2019.

52. Czervionke LF, Fenton DS. Fat-saturated MR imaging in the detection of inflammatory facet arthropathy (facet synovitis) in the lumbar spine. Pain Med. 2008;9(4):400-406.

53. Mehnert MJ, Freedman MK, Surrey DE. Cervicogenic Headache. Available at https://now.aapmr.org/cervicogenic-headache. Last accessed September 16, 2019.

54. Bogduk N, Govind J. Cervicogenic headache: an assessment of the evidence on clinical diagnosis, invasive tests, and treatment. Lancet Neurol. 2009;8(10):959-968.

55. Sjaastad O, Fredriksen TA, Pfaffenrath V. Cervicogenic headache: diagnostic criteria. The Cervicogenic Headache International Study Group. Headache. 1998;38(6):442-445.

56. Moley PJ. Evaluation of Neck and Back Pain. Available at https://www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/neck-and-back-pain/evaluation-of-neck-and-back-pain. Last accessed September 16, 2019.

57. Cooper G. Cervical Myofascial Pain. Available at https://emedicine.medscape.com/article/305937-overview. Last accessed September 16, 2019.

58. Rhee JM, Yoon T, Riew KD. Cervical radiculopathy. J Am Acad Orthop Surg. 2007;15(8):486-494.

59. American Academy of Physical Medicine and Rehabilitation. Cervical Stenosis. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/musculoskeletal-medicine/cervical-stenosis. Last accessed September 16, 2019.

60. American Academy of Physical Medicine and Rehabilitation. Cervical Spondylotic Myelopathy. Available at https://www.aapmr.org/about-physiatry/conditions-treatments/rehabilitation-of-central-nervous-system-disorders/cervical-spondylotic-myelopathy. Last accessed September 16, 2019.

61. Hirpara KM, Butler JS, Dolan RT, O'Byrne JM, Poynton AR. Nonoperative modalities to treat symptomatic cervical spondylosis. Adv Orthop. 2012;2012:294857.

62. State Insurance Regulatory Authority. Guidelines for the Management of Acute Whiplash Associated Disorders for Health Professionals. Available at https://www.sira.nsw.gov.au/resources-library/motor-accident-resources/publications/for-professionals/whiplash-resources/SIRA08104-Whiplash-Guidelines-1117-396479.pdf. Last accessed September 16, 2019.

63. Kaneoka K, Ono K, Inami S, Hayashi K. Motion analysis of cervical vertebrae during whiplash loading. Spine. 1999;24(8):763-769.

64. Zhou JY, Wang D. An update on botulinum toxin A injections of trigger points for myofascial pain. Curr Pain Headache Rep. 2014;18(1):386.

65. Sandrini G, De Icco R, Tassorelli C, Smania N, Tamburin S. Botulinum neurotoxin type A for the treatment of pain: not just in migraine and trigeminal neuralgia. J Headache Pain. 2017;18(1):38.

66. Barnsley L, Lord SM, Wallis BJ, Bogduk N. The prevalence of chronic cervical zygapophysial joint pain after whiplash. Spine. 1995;20(1):20-25.

67. Al-Shatoury HAH. Cervical Spondylosis. Available at https://emedicine.medscape.com/article/306036-overview. Last accessed September 16, 2019.

68. Rubin M. Cervical Spondylosis and Spondylotic Cervical Myelopathy. Available at https://www.merckmanuals.com/professional/neurologic-disorders/spinal-cord-disorders/cervical-spondylosis-and-spondylotic-cervical-myelopathy. Last accessed September 16, 2019.

69. Baron R, Binder A, Attal N, Casale R, Dickenson AH, Treede RD. Neuropathic low back pain in clinical practice. Eur J Pain. 2016;20(6):861-873.

70. Fornasari D. Pharmacotherapy for neuropathic pain: a review. Pain Ther. 2017;6(1):25-33.

71. Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.

72. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162-173.

73. Binder A, Baron R. The pharmacological therapy of chronic neuropathic pain. Dtsch Arztebl Int. 2016;113(37):616-625.

74. Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol. 2013;74(5):630-636.

75. Bannister K, Dickenson AH. What the brain tells the spinal cord. Pain. 2016;157(10):2148-2151.

76. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. Pain. 2015;156(Suppl 1):S24-S31.

77. Davis CG. Mechanisms of chronic pain from whiplash injury. J Forensic Leg Med. 2013;20(2):74-85.

78. Worley SL. New directions in the treatment of chronic pain. PT. 2016;41(2):107-114.

79. Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain. 2000;85(3):317-332.

80. Linton SJ, Shaw WS. Impact of psychological factors in the experience of pain. Phys Ther. 2011;91(5):700-711.

81. Hooten WM. Chronic pain and mental health disorders: shared neural mechanisms, epidemiology, and treatment. Mayo Clin Proc. 2016;91(7):955-970.

82. Sterling M, Hendrikz J, Kenardy J, et al. Assessment and validation of prognostic models for poor functional recovery 12 months after whiplash injury: a multicenter inception cohort study. Pain. 2012;153(8):1727-1734.

83. Baker DG, Nievergelt CM, C'Connor DT. Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology. 2012;62(2):663-673.

84. Edwards RR, Kronfli T, Haythornthwaite JA, Smith MT, McGuire L, Page GG. Association of catastrophizing with interleukin-6 responses to acute pain. Pain. 2008;140(1):135-144.

85. Sterling M, Elliott JM, Cabot PJ. The course of serum inflammatory biomarkers following whiplash injury and their relationship to sensory and muscle measures: a longitudinal cohort study. PLoS One. 2013;8(10):e77903.

86. Carriere JS, Thibault P, Adams H, Milioto M, Ditto B, Sullivan MJL. Expectancies mediate the relationship between perceived injustice and return to work following whiplash injury: a 1-year prospective study. Eur J Pain. 2017;21(7):1234-1242.

87. Fung K, Alden LE. Once hurt, twice shy: social pain contributes to social anxiety. Emotion. 2017;17(2):231-239.

88. McWilliams LA. Adult attachment insecurity is positively associated with medically unexplained chronic pain. Eur J Pain. 2017;21(8):1378-1383.

89. Cruccu G, Truini A. Neuropathic pain: the scope of the problem. Pain Ther. 2017;6(1):1-3.

90. Kosek E, Cohan M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382-1386.

91. Merskey H, Bogduk N. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd ed. Washington, DC: International Association for the Study of Pain; 1994.

92. Jensen TS, Baron R, Haanpaa M, et al. A new definition of neuropathic pain. Pain. 2011;152(10):2204-2205.

93. Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911-1920.

94. Attal N, Perrot S, Fermanian J, Bouhassira D. The neuropathic components of chronic low back pain: a prospective multicenter study using the DN4 questionnaire. J Pain. 2011;12(10):1080-1087.

95. Förster M, Mahn F, Gockel U, et al. Axial low back pain: one painful area—many perceptions and mechanisms. PLoS One. 2013;8(7):e68273.

96. Spahr N, Hodkinson D, Jolly K, Williams S, Howard M, Thacker M. Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioral evaluation and sensory examination. Musculoskelet Sci Pract. 2017;27:40-48.

97. Fornasari D. Pain mechanisms in patients with chronic pain. Clin Drug Investig. 2012;32(1):45-52.

98. Pergolizzi JV, LeQuang JA, Berger GK, Raffa RB. The basic pharmacology of opioids informs the opioid discourse about misuse and abuse: a review. Pain Ther. 2017;6(1):1-16.

99. Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain. 2017;158(2):261-272.

100. Freynhagen R, Tolle TR, Gockel U, Baron R. The PainDETECT Project: far more than a screening tool on neuropathic pain.Curr Med Res Opin. 2016;32(6):1033-1057.

101. Woolf CJ, American College of Physicians, American Physiological Society. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.

102. Glass LS, Harris JS. Cervical and thoracic spine disorders. In: Occupational Medicine Practice Guidelines: Evaluation and Management of Common Health Problems and Functional Recovery of Workers. 2nd ed. Elk Grove, IL: American College of Occupational and Environmental Medicine; 2003: 1-711.

103. Colorado Department of Labor and Employment. Cervical Spine Injury Medical Treatment Guidelines. Available at https://www.colorado.gov/pacific/sites/default/files/Rule_17_Exhibit_8_prior_to_2011.pdf. Last accessed September 16, 2019.

104. Guzman J, Haldeman S, Carroll LJ, et al. Clinical practice implications of the bone and joint decade 2000–2010 task force on neck pain and its associated disorders: from concepts and findings to recommendations. Spine. 2008;33(4):199-213.

105. Alsaadi SM, McAuley JH, Hush JM, et al. Poor sleep quality is strongly associated with subsequent pain intensity in patients with acute low back pain. Arthritis Rheumatol. 2014;66(5):1388-1394.

106. Artner J, Cakir B, Spiekermann JA, et al. Prevalence of sleep deprivation in patients with chronic neck and back pain: a retrospective evaluation of 1016 patients. J Pain Res. 2013;6:1-6.

107. Intermountain Healthcare. Primary Care Management of Neck Pain. Available at https://intermountainhealthcare.org/ext/Dcmnt?ncid=526837557. Last accessed September 16, 2019.

108. Giamberardino MA, Affaitati G, Fabrizio A, Costantini R. Myofascial pain syndromes and their evaluation. Best Pract Res Clin Rheumatol. 2011;25(2):185-198.

109. National Institute for Health and Care Excellence. Head Injury: Assessment and Early Management. Available at https://www.nice.org.uk/guidance/cg176. Last accessed September 16, 2019.

110. Wee B, Reynolds JH, Bleetman A. Imaging after trauma to the neck. BMJ. 2008;336(7636):154-157.

111. National Institute for Health and Care Excellence. Spinal Injury: Assessment and Initial Management. Available at https://www.nice.org.uk/guidance/ng41. Last accessed September 16, 2019.

112. Hadley MN, Walters BC, Aarabi B, et al. Clinical assessment following acute cervical spinal cord injury. Neurosurgery. 2013;72(2):40-53.

113. Hadley MN, Walters BC. Introduction to the guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery. 2013;72(2):5-16.

114. Schneider JP, Jay GW, Goldstein L, Pinzon EG. CDC issues final guidelines for opioid prescribing: PPM editorial board responds. Practical Pain Management. 2019;16(3):1-6.

115. Chaverneff F. CDC Guidelines on Opioids: Reaction from the American Academy of Pain Management. Available at https://www.psychiatryadvisor.com/home/news/cdc-guidelines-on-opioids-reaction-from-the-american-academy-of-pain-management. Last accessed September 16, 2019.

116. Polomano RC, Jungquist CR. Foreword. Am J Nurs. 2017;117(3 Suppl 1):S3.

117. Vartiainen P, Heiskanen T, Sintonen H, et al. Mortality of Chronic Pain Patients, Presentation: 10th Congress of the European Pain Federation. Available at https://www.efic2017.kenes.com/Documents/EFIC%202017%20Website%20Program.pdf. Last accessed September 16, 2019.

118. Yu H, Côté P, Southerst D, et al. Does structured patient education improve the recovery and clinical outcomes of patients with neck pain? A systematic review from the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. Spine J. 2016;16(12):1524-1540.

119. Moore RA, Eccleston C, Derry S, et al. "Evidence" in chronic pain: establishing best practice in the reporting of systematic reviews. Pain. 2010;150(3):386-389.

120. Moore RA, Straube S, Derry S, McQuay HJ. Chronic low back pain analgesic studies: a methodological minefield. Pain. 2010;149(3):431-434.

121. Tuttle AH, Tohyama S, Ramsay T, et al. Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain. 2015;156(12):2616-2626.

122. Nijs J, Malfliet A, Ickmans K, Baert I, Meeus M. Treatment of central sensitization in patients with "unexplained" chronic pain: an update. Expert Opin Pharmacother. 2014;15(12):1671-1683.

123. Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014;8(2):143-151.

124. Holbech JV, Jung A, Jonsson T, Wanning M, Bredahl C, Bach FW. Combination treatment of neuropathic pain: Danish expert recommendations based on a Delphi process. J Pain Res. 2017;10:1467-1475.

125. Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegard A. Acetaminophen for chronic pain: a systematic review on efficacy. Basic Clin Pharmacol Toxicol. 2016;118(3):184-189.

126. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomized controlled trial. Lancet. 2014;384(9954):1586-1596.

127. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomized placebo controlled trials. BMJ. 2015;350:h1225.

128. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev. 2016;(6):CD012230.

129. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75(3):552-559.

130. Nalamachu S. An overview of pain management: the clinical efficacy and value of treatment. Am J Manag Care. 2013;19(14):s261-s266.

131. Machado GC, Maher CG, Ferreira PH, Day RO, Pinheiro MB, Ferreira ML. Nonsteroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. Ann Rheum Dis. 2017;76(7):1269-1278.

132. Bozimowski G. A review of nonsteroidal anti-inflammatory drugs. AANA J. 2015;83(6):425-433.

133. Fanelli A, Ghisi D, Aprile PL, Lapi F. Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications. Ther Adv Drug Saf. 2017;8(6):173-182.

134. The Medical Letter. Celecoxib safety revisited. Med Lett Drugs Ther. 2016;58:159.

135. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998;105(1B):31S-38S.

136. Slater D, Kunnathil S, McBride J, Koppala R. Pharmacology of nonsteroidal anti-inflammatory drugs and opioids. Semin Intervent Radiol. 2010;27(4):400-411.

137. Walker C, Biasucci LM. Cardiovascular safety of non-steroidal anti-inflammatory drugs revisited. Postgrad Med. 2018;130(1):55-71.

138. Speed C, Wolfarth B. Challenges of pain masking in the management of soft tissue disorders: optimizing patient outcomes with a multi-targeted approach. Curr Med Res Opin. 2014;30(5):953-959.

139. Quan M. Hot topics in primary care: the cardiovascular safety of nonsteroidal anti-inflammatory drugs: putting the evidence in perspective. J Fam Pract. 2017;66(4):S52-S57.

140. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.Am J Gastroenterol. 2014;109(6):811-819.

141. Laporte S, Chapelle C, Caillet P, et al. Vleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res. 2017;118:19-32.

142. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152(4):706-715.

143. Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728-738.

144. Guerrero F, Bolier R, Van Cleave JH, Reid MC. Pharmacological approaches for the management of persistent pain in older adults: what nurses need to know. J Gerontol Nurs. 2016;42(12):49-57.

145. Hunt RH, Choquette D, Craig BN, et al. Approach to managing musculoskeletal pain: acetaminophen, cyclooxygenase-2 inhibitors, or traditional NSAIDs? Can Fam Physician. 2007;53(7):1177-1184.

146. Dick IE, Brochu RM, Purohit Y, Kaczorowski GJ, Martin WJ, Priest BT. Sodium channel blockade may contribute to the analgesic efficacy of antidepressants. J Pain. 2007;8(4):315-324.

147. Benbouzid M, Gaveriaux-Ruff C, Yalcin I, et al. Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia. Biol Psychiatry. 2008;63(6):633-636.

148. Mu A, Weinberg E, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844-852.

149. Alev L, Fujikoshi S, Yoshikawa A, et al. Duloxetine 60 mg for chronic low back pain: post hoc responder analysis of double-blind placebo-controlled trials. J Pain Res. 2017;10:1723-1731.

150. Skljarevski V, Ossanna M, Liu-Seifert H, et al. A double-blind, randomized trial of duloxeting versus placebo in the management of chronic low back pain. Eur J Neurol. 2009;16(9):1041-1018.

151. Enomoto H, Fujikoshi S, Funai J, et al. Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies. J Pain Res. 2017;10:1357-1368.

152. Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD011789.

153. Riediger C, Schuster T, Barlinn K, Maier S, Weitz J, Siepmann T. Adverse effects of antidepressants for chronic pain: a systematic review and mate-analysis. Front Neurol. 2017;8:307.

154. Semel D, Murphy TK, Zlateva G, Cheung R, Emir B. Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies. BMC Fam Pract. 2010;11:85.

155. Saldaña MT, Navarro A, Perez C, Masramon X, Rejas J. Patient-reported-outcomes in subjects with painful lumbar or cervical radiculopathy treated with pregabalin: evidence from medical practice in primary care settings. Rheumatol Int. 2010;30(8):1005-1015.

156. Shanthanna H, Gilron I, Rajarathinam M, et al. Benefits and safety of gabapentinoids in chronic low back pain: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2017;14(8):e1002369.

157. Malik KM, Nelson AM, Avram MJ, Robak SL, Benzon HT. Efficacy of pregabalin in the treatment of radicular pain: results of a controlled trial. Anesth Pain Med. 2015;5(4):e28110.

158. Baron R, Martin-Mola E, Muller M, Dubois C, Falke D, Steigerwald I. Effectiveness and safety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study. Pain Pract. 2015;15(5):455-470.

159. Lo YL, Cheong PWT, George JM, et al. Pregabalin and radicular pain study (PARPS) for cervical spondylosis in a multiracial Asian population. J Clin Med Res. 2014;6(1):66-71.

160. Lyndon A, Audrey S, Wells C, et al. Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction. 2017;112(9):1580-1589.

161. Wallwork RS, Chipidza FE, Stern TA. Obstacles to the prescription and use of opioids. Prim Care Companion CNS Disord. 2016;18(1).

162. Nicol AL, Hurley RW, Benzon HT. Alternatives to opioids in the pharmacologic management of chronic pain syndromes: a narrative review of randomized, controlled, and blinded clinical trials. Anesth Analg. 2017;125(5):1682-1703.

163. Rose ME. Are prescription opioids driving the opioid crisis? Assumptions vs facts. Pain Medicine. 2018;19(4):793-807.

164. Ciccone TG. Responses and Criticisms Over New CDC Opioid Prescribing Guidelines. Available at https://www.practicalpainmanagement.com/resources/news-and-research/responses-criticisms-over-new-cdc-opioid-prescribing-guidelines. Last accessed September 16, 2019.

165. Hedegaard H, Chen LH, Warner M. Drug-poisoning deaths involving heroin: United States, 2000–2013. NCHS Data Brief. 2015;(190):1-8.

166. Centers for Disease Control and Prevention. Provisional Drug Overdose Death Counts. Available at https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Last accessed September 16, 2019.

167. Socías ME, Wood E. Epidemic of deaths from fentanyl overdose. BMJ. 2017;358:j4355.

168. Cheatle MD, Gallagher RM, O'Brien CP. Low risk of producing an opioid use disorder in primary care by prescribing opioids to prescreened patients with chronic noncancer pain. Pain Med. 2018;19(4):764-773.

169. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.

170. Minozzi S, Amato L, Davoli M. Development of dependence following treatment with opioid analgesics for pain relief: a systematic review. Addiction. 2013;108(4):688-698.

171. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17(1):85-98.

172. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med. 2011;171(7):686-691.

173. Warner M, Trinidad JP, Bastian BA, Minino AM, Hedegaard H. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. Natl Vital Stat Rep. 2016;65(10):1-15.

174. Ueberall MA, Mueller-Schwefe GHH. Efficacy and tolerability balance of oxycodone/naloxone and tapentadol in chronic low back pain with a neuropathic component: a blinded end point analysis of randomly selected routine data from 12-week prospective open-label observations. J Pain Res. 2016;9:1001-1020.

175. Jones GP, Tripathi SS. Oxycodone and naloxone combination: a 12-week follow-up in 20 patients shows effective analgesia with opioid-induced bowel dysfunction. Pain Ther. 2016;5(1):107-113.

176. Miyazaki T, Choi IY, Rubas W, et al. NKTR-181: a novel mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther. 2017;363(1):104-113.

177. The Medical Letter. Abuse-deterrent opioids. Med Lett Drugs Ther. 2017;59:95-96.

178. DePriest AZ, Miller K. Oxycodone/naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence. Pain Ther. 2014;3(1):1-15.

179. Lee YH, Brown DL, Chen HY. Current impact and application of abuse-deterrent opioid formulations in clinical practice. Pain Physician. 2017;20(7):E1003-E1023.

180. Serpell M, Tripathi S, Scherzinger S, Rojas-Farreras S, Oksche A, Wilson M. Assessment of transdermal buprenorphine patches for the treatment of chronic pain in a UK observational study. Patient. 2016;9(1):35-46.

181. Parkin-Smith GF, Amorin-Woods LG, Davies SJ, Losco BE, Adams J. Spinal pain: current understanding, trends, and the future of care. J Pain Res. 2015;8:741-752.

182. Plosker GL. Buprenorphine 5, 10, and 20 µg/h transdermal patch: a review of its use in the management of chronic non-malignant pain. Drugs. 2011;71(18):2491-2509.

183. The Medical Letter. Buprenorphine buccal film (Belbuca) for chronic pain. Med Lett Drugs Ther. 2016;58:47-48.

184. Baron R, Eberhart L, Kern KU, et al. Tapentadol prolonged release for chronic pain: a review of clinical trials and 5 years of routine clinical practice data. Pain Pract. 2017;17(5):678-700.

185. Sánchez Del Águila MJ, Schenk M, Kern KU, Drost T, Steigerwald I. Practical considerations for the use of tapentadol prolonged release for the management of severe chronic pain. Clin Ther. 2015;37(1):94-113.

186. Steigerwald I, Muller M, Davies A, et al. Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study. Curr Med Res Opin. 2012;28(6):911-936.

187. Galvez R, Schafer M, Hans G, Falke D, Steigerwald I. Tapentadol prolonged release versus strong opioids for severe, chronic low back pain: results of an open-label, phase 3b study. Adv Ther. 2013;30(3):229-259.

188. Pergolizzi J, Alon E, Baron R, et al. Tapentadol in the management of chronic low back pain: a novel approach to a complex condition? J Pain Res. 2011;4:203-210.

189. Buynak R, Rappaport SA, Rod K, et al. Long-term safety and efficacy of tapentadol extended release following up to 2 years of treatment in patients with moderate to severe, chronic pain: results of an open-label extension trial. Clin Ther. 2015;37(11):2420-2438.

190. Billeci D, Coluzzi F. Tapentadol extended release for the management of chronic neck pain. J Pain Res. 2017;10:495-505.

191. Safeer S, Cleary J, Fudin J. A perspective on tapentadol therapy. Practical Pain Management. 2016;16(7).

192. Butler SF, McNaughton EC, Black RA. Tapentadol abuse potential: a postmarketing evaluation using a sample of individuals evaluated for substance abuse treatment. Pain Med. 2015;16(1):119-130.

193. McNaughton EC, Black RA, Weber SE, Butler SF. Assessing abuse potential of new analgesic medications following market release: an evaluation of internet discussion of tapentadol abuse. Pain Med. 2015;16(1):131-140.

194. Dart RC, Surratt HL, Le Lait MC, et al. Diversion and illicit sale of extended-release tapentadol in the United States. Pain Med. 2016;17(8):1490-1496.

195. Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017;158(9):1813-1824.

196. Markman J, Gudin J, Rauck R, et al. SUMMIT-07: a randomized trial of NKTR-181, a new molecular entity, full mu-opioid receptor agonist for chronic low-back pain. Pain. 2019;160(6):1374-1382.

197. Knezevic NN, Tverdohleb T, Nikibin F, Knezevic I, Candido KD. Management of chronic neuropathic pain with single and compounded topical analgesics. Pain Manag. 2017;7(6):537-558.

198. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016;4:CD007400.

199. Derry S, Wiffen PJ, Kalso EA, et al. Topical analgesics for acute and chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017;5:CD008609.

200. Likar R, Kager I, Obmann M, Pipam W, Sittl R. Treatment of localized neuropathic pain after disk herniation with 5% lidocaine medicated plaster. Int J Gen Med. 2012;5:689-692.

201. Baron R, Treede RD, Birklein F, et al. Treatment of painful radiculopathies with capsaicin 8% cutaneous patch. Curr Med Res Opin. 2017;33(8):1401-1411.

202. Cline AE, Turrentine JE. Compounded topical analgesics for chronic pain. Dermatitis. 2016;27(5):263-271.

203. Somberg JC, Molnar J. Retrospective evaluation on the analgesic activities of 2 compounded topical creams and Voltaren gel in chronic noncancer pain. Am J Ther. 2015;22(5):342-349.

204. Hesselink JMK. Topical analgesics: critical issues related to formulation and concentration. J Pain Relief. 2016;5:274.

205. Kalant H. Marihuana: medicine, addictive substance, or both? A common-sense approach to the place of cannabis in medicine. CMAJ. 2013;4(3):4-9.

206. Berlach DM, Shir Y, Ware MA. Experience with the synthetic cannabinoid nabilone in chronic noncancer pain. Pain Med. 2006;7(1):25-29.

207. Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother. 2006;40(2):251-260.

208. Brosseau L, Wells GA, Tugwell P, et al. Ottawa panel evidence-based clinical practice guidelines on therapeutic massage for neck pain. J Bodyw Mov Ther. 2012;16(3):300-325.

209. Lopez-de-Uralde-Villanueva I, Beltran-Alacreu H, Fernandez-Carnero J, Kindelan-Calvo P, La Touche R. Widespread pressure pain hyperalgesia in chronic nonspecific neck pain with neuropathic features: a descriptive cross-sectional study. Pain Physician. 2016;19(2):77-88.

210. Cugalj AP, McManus K. Manual Treatments. Available at https://now.aapmr.org/manual-treatments. Last accessed September 16, 2019.

211. Gross A, Langevin P, Burnie SJ, et al. Manipulation and mobilization for neck pain contrasted against an inactive control or another active treatment. Cochrane Database Syst Rev. 2015;(9):CD004249.

212. Ernst E. Fatalities after CAM: an overview. Br J Gen Pract. 2011;61(587):404-405.

213. Reed ML. Physical Therapy. Available at https://www.spine.org/KnowYourBack/Treatments/Nonsurgical-Treatments/Physical-Therapy. Last accessed September 16, 2019.

214. Griffin A, Leaver A, Moloney N. General exercise does not improve long-term pain and disability in individuals with whiplash-associated disorders: a systematic review. J Orthop Sports Phys Ther. 2017;47(7):472-480.

215. Southerst D, Nordin MC, Côté P, et al. Is exercise effective for the management of neck pain and associated disorders or whiplash-associated disorders? A systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.Spine J. 2016;16(12):1503-1523.

216. Gross A, Kay TM, Paquin JP, et al. Exercises for mechanical neck disorders. Cochrane Database Syst Rev. 2015;1:CD004250.

217. Celenay ST, Akbayrak T, Kaya DO. A comparison of the effects of stabilization exercises plus manual therapy to those of stabilization exercises alone in patients with nonspecific mechanical neck pain: a randomized clinical trial. J Orthop Sports Phys Ther. 2016;46(2):44-55.

218. Celenay ST, Kaya DO, Akbayrak T. Cervical and scapulothoracic stabilization exercises with and without connective tissue massage for chronic mechanical neck pain: a prospective, randomized controlled trial. Man Ther. 2016;21:144-150.

219. Pillastrini P, de Lima E Sa Resende F, Banchelli F. Effectiveness of global postural re-education in patients with chronic nonspecific neck pain: randomized controlled trial. Phys Ther. 2016;96(9):1408-1416.

220. Lauche R, Schuth M, Schwickert M, et al. Efficacy of the Alexander technique in treating chronic non-specific neck pain: a randomized controlled trial. Clin Rehabil. 2016;30(3):247-258.

221. Daenen L, Varkey E, Kellmann M, Nijs J. Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice. Clin J Pain. 2015;31(2):108-114.

222. Vaegter HB. Exercising non-painful muscles can induce hypoalgesia in individuals with chronic pain. Scand J Pain. 2017;15:60-61.

223. Smith A, Rirchie C, Pedler A, McCamley K, Roberts K, Sterling M. Exercise induced hypoalgesia is elicited by isometric, but not aerobic exercise in individuals with chronic whiplash associated disorders. Scand J Pain. 2017;15:14-21.

224. Eccleston C, Crombez G. Worry and chronic pain: a misdirected problem solving model. Pain. 2007;132(3):233-236.

225. Richmond H, Hall AM, Copsey B, et al. The effectiveness of cognitive behavioral treatment for non-specific low back pain: a systematic review and meta-analysis. PLoS One. 2015;10(8):e0134192.

226. Butler AC, Chapman JE, Forman EM, Beck AT. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin Psychol Rev. 2006;26(1):17-31.

227. Monticone M, Ambrosini E, Cedraschi C, et al. Cognitive-behavioral treatment for subacute and chronic neck pain: a Cochrane review. Spine. 2015;40(19):1495-1504.

228. Shearer HM, Carroll LJ, Wong JJ, et al. Are psychological interventions effective for the management of neck pain and whiplash-associated disorders? A systematic review by the Ontatio Protocol for Traffic Injury Management (OPTIMa) Collaboration. Sping J. 2016;16(12):1566-1581.

229. Thompson DP, Oldham JA, Woby SR. Does adding cognitive-behavioral physiotherapy to exercise improve outcome in patients with chronic neck pain? A randomized controlled trial. Physiotherapy. 2016;102(2):170-177.

230. Moon TW, Posadzki P, Choi TY, et al. Acupuncture for treating whiplash associated disorder: a systematic review of randomized clinical trials. Evidence-Based Complementary and Alternative Medicine. 2014:870271.

231. MacPherson H, Vertosick EA, Foster NE, et al. The persistence of the effects of acupuncture after a course of treatment: a meta-analysis of patients with chronic pain. Pain. 2017;158(5):784-793.

232. Cramer H, Klose P, Brinkhaus B, et al. Effects of yoga on chronic neck pain: a systematic review and meta-analysis. Clin Rehabil. 2017;31(11):1457-1465.

233. Lauche R, Stumpe C, Fehr J, et al. The effects of tai chi and neck exercises in the treatment of chronic nonspecific neck pain: a randomized controlled trial. J Pain. 2016;17(9):1013-1027.

234. Jeitler M, Brunnhuber S, Meier L, et al. Effectiveness of jyoti meditation for patients with chronic neck pain and psychological distress: a randomized controlled clinical trial. J Pain. 2015;16(1):77-86.

235. Stout A. Epidural steroid injections for cervical radiculopathy. Phys Med Rehabil Clin N Am. 2011;22(1):149-159.

236. Stout A. Epidural steroid injections for low back pain. Phys Med Rehabil Clin N Am. 2010;21(4):825-834.

237. Rathmell JP, Benzon HT, Dreyfuss P. Safeguards to prevent neurologic complications after epidural steroid injections: consensus opinions from a multidisciplinary working group and national organizations. Anesthesiology. 2015;122(5):974-984.

238. Gross AR, Peloso PM, Galway E, et al. Physician-delivered injection therapies for mechanical neck disorders: a systematic review update (non-oral, non-intravenous pharmacological interventions for neck pain). Open Orthop J. 2013;7:562-581.

239. Bicket MC, Gupta A, Brown CH, Cohen SP. Epidural injections for spinal pain: a systematic review and meta-analysis evaluating the "control" injections in randomized controlled trials. Anesthesiology. 2013;119(4):907-931.

240. Kennedy DJ, Shokat M, Visco CJ. Sacroiliac joint and lumbar zygapophysial joint corticosteroid injections. Phys Med Rehabil Clin N Am. 2010;21(4):835-842.

241. Mazin DA, Sullivan JP. Lumbar and sacral radiofrequency neurotomy. Phys Med Rehabil Clin N Am. 2010;21(4):843-850.

242. Engel A, Rappard G, King W, Kennedy DJ, SIS. The effectiveness and risks of fluoroscopically-guided cervical medial branch thermal radiofrequency neurotomy: a systematic review with comprehensive analysis of the published data. Pain Med. 2016;17(4):658-669.

243. Helm li S, Simopoulos TT, Stojanovic M, Abdi S, El Terany MA. Effectiveness of thermal annular procedures in treating discogenic low back pain. Pain Physician. 2017;20(6):447-470.

244. Oken J, Foorsov V. Spinal Procedures. Available at https://now.aapmr.org/spinal-procedures. Last accessed September 16, 2019.

245. Singh V, Benyamin RM, Datta S, Falco FJ, Helm S, Manchikanti L. Systematic review of percutaneous lumbar mechanical disc decompression utilizing decompressor. Pain Physician. 2009;12(3):589-599.

246. Lavelle W, Carl A, Lavelle ED, Khaleel MA. Vertebroplasty and kyphoplasty. Anesthesiol Clin. 2007;25(4):913-928.

247. Friedly J, Standaert C, Chan L. Epidemiology of spine care: the back pain dilemma. Phys Med Rehabil Clin N Am. 2010;21(4):659-677.

248. Nicol AL, Wu II, Ferrante FM. Botulinum toxin type A injections for cervical and shoulder girdle myofascial pain using an enriched protocol design. Anesth Analg. 2014;118(6):1326-1335.

249. Canadian Agency for Drugs and Technologies in Health. Botulinum Toxin A for Myofascial Pain Syndrome: A Review of the Clinical Effectiveness. Available at https://www.cadth.ca/botulinum-toxin-myofascial-pain-syndrome-review-clinical-effectiveness-1. Last accessed September 16, 2019.

Evidence-Based Practice Recommendations Citations

1. Bier JD, Scholten-Peeters WGM, Staal JB, et al. Clinical practice guideline for physical therapy assessment and treatment in patients with nonspecific neck pain. Phys Ther. 2018;98(3):162-171. Available at http://stoverpt.com/uploads/3/4/8/2/34823947/neeck_pain_guidelines.pdf. Last accessed September 17, 2019.

2. American College of Radiology. ACR Appropriateness Criteria: Cervical Neck Pain or Cervical Radiculopathy. Available at https://acsearch.acr.org/docs/69426/Narrative. Last accessed September 17, 2019.

3. Blanpied PR, Gross AR, Elliott JM, et al. Neck pain: revision 2017. J Orthop Sports Phys Ther. 2017;47(7):A1-A83. Available at https://www.jospt.org/doi/full/10.2519/jospt.2017.0302. Last accessed September 17, 2019.

90781 • Colorectal Cancer

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Colorectal cancer is the third leading cause of cancer death in the United States, and roughly 50% of those who develop colorectal cancer die from the disease. Improved therapies and widespread primary prevention through screening have resulted in the United States being the only developed country with declining colorectal cancer incidence and mortality. However, there is substantial room for improvement, and primary care provider knowledge of colorectal cancer is essential to continue reducing cases through screening and early detection. Improved clinician knowledge of the most recent research on new diagnostic and therapy modalities is required in order to improve patient outcomes and reduce side effects.

Table of Contents

90781 • Colorectal Cancer

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. COLORECTAL CANCER RISK FACTORS

MODIFIABLE FACTORS

NONMODIFIABLE RISK FACTORS

4. COLORECTAL CANCER SCREENING

COMMON COLORECTAL CANCER SCREENING TESTS

PRACTICE GUIDELINE RECOMMENDATIONS FOR COLORECTAL CANCER SCREENING

5. PATHOPHYSIOLOGY

HISTOLOGIC CHARACTERISTICS OF COLORECTAL CANCER

POLYP-TO-CARCINOMA PATHWAYS OF COLORECTAL CARCINOGENESIS

THE INFLAMMATORY BOWEL DISEASE DYSPLASIA PATHWAY

SIGNALING PATHWAY DEREGULATION

PATIENT AND TUMOR CHARACTERISTICS ASSOCIATED WITH KRAS AND BRAFV600E MUTATIONS IN COLON CANCER

PROGNOSTIC/PREDICTIVE RELATIONSHIP TO GENETIC/MOLECULAR PATHOLOGY

6. DIAGNOSIS AND STAGING OF COLON AND RECTAL CANCER

DIAGNOSTIC WORKUP

STAGING OF COLON AND RECTAL CANCER

7. PROGNOSTIC FACTORS

PROGNOSTIC FACTORS ASSOCIATED WITH STAGING

MOLECULAR AND CLINICAL PROGNOSTIC FACTORS

HISTOLOGIC SUBTYPES AS PREDICTORS OF METASTASES

PROGNOSTIC FACTORS FOLLOWING RESECTION OF LIVER METASTASES

SURVIVAL

8. TREATMENT OF COLON AND RECTAL CANCER

MECHANISM OF CHEMOTHERAPY AND TARGETED THERAPIES

GENERAL APPROACH TO TREATMENT

TREATMENT OF COLON CANCER, STAGES I–III

TREATMENT OF RECTAL CANCER, STAGES 0–III

CHEMOTHERAPY AGENTS AND REGIMENS USED IN ADVANCED COLON AND RECTAL CANCER

RESECTABLE STAGE IV METASTATIC AND RECURRENT COLON AND RECTAL CANCER

STAGE IV COLORECTAL CANCER WITH UNRESECTABLE OR MEDICALLY INOPERABLE METASTASES

TREATMENT OF LIVER METASTASES

TREATMENT-INDUCED TOXICITY AND COMPLICATIONS

POST-TREATMENT FOLLOW-UP

9. CONCLUSION

10. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

90781 • Colorectal Cancer

Education Category. Medical / Surgical

Release Date. 04/01/2019

Expiration Date. 03/31/2022

Course Overview

Colorectal cancer is the third leading cause of cancer death in the United States, and roughly 50% of those who develop colorectal cancer die from the disease. Improved therapies and widespread primary prevention through screening have resulted in the United States being the only developed country with declining colorectal cancer incidence and mortality. However, there is substantial room for improvement, and primary care provider knowledge of colorectal cancer is essential to continue reducing cases through screening and early detection. Improved clinician knowledge of the most recent research on new diagnostic and therapy modalities is required in order to improve patient outcomes and reduce side effects.

Audience

This course is designed for physicians, physician assistants, nurses, and other healthcare providers who may improve the identification and care of patients with colorectal cancer.

Course Objective

The purpose of this course is to provide healthcare professionals with information regarding the screening, diagnosis, and treatment of colorectal cancer in order to improve adherence to established guidelines and, by extension, patient outcomes.

Learning Objectives

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

1. Discuss the epidemiology of colorectal cancer.

2. Identify modifiable colorectal cancer risk factors.

3. Describe nonmodifiable risk factors, including familial and genetic colorectal cancer syndromes.

4. Evaluate the role of colonoscopy in colorectal cancer screening, including strategies to improve effectiveness.

5. Identify available modalities used in colorectal cancer screening.

6. Apply the correct colorectal cancer screening interval for patients with specific findings.

7. Describe the pathways by which colorectal cancer develops.

8. Discuss the histologic features of colorectal cancer precursor lesions.

9. Relate the diagnostic and staging criteria for colon and rectal cancers.

10. Identify molecular and clinical factors used to determine prognosis in patients with colorectal cancer.

11. Select the appropriate treatment approach for early stage (I–III) colon cancer.

12. Choose the most effective treatment option for patients with rectal cancer.

13. Analyze the role of chemotherapy in the treatment of colorectal cancer, including the action of specific agents.

14. Discuss the treatment of metastatic and recurrent colorectal cancers.

15. Describe potential treatment-induced toxicities and adverse effects in patients with colorectal cancer.

16. Outline recommended follow-up for patients treated for colorectal cancer.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

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

Division Planners Disclosure

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Colorectal cancer is the second leading cause of cancer death in the United States, and roughly 50% of those who develop colorectal cancer die from the disease [1,2,3]. Improved therapies and widespread primary prevention through screening have resulted in the United States being the only developed country with declining colorectal cancer incidence and mortality [4]. However, there is substantial room for improvement, and primary care provider knowledge of colorectal cancer is essential to continue reducing cases through screening and early detection. While this course addresses important content domains related to colorectal cancer, a few related areas are not addressed: management of cancer-related pain and cancer of the anus. With 90% of anal cancer cases associated with the human papillomavirus (HPV), this malignancy is considered distinct from rectal cancer [5]. In contrast, rectal cancer bears such similarity to colon cancer that both cancers are frequently combined in epidemiologic and clinical reports.

2. EPIDEMIOLOGY

Worldwide, colorectal cancer is the second most common cancer in women and the third most common in men [6]. The incidence varies geographically as much as 10-fold, with the highest estimated rates per 100,000 population in Australia/New Zealand (41.7 in men, 32.1 in women) and lowest in Southcentral Asia (6.1 in men, 3.8 in women). The highest estimated mortality rates per 100,000 population are in Australia/New Zealand (36.7 for men, 11.1 for women) and the lowest are in Southcentral Asia (4.9 for men, 3.6 for women) [6].

In the United States, colorectal cancer is the second leading cause of cancer death, with 145,600 new diagnoses and 51,020 deaths projected for 2019 [7]. From 2005 to 2014, colorectal cancer incidence rates declined by 3.7% per year in adults 55 years of age and older, but increased by about 1.9% per year in adults younger than 55 years of age. The survival rate has been increasing in both men and women for the past 20 years, and in 2015, an estimated 1.33 million persons were living with colon or rectal cancer in the United States [8,9,10].

Trends in the United States suggest a disproportionally higher incidence and death from colorectal cancer in black/African American patients than in white patients. Asian/Pacific Islander individuals have the lowest incidence and mortality from colorectal cancer [11]. The incidence of colorectal cancer is higher in men than in women, with the annual rate in men ranging from 37 per 100,000 for Asian/Pacific Islanders to 56.4 per 100,000 for African Americans. The annual incidence rate in women ranges from 27.0 per 100,000 in Asians/Pacific Islanders to 41.7 per 100,000 in African Americans. The annual age-adjusted mortality rates for men and women are 17.3 and 12.2 per 100,000, respectively.

The risk of colorectal cancer increases after 44 years of age and rises sharply by 65 to 74 years of age, with colorectal cancer risk doubling in every succeeding decade. Most cases of colorectal cancer are diagnosed after 55 years of age; only 6% are diagnosed in persons younger than 55 years of age [1,9,12]. Although colorectal cancer remains more common in older individuals, the incidence is increasing among younger adults. Between 2004 and 2013, the number of young-onset (before 50 years of age) cases increased 11.4% [13]. In that same period, the number of cases in adults 50 years of age or older decreased 2.5%.

Figures for rectal cancer alone are more difficult to ascertain because epidemiologic studies usually report colon and rectal cancer together as colorectal cancer. However, 2019 projections estimate 41,180 new rectal cancer diagnoses [14].

Approximately 4.2% of Americans will be diagnosed with colorectal cancer at some point in their lifetime. Of those diagnosed, 50% will die from the disease. The overall five-year survival rate is 65% [9]. Cancer stage at diagnosis strongly influences duration of survival. With colon and rectum cancer, the five-year survival is approximately 92% in patients diagnosed with localized cancer, 72% with limited regional extension, and 12% with distant metastases [15]. Despite advances in surgical techniques and adjuvant therapy, the modest survival improvements in patients with advanced neoplasm provide the rationale for implementing primary and secondary preventive approaches to reduce morbidity and mortality from colorectal cancer [1,2,3].

3. COLORECTAL CANCER RISK FACTORS

For most people, the dominant risk factor for colorectal cancer is increasing age. As noted, risk increases dramatically after 50 years of age. Other nonmodifiable factors, such as family history of colorectal cancer, personal history of colorectal cancer or high-risk adenomas, genetic predisposition, and inflammatory bowel disease, also elevate the risk of colorectal cancer [16]. There are also modifiable factors that increase (or decrease) an individual's risk of colorectal cancer, including alcohol use, cigarette smoking, diet, and physical activity.

MODIFIABLE FACTORS

Factors Associated with Increased Risk of Colorectal Cancer

Excessive Alcohol Use

Solid evidence indicates that excessive alcohol use is associated with increased risk of colorectal cancer. Analysis of pooled data found that alcohol consumption greater than 45 g/day was associated with a 41% increase in risk of colorectal cancer [17,18]. The more pronounced association between current alcohol intake and larger adenomas suggests that alcohol may act during the promotional phase of the adenoma-carcinoma sequence [17,18].

Cigarette Smoking

Cigarette smoking is associated with an increased risk of colorectal cancer incidence and mortality, significantly increased risk of small and large adenomas, adenoma recurrence following polypectomy, and a long cancer induction period (35 years minimum). Rates of colorectal cancer mortality are highest in current smokers, intermediate in former smokers, and lowest in nonsmokers. Increased risk was observed after 20 years of smoking in men and women. Estimates from U.S. data attribute 12% of all colorectal cancer deaths to smoking [19,20]. Current smoking (vs. never smoking) increases the risk of developing colorectal cancer by 18% [21,22].

Obesity

Obesity, defined as a body mass index (BMI) ≥30, has been consistently associated with increased incidence and mortality from colorectal cancer, particularly in men. Compared with BMI <22, the risk of colorectal cancer increases with a BMI >28.5 by 60% in men and 30% in women. A BMI ≥30 increases the overall risk of colorectal cancer by 45%. The mechanism of increased vulnerability to colorectal cancer in obese patients is not known but may involve the elevated release and bioavailability of growth factors, insulin, and insulin-like growth factor 1. Heightened risk in obese patients appears to be mitigated by high levels of physical activity [23,24].

BMI is associated with risk of colorectal adenomas and colorectal cancer, but few studies have accrued large enough sample sizes to allow stratified analyses. Evaluation of pooled data from 8,213 participants in seven prospective studies found higher BMI was significantly associated with most histologic characteristics of metachronous adenomas in men, but not in women. The researchers concluded that body mass may affect colorectal carcinogenesis at comparatively early stages, particularly in men [25].

A study of 11,598 survivors of incident primary colorectal cancer examined the effect of obesity on risk of developing a second obesity-associated cancer (e.g., postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium). Compared with colorectal cancer survivors of normal prediagnostic BMI, the risk of developing a second obesity-associated cancer was increased 39% in overweight patients and 47% in obese patients [26]. This compares to the risk for developing a first primary obesity-associated cancer, which was increased by 18% in overweight persons and 61% in obese persons. The authors state that colorectal cancer survivors who were overweight or obese before diagnosis had an increased risk of second obesity-associated cancers relative to normal-weight survivors. Elevated risk of developing a second cancer in colorectal cancer survivors is more likely the result of the increased prevalence of overweight and obesity rather than increased susceptibility [26].

Researchers have associated a common mutation in colorectal cancer with elevated risk of metabolic disease. APC is a tumor-suppressor gene that indirectly regulates cell proliferation by encoding a protein called beta-catenin. APC inactivation by mutation leads to loss of beta-catenin function, which results in unchecked cellular replication and other processes that drive progression to malignant phenotype. Activation of the Wnt signaling pathway, normally mediated by beta-catenin, also occurs. Beta-catenin-Wnt signaling is involved in glucose metabolism and metabolic diseases such as obesity and type 2 diabetes. Using a molecular pathologic epidemiology database, researchers found that risk of beta-catenin-negative colorectal cancer was significantly higher with greater BMI and lower with increased physical activity level. Risk of beta-catenin-positive colorectal cancer was unrelated to BMI or physical activity level [27].

Factors Associated with a Decreased Risk of Colorectal Cancer

Polyp Removal

Removal of adenomatous polyps significantly reduces the risk of colorectal cancer. This will be discussed in detail later in this course.

Physical Activity

A sedentary lifestyle has been associated with an increased risk of colorectal cancer, although this finding has not been consistent [16]. More consistent is the association between regular physical activity and a decreased incidence of colon but not rectal cancer, with an estimated 22% to 27% risk reduction [28,29,30,31].

Diet Low in Fat and Meat

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat [32]. On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories [33]. Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake [34]. Positive associations with meat consumption or fat intake have been found frequently but have not always achieved statistical significance [35]. One hypothesis is that heterocyclic amines formed when meat or fish are cooked at high temperatures may contribute to the increased risk of colorectal cancers associated with meat consumption observed in epidemiologic studies [36,37].

Diet High in Fiber

Despite evidence from case-control studies of a protective effect, results from a large prospective study found no difference in the risk of colorectal cancer between women in the highest quintile group compared with the lowest quintile group with respect to dietary fiber, after adjusting for age, known risk factors, and total energy intake [38]. One study evaluated the associations between dietary fiber, fat, and colorectal cancer risk in the Women's Health Initiative prospective cohort, which included 134,017 women [39]. During a mean 11.7 years follow-up (1993–2010), 1,952 incident cases of colorectal cancer were identified. When fiber and fat intake were assessed individually, the authors found a modest trend toward lower cancer risk with increased intakes of total fiber, suggesting a mild protective effect of higher fiber intake on risk of colorectal cancer, but not when combined with intake of dietary fats [39]. Results of a pooled analysis of 3,209 participants combined from two trials indicate that men may experience more benefit from dietary fiber than women [40].

Diet High in Fruits and Vegetables

Overall, results from more rigorously designed randomized controlled trials have washed out findings of significant correlation in earlier studies that linked higher fruit and vegetable consumption with lower rates of colorectal cancer. Diets low in fat and meat and high in fiber, fruits, and vegetables started as an adult do not appear to reduce the risk of colorectal cancer by a clinically important degree [39,41].

Lifestyle and Diet Modification in Recurrence Risk Reduction

Cohort studies have demonstrated associations between specific diet or exercise regimens with improvements in disease-specific and/or overall survival in patients following treatment for colorectal cancer, but these results have not been replicated by prospective randomized trials. When verification by more rigorous studies is absent, cohort study data should be interpreted with caution, because numerous uncontrolled variables are present that may confound the observational findings [16].

Physical Activity

A meta-analysis of prospective cohort studies evaluating physical activity in patients found a 25% reduction in colorectal cancer-specific mortality associated with any amount of physical activity (vs. no activity) and a 30% reduction associated with a high amount of physical activity (vs. low amount). After colorectal cancer was diagnosed, a 26% reduction in colorectal cancer-specific mortality was associated with participation in any physical activity (vs. no activity), and a 35% reduction was associated with a high amount of physical activity (vs. a low amount) [42].

Diet

Among the observational study findings, patients with stage III colon cancer who had the lowest Western dietary pattern post-treatment showed significantly greater rates of disease-free survival and overall survival versus patients with highest Western dietary pattern [43,44]. Also, patients with highest dietary glycemic load showed significantly greater overall survival rates compared with those with the lowest dietary glycemic load. Another uncontrolled cohort study of patients diagnosed with colorectal cancer found the extent of red and processed meat ingestion was associated with a 29% greater risk of death before colorectal cancer diagnosis, but red meat ingestion after diagnosis had no effect on overall mortality [45].

Plasma Vitamin D Level

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network does not currently recommend routine screening for vitamin D deficiency or supplementation of vitamin D in patients with colorectal cancer.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

There is evidence that vitamin D may be an important cofactor in immune protection against colorectal cancer risk. A large, population-based case-control study, derived from the Nurses' Health Study and Health Professionals Follow-Up Study, found a significant association between plasma vitamin D level and colorectal cancer risk according to the degree of local antitumor immune response. The study consisted of 318 colorectal cancer cases and 624 matched controls. Subjects were divided into three groups based on the median plasma vitamin D level (tertile I 19.0 ng/mL, tertile III 37.4 ng/mL) and analyzed according to the degree of lymphocytic immune reactivity within and surrounding the tumor. Subjects in the highest vitamin D tertile were seen to have a significantly lower risk of developing colorectal cancer subtype showing an intense intratumoral cellular immune reaction. This association was not found for tumor subtypes characterized by a poor intratumoral immune response. The authors discuss possible mechanisms and conclude that these observations support a role for vitamin D in cancer immunoprevention through tumor-host interaction [46].

Chemoprevention

Chemopreventive agents are often prescribed to healthy subjects at risk for colorectal cancer, who will take the agent for the rest of their lives to prevent a potential cancer. In addition to the preventive benefit, this raises the bar very high when defining acceptable safety and toxicity [47].

Practice guidelines and expert opinion have been hesitant to recommend chemoprevention of colorectal cancer. One reason is that very promising earlier findings have often washed out under rigorous evaluation. Epidemiologic and large cohort studies have found a number of agents with significant association to reduced colorectal cancer risk. Not infrequently, these findings were verified by other observational studies, followed by identification in pre-clinical research of plausible mechanisms for a cause-effect relationship. However, results from rigorous investigation using well-designed randomized controlled trials reveal new safety concerns or fail to confirm the significant relationships suggested by data from uncontrolled trials. Thus, guideline authors and experts are reluctant to suggest chemoprevention in the absence of large-scale, long-term, randomized controlled trials [48].

Use of surrogate endpoint markers in many chemoprevention trials may also dissuade recommendation. As the precursor of most colorectal cancers, adenomas have often been used as surrogate endpoints in efficacy evaluation of agents for prevention. Their use as surrogate markers of colorectal cancer in chemoprevention randomized controlled trials permits the reduction of the study observation period from roughly 10 years required for assessing colorectal cancer development to around 2 years. Despite the theoretical and pragmatic basis, preventive efficacy based on this surrogate endpoint may contribute to reluctance in recommending colorectal cancer chemoprevention [47].

The true benefit of chemoprevention is reliant on lifetime colorectal cancer risk in the patient population. Greatest potential benefit may come from use in patients diagnosed by colonoscopy with pre-malignant lesions, with family history of colorectal cancer, or genetically diagnosed and surgically resected for colorectal tumors. Chemoprevention will probably show modest benefit at best when used as prevention in average-risk patients [49,50].

Cyclooxygenase Inhibitors

A 2015 prospective observational study published the first-ever results of cyclooxygenase-2 (COX-2) inhibitor and aspirin use as adjuvant therapy following resection in patients with stage III colon cancer. All patients received standard adjuvant chemotherapy with fluorouracil (5-FU) plus leucovorin with or without irinotecan. In the aspirin arm of 799 patients, 75 (9.4%) used aspirin during and after chemotherapy. In the COX-2 inhibitor arm of 843 patients, 59 (7.5%) used celecoxib or rofecoxib after completing chemotherapy. Both groups had a median follow-up of 6.5 years [51]. Among patients taking aspirin (vs. no aspirin), recurrence-free survival (i.e., time period until tumor recurrence, death with recurrence, or development of a new invasive colon cancer) was increased by 49%, disease-free survival (i.e., time period until tumor recurrence, occurrence of a new colon cancer, or death from any cause) was increased by 32%, and overall survival (i.e., time period until death from any cause) was increased by 37%. Adjusted hazard ratios were censored at five years to minimize misclassification from non-cancer death and showed increases in disease-free survival by 39% and overall survival by 52% (vs. no aspirin). Patients taking a COX-2 inhibitor (vs. no COX-2 inhibitor) found increases in recurrence-free survival by 47%, disease-free survival by 40%, and overall survival by 50%. Censor of survival data at five years found disease-free survival increased by 53% and overall survival by 74% [51].

Although this study was not designed to identify the optimal dose and duration of aspirin or COX-2 inhibitors for protection against colorectal cancer, the data suggest a dose-response relationship in aspirin with increased frequency, while any dose of COX-2 inhibitors was associated with benefit. The statistically significant associations between aspirin and COX-2 inhibitor use and reduced colon cancer recurrence and mortality found in this study will continue to be evaluated [51].

Celecoxib, rofecoxib, and aspirin share a similar mechanism of action in colon (and presumably rectal) cancer involving COX-2 inhibition. COX synthesizes the conversion of arachidonic acid to prostaglandins. Prostaglandins mediate tumor growth by altering stem cell gene expression, hypermethylating genes involved in proliferation and differentiation, promoting angiogenesis and Wnt/CTNNB1 signaling, and inhibiting apoptosis. Thus, suppression of prostaglandin synthesis through COX inhibition interferes with the processes involved in tumor promotion and growth [51,52].

Long-term follow-up data from two large studies initiated in the 1980s found that ≥300 mg aspirin daily taken for five or more years was associated with a 37% overall reduction in colorectal cancer risk. In subjects who remained adherent to the protocol for 5 or more years, those randomized to aspirin were found to have a 40% risk reduction in colorectal cancer mortality after 20 years and absolute risk reduction from 3.1% to 1.9% relative to those receiving placebo. Mortality reduction was primarily from the effect of aspirin on proximal colon cancer. These findings were serendipitous, because the research was designed to examine the protective effects of aspirin against cardiovascular events [53,54].

Prospective studies have demonstrated significant reduction in colorectal cancer among regular aspirin users [55]. In a randomized controlled trial of 861 persons with Lynch syndrome, primary colorectal cancer developed in 4.2% of patients taking daily aspirin 600 mg, compared with 6.9% in those receiving daily placebo (mean follow-up: 55.7 months). Time to first colorectal cancer was increased 37% with aspirin versus placebo; with regression analysis incorporating multiple primary events, aspirin led to a 44% reduction in colorectal cancer incidence. In subjects completing at least two years of intervention, time to first colorectal cancer was increased 59% and incidence of colorectal cancer was reduced 63%. Adverse events did not differ between aspirin and placebo groups during the intervention [56]. Likewise, a randomized controlled trial of patients with a history of adenomas or colorectal cancer found a statistically significant 21% reduction in risk of adenoma recurrence in patients randomized to aspirin (versus placebo) [57].

A prospective cohort study examined the effects of aspirin in participants following a diagnosis of colorectal cancer. Regular use of aspirin after colorectal cancer diagnosis was associated with a 29% increase in colorectal cancer-specific survival and a 21% increase in overall survival [58]. In the long-term Nurses' Health Study and the Health Professional Follow-up Study, 964 patients diagnosed with rectal or colon cancers were evaluated. In those with PI3K-mutant colorectal cancer, regular use of aspirin was associated with a 46% increase in overall survival [59].

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with potentially serious adverse effects that should be considered when determining the risk-benefit ratio [57]. Aspirin use can result in excessive bleeding, gastrointestinal bleeds, and hemorrhagic stroke. The estimated average increased risk of upper gastrointestinal complications was 10 to 30 per 1,000 people over a 10-year period, with men on the higher end and women on the lower end. Risk increases with age [60].

While no studies have assessed adenoma or colorectal cancer risk reduction with use of NSAIDs in the general (and presumably average-risk) population, multiple lines of evidence from epidemiologic studies, observational cohort studies, and randomized controlled trials have consistently affirmed the association between NSAID use and a 30% to 50% reduction in adenomatous polyps, incident disease, and death from colorectal cancer [57,61,62,63]. In one study, patients with familial adenomatous polyposis (FAP) who were followed over four years of treatment with NSAIDs showed a trend in reduction in adenoma incidence and statistically significant reductions in polyp number and size. A 34% reduction in adenoma recurrence risk and a 55% reduction in advanced adenoma incidence were found in patients with a history of adenomas [57].

The NSAIDs sulindac and celecoxib have been shown in randomized controlled trials to induce adenoma regression in patients with FAP, which, together with supportive preclinical data, led the U.S. Food and Drug Administration (FDA) to approve celecoxib for patients with FAP in 1999. However, in 2011, the FDA requested Pfizer voluntarily withdraw the FAP indication for celecoxib, because the company never fulfilled a condition for approval requiring postmarketing evaluation to verify clinical benefit, which Pfizer did [64]. Despite the change of celecoxib use in FAP to off-label status and withdrawal of regulatory approval, several health insurance companies have codified the use of celecoxib in FAP as an authorized indication [65].

The consistently positive findings of NSAID benefit in suppressing the development of adenomas and improving recurrence-free, disease-free, and overall survival in patients with histories of adenomas and colon cancer has posed a dilemma for researchers and clinicians, given the known toxicity profile. NSAID-related morbidity is fairly common and potentially serious and includes upper gastrointestinal bleeding, renal dysfunction, and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke. Among other findings, use of NSAIDS increases the risk of serious cardiovascular events by 50% to 60% [61,66].

Hormones (for Women Only)

The Women's Health Initiative (WHI) randomized participants to estrogen plus progestin or placebo. At a mean follow-up of 11.6 years, women receiving active hormone therapy had a 28% lower risk of colorectal cancers [67]. However, in the hormone therapy group, colorectal cancers that developed were significantly more likely to exhibit lymph node involvement and higher stages (regional and distant) compared with those in the placebo group. Deaths from colorectal cancers in the active group were somewhat higher, but the difference from placebo was not statistically significant [67]. A meta-analysis of cohort studies observed a 14% risk reduction for incidence of colorectal cancer associated with combined hormone therapy [68].

Conjugated equine estrogens do not improve incidence or survival in invasive colorectal cancer [67]. Definite harms have been established in using combined estrogen plus progestin hormone in postmenopausal women. The WHI trial found increased risks of invasive breast cancer, coronary heart disease events, and thromboembolic events [67,69].

Vitamin Supplementation

Vitamin E

A prospective cohort study of 35,215 women found an inverse association between the risk of colon cancer and vitamin E intake [70]. However, a later cohort study found no relationship between every-other-day use of vitamin E 600 IU and colorectal cancer, and a meta-analysis of 14 randomized trials of supplemental antioxidant vitamins involving 170,025 individuals found no evidence for prevention of colorectal adenoma or colorectal cancer [71,72].

Vitamin D

A systematic review of published cohort studies found that daily intake of 1,000 IU of vitamin D and 25-hydroxyvitamin D serum concentration of 33 ng/mL were each associated with a 50% risk reduction of colorectal cancer [73]. A population-based case-control study found an inverse relationship between vitamin D intake and colorectal cancer risk [74]. More recent research is focused on the role of vitamin D as an adjunct treatment after a diagnosis of colorectal cancer. For example, two randomized, placebo-controlled trials of vitamin D in patients with metastatic colorectal cancer are underway to assess patient survival as a primary endpoint. The first study is a phase II trial comparing high-dose vitamin D3 (8,000 IU/day for two weeks followed by 4,000 IU/day) versus a standard dose (400 IU/day). The second study is a phase I–II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80–100 ng/mL versus 2,000 IU/day. The results of these and subsequent phase III trials may provide more definitive answers about the role of vitamin D in the treatment of colorectal cancer [75].

Folate

An observational study of women with a family history of colon cancer found use of folic acid supplements for more than 15 years was associated with a 75% lower risk of colorectal cancer [76]. One hypothesis is that folate is required for DNA synthesis, and suboptimal amounts may cause abnormalities in DNA synthesis or repair [77]. However, a trial that randomized 1,021 men and women with recent colorectal adenoma history to daily folic acid 1 mg or placebo found folic acid was associated with greater risks of developing ≥1 advanced adenoma, ≥3 adenomas, and extra-colonic malignancy compared with placebo [78]. General population studies have not found benefit of folic acid on colorectal cancer risk, but outcomes obtained over relatively short duration may have missed detection of benefit from longer exposure and/or follow-up [57].

Calcium

Researchers have suggested that calcium's action of binding bile acids and fatty acids may lower colon cancer risks through reducing exposure to toxic intraluminal compounds [79]. To study the effects of calcium on adenoma recurrence, persons with a recent history of colorectal adenomas were randomized to daily 3 g calcium carbonate (1,200 mg elemental calcium) or placebo. At four-year follow-up, those receiving calcium (compared with placebo) showed a 19% reduction in developing one or more recurrent adenoma and the average number of adenomas was 24% lower. This reduced risk was likely to extend up to five years following cessation of calcium supplementation [80,81].

Calcium has not shown benefit in patients with FAP. In the general population, there was no significant effect of calcium on risk of colorectal cancer, although studies were of relatively short duration [57]. There is fair evidence that 1,000–1,200 mg/day oral calcium without vitamin D supplementation increases the risk of myocardial infarction. Calcium supplementation with vitamin D at doses less than 1,000 mg/day has few harmful effects [82,83].

NONMODIFIABLE RISK FACTORS

While most cases of colorectal cancer result from complex interactions between inherited susceptibility and environmental or lifestyle factors, certain heritability factors place the individual at very high risk of colorectal cancer, while other patterns of familial colorectal cancer elevate individual risk. Furthermore, specific medical conditions are associated with colorectal cancer risk. The presence or absence of these nonmodifiable risk factors influences the probability that colorectal cancer will develop. Assessment and identification of these risk factors determines the timing, frequency, and modality of colorectal cancer screening and intervention [84,85].

Assessment of Nonmodifiable Colorectal Cancer Risk Factors

Clinicians should perform an individualized assessment of colorectal cancer risk in all adults in order to understand patient risk level for colorectal cancer. Patient risk is assessed by a thorough personal and family history to identify factors associated with increased vulnerability to colorectal cancer. The colorectal cancer risk factors of smoking, obesity, coronary artery disease, diabetes, acromegaly, renal transplantation, and cholecystectomy have no bearing on the timing, frequency, and modality of colorectal cancer screening or intervention (in the absence of adenomatous polyps or colorectal cancer) [86].

Familial Colorectal Cancer Risk Factors

A targeted colorectal cancer family history should include a detailed family history of cancer and polyps, especially in first-degree (e.g., parent, sibling, child) and second-degree (e.g., grandparent, uncle/aunt, half sibling) relatives on both sides of the family [87,88]. Clinicians should ask about polyps in relatives, including [89]:

- Age at first colon exam

- How diagnosed (e.g., colonoscopy, flexible sigmoidoscopy, barium enema)

- How many (during each colonoscopy or lifetime total)

- Type (adenomas, hyperplastic, juvenile, serrated, hamartomas)

- Polyp surgery

- Diagnoses:

- Colorectal cancer (and age at diagnosis)

- Polyposis syndrome

- Extracolonic conditions such as osteoma, sebaceous cysts, desmoid tumors, congenital hypertrophy of retinal pigment epithelium (CHRPE), or extra teeth

- Genetic testing for polyposis or hereditary cancer

- Is relative willing to sign release to share relevant medical records?

In addition to familial factors, patients' personal risk factors should also be assessed (Table 1).

Table 1: PERSONAL COLORECTAL CANCER RISK FACTORS

Age

Older than 50 years

Medical conditions

Inflammatory bowel disease

History of ≥1 adenomatous polyps (size ≥1 cm, with high-grade dysplasia or villous features that confer higher risk)

Cancer history

Personal history of colorectal cancer

Personal history of other Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancers, including endometrial, ovarian, small bowel, gastric, ureteral/renal pelvis, hepatobiliary/pancreas, brain (particularly glioblastoma), or sebaceous adenoma/cancer

Early-onset colorectal cancer or Lynch syndrome-associated cancer

Genetic factors

Confirmed carrier of a mutation that causes a hereditary colorectal cancer syndrome

Lifestyle, behavioral, and dietary risk factors

Diet high in saturated fats and red and processed meats

Diet low in folate

Physical inactivity

Obesity

Smoking

≥2 alcoholic drinks/day

Source: [87,88]

Patients should be assessed for all cancer types. Cancer syndromes include risk for multiple types of malignancy; colorectal cancer is not always a presenting cancer. A three-generation pedigree is the gold standard. The minimum for colorectal cancer should include cancer and polyp history for the patient's generation and two previous generations. The patient's risk status can change over time with updated personal or family history.

Assessment Red Flags

Findings suggestive of heritable colorectal cancer risk are termed "red flags" and direct the healthcare provider to probe further. One red flag is a personal history of colon cancer diagnosed before 60 years of age or endometrial cancer diagnosed before 50 years of age [87,88]. Early age at diagnosis suggests that genetic factors are playing a strong role in the development of disease.

A family history of colon or endometrial cancer diagnosed before 50 years of age is another red flag. Early age at diagnosis of cancer in a closely related family member suggests that genetic factors are playing a role in the development of disease, and these factors can be passed on to other relatives. If multiple family members have been diagnosed with colorectal cancer, or other Lynch/hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers, this strongly suggests genetic factors are increasing individual cancer risks, especially among first-degree relatives [87,88].

One to two polyps in a lifetime is common, but more than 10 in a lifetime is unusual and suggests genetic contribution. Polyposis is associated with increased colorectal cancer risk. In addition, diagnosis of two or more Lynch/HNPCC-associated cancers suggests an inherited mutation, increasing the overall risk for cancer in different organs.

Past diagnosis of Lynch/HNPCC, FAP, or other inherited cancer syndrome in a family member is another risk factor. Many of these conditions are inherited in a dominant pattern, but not everyone who inherits gene mutations for these conditions develops cancer. Therefore, a diagnosis of HNPCC in a grandparent may be relevant to the patient.

Patient Colorectal Cancer Risk Level

Of total colorectal cancer cases, 75% are due to sporadic disease without apparent inherited origin, 10% to 30% are due to familial risk factors, and 5% to 6% are due to heritable genetic mutations. The absolute risk of colorectal cancer by 79 years of age is [90,91]:

- 4% with no family history

- 9% with colorectal cancer in one first-degree relative

- 16% with colorectal cancer in two or more first-degree relatives

- 15% with colorectal cancer in one first-degree relative diagnosed before 45 years of age

- 8% with colorectal adenoma in one first-degree relative

Family history of two or more relatives with colorectal cancer substantially increases the possibility of a genetic syndrome, and relative to older individuals, young patients reporting a positive colorectal cancer family history are more likely to represent a high-risk pedigree [92,93]. Patient risk level is categorized as high, increased (moderate), or average based on the presence of specific factors (Table 2) [94].

Table 2: COLORECTAL CANCER RISK LEVELS

Risk Level

Factors

Average

Lack of specific risk factors

Increased (moderate)

Inflammatory bowel disease

Previous colonoscopy polyp findings:

- Small rectal hyperplastic polyps

- 1–2 small tubular adenomas with low-grade dysplasia

- 3–10 adenomas

- 1 adenoma >1 cm

- Any adenoma with villous features or high-grade dysplasia

- >10 adenomas on a single examination

- Sessile adenomas removed piecemeal

Family history:

- Colorectal cancer or adenomatous polyps in a first-degree relative

- Two second-degree relatives with colorectal cancer

High

Diagnosis of Lynch/HNPCC or FAP

Family or medical history highly suggestive of hereditary colorectal cancer syndrome

Source: [94]

Familial and Genetic Colorectal Cancer Syndromes

Heritable gene mutations that confer elevated risk of colorectal cancer broadly cluster into two groups: stability genes, including mutations in DNA mismatch repair (MMR) genes responsible for Lynch syndrome, and tumor suppressor genes, including APC gene mutations responsible for FAP. Lynch syndrome and FAP account for the vast majority of heritable colorectal cancer cases and 5% to 6% of all colorectal cancer cases [95]. The absolute risks for colorectal cancer in mutation carriers of hereditary colorectal cancer syndromes are [95]:

- Lynch syndrome: 50% to 75% by 75 years of age

- FAP: Nearly 100% by 45 years of age

- Attenuated FAP: 70% lifetime

- MYH-associated polyposis: 80% to 100% by 65 years of age

- Peutz-Jeghers syndrome: 39% by 70 years of age

- Juvenile polyposis syndrome: 10% to 38% by 60 years of age

Individuals with single-gene disorders are at increased risk of developing colorectal cancer, and single-gene disorders related to known syndromes account for 10% to 15% of colorectal cancer cases. The hereditary syndromes and involved genes include Lynch syndrome, FAP, familial colorectal cancer, and rare genetic syndromes [89].

Lynch Syndrome

Lynch syndrome is the most prevalent form of hereditary colorectal cancer, accounting for 3% to 5% of all cases. It primarily involves defects in MMR genes, most commonly MSH2, MLH1, PMS1, PMS2, or MSH6. In affected families, 15% to 60% of family members possess MSH2 or MLH1 mutations [90,95,96].

Lynch syndrome is an autosomal dominant disorder in which families and patients possess a germline mutation in a DNA MMR gene or loss of expression of the MSH2 gene due to deletion in the EPCAM gene. These genes function to maintain DNA fidelity during replication and are inactivated in Lynch syndrome [97].

Genetic Testing. Genetic risk assessment of Lynch syndrome considers family cancer history and patient age if diagnosed with colorectal cancer or malignancies associated with Lynch syndrome. Mutation in MMR genes can be detected using immunohistochemistry techniques (IHCs) or DNA microsatellite instability (MSI) analysis. Several validated computer models predict MMR gene mutation probability (even when MSI or IHC information is absent) and also incorporate family history of endometrial cancer. Mutation detection rates are higher for patients with more striking family histories or informative tumor testing data [98,99].

Clinical Features. Colorectal cancer and extracolonic malignancies are the primary consequences of Lynch syndrome. Colorectal cancer associated with Lynch syndrome is characterized by early age of onset, excess synchronous and metachronous colorectal neoplasm, right-sided dominance (roughly 67%), and extracolonic tumors. The average age of colorectal cancer diagnosis in patients with Lynch syndrome is 44 to 52 years, versus 71 years in sporadic colorectal cancer. MLH1 and MSH2 account for close to 90% of gene mutations, and the lifetime risk of colorectal cancer in MLH1 and MSH2 mutation carriers is 68.7% in men and 52% in women [97].

Risk of extracolonic malignancy is greatest for endometrial cancer. At least one female member in about half of all Lynch syndrome pedigrees is affected, and 50% of women with an MMR gene mutation present with endometrial cancer as first malignancy. Patients with Lynch syndrome have an elevated risk of several other cancers. Risk of extracolonic tumor development by 70 years of age in Lynch syndrome is shown below, with prevalence rate ranges reflecting differences between specific MMR mutations [97]:

- Endometrial (MLH1/MSH2): 14% to 54%

- Ovarian: 4% to 20%

- Urinary tract: 0.2% to 25%

- Stomach: 0.2% to 13%

- Small bowel: 0.4% to 12%

- Brain/central nervous system: 1% to 4%

- Prostate: 9% to 30%

- Breast: 5% to 18%

The adenoma-carcinoma sequence of polyp-to-cancer dwell time is an estimated mean 35 months, considerably more rapid than the 10- to 15-year average in sporadic colorectal cancer. This accelerated rate is likely the result of MMR gene dysfunction that creates frequent DNA mismatches in multiple genes to disrupt their normal function [97]. Until recently, Lynch syndrome was termed hereditary nonpolyposis colorectal cancer, a misnomer because polyps are usually present [100].

Diagnosis. Clinical criteria to identify patients with Lynch syndrome were published in 1990 and termed the Amsterdam criteria. These were revised and expanded with the 1999 Amsterdam II criteria, which included extracolonic cancers. The Amsterdam II defines minimum criteria for a clinical diagnosis of Lynch syndrome as at least three relatives with a Lynch-associated cancer (e.g., colorectal cancer, endometrial, small bowel, ureter, renal pelvis) and [95,101]:

- Two or more successive generations affected

- One or more relatives diagnosed before 50 years of age (at least one first-degree relative)

- FAP excluded

- Tumors verified by pathologic examination

The 2004 updated Bethesda Guidelines were developed to improve the false-negative rates with Amsterdam II and outline criteria to prompt MSI tumor testing to identify Lynch syndrome. Tumors meeting one or more of these criteria require testing for MSI [95,102]:

- Colorectal cancer diagnosed at 50 years of age or younger

- Synchronous or metachronous Lynch-associated cancer present, regardless of age

- Colorectal cancer with Lynch-like histology (e.g., tumor infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) in patients younger than 60 years of age

- Colorectal cancer in a patient with one or more first-degree relatives with Lynch-associated cancer diagnosed at or before 50 years of age

- Colorectal cancer in a patient with two or more first- or second-degree relatives with a Lynch-associated tumor, regardless of age

Although more sensitive than Amsterdam II in identifying families with Lynch syndrome, only 15% to 30% of families not meeting Amsterdam II but meeting Bethesda criteria exhibit MSI gene mutation. Thus, Amsterdam II or Bethesda criteria may be used to help identify patients who should receive genetic testing, but they should not be used as diagnostic instruments [95,103].

Surveillance. The differing surveillance approach in persons with Lynch syndrome relative to average-risk persons is dictated by the biologic behavior of Lynch syndrome [89]. Lynch syndrome develops earlier than sporadic colorectal cancer, which suggests screening should begin earlier in life. Most Lynch syndrome colorectal cancers occur in the right colon, making sigmoidoscopy alone insufficient. Annual colonoscopic surveillance is recommended [95]. The accelerated progression from normal mucosa to adenoma to cancer suggests a shorter colonoscopy screening interval (i.e., every one to two years). The substantially higher lifetime incidence of colorectal cancer suggests that surveillance should use the most sensitive test available.

Patients with Lynch syndrome are at an elevated risk of extracolonic cancers, especially endometrial and ovarian. While routine screening in women with Lynch syndrome is recommended due to substantially increased risk of endometrial cancer, routine transvaginal ultrasound screening for endometrial cancer is insensitive, nonspecific, and without benefit in the general population.

Interventions. A study randomized 861 Lynch mutation carriers to daily aspirin 600 mg or placebo. No difference was found at 24 months, but 56-month follow-up found somewhat lower adenoma rate and colorectal cancer risk in the aspirin group. Further analysis found decreased incidence of all Lynch-associated cancers in the aspirin group [56].

Prophylactic surgery is an alternative to annual colorectal cancer and endometrial cancer screening. The high risk of developing metachronous lesions is the basis for prophylactic surgery [103]. The incidence of metachronous colorectal cancers has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years following segmental colectomy [104]. With the increased incidence of synchronous and metachronous neoplasms, the treatment of choice for a patient with Lynch syndrome with neoplastic lesions in the colon is generally an extended colectomy. The results of a follow-up study help in the selection of surgical approach. In this trial, 382 MMR mutation carriers were followed over time after surgery. During follow-up, metachronous colorectal cancer developed in no patient receiving total or subtotal colectomy compared with 22% of patients receiving segmental colectomy [105,106]. An important factor in the decision to offer prophylactic surgery is the ability of the patient to comply with surveillance examinations.

Consideration of total or subtotal colectomy should be balanced with patient comorbidities, clinical stage of the disease, patient wishes, and surgical expertise. One retrospective study examined data collected on 242 patients with Lynch syndrome who underwent surgery for a first colon cancer between 1984 and 2009 [107]. Patients underwent either standard segmental colectomy or extended colectomy. Primary outcomes measured were risk of subsequent colorectal cancer, overall and disease-specific survival, and operative mortality. One patient died of postoperative septicemia within 30 days after segmental colectomy. Subtotal colectomy decreased the risk of subsequent colorectal cancer compared with segmental resection. The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection, and 4% and 9% after extended surgery, respectively. However, disease-specific and overall survival within 25 years did not differ significantly between the standard and extended surgery groups (82.7% vs. 87.2%) [107]. Although no data have been published showing a survival advantage in extended versus segmental resection for patients with Lynch syndrome, clinicians might consider extensive colectomy to prevent subsequent colorectal cancer in patients with Lynch syndrome [108]. Also, subtotal or total colectomy does not eliminate rectal cancer risk, and the risk of developing rectal cancer following abdominal colectomy is estimated at 12% at 12 years post-surgery [104,109].

Familial Adenomatous Polyposis

FAP accounts for 1% of all colorectal cancers and involves germline mutations in the tumor suppressor gene APC [90,96]. Ashkenazi Jews have elevated risk of colorectal cancer due to APC gene mutation, which occurs in 6% to 7% of this population [110]. Other FAP disorder variants include [90,96]:

- Attenuated FAP: APC gene

- Turcot syndrome: APC gene, MMR genes

- Hyperplastic polyposis syndrome: BRAF and KRAS2 genes

- MYH-associated polyposis: MYH gene

Genetic diagnosis of FAP in pre-symptomatic patients is performed with linkage or direct detection of APC mutations by analyzing lymphocyte DNA in a blood sample. Linkage analysis tests blood samples from multiple persons to identify gene carriers in close and ancillary family members [90,96,103].

Clinical Features. FAP is caused by parental transmission of mutation in the APC gene, a tumor suppressor or gatekeeper gene that controls cell proliferation. The most common FAP phenotype is development of hundreds to thousands of colorectal polyps, with usual onset during adolescence or early adulthood. Malignancy develops in one or more polyps as early as 20 years of age, and colorectal cancer develops in almost 100% of patients by 40 years of age if the colon is not removed for primary prevention. Other characteristics of FAP can include polyps in the upper gastrointestinal tract; extracolonic manifestations, such as congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, and desmoid formation; and other malignancies, such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors (particularly medulloblastoma) [90,96,103]. The lifetime risk of extracolonic tumor development in FAP is [111]:

- Desmoid: 15%

- Duodenum: 5% to 12%

- Thyroid: 2%

- Brain: 2%

- Ampullary: 1.7%

- Pancreas: 1.7%

- Hepatoblastoma: 1.6%

- Gastric: 0.6%

Diagnosis. The clinical diagnostic criteria of FAP is a patient with 10 to 99 adenomatous colon polyps diagnosed by 40 years of age, or more than 100 polyps diagnosed at an older age than expected [89].

Surveillance. The recommended age at which surveillance for polyposis should begin involves a trade-off. On one hand, a patient who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, colorectal cancer can develop in a teenager who carries an APC mutation. On the other hand, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance is usually begun in the early teenage years (10 to 15 years of age). Surveillance has consisted of either flexible sigmoidoscopy or colonoscopy every year. If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Historically, sigmoidoscopy may have been a reasonable approach at the time in identifying early adenomas in a majority of the patients [112]. However, colonoscopy should be considered the tool of choice in light of improved instrumentation for full colonoscopy, safer and deeper sedation (with propofol), recognition that malignancy is more common in the right colon with attenuated FAP, and the growing tendency to defer surgery for a number of years. Individuals testing negative for an otherwise known family mutation do not need FAP-oriented surveillance and can undergo average-risk population screening. In the case of families where no family mutation has been identified in an affected person, clinical surveillance is warranted [90,96,103].

Colon surveillance should not be stopped in carriers of an APC mutation who do not yet manifest polyps, because adenomas occasionally do not appear before the fourth and fifth decades of life. In some circumstances, full colonoscopy is preferred over the more limited sigmoidoscopy. Tolerability of endoscopic procedures among pediatric patients has improved with the use of deeper intravenous sedation [90,96,103].

Interventions. After an APC mutation is identified in a patient or member of their family, evaluation for polyposis by flexible sigmoidoscopy or colonoscopy begins promptly. In those showing polyps, the only effective management to prevent colorectal cancer is eventual colectomy. In patients with early-stage classic FAP, the surgeon, endoscopist, and patient/family may opt to delay surgery for several years in the interest of achieving social milestones. Carefully selected patients with attenuated FAP who show minimal polyp burden and are of advanced age may also defer decision-making about colectomy [113].

The timing of risk-reducing surgery is based on symptomatology and the number, size, and histology of polyps. Surveillance colonoscopy is not useful after numerous polyps have developed, because it is no longer possible to remove and biopsy all of them. It is appropriate for patients at this time to consult with a surgeon experienced with available options, including total colectomy and postcolectomy reconstruction techniques. Rectum-sparing surgery followed by sigmoidoscopic surveillance of the remaining rectum is an option for patients who wish to avoid total colectomy, provided they are able to understand the risks and consequences and to follow through with surveillance recommendations [113].

Familial Colorectal Cancer

Many families exhibit aggregation of colorectal cancer and/or adenomas in the absence of known or identifiable genetic susceptibility factors; this is termed familial colorectal cancer [114]. The presence of colorectal cancer in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Familial colorectal cancer accounts for 20% of all colorectal cancer cases [115].

In the general population, 7% to 10% of individuals have a first-degree relative with colorectal cancer and 14% to 20% have either a first-degree or a second-degree relative with colorectal cancer [90,96,103]. A simple family history of colorectal cancer (i.e., colorectal cancer in one or more close relatives, known hereditary colon cancer absent) confers a two- to six-fold increase in risk, with degree of risk influenced by family member's age of colorectal cancer onset, the number of affected relatives, closeness of the genetic relationship, and whether colorectal cancer has occurred across generations. A positive family history of colorectal cancer appears to increase the risk of colorectal cancer earlier in life such that at 45 years of age, the annual incidence is more than three times higher than in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals. The incidence in individuals 35 to 40 years of age is about the same as that of an average-risk person at 50 years of age. There is no evidence to suggest that colorectal cancer in people with one affected first-degree relative is more likely to be proximal or more rapidly progressive [90,96,103].

Although controlled comparisons have not been performed of genetic screening in persons with modest family history of colorectal cancer, expert opinion is fairly consistent that colorectal cancer screening should begin earlier in life (35 to 40 years of age, when risk magnitude approximates that of an individual 50 years of age). Screening in persons with average risk of colorectal cancer should begin at 50 years of age with repeat screening every 10 years. Increased risk with greater extent of family history warrants room for clinical judgment in favor of even earlier screening based on family history, and shortening the frequency of screening interval to every five years. There is no empirical or logical support to initiate colorectal cancer screening 10 years younger in age than the family member with youngest age of colorectal cancer detection [90,116].

Other Genetic Factors

In addition to FAP and Lynch syndrome, several rare genetic syndromes confer an increased risk for colorectal cancer, including [90,96]:

- Peutz-Jeghers syndrome: STK11/LKB1 gene

- Juvenile polyposis syndrome: SMAD4/DPC4 and BMPR1A genes

- Cowden syndrome: PTEN gene

- Ruvalcaba-Myhre-Smith syndrome: PTEN gene

- Hereditary mixed polyposis syndrome

Factors that Suggest Hereditary Colorectal Cancer Predisposition Syndrome

With the exception of autosomal recessive inheritance with MYH-associated polyposis, all gene mutations known to cause colorectal cancer predisposition are inherited in an autosomal dominant fashion [114]. Thus, family characteristics consistent with autosomal dominant inheritance of cancer predisposition are important to identify because they indicate high risk and possibly the presence of a cancer-predisposing mutation. Factors that suggest a hereditary colorectal cancer predisposition syndrome include [113,114]:

- Vertical transmission (i.e., presence of a genetic predisposition in sequential generations) of cancer predisposition in autosomal dominant conditions

- Inheritance risk of 50% for both men and women because when a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition regardless of sex

- Other clinical characteristics:

- Cancers with an earlier age of onset than sporadic (non-genetic) cases

- Predisposition to other cancers, such as endometrial cancer

- Two or more primary cancers in a single individual, including multiple primary cancers of the same type (e.g., two separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer)

- Presence of non-neoplastic extracolonic features, as with congenital retinal pigment epithelium hypertrophy and desmoids in FAP

- Uncommon tumors such as adrenocortical, sebaceous carcinoma, ampullary, and small bowel

- The presence of multiple polyps, even when family history appears negative

Oligopolyposis (i.e., polyp count greater than expected) can involve as few as 10 to 15 polyps, and the diverse pathology of polyps requires careful attention to polyp count and histology to determine whether genetic testing and/or further clinical evaluation is appropriate [113].

Genetic Testing

As discussed, many genes associated with inherited colorectal cancer syndromes have been identified, and genetic testing is available for diagnosis and is the accepted standard of clinical care. Genetic testing of asymptomatic persons without colorectal cancer symptoms or precursors (adenomatous polyps) is performed to identify increased probability of developing colorectal cancer. Positive findings should lead to diagnostic testing to investigate the presence of occult cancer, followed by treatment if cancer or precursors are found. The intent is to prevent the development of colorectal cancer or increase the likelihood of curative outcome afforded by early detection. Patients can also use this information for decisions related to family planning, work, or retirement [8].

Disease-causing mutations can be found in most families affected by one of the inherited syndromes, and once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near-100% accuracy. Cancer screening and management is then based on the genetic testing results [117].

Clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing. Genetic screening for inherited colorectal cancer syndromes can be hampered by patient or proband resistance, but consent to testing is greatly improved with coordination between the pathologist, referring surgeon or oncologist, and a cancer genetics counselor [98,117].

Clinical criteria used to identify candidates for genetic testing to determine the presence of an inherited susceptibility to colorectal cancer include [90,96,103]:

- A strong family history of colorectal cancer and/or polyps

- Multiple primary cancers in a patient with colorectal cancer

- Family history of other cancers consistent with known inherited syndromes causing a high risk of colorectal cancer

- Early age at colorectal cancer diagnosis

Screening/Surveillance Recommendations for Hereditary Colorectal Cancer

Patients diagnosed with a hereditary colorectal cancer syndrome or with a highly suggestive family or personal history require a more intensive and frequent screening and surveillance protocol than patients with average risk because of their high risk for colorectal and extracolonic malignancies. Table 3 provides a summary of recommendations for patients with specific hereditary colorectal cancer syndromes [113]. For each hereditary colorectal cancer syndrome, the left column lists malignancies associated with the syndrome, and the corresponding right column describes screening or surveillance approach specific to the at-risk malignancy.

Table 3: SCREENING AND SURVEILLANCE RECOMMENDATIONS FOR COLORECTAL CANCER AND EXTRACOLONIC MALIGNANCIES IN PATIENTS WITH HEREDITARY COLORECTAL CANCER SYNDROMES

Cancer Screening

Recommendations

Lynch syndrome/HNPCC

Colorectal

Colonoscopy every one to two years starting at 20 to 25 years of age or two to five years before earliest colorectal cancer in the family if diagnosed before 25 years of age

Gastric and small bowel

EGD with extended duodenoscopy and polypectomy beginning at 30 to 35 years of age and repeated every three to five years

Urothelial

Annual urinalysis beginning at 30 to 35 years of age

CNS

Annual physical exam, no added screening

Pancreatic

No recommendations

Endometrial and ovarian (women)

Endometrial sampling every one to two years

Transvaginal ultrasound is not recommended

May consider prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is completed

Diagnosis of familial adenomatous polyposis (FAP)

Colorectal: APC gene-positive

Flexible sigmoidoscopy or colonoscopy annually starting at 10 to 15 years of age, then every two to three years

Consider colectomy

Colorectal: Suspected FAP, not tested

Flexible sigmoidoscopy or colonoscopy starting 10 to 15 years of age, then annually until 24 years of age, every two years until 34 years of age, and every three years until 44 years of age, then every three to five years thereafter

Personal history of FAP, post-colectomy

Colorectal

Endoscopic evaluation every six months to three years, depending on proctocolectomy or colectomy status

NSAID chemoprevention to reduce polyp burden as pharmacologic adjunct to endoscopy

Duodenal, gastric, or periampular

Baseline upper endoscopy (including side-viewing exam), repeated every one to three years depending on severity of polyposis

Examine stomach at time of duodenoscopy

Thyroid

Annual thyroid exam starting in late teens

CNS cancer

Annual physical exam, no added screening

Intra-abdominal desmoids

Annual abdominal palpation

With a family history of desmoids, consider abdominal CT or MRI every 1 to 3 years post-colectomy and then at 5- and 10-year intervals

Small bowel polyps and cancer

Add small bowel visualization with CT or MRI for desmoids as outlined above, especially with advanced duodenal polyps

Hepatoblastoma (childhood cancer associated with FAP)

Liver palpation, abdominal ultrasound, and measurement of α-fetoprotein every three to six months until 5 years of age

FAP genetic testing in untested children with hepatoblastoma

Pancreatic

No recommendations

Personal history of AFAP

Colorectal: <21 years, small adenoma burden

Colonoscopy and polypectomy every one to two years; surgical evaluation and counseling

Colorectal: 21–40 years, small adenoma burden

Colectomy with IRA or colonoscopy and polypectomy every one to two years; surgical evaluation and counseling

Colorectal: >40 years, small adenoma burden

Colectomy with IRA; surgical evaluation and counseling

Colorectal: Significant polyposis not manageable with polypectomy

Colectomy with IRA (preferred) or proctocolectomy with ileal J-pouch anal anastomosis

Colorectal

If patient had colectomy with IRS, endoscopic exam of rectum every 6 to 12 months depending on polyp burden

Annual physical exam; annual thyroid exam

NSAID chemoprevention

Baseline upper endoscopy every six months to four years starting at 25 to 30 years of age

Family history of AFAP

Colorectal: APC positive or not tested

Colonoscopy starting in late teens, then every two to three years

Colorectal: APC negative

Average risk screening

Diagnosis of MYH-associated polyposis or family history of sibling with MYH polyposis

Colorectal: Sibling with MYH polyposis and patient is asymptomatic

Colonoscopy starting at 25 to 30 years of age and every three to five years if negative (shorter intervals with advancing age)

Colorectal: MYH mutation positive or untested

Upper endoscopy and side viewing duodenoscopy starting at 30 to 35 years of age and every three to five years

Patients with duodenal adenomas are treated as in FAP

Genetic counseling and testing for the familial MYH polyposis mutation(s)

Personal history of MYH-associated polyposis

Colorectal: Personal history of positive MYH mutation, polyposis, and negative APC testing

Genetic counseling and testing for MYH polyposis mutation(s); if negative, refer to increased risk colorectal cancer screening guidelines for multiple adenomatous polyps

Colorectal: History of adenomatous polyposis and negative APC testing (>10 at one time or >15 in 10 years)

If adenomas are manageable with colonoscopy and polypectomy:

- Colonoscopy and polypectomy every one to two years

- Upper endoscopy and side viewing duodenoscopy starting at 30 to 35 years of age every three to five years

- Patients with duodenal adenomas treated as in FAP

If dense or large polyps are not manageable with colonoscopy and polypectomy:

- Subtotal colectomy or proctocolectomy depending on adenoma density and distribution; counseling regarding surgical options

- Upper endoscopy and side viewing duodenoscopy starting at 30 to 35 years of age every three to five years

- Patients with duodenal adenomas treated as in FAP

- Counseling regarding surgical options

AFAP = attenuated familial adenomatous polyposis, CNS = central nervous system, CT = computed tomography, EGD = esophagogastroduodenoscopy, FAP = familial adenomatous polyposis, HNPCC = hereditary nonpolyposis colorectal cancer, IRA = ileorectal anastomosis, MRI = magnetic resonance imaging, NSAID = nonsteroidal anti-inflammatory drug.

Source: [113]

Inflammatory Bowel Disease as Colorectal Cancer Risk Factor

Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn disease, have an elevated risk of developing colorectal cancer. The extent that colorectal cancer risk is elevated depends on the extent and duration of disease, but earlier age at onset is not associated with greater risk. Older estimates of colorectal cancer risk in patients with ulcerative colitis indicated a 2% greater risk after 10 years, 7.7% to 8% after 20 years, and 15.8% to 18% after 30 years of disease [118]. More recent estimates are somewhat lower, the result of more widespread prescribing of chemoprotective aminosalicylates, earlier and more liberal use of colectomy for medically refractory disease, and higher rates of surveillance colonoscopy. Studies involving patients with either ulcerative colitis or Crohn disease have shown comparable risk in both diseases [118].

The extent of inflammatory bowel syndrome is defined as the point in time when histologically identified disease is most extensive. Most colorectal cancers develop in patients with pancolitis, and disease extent is a major risk factor for colorectal cancer in patients with inflammatory bowel syndrome [118]. Patients with left-sided disease (up to the splenic flexure) have an intermediate risk level, while proctitis, ulcerative proctosigmoiditis, and backwash ileitis have little to no influence on risk level. A family history of sporadic colorectal cancer in a first-degree relative doubles the risk of colorectal cancer, and risk increases nine-fold if the first-degree relative was younger than 50 years of age when first diagnosed with colorectal cancer.

The extent of macroscopic and histologic inflammation is associated with increased risk of colorectal cancer, which can develop in areas of endoscopically normal but histologically active colitis. Colorectal cancer can occur in areas where colitis has remitted or where histologic findings show inactive colitis such as crypt distortion in the absence of active inflammation. Lack of endoscopic inflammation at the time of neoplastic detection does not mean absence of inflammation in the area before neoplastic development, and risk of neoplasia is not increased in mucosa that has never been inflamed. Thus, histologic instead of macroscopic evidence of tissue changes from inflammatory bowel syndrome serves as a more accurate determinant for assessing colorectal cancer risk. In the context of surveillance, extent of disease should be defined histologically [118].

Practice recommendations for the diagnosis and treatment of colorectal cancer in inflammatory bowel syndrome patients were developed and published by the American Gastroenterology Association [118]. The guideline format presents a series of clinically relevant questions raised by an expert panel, followed by the response based on analysis of the published research.

Natural History of Dysplasia

Colorectal cancer in inflammatory bowel syndrome develops from dysplasia in most cases, and although imperfect, dysplasia is considered the best marker of colorectal cancer risk in inflammatory bowel syndrome. Predicting the natural history of dysplasia is more difficult, because dysplasia is present in 75% to 90% of patients with inflammatory bowel syndrome and colorectal cancer, but colorectal cancer can develop in the absence of previous history of dysplasia. Not all patients with low-grade dysplasia progress through a phase of detectable high-grade dysplasia before developing cancer. Importantly, interpretation of dysplasia in mucosal biopsy specimens is highly subject to observer subjectivity. Therefore, pathologists with particular expertise in gastrointestinal disorders should review all cases diagnosed as indefinite, low-grade dysplasia, or high-grade dysplasia.

Colectomy

Strong evidence indicates that patients with inflammatory bowel syndrome and a non-adenoma-like dysplasia-associated lesion or mass should receive a colectomy. Patients with inflammatory bowel syndrome and an adenoma-like dysplasia-associated lesion or mass, without evidence of flat dysplasia elsewhere in the colon, can be managed safely by polypectomy and continued surveillance.

There is also strong evidence that colectomy for flat high-grade dysplasia treats undiagnosed synchronous cancer and prevents metachronous cancer. However, current evidence is insufficient to assess the balance of benefits and harms.

Surveillance Colonoscopy

Surveillance colonoscopy is at least moderately effective in reducing colorectal cancer risk in patients with inflammatory bowel syndrome. It is recommended for patients with inflammatory bowel disease who are at an increased risk of colorectal cancer. Patients most likely to benefit are those with extensive ulcerative colitis or Crohn disease.

Surveillance colonoscopy in patients with inflammatory bowel syndrome should include extensive biopsies of all anatomic segments of colorectal mucosa. Definitive data are lacking to inform the optimal surveillance intervals, but one- to three-year intervals are suggested. Careful mucosa inspection and sufficient number of biopsy specimens should be obtained from all anatomic segments of the colon.

Newer Imaging Techniques

Chromoendoscopy is more sensitive in dysplasia detection than white-light endoscopy when used by endoscopists with expertise. However, the natural history of chromoendoscopically detected dysplasia is unknown. In addition, more research is needed to determine the utility of narrow band imaging and confocal endomicroscopy in detecting dysplasia.

Chemopreventive Agents

Ursodeoxycholic acid has demonstrated significant reductions in colorectal cancer in patients with ulcerative colitis who also have primary sclerosing cholangitis. Aminosalicylates are also considered chemopreventive against colorectal cancer. Oral or topical corticosteroids, while demonstrating antineoplastic effects in clinical trials, are associated with too many side effects for routine chemopreventive use. There is insufficient evidence to inform a recommendation for or against the use of azathioprine, 6-mercaptopurine, folic acid, calcium or multivitamin supplements, or statins.

4. COLORECTAL CANCER SCREENING

As noted, the United States is the only developed country experiencing declining incidence rates of colorectal cancer, despite the increase in colorectal cancer risk factors such as obesity [4]. Increasingly widespread colorectal cancer screening is believed to be the root of this seeming paradox.

Colorectal cancer is a serious disease but in many cases is preventable, and its incidence, mortality, and financial burden to society make it an important healthcare concern. The usually long and often asymptomatic premalignant natural history and the clinical features of colorectal cancer make the malignancy amenable to prevention by screening. Colonoscopy has become the dominant screening approach, and optical (versus computed tomography [CT] or "virtual") colonoscopy has the advantage of providing cure via polypectomy during the session [119].

Evidence supports screening for colorectal cancer as part of routine care for all adults 45 to 50 years of age or older, especially those with first-degree relatives with colorectal cancer, for the following reasons [120,161]:

- Increased incidence in those 50 years and older

- Ability to identify high-risk groups

- Slow growth of primary lesions

- Better survival of patients with early-stage lesions

- Relative simplicity and accuracy of screening tests

Consistent evidence supports population-level colorectal cancer screening, which has become the foundation for primary colorectal cancer prevention. In a 2012 study involving 2,602 patients initially referred to colonoscopy for adenomas and nonadenomatous polyps from 1980 to 1990, participants were followed up to 23 years (median: 15.8 years). Their mortality from colorectal cancer was compared against the expected colorectal cancer mortality in the general population. Colonoscopy was associated with a 53% reduction in mortality (12 colorectal cancer death versus 25.4 expected). During the first 10 years post-polypectomy, colorectal cancer mortality was comparable between patients with adenomas or nonadenomatous polyps [121].

In another study, 46,551 healthy subjects between 50 and 80 years of age were randomized to annual or biennial fecal occult blood testing (FOBT) or no screening from 1976 to 1992. Those with positive FOBT screens received colonoscopy and treatment for malignant findings. At 30-year follow-up, 33,020 had died, 732 from colorectal cancer, including 200/11,072 (1.8%) with annual, 237/11,004 (2.2%) with biennial, and 295/10,944 (2.7%) with no screening. At 30 years, colorectal cancer mortality was reduced by 32% with annual screening and 22% with biennial screening compared with no colorectal cancer screening [122].

Researchers compared 3,148 patients with first diagnosis of colorectal cancer with 3,274 non-colorectal cancer subjects to assess associations between colonoscopy for specific indications and the risk of colorectal cancer over a 10-year period. History of screening colonoscopy was associated with a reduction of colorectal cancer risk of 89% and of malignancy in the right colon of 78%. History of diagnostic colonoscopy (and indication) was associated with colorectal cancer risk reduction of 67% with assessment of positive FOBT; 67% with surveillance after a preceding colonoscopy; 72% with assessment of rectal bleeding; and 85% with assessment of abdominal symptoms [123].

Another large study followed 40,826 patients for a median 7.7 years to study the impact of adenoma removal during screening colonoscopy on colorectal cancer mortality. Using data from the Norway national cancer and cause-of-death registries, researchers found that, relative to expected colorectal cancer mortality (the general Norwegian population), adenoma removal during screening was associated with a 25% reduction in mortality rate [124].

Unfortunately, despite sophisticated nationwide efforts to elevate screening awareness, routine screening of eligible individuals remains low [125]. Currently, only about half of Americans 50 years of age or older, for whom screening is recommended, report having had colorectal cancer testing consistent with current guidelines [8].

To better understand potential provider and systemic obstacles to achieving higher utilization rates of colorectal cancer screening, a national survey of colorectal cancer screening education, prioritization, and self-perceived preparedness was performed of 835 primary care residents. In regards to advising patients about colorectal cancer screening, current colorectal cancer screening guidelines, and criteria for familial colorectal cancer syndromes, a significant proportion of respondents felt they lacked sufficient knowledge in these areas. These data suggest opportunities to improve the colorectal cancer screening curriculum in primary care residency programs [126].

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends universal screening for Lynch syndrome in all patients with colorectal cancer, in order to maximize sensitivity for Lynch syndrome detection and simplify care processes.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

As colonoscopy has increasingly become widespread and preferred as a colorectal cancer screening approach, questions concerning its optimal use have emerged. Research has now established that the ability of colonoscopy to detect precancerous polyps and malignant tissue critically depends on examination quality. Patient adherence to pre-colonoscopy preparation is also essential. Practice guidelines addressing these important issues have been published to bridge the knowledge gaps between the latest research, primary care, and specialist providers. Practice guidelines for colorectal cancer screening are updated as new information becomes available. For example, in 2014 the National Comprehensive Cancer Network (NCCN) expanded its recommendation for screening for Lynch syndrome to all patients diagnosed with colorectal cancer [127].

COMMON COLORECTAL CANCER SCREENING TESTS

There are several screening tests available for colorectal cancer, with varying levels of efficacy and clinical utility (Table 4). Of these, the criterion standard is colonoscopy.

Table 4: EFFICACY OF COLORECTAL CANCER SCREENING TESTS

Screening Approach

Magnitude of Effect

Effect on colorectal cancer mortality reduction

Fecal occult blood test (FOBT)

15% to 33%

Sigmoidoscopy

About 25% to 50% for left colon

Digital rectal examination

No effect

Colonoscopy

About 60% to 70% for left colon,
uncertain for
right colon

Effect on surrogate endpoints (e.g., stage at diagnosis, adenoma detection)

Sigmoidoscopy

45% decrease in cancer detection rate vs. colonoscopy

FOBT/sigmoidoscopy

No difference between sigmoidoscopy and FOBT vs. sigmoidoscopy alone

Barium enema

Detects 30% to 50% of
cancers detected by colonoscopy

Colonoscopy

About 3% of patients with no
distal adenomas
have advanced proximal neoplasia, with a 3-fold increase in this rate in patients with distal adenomas

Computed tomography colonography

May have similar sensitivity to colonoscopy

Stool DNA mutation tests

Unknown

Immunochemical FOBT

60% to 90%
of colorectal cancers

Source: [1]

Colonoscopy

With screening colonoscopy, a colonoscope (a thin tube with a light and video camera on one end connected to a display monitor) is inserted through the rectum and guided through the length of the colon for observation on the monitor screen. Instruments to remove polyps and obtain biopsy are inserted through the rectum as needed [8]. Colonoscopy allows direct visualization of the colonic mucosa, lesion biopsy, and polyp removal over the entire colon. The sensitivity and specificity for colorectal cancer and advanced adenomas are very high, and colonoscopy is the confirmatory test used with all other screening approaches when positive findings occur [120].

Potential Complications and Harms

Colonoscopy may fail to detect as many as 6% of colorectal malignancies, and the miss rate for adenomas smaller than 1 cm has ranged from 12% to 17% [128]. This is largely the result of high inter-operator variability in adenoma detection rate. Greater awareness of this hazard from inadequate colonoscopy performance has led to heightened emphasis on training and continuous quality assurance of endoscopists [120]. In addition, colonoscopy is an invasive procedure, requires an invasive bowel cleansing, is time-consuming and uncomfortable, and thus possesses several characteristics that negatively affect patient acceptance as a first-line screening test [120].

Clinically significant complications that require medical intervention are rare and include perforation, bleeding, and cardiovascular events. Complication rates may increase in older patients [129,130]. More than 85% of serious colonoscopy complications occur during polypectomy, and a study of 97,000 colonoscopies found polypectomy associated with a seven-fold increase in risk of bleeding or perforation [131]. Up to 33% of patients report one or more minor, transient gastrointestinal symptoms after colonoscopy, and a review of 12 studies involving 57,742 colorectal cancer screening colonoscopies in average-risk patients found the aggregate rate of serious complications was 2.8 per 1,000 procedures [130,132].

Recommendations to Optimize the Adequacy of Colonoscopy Bowel Preparation

The U.S. Multi-Society Task Force on Colorectal Cancer has published guidelines for adequate pre-colonoscopy bowel cleansing [133]. The goals of this consensus document are to provide expert, evidence-based recommendations for clinicians to optimize colonoscopy preparation quality and patient safety.

The adequacy of pre-procedure bowel cleansing merits special attention because this patient factor is strongly associated with colonoscopy success. Up to 20% to 25% of colonoscopies are attempted in patients with inadequate bowel preparation, leading to diminished adenoma detection rates, longer procedural time, lower cecal intubation rates, and increased electrocautery risk [134,135,136].

Patient risk factors for inadequate preparation include older age, male sex, higher BMI, history of inadequate preparation, history of constipation, and use of opioids or other constipating medications. Patients with complex past medical histories or current conditions, including previous gastric or colonic resection, spinal cord injury, Parkinson disease, and stroke, are generally more difficult to prepare adequately. Diabetes is associated with the highest prevalence of inadequate bowel preparation [133].

A preliminary assessment of preparation quality should be done in the recto-sigmoid colon. If the indication is screening or surveillance and the preparation is clearly inadequate for polyp detection greater than 5 mm, terminate and reschedule the procedure or attempt an additional bowel cleansing approach without canceling the procedure that day. If the colonoscopy is complete to cecum, and the preparation ultimately is deemed inadequate, the examination should be repeated, generally within one year; intervals shorter than one year are indicated when advanced neoplasia is detected and there is inadequate preparation.

Adequacy of bowel preparation should be assessed after completing appropriate efforts to clear residual bowel debris. The rate of adequate preparation should be routinely recorded, and adequate patient preparation should be achieved in at least 85% of all examinations per physician [133].

Split-dose bowel-cleansing regimens are strongly recommended for screening colonoscopy. A same-day regimen is an acceptable alternative to split dosing, especially for patients undergoing afternoon examination. The second dose of split preparation should ideally begin four to six hours before the time of colonoscopy, with completion of the last dose at least two hours before the procedure time. With split-dose bowel-cleansing regimens, diet recommendations include low-residue or full liquids until evening on the day before colonoscopy.

Healthcare professionals should give oral and written patient instructions for all components of colonoscopy preparation and emphasize the importance of compliance. The physician performing the colonoscopy should ensure that appropriate support and process measures are in place for patients to achieve adequate colonoscopy preparation quality.

Selection of a bowel-cleansing regimen should consider patient's medical history, medications, and, when available, previously reported bowel preparation adequacy. A split-dose regimen of a 4-L polyethylene glycol electrolyte lavage solution (PEG-ELS)-based cleansing agent provides high-quality bowel cleansing. In healthy, non-constipated individuals, a 4-L PEG-ELS formulation produces a bowel-cleansing quality comparable to lower-volume PEG formulations.

Over-the-counter bowel cleansing agents have variable efficacy depending on the agent, dose, timing of administration, and whether used alone or in combination. Regardless of the agent, efficacy and tolerability are enhanced with a split-dose regimen. Although over-the-counter purgatives are generally safe, caution is required in certain populations, such as strictly avoiding magnesium-based preparations in patients with chronic kidney disease. Routine use of adjunctive agents for bowel cleansing before colonoscopy is not recommended.

Split-dose bowel cleansing is associated with greater willingness to repeat the regimen compared with day-before regimens. In addition, low-volume bowel cleansing agents are associated with greater compliance in repeat colonoscopies.

There is insufficient evidence to recommend specific bowel preparation regimens for children, adolescents, and elderly persons, but sodium phosphate preparations should be avoided in the elderly, in children younger than 12 years of age, and in those with risk factors for complications from this medication, including known or suspected inflammatory bowel disease.

Additional bowel purgatives should be considered in patients with risk factors for inadequate preparation. Low-volume preparations or extended time delivery for high-volume preparations are recommended for patients after bariatric surgery. Tap water enemas should be used to prepare the colon for sigmoidoscopy in pregnant women. There is insufficient evidence to recommend specific regimens for persons with a history of spinal cord injury; additional bowel purgatives should be considered.

There is also insufficient evidence to recommend a single salvage strategy for patients whose poor preparation precludes effective colonoscopy completion. In these cases, large-volume enemas may be attempted in patients who present for colonoscopy and report brown effluent despite compliance with the colon-cleansing regimen. Through-the-scope enema with completion of colonoscopy the same day may also be considered, especially for patients receiving propofol sedation. Waking the patient from sedation and continuing with further oral ingestion of cathartic with same-day or next-day colonoscopy is associated with better outcomes than delayed colonoscopy.

Quality Indicators for Colonoscopy Performance

In 2015, an estimated 11 million outpatient colonoscopies were performed in the United States [137]. In addition to patient bowel preparation, optimal colonoscopy efficacy depends on operator performance. Inadequate colonoscopy performance demonstrably worsens the ability to prevent colorectal cancer diagnoses and deaths, and practice recommendations have been developed to better ensure quality colonoscopy performance [138].

Cecal Intubation. Cecal intubation involves advancing the colonoscope beyond the ileocecal valve, allowing the colonoscopist to visualize the medial wall of the cecum between the ileocecal valve and the appendiceal orifice. Cecal intubation is essential for optimal colonoscopy because many colorectal neoplasms are harbored in the proximal colon, including the cecum, and low cecal intubation rates are linked to higher rates of interval proximal colon cancer [139]. Colonoscopists should be able to intubate the cecum in ≥95% of screening colonoscopies in healthy adults. Photography of the cecum is mandated to verify intubation [138].

Adenoma Detection. Missed adenoma detection is strongly associated with failure to prevent colorectal cancer during multi-year follow-up colonoscopy trials, and most interval colorectal cancers are due to missed lesions and incomplete polypectomy. The marked variation in colonoscopist adenoma detection rates within practice groups, and the essential role of adenoma detection in colorectal cancer prevention led to adenoma detection as a performance target [140,141,142]. The examination is considered adequate if detection of polyps >5 mm is unimpeded.

In screening colonoscopies of asymptomatic, average-risk persons, a minimum adenoma detection target rate of 25% is recommended. Adenoma detection rates of less than 25% indicate that performance improvement steps should be initiated. Adenoma detection rate is considered the primary measure of mucosal inspection quality and is the single most important quality measure in colonoscopy. Colonoscopists with high adenoma detection rates clear colons better, and patients with precancerous lesions are brought back earlier for their next colonoscopy. Colonoscopists with low adenoma detection rates fail to identify patients with precancerous lesions and multiple lesions, placing these patients at elevated risk for cancer from inappropriately long intervals between colonoscopy [138].

Withdrawal Time. The time taken to remove the colonoscope after cecum intubation (excluding time for biopsies or polypectomy) is termed withdrawal time, and colonic mucosa should be carefully examined for polyps during scope withdrawal. The recommended colonoscope withdrawal time should be at least six minutes in colorectal cancer screening of patients without previous bowel surgery (when no biopsies or polypectomies are performed) [138]. Numerous studies have demonstrated increased detection of significant neoplastic lesions in colonoscopic examinations with an average withdrawal time of at least six minutes, and longer withdrawal time is associated with higher detection rates [143,144,145].

Correction of Poor Performance. The objective for measuring quality indicators is to improve patient care by identifying poor performers for retraining or removal of their privileges to perform colonoscopy if performance cannot be improved. Most quality indicators are amenable to improvement. An exception may be withdrawal time; despite overwhelming evidence that withdrawal time is positively associated with detection, imposing longer withdrawal times on colonoscopists has not been found effective [138].

Computed Tomographic Colonography

CT colonography, also termed virtual colonoscopy, involves examination of computer-generated colorectal images constructed from abdominal CT imaging that simulate a conventional colonoscopy. Pre-procedure laxatives are required to clean the colon, and the colon is insufflated with air just prior to the CT examination, which may be uncomfortable [146]. The risk of complications is extremely low because the test is non-invasive. CT colonography is now in use to perform screening and diagnostic imaging in patients with incomplete colonoscopy or for whom colonoscopy is contraindicated. Randomized trials are in progress comparing CT colonography with immunochemical FOBT (iFOBT) and colonoscopy, and should produce valuable information concerning patient acceptance, diagnostic yield, and costs [120].

Potential Complications and Harms

Specificity for polyp detection is consistently high with CT colonography, but the broadly variable sensitivity requires confirmatory colonoscopy for findings suggestive of colorectal cancer. Another disadvantage with CT colonography is the inability to remove polyps [147]. Extracolonic abnormalities are common in CT colonography, most commonly renal, splenic, uterine, hepatic, ovarian, pancreatic, and gallbladder abnormalities. Very little information is available on the clinical value of their detection or the impact on patient anxiety and psychologic function [148,149].

Flexible Sigmoidoscopy

Flexible sigmoidoscopy involves anal insertion of a sigmoidoscope (similar to the colonoscope) to visualize the rectum and sigmoid colon—the lower one-third of the colon. The scope inflates the large bowel with air to improve imaging, and polyp removal or biopsy may be performed during the procedure [150]. A 60-cm flexible sigmoidoscope was introduced decades ago that is more tolerable to patients than the older, rigid sigmoidoscope. It allows a more complete distal colon examination and can discover up to 65% of polyps, compared with 25% using the older instrument [151].

Potential Complications and Harms

Sigmoidoscopy can be an uncomfortable or painful procedure. Women may have more pain during the procedure, which may discourage them from returning for future screening sigmoidoscopies. Sigmoidoscopy can also cause perforation and bleeding, although this is rare [84].

Double-Contrast Barium Enema

Double-contrast barium enema (DCBE) consists of the patient receiving an enema with a barium solution. Air is then pumped into the colon, and a series of x-rays are performed to image the entire colon and rectum [8].

Potential Complications and Harms

DCBE is no longer recommended as an alternative test for colorectal cancer screening, and its use has declined dramatically. DCBE effectiveness for polyp detection is substantially lower than that of colonoscopy and CT colonography [152].

Fecal Occult Blood Tests

In FOBT testing, the patient collects stool samples that are analyzed for presence of blood. Different FOBT tests involve different collection approaches but commonly require collection of consecutive stool specimens for up to three days. The first FOBTs to enter clinical use were guaiac-based (gFOBT); more recent versions employ immunochemical tests (iFOBT) or markers of DNA mutation (stool DNA tests or sDNA) [1].

Colorectal lesions and adenomatous polyps tend to bleed, and the resulting presence of hemoglobin in stool that is detectable even with intermittent or minimal bleeding formed the basis for gFOBT use in colorectal cancer screening. Hemoglobin is used as a biomarker for detecting blood in stool with guaiac, which identifies peroxidase-like activity that characterizes hemoglobin. However, gFOBT cannot discriminate human from nonhuman or intact from partially digested hemoglobin and is being phased out of clinical use. This results in detection of blood from ingested meat and upper airway and gastrointestinal bleeding as well as colorectal lesions. The low specificity of gFOBT requires confirmatory colonoscopy to validate positive findings [153].

iFOBT was developed to detect intact human hemoglobin originating from colorectal tissue. Unlike gFOBT, it does not detect hemoglobin from nonhuman dietary sources or partly digested human hemoglobin originating from the upper respiratory or gastrointestinal tract [154]. The sDNA variation of FOBT incorporates markers of DNA mutation that detect molecular genetic changes associated with colorectal cancer gene mutations shed into the stool [155].

Potential Complications and Harms

The very low sensitivity of gFOBT leads to a high proportion of false-positive results when confirmed by colonoscopy or DCBE plus flexible sigmoidoscopy, which a systematic review of published clinical trials estimated at greater than 80% [156]. iFOBT is increasingly recognized as superior to gFOBT for sensitivity, accuracy, and compliance, and it shows greater ability in detecting advanced neoplasia. While iFOBT requires colonoscopy confirmation of positive results and cannot detect many precancerous polyps, higher participation in iFOBT than in colonoscopy screening may offset some of its comparative limitations [120].

DNA fecal testing is emerging as a potentially important addition to the stool-based tests for colorectal cancer screening. More research is needed to understand the role of sDNA testing in organized colorectal cancer screening and unaddressed factors, such as screening interval, patient adherence, and costs [120].

PRACTICE GUIDELINE RECOMMENDATIONS FOR COLORECTAL CANCER SCREENING

American College of Physicians

The American College of Physicians (ACP) published their practice recommendations for colorectal cancer screening based on the review and synthesis of guidelines for screening colorectal cancer produced by several other professional organizations. Several tests to detect adenomatous polyps and cancer were evaluated for colorectal cancer screening efficacy, including flexible sigmoidoscopy, colonoscopy, DCBE, and CT colonography. Tests to primarily detect cancer (e.g., gFOBT, iFOBT, and sDNA) were also assessed [84].

Screening Initiation

The ACP recommends that individualized assessment of colorectal cancer risk should be performed in all adults [84].

Average-risk patients should begin at 50 years of age with a stool-based test, flexible sigmoidoscopy, or optical colonoscopy [329]. High-risk patients should begin at 40 years of age or 10 years younger than age of colorectal cancer diagnosis in the youngest family member. Test selection should be based on the benefits and harms of the specific test, the availability of the test, and patient preference. Screening is not recommended in adults older than 75 years of age or with a life expectancy of less than 10 years [84,329].

Note: The National Cancer Institute disputes recommendations of initiating colorectal cancer screening 10 years before the age at diagnosis in the youngest family colorectal cancer case, stating that direct evidence or strong rational argument is absent for aggressive screening methods in patients with modest family history of colorectal cancer [1].

In response to raising rates of colorectal cancer among persons younger than 50 years of age, the U.S. Preventive Services Task Force (USPSTF) lowered its recommended age of initiation of screening to 46 years of age, though the strength of recommendation is slightly lower than for those 50 years of age and older [161].

Clinical Considerations and Best Practice Advice for Colorectal Cancer Screening

African American individuals with average risk should begin colorectal cancer screening at 40 years of age due to the higher colorectal cancer incidence and mortality rates. Healthcare professionals should consider patients' personal, cultural, and religious preferences in screening test selection. For example, annual FOBT is not a good strategy for patients who may be unwilling or unable to follow-up yearly. Some women prefer a female endoscopist, and colonoscopy by a male endoscopist should be recommended only after discussion and patient consent.

Recommended Colorectal Cancer Screening Intervals

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends screening for persons at average risk for colorectal cancer begin at 50 years of age after available options have been discussed. Currently, recommended options include: colonoscopy every 10 years; annual fecal-based tests (every 3 years with DNA-based testing); flexible sigmoidoscopy every 5 to 10 years with or without interval high-sensitivity guaiac-based or immunochemical-based testing at year 3; or CT colonography every 5 years.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

Patients 50 years of age or older with average risk should be screened [84]:

- Every 10 years for colonoscopy

- Every 5 years for flexible sigmoidoscopy, DCBE, and CT colonography

- Annually for gFOBT and iFOBT

- Uncertain for sDNA

These recommended intervals, especially for colonoscopy, are based on the assumption of optimal patient preparation and operator performance in the initial screen, allowing removal and biopsy of all polyps and detection of any precancerous lesion. Inadequate colonoscopy performance and resultant failure to detect adenomas or precancerous lesions places the patient at much greater risk of developing colorectal cancer (referred to as interval colorectal cancer) and renders the recommended interval unsafe [128].

Recommended Colonoscopy Surveillance after Screening and Polypectomy

The timing of follow-up surveillance colonoscopy after initial colorectal cancer screening colonoscopy is an essential component of colorectal cancer prevention (Table 5). Adenomatous polyps are cancer precursor lesions and the most common neoplasm found during colorectal cancer screening. Their detection and removal reduces colorectal cancer incidence and mortality, but patients with adenomas have heightened risk of developing interval cancers (metachronous adenomas or colorectal cancer) within three to five years of colonoscopy and polypectomy [94].

Table 5: RECOMMENDED SURVEILLANCE INTERVALS FOR AVERAGE-RISK PATIENTS

Baseline Colonoscopy Findings

Surveillance Interval

No polyps

10 years

Small (<10 mm) hyperplastic polyps in rectum or sigmoid

10 years

1–2 small tubular adenomas

5 to 10 years

3–10 tubular adenomas

3 years

>10 adenomas

<3 years

One or more tubular adenomas ≥10 mm

3 years

One or more villous adenomas

3 years

Adenoma with high-grade dysplasia

3 years

Serrated lesions

Sessile serrated polyp(s) <10 mm with no dysplasia

5 years

Sessile serrated polyp(s) ≥10 mm OR sessile serrated polyp with dysplasia OR traditional serrated adenoma

3 years

Serrated polyposis syndrome

1 year

Source: [94]

The basis for recommended time intervals between screening and surveillance colonoscopy should involve evidence that examinations prevent interval cancers and cancer-related mortality. Interval diagnosis of advanced adenomas has been used as a surrogate marker for colorectal cancer incidence or mortality. The U.S. Multi-Society Task Force guidelines for post-polypectomy surveillance in average-risk patients emphasize use of baseline colonoscopy findings for risk stratification, which is clustered into two groups [157]:

- Low-risk adenomas: One to two tubular adenomas <10 mm

- High-risk adenomas: Adenoma with villous histology, high-grade dysplasia, size ≥10 mm, or numbering three or more

The British Society of Gastroenterology surveillance guidelines categorizes patients into three risk groups [158]:

- Low risk: One to two adenomas <10 mm

- Intermediate risk: Three or four small adenomas, or one adenoma ≥10 mm

- High risk: More than five small adenomas, or three or more adenomas with at least one ≥10 mm

Surveillance at one year was recommended for high-risk patients over concerns of missed lesions at baseline, differing from U.S. guideline emphasis (and assumption) of high-quality baseline examination [94]. This update of surveillance recommendations was developed to address emerging issues in post-colonoscopy surveillance [94].

Limitations of Colonoscopic Surveillance

As discussed, interval colorectal cancers are advanced adenomas that develop after polypectomy or negative baseline colonoscopy and before the next screening colonoscopy, a 10-year period for most patients. Within five years of negative screening colonoscopy, the risk of developing advanced adenomas is 1.3% to 2.4%. The greatest risk of interval colorectal cancer is within five years of screening colonoscopy, usually resulting from missed lesions progressing to diagnosable colorectal cancer [159].

Studies suggest that most interval colorectal cancers result from missed lesions during baseline colonoscopy. Failure to detect lesions is directly associated with colonoscopy examination quality [142,160]. Residual neoplastic tissue from incomplete adenoma removal can also progress to malignancy. Interval colorectal cancers may differ from prevalent colorectal cancers by more frequent location in the proximal colon and by molecular/genetic properties that confer more aggressive growth. The relationship is established between inadequate colonoscopy quality and risk of interval cancer following colonoscopy.

Halting Surveillance

Colonoscopy risks increase with advancing age and at some point outweigh the benefits of surveillance and screening. The USPSTF recommends clinicians selectively offer screening for colorectal cancer in adults 76 to 85 years of age [161]. Evidence indicates that the net benefit of screening all persons in this age group is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the patient's overall health, prior screening history, and preferences. Patients with high-risk adenoma may especially benefit from continued surveillance.

5. PATHOPHYSIOLOGY

The pathogenesis and pathophysiology of colorectal cancer is very complex, and the following section is intended to be a brief overview.

There are three broad pathways by which colorectal carcinoma develops [162]:

- The chromosome instability (CIN) pathway

- The microsatellite instability (MSI) pathway

- Inflammatory bowel disease dysplasia

Colorectal tumors first develop through one of these pathways, but once established as malignancy, the final common pathway to metastases is identical and involves the spread of cancer cells to locoregional lymph nodes and dissemination to and colonization of the liver (through enteric venous drainage) and the lungs (via hematogenous transport) [163].

Importantly, sporadic (i.e., in the absence of an apparent inherited disorder) colorectal cancers originating from polyps and hereditary colorectal cancers (i.e., originating from inherited colorectal cancer predisposition syndromes) share in common the sequences of gene-level altered function and mutation that transform benign tissue to precancerous lesion to malignancy. The distinction is that germline mutations underlie the well-described inherited colorectal cancer syndromes, while sporadic cancers arise from a stepwise accumulation of somatic genetic mutations [164].

With very few exceptions, the pathogenesis and pathophysiology of colon and rectal cancer is identical. Unless otherwise stated, the following information pertains to both.

HISTOLOGIC CHARACTERISTICS OF COLORECTAL CANCER

Cellular Classification

Data from more than 180,000 patients with colorectal cancer were entered into the Surveillance, Epidemiology, and End Results (SEER) cancer database from 1975–2015 and analyzed [9]. Histologic subtypes in the population were overwhelmingly adenocarcinoma (92.1%); others included neuroendocrine carcinoid (4.4%), unspecified carcinoma (0.8%), and squamous cell (0.7%). The relative five-year survival rates were highest for carcinoid tumors (90.1%) and lowest for neuroendocrine tumors (14.4%) [9].

Colorectal Cancer Precursor Lesions

Colorectal lesions present as a broad spectrum of neoplasms that range from benign growths to invasive tumors. Most colorectal cancers develop slowly over years, typically beginning as non-cancerous polyps on the inner lining of the colon or rectum. Some, but not all, polyps develop into cancer, and the risk of malignant progression is influenced by polyp type. Colorectal lesions are classed into three groups [165]:

- Adenomatous polyps (adenomas): These polyps have the greatest malignant potential and are termed pre-cancerous.

- Non-neoplastic and inflammatory polyps: These are generally not pre-cancerous, but when located in the ascending colon, the risk of pre-cancerous status or development into adenomas and cancer is increased. Includes hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps.

- Dysplasia: A non-polyp pre-cancerous condition of the colorectal lining, usually associated with inflammatory bowel disease.

Adenomas are the primary precursor lesion of colorectal cancer. These polyps are benign tumors that may transform into malignancy. Of all patients with adenomatous polyps discovered by screening colonoscopy, one-year follow-up colonoscopy reveals additional polyps in 29%. The risk of colorectal malignancy in patients with history of polyp removal is 2.7 to 7.7 times that of the general population [166,167].

Epithelial-derived adenoma or adenocarcinoma tumors represent the predominant colorectal cancer tumor type. More than 95% of colorectal cancers are carcinomas, and more than 95% of these adenocarcinomas. Other histologic types account for the remaining 2% to 5%. Adenomas are histologically classified, by order of increasing malignant potential, as tubular, tubulovillous, or villous adenomas. Characteristics of adenomas that highly predict malignant transformation include [1,168]:

- Larger size

- Villous pathology

- Degree of dysplasia within the adenoma

Adenomas may reflect an innate or acquired tendency of the colon to form tumors. Benign and malignant tissue occurs within colorectal tumors, and 20-year follow-up of patients with adenomas has found a 25% malignancy rate in adenoma sites. Removal of adenomatous polyps is linked with reduced colorectal cancer incidence and represents the foundation of primary colorectal cancer prevention [163].

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events. The mucosa in the large intestine regenerates roughly every six days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation and maturation and ultimately lose the ability to replicate. As noted, most colorectal carcinomas are adenocarcinomas. Adenomas precede adenocarcinomas, with roughly 10% of adenomas eventually developing into adenocarcinomas during a process that occurs over up to 8 to 10 years with sporadic colorectal cancers. Dysplastic adenomas progress to colorectal malignancies through a multistep process involving inactivation of a variety of tumor-suppressor and DNA-repair genes and simultaneous activation of oncogenes. Colonic epithelial cells are selectively vulnerable to the transformation from normal colonic epithelium to adenomatous polyp to invasive carcinoma [164,169,170].

POLYP-TO-CARCINOMA PATHWAYS OF COLORECTAL CARCINOGENESIS

The accumulation of acquired genetic and epigenetic changes transform normal epithelial cells into benign neoplasms (adenomas and sessile serrated polyps), invasive adenocarcinomas, and ultimately, metastatic colorectal cancer. The polyp-to-carcinoma progression sequence of colorectal carcinogenesis occurs through at least two well-recognized pathways: the CIN pathway and the MSI pathway [162].

The CIN Pathway

CIN is the most common form of genomic instability and is found in as many as 85% of colorectal cancers. The hallmark of the CIN phenotype is mutations that inactivate the APC gene, found in up to 70% of sporadic colorectal cancers, and that cause FAP. APC mutations occur during the earliest stages of neoplasia and are predominantly associated with the classic tubular adenoma pathway and CIN tumor [162]. Increasing size, increasing number, and worsening histology of polyps reflect the linear process of carcinogenesis along the CIN pathway [171].

As discussed, the APC gene is a tumor-suppressor gene that indirectly regulates the transcription of several critical cell proliferation genes by encoding transcription factor beta-catenin, a protein involved in cell adhesion, signal transduction, transcription regulation, cell cycle control, apoptosis, and maintenance of chromosomal segregation fidelity. APC inactivation produces loss of beta-catenin function, allowing unchecked cellular replication at the crypt surface, and activation of oncogenes c-myc and cyclin D1 that drive the progression to malignant phenotype [103,164,172].

The MSI Pathway

MSI tumors are characterized by MMR system defects. DNA MMR genes correct nucleotide base miss-pairs and small insertions or deletions that occur during DNA replication. The MMR defect promotes adenoma development and accelerates the progression from adenoma to carcinoma. These colorectal malignancies are distinguished at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, termed DNA microsatellites. Microsatellite unstable tumors are generally considered mutually exclusive of CIN tumors [162,173].

The mechanisms that underlie MSI involve MMR gene inactivation by aberrant methylation or somatic mutation. Roughly 20% to 30% of colorectal cancers display a characteristic pattern of gene hypermethylation, termed the CpG island methylator phenotype (CIMP). Some CIMPs display MSI, and these account for roughly 90% of Lynch syndrome cases and 15% to 20% of sporadic colon and rectal cancers [106,164,174].

THE INFLAMMATORY BOWEL DISEASE DYSPLASIA PATHWAY

A separate carcinogenic pathway is described for inflammatory bowel syndrome that does not involve an adenoma-carcinoma sequence. Chronic inflammation, such as ulcerative colitis, can result in genetic alterations that promote dysplasia and carcinoma formation [171]. The elevated risk of colorectal cancer in ulcerative colitis and Crohn disease is mediated through an intermediate step of intraepithelial dysplasia [164].

Chronic colorectal inflammatory disease is a risk factor for colorectal cancer, and such tumors may result from longstanding, continuous damage, inflammation, and repair (LOCDIR). LOCDIR changes cellular features of the epithelium, causing loss of cellular differentiation (loss of cellular mucus) and development of cellular atypia and mutations at multiple sites. DNA damage, with MSI and genomic instability, may arise within one year [175]. LOCDIR may play a role in the commonly observed inactivation of Kruppel-like factor 6 (KLF-6), a tumor-suppressor gene [176].

As cellular atypia increase, there may be progression from low- to high-grade dysplasia. After 10 or more years, carcinomas may develop without an exophytic feature. After 10 years of ulcerative colitis, the risk of colorectal cancer is 20 to 30 times that for a matched population. As an effective preventive measure, most patients with ulcerative colitis undergo total colectomy with ileostomy. A more controversial but also effective procedure is proctocolectomy with distal rectal mucosectomy. Although Crohn disease had long been thought to lack association with the development of colorectal cancers, it is now known that there is an 8% risk of developing colorectal cancer over a 20-year period. The problem of chronic inflammation with healing and epithelial changes at the cellular and molecular levels may be involved, as most of these cancers occur in strictured areas of the large bowel [171,175].

SIGNALING PATHWAY DEREGULATION

Important contributions to the pathogenesis of colorectal cancer come from accumulated mutations in specific genes and resultant deregulation in signaling pathways that mediate cell proliferation, differentiation, apoptosis, immortalization, angiogenesis, and invasion [162].

Transforming Growth Factor-Beta Pathway

Transforming growth factor-beta signaling is a tumor-suppressor pathway in the colon. Deregulation in this pathway occurs by inactivating mutations in receptor genes, post-receptor signaling pathway genes, and transforming growth factor-beta superfamily members [162,173].

Functionally significant mutations in TGFBR2, a signaling receptor gene, are detected in up to 30% of all colorectal cancers. They are most common in MSI tumors but also occur in 15% of CIN tumors and are associated with transformation of late adenomas to malignancy.

Mediators of Epidermal Growth Factor Receptor Signaling

Mutations of PI3K pathway genes occur in up to 40% of colorectal cancer cases and may promote the transition from adenoma to carcinoma. PTEN, a tumor suppressor gene that negatively regulates PI3K signaling, is mutated in up to 30% of MSI tumors and 9% of CIN tumors. The PI3K pathway is modulated by epidermal growth factor receptor (EGFR) signaling in part via KRAS activation [162,173].

The most clinically important oncogene in colorectal cancer, KRAS is a downstream effector of EGFR that signals (through BRAF) the activation of mitogen activated kinase (MAPK) pathways and promotion of cell growth and survival. KRAS mutations occur in roughly 40% of colorectal cancers, primarily in CIN tumors secondary to inactivating APC mutations [162,173].

Mutated in roughly 10% to 15% of colorectal cancers, BRAF encodes a protein kinase that acts as the downstream effector of KRAS in the RAS/RAF/MAPK signaling pathway. KRAS and BRAF mutations are mutually exclusive; activating mutation in either gene is sufficient to promote tumorigenesis via increased MAPK signaling. BRAF mutations are more frequent in MSI tumors (35%) than CIN tumors (5%) [162,173].

PATIENT AND TUMOR CHARACTERISTICS ASSOCIATED WITH KRAS AND BRAFV600E MUTATIONS IN COLON CANCER

KRAS and BRAFV600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but until recently little has been known about the associated patient and clinical characteristics. Analysis of 2,326 patients with stage III colon cancer found that 35% showed KRAS mutations and 14% BRAF mutations, which were near-100% mutually exclusive [177].

KRAS mutations were more frequent in patients with negative family history of colon cancer and never smokers. Tumors with KRAS mutations were significantly less likely to have defective MMR (dMMR) and high-grade histology and were more often right-sided [177].

Tumors with BRAFV600E mutations were more frequent in patients 70 years of age or older and current or former smokers, and less frequent in non-whites and men. Tumors with BRAFV600E mutations were more frequently right-sided, with four or more positive lymph nodes, high-grade histology, and dMMR [177].

PROGNOSTIC/PREDICTIVE RELATIONSHIP TO GENETIC/MOLECULAR PATHOLOGY

Advances in the understanding of genetic and molecular alterations in the pathogenesis of colorectal cancer have been used to link specific gene mutations in colorectal cancer with treatment response and prognosis in colorectal cancer [162,173,178]:

- MSI vs. CIN: Numerous studies have established a better prognosis, independent of colorectal cancer stage, in patients with MSI tumors and unfavorable prognosis with CIN tumor.

- KRAS codon 12/13 mutations: Present in roughly 40% of colorectal cancers, strong evidence demonstrates this mutation predicts resistance to anti-EGFR therapy.

- BRAFV600E mutations: Occurring in 10% of colorectal cancers, moderate evidence suggests this mutation is likely to predict resistance to anti-EGFR therapy.

- MSI: Present in 15% of colorectal cancers, moderate evidence suggests this mutation may predict response to 5-FU and irinotecan.

- 18qLOH/SMAD4 loss: Present in 50% of colorectal cancers, moderate evidence suggests this mutation may predict resistance to 5-FU.

- COX-2 overexpression: Emerging data show that colorectal cancer tumors with COX-2 overexpression are significantly associated with worse outcomes. This is consistent with the body of research associating long-term COX-2 inhibitor use with decreased rates of adenoma and colorectal cancer development and/or recurrence.

6. DIAGNOSIS AND STAGING OF COLON AND RECTAL CANCER

DIAGNOSTIC WORKUP

Patients with colorectal cancer typically present in one of three ways:

- Outpatients with suspicious symptoms and signs

- Asymptomatic persons discovered by routine screening

- Emergency admission with intestinal obstruction, peritonitis, or bleeding

A diagnosis of colorectal cancer is confirmed and other conditions ruled out by conducting a thorough patient history and physical examination and using appropriate testing. During the workup, the clinician should be mindful that, unless otherwise indicated, surgical resection is the first-line treatment for localized malignancy and is the only curative option for colorectal cancer. Thus, the diagnostic workup involves characterization of the malignancy and preoperative assessment.

History

Patient history and physical examination are the foundations of assessment. A thorough disease history should be obtained by eliciting disease-specific symptoms, associated symptoms, and family history. A cancer-specific history helps direct the exploration of associated pathology or metastatic disease and any further workup. When possible, all patients should undergo a full colonic evaluation with histologic assessment of the colorectal lesion before treatment. Patients should also be assessed for their fitness to undergo surgery, including assessment of cardiac risk, and preoperative radiologic staging should be routinely performed [179,180].

The incidence of colorectal cancer increases with age. Patients younger than 44 years of age account for fewer than 5% of cases, and the mean age at diagnosis is 71 years. Men and women older than 50 years of age have similar rates of colorectal cancer. However, the colorectal cancer prevalence in men increases in tandem with age beyond 50 years [97].

Physical Examination

With increasingly widespread and effective screening, colorectal cancer is frequently detected at an earlier, asymptomatic phase. Physical examination findings early in the disease course can be normal or nonspecific (e.g., fatigue, weight loss) [115,179]. With more advanced colon cancer, common clinical presentations include iron-deficiency anemia, rectal bleeding, abdominal pain and tenderness, change in bowel habits, intestinal obstruction or perforation, hepatomegaly, and ascites. Right-sided lesions are more likely to bleed and cause diarrhea, while left-sided tumors are usually detected later and may present as bowel obstruction [115,179].

In addition to these signs and symptoms in colon cancer, physical examination of patients with rectal cancer may reveal a palpable mass and bright red blood in the rectum. Adenopathy, hepatomegaly, or pulmonary signs may be present with metastatic rectal cancer. Proctosigmoidoscopy and digital rectal examination should be performed to determine tumor distance from the anal verge, mobility, and position relative to the sphincter complex.

Signs and Symptoms

Healthcare professionals should be attentive to both common and uncommon signs and symptoms during the history and physical exam that suggest colorectal cancer. More common diagnostic factors include increasing age, rectal bleeding, rectal mass, change in bowel habits, family history, abdominal mass or distension, and anemia [164,181,182,183].

Rectal Bleeding

Although patients presenting with rectal bleeding may have a benign condition, this is a common symptom in patients with colon and rectal cancer. A primary care study found a positive correlation between each new episode of rectal bleeding in patients older than 45 years of age and colorectal cancer [183].

Change in Bowel Habit

Especially with rectal bleeding present, an increased frequency or looser stools is common in left-sided colorectal cancer. Bowel habit changes with reduced frequency and hard stools have low predictive value for colorectal cancer.

Rectal Mass

Palpable rectal mass is present in 40% to 80% of patients with rectal cancer [184]. Assessment using digital rectal examination is useful to estimate tumor proximity to the sphincter but unreliable to determine tumor involvement of the pelvic wall and suitability for surgery. These latter investigations are more accurately assessed by magnetic resonance imaging (MRI) and transrectal endoscopic ultrasound.

Positive Family History

Although only 10% to 20% of patients with colorectal cancer have a positive family history of colorectal cancer, persons with one affected first-degree relative are more than twice as likely to develop colorectal cancer, while those with two affected first-degree relatives are four times more likely to develop colorectal cancer [87,88].

Abdominal Changes

The abdominal examination is typically unremarkable in patients with colorectal cancer, but the presence of a palpable tumor mass is common in advanced disease. Presence of abdominal distension indicates ascites or intestinal obstruction secondary to advanced disease. Patients are unlikely to have colorectal cancer when abdominal pain is present in the absence of other gastrointestinal symptoms, but those with colorectal cancer often have abdominal pain in addition to other symptoms.

Anemia

Anemia is present in close to 90% of patients with right-sided colon cancer at the time of diagnosis [182].

Other Signs and Symptoms

Weight loss and anorexia are more associated with advanced disease, as are palpable lymph nodes.

Endoscopic Evaluation

Patients with suspected colorectal cancer require a complete colon examination, and this is best performed with colonoscopy [185,186]. Flexible sigmoidoscopy may be appropriate for low-risk patients, such as those with isolated rectal bleeding or who are younger than 50 years of age. However, positive findings with flexible sigmoidoscopy require pre- or postoperative confirmation and additional visualization of the entire colon, because roughly 5% of patients also harbor synchronous tumors [164,187].

In the absence of intestinal obstruction contraindicating the administration of bowel preparation, colonoscopy is the first-line investigational choice because it demonstrates the highest sensitivity for colorectal cancer of any diagnostic modality, lacks the radiation exposure of CT, and enables the removal of incidental polyps and biopsy of suspicious lesions. The disadvantages of colonoscopy include a false-negative rate of 2% to 6% and accuracy that is highly operator-dependent and strongly influenced by patient adherence to proper preparatory bowel cleansing. Tumor localization is improved with administration of intraluminal ink or tattooing of the suspected cancer site [128,187].

Diagnostic Imaging

CT colonography sensitivity in colorectal cancer detection is comparable to optical colonoscopy and has been used following incomplete colonoscopy assessment. DCBE has also been used in cases of poor colonoscopy visualization of the sigmoid colon (e.g., with severe diverticular disease), usually combined with flexible sigmoidoscopy. However, the superior sensitivity and specificity of CT colonography have led to the phasing out of DCBE for these indications [185,186].

Elderly or frail patients may have difficulties with immobility or an inability to tolerate bowel preparation, which can impede conventional colonoscopy. One alternative is colorectal imaging using plain CT scan. Plain abdominal CT scan with oral contrast (but without bowel preparation) of symptomatic patients has shown an 88% to 94% sensitivity for colon cancer detection at 12- to 30-month follow-up [188,189].

Laboratory Tests

Serum concentrations of carcinoembryonic antigen (CEA) are elevated in about 80% of patients with colorectal cancer, but CEA lacks sufficient sensitivity or specificity for use in screening or diagnosis. Instead, its greatest value comes from detecting colorectal cancer recurrence in patients who have undergone surgical resection. Patients should have baseline CEA values measured for comparison during the surveillance period to monitor for signs of recurrence [180].

Routine complete blood count, liver biochemistry, bone mineral density profile, and renal function are recommended before treatment to establish patient baseline values, to assess for hepatic and renal metastases, and to identify anemia [180].

Differential Diagnosis

During the diagnostic workup, other conditions with similarity to colon or rectal cancer should be considered and ruled out. These include [115,164]:

- Irritable bowel syndrome

- Crohn disease

- Ulcerative colitis

- Ileus

- Diverticular disease

- Ischemic bowel

- Arteriovenous malformation

- Hemorrhoids and anal fissure in suspected rectal cancer

Rare gastrointestinal tumors should also be ruled out, such as:

- Carcinoid/neuroendocrine tumors

- Small-intestine carcinomas

- Gastrointestinal lymphoma

STAGING OF COLON AND RECTAL CANCER

Accurate staging provides crucial information about the location and size of the primary tumor, and if present, the size, number, and location of metastases. Accurate initial staging influences therapy by guiding the selection of surgical intervention and choice of neoadjuvant therapy to maximize an outcome of resection with clear margins.

Imaging Modality

After colorectal cancer is diagnosed, additional imaging is required for disease staging. Liver and chest imaging, preferably using CT, is necessary to detect metastases. Rectal cancers should be staged using endorectal ultrasonography or MRI. Positron emission tomography (PET) imaging is increasingly used in colorectal cancer to detect extrahepatic metastases in patients considered for hepatic resection of presumed liver-only metastatic disease. PET is also used to localize disease in patients thought to have a recurrence, as reflected by emergent symptoms or rising CEA [164,190,191].

Practice guideline recommendations for imaging to stage colorectal cancer have been published by the American Society of Colon and Rectal Surgeons (ASCRS) and by Cancer Care Ontario [180,192]. They recommend contrast-enhanced CT of the chest, abdomen, and pelvis should be performed in all patients with colon cancer (unless contraindicated) to estimate disease stage and identify metastases. If local excision is considered for low rectal cancer (0–5 cm from the anal verge), transrectal ultrasonography is preferred over MRI to improve discrimination between T1 and T2 lesions. For upper rectal cancers (10–15 cm above the anal verge), whereby the mesorectal fascia is not threatened, MRI is not considered superior to pelvic CT.

MRI can stage the local rectum but is not adequate to assess regional disease at the level of the inferior mesenteric artery or distant disease. CT of the abdomen and pelvis should be used to assess for distant metastases and regional disease, including lymph node involvement along the inferior mesenteric artery. Pelvic CT and/or transrectal ultrasonography are recommended with contraindications to MRI. All patients with rectal cancer should have preoperative radiologic staging with contrast-enhanced CT to assess for metastatic disease [180,192].

Histologic Assessment

Histologic confirmation of colon cancer is ideal, and for rectal cancer, it is essential [164]. Research has demonstrated an association between the number of lymph nodes examined in colon and rectal cancer surgery and oncologic outcomes [193]. In patients with colon or rectal cancer, the American Joint Committee on Cancer (AJCC) and National Cancer Institute jointly recommend examination of a minimum of 12 lymph nodes to rule out regional lymphatic node involvement [194].

The TNM Classification System

The AJCC has developed the TNM classification system, and this approach is the universal standard in clinical cancer care [194]. The AJCC TNM classification system is identical for colon and rectal cancer. The 2018 update to the AJCC system uses the pathologic stage (also called the surgical stage), as this is likely to be more accurate than the clinical stage, which takes into account the results of the physical exam, biopsies, and imaging tests done prior to surgery (Table 6) [194,195,196]. The system was initially developed as a prognostic tool. While numerous studies have evaluated other clinical, pathologic, and molecular parameters for validity in outcome prediction, none have been validated in multi-institutional prospective trials, and the TNM system remains the only prognostic tool validated in multi-institutional prospective studies. With TNM [8]:

- T describes the extent of primary tumor growth into the intestinal wall or adjacent areas. This grade reflects the extent of tumor spread in the colon and rectum wall, from the inner to the outermost layers.

- N describes the extent of primary tumor spread to nearby (regional) lymph nodes.

- M indicates whether the tumor has metastasized to other organs (most commonly, the liver or lungs)

Table 6: AMERICAN JOINT COMMISSION ON CANCER TNM CLASSIFICATION FOR COLON AND RECTAL CANCER

Code

Description

Primary Tumor (T)

TX

Primary tumor cannot be evaluated

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor extends through the mucosa and into the submucosa

T2

Tumor extends through the submucosa and into muscularis propria

T3

Tumor extends through the muscularis propria and into the subserosa but not to any neighboring organs or tissues

T4a

Tumor penetrates to the surface of the visceral peritoneum

T4b

Tumor directly invades or is adherent to adjacent organs or structures

Regional Lymph Node Involvement (N)

NX

Regional lymph nodes cannot be evaluated

N0

No regional nodal involvement

N1

Metastasis in 1–3 regional lymph nodes

N1a

Metastasis in 1 regional lymph node

N1b

Metastasis in 2–3 regional lymph nodes

N1c

Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolorectal tissues without regional nodal metastasis

N2

Metastasis in 4 or more regional lymph nodes

N2a

Metastasis in 4–6 regional lymph nodes

N2b

Metastasis in 7 or more regional lymph nodes

Distant Metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

M1a

Metastasis confined to one organ or site

M1b

Metastasis in more than one organ/site or the peritoneum

Source: [194]

When the T, N, and M categories have been determined (usually after surgery), the information is combined for stage grouping, with stage I the least advanced and stage IV the most advanced (Table 7) [8,179,180].

Table 7: STAGES OF COLORECTAL CANCER

Stage

TNM Classification

Description

Stage 0

Tis, N0, M0

Tumor is in the earliest stage and has not grown beyond the colon or rectum mucosa. Also termed carcinoma in situ.

Stage I

T1–2, N0, M0

Tumor extends through the muscularis mucosa into the submucosa (T1) or into the muscularis propria (T2).

Stage IIA

T3, N0, M0

Tumor extends into the outermost layers of the colon or rectum but not beyond (T3).

Stage IIB

T4a, N0, M0

Tumor extends through the wall of the colon or rectum but not into adjacent tissues or organs (T4a).

Stage IIC

T4b, N0, M0

Tumor extends through the wall of the colon or rectum and is attached to or has grown into adjacent tissues or organs (T4b).

Stage IIIA

T1–2, N1/N1c, M0

Tumor extends through the mucosa into the submucosa (T1) or into the muscularis propria (T2). It has spread to 1–3 regional lymph nodes (N1) or into areas of fat near regional lymph nodes but not into the nodes (N1c).

T1, N2a, M0

Tumor extends through the mucosa into the submucosa (T1) and has spread to 4–6 regional lymph nodes (N2a).

Stage IIIB

T3–4a, N1/N1c, M0

The cancer has grown into the outermost layers of the colon or rectum (T3) or through the visceral peritoneum (T4a) but has not reached nearby organs. It has spread to 1–3 regional lymph nodes (N1a/N1b) or into areas of fat near regional lymph nodes but not the nodes themselves (N1c).

T2–3, N2a, M0

The cancer has grown into the muscularis propria (T2) or into the outermost layers of the colon or rectum (T3). It has spread to 4–6 regional lymph nodes (N2a).

T1–2, N2b, M0

The cancer has grown through the mucosa into the submucosa (T1) or it may also have grown into the muscularis propria (T2). It has spread to 7 or more regional lymph nodes (N2b).

Stage IIIC

T4a, N2a, M0

The cancer has grown through the wall of the colon or rectum (including the visceral peritoneum) but has not reached nearby organs (T4a). It has spread to 4–6 regional lymph nodes (N2a).

T3–4a, N2b, M0

The cancer has grown into the outermost layers of the colon or rectum (T3) or through the visceral peritoneum (T4a) but has not reached nearby organs. It has spread to 7 or more regional lymph nodes (N2b).

T4b, N1–2, M0

The cancer has grown through the wall of the colon or rectum and is attached to or has grown into other nearby tissues or organs (T4b). It has spread to at least one regional lymph node or into areas of fat near the lymph nodes (N1 or N2).

Stage IVA

Any T, Any N, M1a

The cancer may or may not have grown through the wall of the colon or rectum, and it may or may not have spread to regional lymph nodes. It has spread to one distant organ or set of lymph nodes (M1a).

Stage IVB

Any T, Any N, M1b

The cancer may or may not have grown through the wall of the colon or rectum, and it may or may not have spread to regional lymph nodes. It has spread to more than one distant organ or set of lymph nodes, or it has spread to distant parts of the peritoneum (M1b).

Source: [8,196]

In rectal cancer, AJCC staging does not apply to the following malignant histologies [197]:

- Sarcoma

- Lymphoma

- Carcinoid tumors

- Melanoma

7. PROGNOSTIC FACTORS

PROGNOSTIC FACTORS ASSOCIATED WITH STAGING

As discussed, KRAS mutations are present in 40% of colon adenocarcinomas and affect sensitivity to treatment with biologic agents directed against EGFR. The FDA has approved a qualitative real-time polymerase chain reaction assay, the therascreen KRAS RGQ PCR Kit, for detection of specific mutations in the KRAS oncogene [198].

dMMR is associated with high-frequency MSI (H-MSI), a predictor of better clinical outcomes for resectable colon cancer based on analysis of several large trials. In addition, patients with stage II dMMR (H-MSI) do not appear to benefit from 5-FU-based adjuvant therapy. Among patients with stage III disease, the predictive impact of dMMR status for adjuvant chemotherapy remains controversial [199,200,201].

Testing for dMMR with H-MSI may become useful for prognosis and treatment planning in patients with resectable colon cancer [201]. Some research also emphasizes the role of immune regulation in the natural course and prognosis of patients with colorectal cancers [202].

MOLECULAR AND CLINICAL PROGNOSTIC FACTORS

There are a variety of molecular/genetic and clinical factors that impact the disease course and prognosis. Molecular prognostic factors include [203]:

- p53

- Loss of heterozygosity for 18q

- Mutations of deleted in colon cancer (DCC) gene

- EGFR gene amplification

Specific clinical features associated with worse prognosis are [203]:

- Bowel obstruction at diagnosis

- Ulcerative growth pattern

- Perforation

- Elevated preoperative CEA level

HISTOLOGIC SUBTYPES AS PREDICTORS OF METASTASES

A study of autopsy results from 1,675 patients with metastasized colorectal cancer and from 88 patients with synchronous metastases observed that histologic subtype and localization of the primary colorectal cancer tumor strongly influenced metastatic pattern [204]. Metastatic disease was more prevalent, and more frequent in multiple sites, in patients with mucinous adenocarcinoma (33.9% and 58.6%, respectively) or signet-ring cell carcinoma (61.2% and 70.7%) than with adenocarcinoma (27.6% and 49.9%) [204]. Liver metastases were more frequent in patients with adenocarcinoma (73.0%) or mucinous adenocarcinoma (52.2%) than in those with signet-ring cell carcinoma (31.7%). Peritoneal metastases were more common in patients with signet-ring cell carcinoma (51.2%) or mucinous adenocarcinoma (48.2%) than in those with adenocarcinoma (20.1%) [204]. Metastases to distant lymph nodes occurred in more signet-ring cell carcinoma patients (43.9%) than patients with either mucinous adenocarcinoma (22.3%) or adenocarcinoma (19.9%). Abdominal metastases were more frequent with colon cancer, and extra-abdominal metastases more common with rectal cancer [204].

PROGNOSTIC FACTORS FOLLOWING RESECTION OF LIVER METASTASES

Approximately one in three patients who undergo resection for colorectal liver metastases become actual five-year survivors. Of those, approximately half survive 10 years and are considered "cured" of colorectal liver metastases [205]. A multivariate analysis of 1,001 patients who underwent potentially curative resection of liver metastases identified five factors as independent predictors of worse outcome [206]:

- Tumor size >5 cm

- Disease-free interval less than one year

- More than one tumor

- Primary lymph-node positivity

- CEA level >200 ng/mL

SURVIVAL

Prognostic Factors of Survival by TNM Stage

Patient prognosis is most powerfully associated with clinical and histopathologic stage of colorectal cancer at diagnosis as reflected by the TNM classification and staging. Data obtained from the National Cancer Institute SEER database in patients diagnosed from 2004–2010 found five-year survival rates of 92% for earliest stage colon cancer and 87% for earliest stage rectal cancer (Table 8) [8].

Table 8: COLORECTAL CANCER FIVE-YEAR SURVIVAL RATES BY STAGE

Stage

Survival Rate

Colon cancer

I

92%

IIA

87%

IIB

63%

IIIA

89%

IIIB

69%

IIIC

53%

IV

11%

Rectal cancer

I

87%

IIA

80%

IIB

49%

IIIA

84%

IIIB

71%

IIIC

58%

IV

12%

Source: [8]

However, these figures are based on a previous staging system, so they can be difficult to apply to the current system. At the time, there was no stage IIC; these cancers were classed stage IIB. Some cancers now classed as stage IIIC were classed as stage IIIB, and vice versa [8].

Other Prognostic Factors of Survival

Several other factors have shown prognostic significance, including the number of harvested and processed lymph nodes, histologic grade, and evidence of lymphovascular and perineural invasion. In patients with metastatic colorectal cancer, the level of circulating tumor cells measured at baseline after the initiation of new therapy was an independent predictor of survival. In patients with baseline CEA values ≥25 ng/mL, those with low baseline levels of circulating tumor cells (fewer than three) had longer survival, and measurements of both circulating tumor cell number and CEA level at 6 to 12 weeks independently predicted survival [207]. Additionally, an emerging focus in research and literature is the role of host immune-centered factors (e.g., anti-tumor cells in the liver) in the clinical outcomes of colorectal liver metastases [208,209].

8. TREATMENT OF COLON AND RECTAL CANCER

MECHANISM OF CHEMOTHERAPY AND TARGETED THERAPIES

The chemotherapy agent 5-FU entered clinical use for patients with colorectal cancer more than 40 years ago and remains a mainstay of colorectal cancer treatment today. In the mid-1990s, the drugs irinotecan hydrochloride and oxaliplatin became available for colorectal cancer, and standard chemotherapy regimens were refined through extensive trials. Patients with metastatic colorectal cancer unsuitable for surgery represent more than 50% of those diagnosed with disseminated disease, and while they did benefit, the modest increases in life expectancy came with substantial toxicities. These patients, and their overall prognoses, remained poor. The therapeutic outlook improved with introduction of bevacizumab, the first FDA-approved antiangiogenic agent for metastatic colorectal cancer. Several additional targeted biologic agents have received FDA approval for metastatic colorectal cancer. As of 2019, these include cetuximab, panitumumab, ziv-aflibercept, regorafenib, and ramucirumab. Subsequent-line treatment options include pembrolizumab, nivolumab, nivolumab plus ipilimumab, and trifluridine/tipiracil (TAS-102) [210,211,212,213,214,215].

EGFR is a glycoprotein with three primary components: an extracellular ligand binding domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain. EGFR is activated by ligand binding from EGF or transforming growth factor-alpha, which triggers downstream activation in signaling pathways that facilitate development and progression of colorectal cancer. This critical role of EGFR in oncogenesis has made it an attractive target for colorectal cancer therapy, and the targeted biologic agents cetuximab and panitumumab primarily act through binding EGFR to inhibit downstream signaling [162,216].

Colorectal tumors that grow beyond 1–2 mm^3 require increased access to oxygen and nutrients and develop neoangiogenesis to enable tumor growth and metastases. Neoangiogenesis originates from complex interactions between pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF), the most potent pro-angiogenic factor known to date, is overexpressed in gastrointestinal tumors and is essential for the proliferation and metastases of colorectal cancer [217]. VEGF overexpression is associated with increased tumor vascularity, proliferation, progression, invasion, and metastasis. VEGF binds to and activates one of the three VEGF receptors located on the vascular endothelium. Among the VEGF receptor types, VEGFR-2 is the primary mediator of the mitogenic and angiogenic effects of VEGF, while VEGFR-3 is involved in lymphangiogenesis [210].

Following VEGF binding, VEGF receptors activate several downstream intracellular signal transduction pathways that promote inhibition of apoptosis, degradation of the extracellular matrix to facilitate endothelial cell proliferation and migration to form new blood vessels, and stimulation of mitosis and cytoskeletal changes associated with motility. Colorectal tumors also express VEGF and other proangiogenic factors on their cell surface; their presence is associated with increased vascularity, advanced disease, and poor prognosis [217].

Findings of elevated VEGF levels in patients with metastatic colorectal cancer led to the development and FDA approval of several anti-VEGF agents (i.e., bevacizumab, ramucirumab, regorafenib, and ziv-aflibercept) [214,215]. In addition to the therapeutic targeting of VEGF, VEGF antagonists have also shown the ability to increase intratumoral delivery of chemotherapeutic agents to improve their antitumor efficacy [209,210].

Secondary Drug Resistance

Patients with chemotherapy-refractory colorectal cancer who initially respond and then become resistant to cetuximab or other monoclonal antibodies have essentially run out of therapeutic options. This emergence of secondary drug resistance within 9 to 18 months of initiation is a major limitation of anti-EGFR therapies. A substantial proportion of patients with colorectal cancer who initially respond to anti-EGFR therapies have, at the time of disease progression, tumors with focal amplification or somatic mutations in KRAS that were undetectable before initiation of anti-EGFR therapy. Drug-resistant KRAS alteration results from pre-existent KRAS mutant and amplified clones and from new mutations arising from ongoing mutagenesis [218]. A mechanism by which KRAS mutation nullifies anti-EGFR therapy involves bypassing the need for upstream EGFR signals to activate downstream oncogenic processes [162,173]. It is now established that patients with any KRAS or NRAS mutation should not be treated with cetuximab or panitumumab, as these mutations strongly predict resistance to EGFR inhibitor agents. In contrast, non-mutational KRAS, termed wild-type KRAS, responds to targeted therapy [113,209,214,219,220].

GENERAL APPROACH TO TREATMENT

Overall, there is a substantial overlap between treatment approaches for colon and rectal cancer, especially in stage IV and metastasized cancer. Treatment approaches for stage I–III cancer (earlier stage) differs the most. In this section, treatment of earlier-stage colon and rectal cancer are discussed separately, and discussion of metastatic colon and rectal cancer is combined. For both cancers, the foundation of care is surgical resection for patients with local or locally advanced tumor, and chemotherapy for stage IV, metastatic, and recurrent tumor. Unlike rectal cancer, radiotherapy has limited use in colon cancer.

The timing of chemotherapy and/or radiotherapy is sequenced in relation to surgery as follows:

- Neoadjuvant chemotherapy and/or radiation therapy: Delivered before surgery, to downsize the tumor. Most often used in rectal cancer.

- Adjuvant chemotherapy and/or radiation therapy: Delivered following surgery with the intent to destroy remaining local or micro-metastasized malignant cells and colonies.

- Palliative chemotherapy or radiotherapy: Delivered to downsize or eradicate colorectal cancer tumors that have metastasized to other organs. The objective is to relieve symptoms and pain, instead of cure or prolonging survival.

- Liver metastases: The liver is the most common site of metastatic colon and rectal cancer. Treatment of hepatic metastases of primary colorectal cancer can involve surgery with neoadjuvant or adjuvant chemotherapy, local ablation, or intra-arterial chemotherapy.

The use of chemotherapy in stage IV, metastatic, or recurrent disease involves the combination of agents. A number of chemotherapy regimens have been evaluated and represent the core of therapy. Newer biologically targeted agents are added to the established chemotherapy regimens to gain the advantage of synergistic drug action, and NCCN guidelines recommend the use of as many chemotherapy drugs as possible to maximize the effect of adjuvant therapies for colon and rectal cancer [212,221].

Several practice guidelines for the treatment of colon and rectal cancer are available and are updated and revised on a regular basis. The importance of guideline-adherent treatment was underscored by a 2015 study of all patients receiving primary treatment for colorectal cancer in a major academic medical center between 2003 and 2010. The results showed that treatment non-adherent to NCCN guidelines was associated with 3.6 times the risk of death in the first year after diagnosis and an 80% increased risk of death after two to five years. The authors state that while medically justifiable reasons for guideline deviation do occur, the overall impact on patients is a markedly greater risk of death, especially in the first year following diagnosis [222].

TREATMENT OF COLON CANCER, STAGES I–III

The standard treatment options for colon cancer are [193]:

- Stage 0: Surgery

- Stage I: Surgery

- Stage II: Surgery

- Stage III: Surgery, adjuvant chemotherapy

- Stage IV and recurrent: Surgery, chemotherapy, and targeted therapy

Surgical Resection

Treatment of localized and locally advanced colon cancer primarily involves surgical resection, and roughly 80% of colon cancer patients exhibit localized disease amenable to resection with curative intent [180]. Aside from palliative resection (e.g., alleviating obstruction), the objective of surgery is curative resection based on clear macroscopic and histologic resection margins. Practice recommendations from the ASCRS were published to optimize surgical care of these patients (Table 9) [180].

Table 9: ASCRS GUIDELINES FOR SURGICAL MANAGEMENT OF COLON CANCER

Surgical Treatment of the Primary Tumor

A thorough surgical exploration should be performed and documented.

The extent of colon resection should correspond to the lymphovascular drainage of the colon cancer site. The lymphadenectomy should be complete and en bloc with (i.e., at the same time as) the bowel segment.

Clinically positive lymph nodes located outside the standard field of resection identified at the time of resection and suspected to contain metastatic disease should be biopsied or removed at the time of primary resection.

Resection of involved adjacent organs should be en bloc.

Synchronous colon cancers can be treated by two separate resections or subtotal colectomy.

Sentinel lymph node (SLN) mapping for colon cancer does not replace standard lymphadenectomy.

Laparoscopic and open colectomy achieve equivalent oncologic outcomes for localized colon cancer. The use of the laparoscopic approach should be based on the surgeon's documented experience in laparoscopic surgery as well as on patient- and tumor-specific factors.

Treatment of the malignant polyp is determined by the morphology and histology of the polyp.

Prophylactic Oncologic Resection of Extraintestinal Organs

Oophorectomy is advised for grossly abnormal ovaries or contiguous extension of the colon cancer, but routine prophylactic oophorectomy is not necessary

Management of Synchronous Stage IV Disease

Resectable stage IV disease: The treatment of patients with resectable stage IV colon cancer should be individualized based on comprehensive multidisciplinary evaluation.

Unresectable stage IV disease: Palliative intervention or resection of the symptomatic primary tumor should be considered, but routine resection of the asymptomatic primary tumor is not recommended.

Tumor-Related Emergencies

Bleeding: Surgical resection to stop severe blood loss from localized colon cancer should follow the same oncologic principles as in elective resection.

Perforation: Perforation is a life-threatening complication. After resuscitation of the patient, surgical resection to address both the perforation and the tumor should be performed, if at all possible.

Obstruction: The management of patients with an obstructing cancer should be individualized but may include a definitive surgical resection with primary anastomosis.

Management of Locoregional Recurrence

The treatment of patients with locoregionally recurrent colon cancer should be multidisciplinary, and curative resection should adhere to the principles of primary resection

Management of Peritoneal Carcinomatosis

The treatment of patients with peritoneal carcinomatosis should be multidisciplinary and individualized and may include surgical cytoreduction (debulking). The role of intraperitoneal chemotherapy remains insufficiently defined.

Palliative Procedures

In patients with extensive incurable extent of tumor burden, palliative surgical interventions should be individualized based on the presence of symptoms.

Adjuvant Therapy

Adjuvant chemotherapy may be considered for patients with high-risk stage II colon cancer.

Adjuvant chemotherapy should be recommended for patients with stage III colon cancer.

Source: [180]

Evidence Based Practice Recommendation

For resectable non-metastatic colon cancer, the National Comprehensive Cancer Network preferred surgical procedure is colectomy with en bloc removal of the regional lymph nodes.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

The primary treatment for localized resectable colon cancer is colectomy with en bloc removal of all associated regional lymph nodes and involved adjacent structures. The extent of a curative resection for colon cancer depends on the site of the primary lesion and lymphovascular drainage of the cancer site. The length of bowel resected is governed by the blood supply to that segment. In the absence of synchronous pathology, an anatomic colon resection for cancer should achieve at least a 5-cm negative margin on either side of the tumor. Colectomy with local excision is not adequate for curative resection, because it increases risks of tumor spillage into the peritoneal cavity and tumor progression from lack of lymphadenectomy [180,212].

Surgery is curative in 25% to 40% of highly selected patients who develop resectable metastases in the liver and lung. Refinements in surgical technique and preoperative imaging have improved patient selection and resection outcomes [193,223,224,225].

Before surgery, all patients should be given information about the likelihood of having a stoma, why it might be necessary, and how long it might be needed. The psychologic and emotional impacts of having a stoma should not be overlooked. Between 16% and 26% of patients with a stoma will experience negative psychologic symptoms immediately postoperatively, including anxiety, depression, and suicidal ideation [226,227]. Having a stoma also can potentially decrease patients' quality of life as they experience changes to body image, sexual function, social isolation, stigma, embarrassment, and decreased mood [228]. A trained stoma professional should provide specific information on the care and management of stomas to all patients considering surgery that might result in a stoma [229].

Post-Resection Staging

Given that tumor depth, nodal metastasis, and distant metastasis strongly predict post-surgical prognosis in colon cancer, staging should be performed following surgical resection using TNM staging, histologic grade of the tumor, and resection completeness [180].

Adjuvant Chemotherapy

Stage II

The value of adjuvant chemotherapy for stage II colon cancer is controversial. In one study, adjuvant 5-FU-based chemotherapy was evaluated in patients with high-risk stage II colon cancer following curative resection. Compared with surgery alone, adjuvant 5-FU showed inconsistent benefit; these and other results led to guidelines issued by the American Society of Clinical Oncology (ASCO) stating that evidence does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer [230,231].

The NCCN guideline also states there is no survival advantage by adding oxaliplatin to 5-FU/leucovorin, including in patients 70 years of age or older [212]. The combination of folic acid, 5-FU, and oxaliplatin (FOLFOX) is considered reasonable in high-risk cases, but it is not indicated in good-to-average-risk stage II cancers.

Stage III

Stage III colon cancer denotes lymph node involvement. Studies have shown that prognosis is related to the number of involved lymph nodes; patients with one to three involved nodes have a significantly better survival than those with four or more involved nodes. Before 2000, 5-FU was the only adjuvant chemotherapy with activity in stage III colon cancer. With patients in many earlier trials of adjuvant 5-FU not showing a survival benefit, modifications and additions to the core 5-FU therapy were investigated in stage III colon cancer. More recently, capecitabine was established as comparable to 5-FU/leucovorin. The addition of oxaliplatin to 5-FU/leucovorin (FLOX) improved overall survival compared with 5-FU/leucovorin alone and has become the reference standard for the future generation of clinical trials for stage III colon cancer [193,212,232].

For stage II/III colon cancer, the NCCN asserts that adjuvant bevacizumab, cetuximab, panitumumab, or irinotecan should not be used outside of clinical trials [212]. In stage III colon cancer, FOLFOX is superior to 5-FU/leucovorin, and capecitabine/oxaliplatin (CapeOx) is superior to bolus 5-FU/leucovorin. FLOX is an alternative to FOLFOX or CapeOx, but FOLFOX or CapeOx are preferred [212].

Adjuvant Radiation Therapy

Unlike in rectal cancer, the role of adjuvant radiation therapy is poorly defined in colon cancer treatment. Radiation therapy has no current adjuvant role following curative resection but may have a potential role in patients with residual disease [212]. If used, radiation fields should include the tumor bed, as defined by preoperative radioimaging or surgical clips. Radiation should be given in doses of 45–50 Gy in 25 to 28 fractions; the dose in the small bowel should be no greater than 45 Gy [212]. Neoadjuvant chemoradiotherapy that includes 5-FU should be delivered concurrently to aid resectability. Conformal external beam radiation is preferred; intensity-modulated radiation therapy should be limited to unique clinical situations. Intraoperative radiation therapy should be considered in T4 or recurrent cancer [212].

TREATMENT OF RECTAL CANCER, STAGES 0–III

The standard treatment options for rectal cancer are [197]:

- Stage 0: Polypectomy or surgery

- Stage I: Surgery with or without chemoradiation therapy

- Stage II and III: Surgery, neoadjuvant chemoradiotherapy, short-course neoadjuvant radiotherapy, and adjuvant chemoradiotherapy

- Stage IV, metastatic, and recurrent: Surgery with or without chemotherapy or radiotherapy, chemotherapy, and targeted therapy

Approximately 28% of colorectal malignancies are attributable to rectal carcinoma. Although surgical resection is the only curative option for rectal cancer, complete resection is rendered technically difficult by the lack of serosa covering the rectum and proximity of the rectum to the bony pelvis and other pelvic organs. Local tumor invasion is promoted by this extra-colorectal proximity to other organs, which, along with surgical difficulty, contributes to high local recurrence rates [179].

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends combined-modality therapy consisting of surgery, concurrent fluoropyrimidine-based chemotherapy with ionizing radiation to the pelvis, and chemotherapy for the majority of patients with stage II or stage III rectal cancer.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

Compared with colon cancer, the increased risk of local recurrence and poorer overall prognosis in rectal cancer has led to differences in the management of localized or locally advanced disease, including greater emphasis on multimodal treatment to minimize morbidity, decrease recurrence risk, and prolong survival. Other differences in rectal cancer treatment include surgical techniques, use of radiation therapy, and chemotherapy protocol. In stage II or III rectal cancer, neoadjuvant therapy is now favored over adjuvant therapy based on evidence of improved local control and increased rates of sphincter preservation [233,234,235].

An important consideration is the impact of rectal cancer surgery on the structure and function of adjacent sensitive tissues, and the therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary, and sexual function [236,237]. Practice recommendations for the surgical treatment of localized rectal cancer have been published by the ASCRS (Table 10) [179].

Table 10: ASCRS GUIDELINES FOR SURGICAL MANAGEMENT OF RECTAL CANCER

Surgical Techniques and Operative Considerations, Local Excision

Local excision is appropriate for carefully selected T1 rectal cancers without high-risk features.

Surgical Techniques and Operative Considerations, Radical Excision

A thorough surgical exploration should be performed and the findings documented in the operative report.

Total mesorectal excision should be used for curative resection of tumors of the middle and lower thirds of the rectum, either as part of low anterior or abdominoperineal resection. For tumors of the upper third of the rectum, a tumor- specific mesorectal excision should be used with the mesorectum divided ideally no less than 5 cm below the lower margin of the tumor.

A 2-cm distal mural margin is adequate for most rectal cancers when combined with a total mesorectal excision. For cancers located at or below the mesorectal margin, a 1-cm distal mural margin is acceptable.

Proximal vascular ligation at the origin of the superior rectal artery with resection of all associated lymphatic drainage is appropriate for most rectal cancer resections.

In the absence of clinical involvement, extended lateral lymph node dissection is not necessary in addition to total mesorectal excision.

Patients with an apparent complete clinical response to neoadjuvant therapy should still be offered definitive resection.

After low anterior resection and total mesorectal excision, the formation of a colonic reservoir may be considered.

Intraoperative anastomotic leak testing should be performed to help identify an anastomosis at increased risk of a subsequent clinical leak.

A diverting ostomy should be considered for patients undergoing a total mesorectal excision for rectal cancer.

In patients undergoing a total mesorectal excision, an intraoperative rectal washout may be considered.

In patients with T4 rectal cancers, resection of involved adjacent organs should be performed with an en bloc technique.

Current evidence indicates that laparoscopic total mesorectal excision can be performed with equivalent oncologic outcomes in comparison with open total mesorectal excision when performed by experienced laparoscopic surgeons possessing the necessary technical expertise.

Oophorectomy is advised for grossly abnormal ovaries or contiguous extension of a rectal cancer, but routine prophylactic oophorectomy is not necessary.

Tumor-Related Emergencies

In patients with large-bowel obstruction, an expanding stent is an acceptable treatment option in the palliative setting or as a bridge to definitive resection.

Multimodality Neoadjuvant Therapy

Neoadjuvant therapy should be used for locally advanced cancers of the mid or distal rectum.

Multimodality Adjuvant Therapy

Adjuvant chemoradiotherapy should be recommended for select patients with stage III or high-risk stage II rectal cancer who have not received neoadjuvant therapy.

Adjuvant chemotherapy should be recommended for patients with high-risk stage II and all stage III disease previously treated with neoadjuvant therapy.

Source: [179]

Treatment of rectal cancer is determined by clinical disease stage and the risk of local recurrence. Low-risk, early-stage disease is generally treated with primary surgical therapy, while locally advanced or high-risk disease requires multimodality therapy that includes neoadjuvant radiation or chemoradiation [179]. The risk of local recurrence is estimated using MRI imaging before surgical intervention. Risk level is defined as low, moderate, or high based on the following criteria [238]:

Low Risk

- Clinical stage T1, T2 or T3a, AND

- No lymph node involvement

Moderate Risk

- T3b or greater, in which the potential surgical margin is not threatened, OR

- Any suspicious lymph node not threatening surgical resection margins, OR

- The presence of extramural vascular invasion

High Risk

- A threatened (<1 mm) or breached resection margin, OR

- Low tumors encroaching onto the intersphincteric plane or with levator involvement

Primary Surgical Therapy

Rectal cancer surgery involves surgical resection of the primary tumor. Surgical approach is guided by tumor location, disease stage, and presence of high-risk features (e.g., positive margins, lymphovascular invasion, perineural invasion, poorly differentiated histology) [197].

Polypectomy alone may be sufficient when polyps with invasive cancer can be completely resected with clear margins and show favorable histologic features, generally select T1 cancers [239]. Approaches with minimal morbidity and mortality include transanal excision and transanal endoscopic microsurgery. Local excision is appropriate in selected T1 tumors, with mesorectal excision preferred for all other T1–T2/N0 tumors. Endoscopic microsurgery cannot perform excision and staging of mesorectal lymph nodes, a limitation because T1 lesions have a 6% to 11% risk of harboring nodal metastasis [240]. Local recurrence rates range from 7% to 21% for T1 lesions and 26% to 47% for T2 lesions [240,241,242].

Total mesorectal excision with autonomic nerve preservation via low-anterior resection is preferred, followed by colorectal anastomosis in advanced mid- to upper-rectal tumor. Low anterior rectal resection is associated with bowel urgency, increased bowel frequency, clustering, and fecal incontinence from loss of rectum reservoir function. The colonic J-pouch is the superior approach for improving postoperative bowel function [59,243]. In patients unsuitable for sphincter-preservation, total mesorectal excision via abdominoperineal resection is preferred, although this leaves patients with a permanent colostomy [244,245,246].

Despite the low rate of local relapse after meticulous mesorectal excision, the heightened tendency for first failure to solely occur in locoregional sites requires the ongoing routine use of adjuvant radiation therapy [179].

Multimodality Therapy

Multimodality therapy has been the standard of care for patients with locally advanced rectal cancer since 1990, when the National Cancer Institute recommended adjuvant therapy for stage II and III disease [247]. This was based on findings of 33% to 55% reduction in local recurrence and significant prolongation in disease-free survival. Although the National Cancer Institute recommended adjuvant therapy, subsequent findings have shown superior efficacy, lower toxicity, and better long-term outcomes with neoadjuvant therapy [248,249,250].

Preoperative radiation therapy is more effective because well-oxygenated tissue responds better to irradiation; postoperative tissue is relatively hypoxic from surgery and may be more resistant to radiation therapy. Also, postoperative complications may delay initiating adjuvant therapy [251].

Neoadjuvant Chemoradiation Therapy

Neoadjuvant chemoradiation therapy is the preferred treatment option for patients with stage II or III disease, although adjuvant chemoradiation therapy remains an acceptable option. Preoperative chemoradiation therapy is the standard of care for patients with clinically staged T3–T4 or node-positive disease (stages II/III) with benefits found in multiple trials, including [248]:

- Tumor regression and downstaging

- Improved tumor resectability

- Higher rates of local control

- Improved toxicity profile of chemoradiation therapy

- Higher rates of sphincter preservation

The most common neoadjuvant regimens for locally advanced tumors of the mid and lower third of the rectum are [251,252,253]:

- Short-course radiation therapy with 5 Gy daily for five days, followed by surgery within one week. This approach results in a lower rate of grade 3/4 acute toxicity and better compliance. It is more commonly used when tumor regression and downsizing would not improve resection or sphincter preservation.

- Long-course chemoradiation therapy using 45 to 50.4 Gy over 5 to 6 weeks with concurrent administration of 5-FU, followed by surgery 8 to 12 weeks later. Tumor regression and downsizing is more likely, making sphincter-preserving surgical procedures more feasible.

When followed by proper surgical approach and execution, both regimens provide excellent local control for locally advanced tumors. Combined neoadjuvant radiation therapy and surgery may result in substantial long-term morbidity, including chronic bowel, sphincter, and sexual dysfunction, making careful selection of patients with greatest potential benefit from radiation therapy essential [254,255]. Neoadjuvant radiation therapy or chemoradiation therapy should not be used in low-risk operable rectal cancer [238].

Adjuvant Therapy

Compared with adjuvant chemoradiation therapy, preoperative chemoradiation therapy is preferred because it decreases local recurrence and adverse effects. However, the evidence demonstrates that compared to observation alone or radiation therapy alone following surgery, adjuvant chemoradiation therapy improves survival and reduces local recurrence rates in patients with resected stage II or III rectal cancer who have not received preoperative radiation therapy [248].

Many patients do not benefit from conventional 5-FU therapy, and introduction of newer chemotherapy regimens and biologic agents in colon cancer have prompted efforts to enhance survival benefits by optimizing radiation sensitization and chemotherapeutic selection and delivery. The NCCN now recommends FOLFOX or CapeOx (preferred), or FLOX, 5-FU/leucovorin, or capecitabine as adjuvant chemotherapy in stage II/III rectal cancer. This comes with the caveat that conclusive data in rectal cancer are lacking, with recommendation for use in rectal cancer based solely on extrapolation of colon cancer data [221]. The merit of adding oxaliplatin to adjuvant 5-FU/leucovorin in stage II/III rectal cancer is the subject of ongoing debate [213].

Radiotherapy Toxicity

The greater toxicity concerns with pelvic irradiation of rectal cancer involve potential late-onset morbidity. Relative to patients receiving surgical resection alone, those with additional radiation therapy treatment have shown increased risks of chronic bowel problems, sphincter dysfunction, sexual dysfunction, and elevated risk of surgical morbidity [248].

The improved local tumor control with neoadjuvant radiation therapy should be weighed against greater risks for acute toxicity (e.g., pelvic or perineal wound infection) and chronic/late-onset toxicity (e.g., stool frequency and incontinence problems, pelvic fractures, worsening sexual function). The frequency of these adverse effects found in patients receiving radiation therapy plus surgery versus surgery-only includes fecal incontinence in 62% vs. 38%, and urinary incontinence requiring pad wearing in 56% vs. 33%, respectively [248].

CHEMOTHERAPY AGENTS AND REGIMENS USED IN ADVANCED COLON AND RECTAL CANCER

Chemotherapy is the primary therapeutic modality for stage IV, metastatic, and recurrent colorectal cancer and the first treatment option for unresectable or metastatic tumors. Metastases develop in at least 50% of colorectal cancer patients, and most metastatic tumors are unresectable. Management of metastatic colorectal cancer involves a continuum of care with sequential use of a variety of active agents in combination or as single agents. The choice of therapy is based on treatment goals, the type and timing of previous therapy, specific efficacy and toxicity profiles, tumor mutational status, and patient preference [256].

The specific chemotherapy agents and combinations used in colon cancer and rectal cancer overlap substantially. The following agents have received FDA approval for use in colorectal cancer [257,258,259].

5-Fluorouracil (5-FU)

As discussed, 5-FU has been the foundation of chemotherapy for colorectal cancer for more than four decades. As a single agent, it inhibits tumor cell growth through at least three different mechanisms that ultimately disrupt cellular viability or DNA synthesis, transcription, and replication.

Capecitabine

Capecitabine is an oral fluoropyrimidine that undergoes a three-step enzymatic conversion to 5-FU, with the last step occurring in the tumor cell.

Leucovorin Calcium

Leucovorin is a reduced form of folic acid that does not require enzymatic reduction reaction for activation. This agent allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Leucovorin counteracts the toxic effects of current standard combination chemotherapy for colorectal cancer and potentiates the effects of 5-FU and its derivatives by stabilizing the binding of the drug's metabolite to its target enzyme to prolong drug activity.

Irinotecan Hydrochloride

Irinotecan is inactive in its parent form and is converted by the carboxylesterase enzyme to its active metabolite form SN-38, which is 1,000 times more potent than its parent compound. SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA after it has been cleaved by topoisomerase I, inhibiting DNA replication. Irinotecan is a current standard therapy for metastatic colon cancer as the combination 5-FU/leucovorin/irinotecan.

Oxaliplatin

A third-generation platinum-based antineoplastic agent, oxaliplatin is used in combination with 5-FU/leucovorin for metastatic colorectal cancer. As with other platinum compounds, oxaliplatin destroys tumor cells through interaction with DNA to form intra-strand/inter-strand DNA cross-linking that interferes with DNA base pairing, replication, and gene transcription, resulting in cell death [260].

Cetuximab

Cetuximab is a partially humanized monoclonal antibody against EGFR that specifically binds to the extracellular domain of EGFRs. The cetuximab-bound EGFR inhibits activation of receptor-associated kinases, which inhibit cell growth, induce apoptosis, and decrease production of matrix metalloproteinase and VEGF. Cetuximab is indicated for the treatment of KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer. Importantly, patients with mutant KRAS tumors may experience worse outcome when cetuximab is added to multiagent chemotherapy regimens containing bevacizumab.

Bevacizumab

Bevacizumab is a partially humanized monoclonal antibody that binds to VEGF to inhibit angiogenesis. The inhibition of new blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth.

Panitumumab

Panitumumab is a fully humanized antibody that binds to EGFR. It is approved by the FDA for use in chemotherapy-refractory metastatic colorectal cancer and is indicated for wild-type KRAS metastatic colorectal cancer.

Ziv-Aflibercept

Ziv-aflibercept is a novel anti-VEGF molecule that acts as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor. The antiangiogenic mechanism of ziv-aflibercept involves competition with VEGF in the blood and extravascular space to prevent VEGF from interacting with its receptors on endothelial cells. It is indicated for metastatic colorectal cancer that is resistant to or has progressed after an oxaliplatin regimen [261].

Regorafenib

Regorafenib inhibits multiple tyrosine kinase pathways, including VEGF, and was approved in 2012 for the treatment of metastatic colorectal cancer in patients previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy (e.g., bevacizumab, ziv-aflibercept); and, if KRAS wild type, an anti-EGFR therapy (e.g., cetuximab, panitumumab).

Combination Regimens

The basis of chemotherapy for the treatment of colon and rectal cancer is combination therapy, with agents identified to work synergistically to manage unresectable lesions and minimize drug resistance. These combinations are generally known by their acronyms (Table 11).

Table 11: COMBINATION CHEMOTHERAPY REGIMENS USED IN THE TREATMENT OF COLON AND RECTAL CANCER

Name

Agents

Regimen

Arbeitsgemeinschaft Internistische Onkologie (AIO) or German AIO

Folic acid (leucovorin), 5-FU, and irinotecan

Irinotecan (100 mg/m^2) and leucovorin (500 mg/m^2) administered as two-hour infusions on day 1, followed by 5-FU (2,000 mg/m^2) IV bolus administered via ambulatory pump weekly over 24 hours, four times per year (52 weeks)

CAPOX

Capecitabine and oxaliplatin

Capecitabine (1,000 mg/m^2) twice daily on days 1 through 14, plus oxaliplatin (70 mg/m^2) on days 1 and 8 every three weeks

Douillard

Folic acid (leucovorin), 5-FU, and irinotecan

Irinotecan (180 mg/m^2) administered as a two-hour infusion on day 1, leucovorin (200 mg/m^2) administered as a two-hour infusion on days 1 and 2, followed by a loading dose of 5-FU (400 mg/m^2) IV bolus, then 5-FU (600 mg/m^2) administered via ambulatory pump over 22 hours every two weeks on days 1 and 2

FOLFIRI

Leucovorin, 5-FU, and irinotecan

Irinotecan (180 mg/m^2) and leucovorin (400 mg/m^2) administered as two-hour infusions on day 1, followed by a loading dose of 5-FU (400 mg/m^2) IV bolus administered on day 1, then 5-FU (2,400–3,000 mg/m^2) administered via ambulatory pump over 46 hours every two weeks

FOLFOX6

Oxaliplatin, leucovorin, and 5-FU

Oxaliplatin (85–100 mg/m^2) and leucovorin (400 mg/m^2) administered as two-hour infusions on day 1, followed by a loading dose of 5-FU (400 mg/m^2) IV bolus on day 1, then 5-FU (2,400–3,000 mg/m^2) administered via ambulatory pump over 46 hours every two weeks

FOLFOX7

Oxaliplatin, leucovorin, and 5-FU

Oxaliplatin (130 mg/m^2) and leucovorin (400 mg/m^2) administered as two-hour infusions on day 1, followed by a loading dose of 5-FU (400 mg/m^2) IV bolus administered over 46 hours on day 1, then 5-FU (2,400 mg/m^2) administered via ambulatory pump over 46 hours beginning on day 1, every two weeks, for a total of eight cycles

FOLFOXIRI

Irinotecan, oxaliplatin, leucovorin, and 5-FU

Irinotecan (165 mg/m^2) administered as a 60-minute infusion, then concomitant infusion of oxaliplatin (85 mg/m^2) and leucovorin (200 mg/m^2) over 120 minutes, followed by 5-FU (3,200 mg/m^2) administered as a 48-hour continuous infusion.

FU-LV (Roswell Regimen)

5-FU and leucovorin

Leucovorin (200 mg/m^2) administered as a 2-hour infusion days 1 and 2, followed by a loading dose of 5-FU (600 mg/m^2) IV bolus over 22 hours on days 1 and 2 every two weeks

IFL (or Saltz)

Irinotecan, 5-FU, and leucovorin

Irinotecan (125 mg/m^2) plus 5-FU (500 mg/m^2) IV bolus and leucovorin (20 mg/m^2) IV bolus administered weekly for four out of six weeks

XELOX

Oxaliplatin and capecitabine

Oral capecitabine (1,000 mg/m^2) administered twice daily for 14 days plus oxaliplatin (130 mg/m^2) IV infusion administered over 2 hours on day 1 every 3 weeks

Source: [213,214,262]

RESECTABLE STAGE IV METASTATIC AND RECURRENT COLON AND RECTAL CANCER

With recurrent or advanced colon and rectal cancer, treatment is determined by disease location. For patients with locally recurrent or liver- and/or lung-only metastatic disease, surgical resection, if feasible, is the only potentially curative treatment [193]. At any point, symptom emergence from the primary tumor should become the treatment priority in stage IV colorectal cancer [238].

Stage IV colon cancer denotes distant metastatic disease, and therapeutic options for stage IV and recurrent disease include [212]:

- Surgical resection of locally recurrent cancer

- Surgical resection and anastomosis or bypass of obstructing or bleeding primary lesions in selected metastatic cases

- Resection of liver metastases in selected metastatic patients (i.e., those for whom the five-year cure rate for resection of solitary or combination metastases exceeds 20%) or ablation in selected patients

- Resection of isolated pulmonary or ovarian metastases in selected patients

- Palliative radiation therapy

- Palliative chemotherapy

- Targeted therapy

- Clinical trial enrollment

As with colon cancer, surgical resection is the only potentially curative treatment for patients with locally recurrent, liver-only, or lung-only metastatic rectal cancer. Patients with limited pulmonary metastasis and patients with both pulmonary and hepatic metastasis may also be considered for surgical resection, with five-year survival possible in highly selected patients [263,264]. The presence of hydronephrosis associated with recurrence appears to be a contraindication to surgery with curative intent [265].

Locally recurrent rectal cancer may be resectable, particularly after an inadequate prior operation. For patients with local recurrence alone after an initial attempted curative resection, aggressive local therapy with repeat low anterior resection and coloanal anastomosis, abdominoperineal resection, or posterior or total pelvic exenteration can lead to long-term disease-free survival [179,266,267].

The use of induction chemoradiation therapy for previously nonirradiated patients with locally advanced pelvic recurrence (i.e., pelvic side-wall, sacral, and/or adjacent organ involvement) may increase resectability and allow for sphincter preservation [253]. Intraoperative radiation therapy in patients who previously received external-beam radiation therapy may improve local control in patients with locally recurrent disease, with acceptable morbidity [268].

STAGE IV COLORECTAL CANCER WITH UNRESECTABLE OR MEDICALLY INOPERABLE METASTASES

Pivotal studies have established the clinical use and/or FDA approval of chemotherapy and targeted therapy agents and regimens in metastatic colorectal cancer treatment. Unless stated otherwise, all outcomes are median values and all studies were randomized double-blinded with active or placebo control group. Outcomes are time-to-progression, progression-free survival, disease-free survival, and overall survival.

5-FU

When 5-FU was the only available chemotherapeutic option with colorectal cancer activity, trials in patients with locally advanced, unresectable, or metastatic disease showed partial response, prolonged time-to-progression of disease, and improved survival and quality of life compared with best supportive care only. Several trials analyzing the activity and toxicity of various 5-FU/leucovorin regimens found comparable results and median survival of roughly 12 months [269,270,271].

Capecitabine

Randomized studies found capecitabine equivalent in efficacy to the 5-FU/leucovorin regimen [272,273]. Other studies in metastatic colorectal cancer as first-line therapy found non-inferiority between capecitabine/oxaliplatin (CAPOX) and 5-FU/oxaliplatin regimens [274,275].

Irinotecan and Oxaliplatin

In patients with previously untreated metastatic colorectal cancer, adding irinotecan or oxaliplatin to 5-FU/leucovorin has led to improved treatment response, progression-free survival, and overall survival [276,277,278].

A comparison of FOLFOX4 against irinotecan, 5-FU, and leucovorin (IFL) showed progression-free survival of 8.7 vs. 6.9 months and overall survival of 19.5 vs. 15.0 months [279]. Comparisons of FOLFOX and FOLFIRI found identical progression-free survival and overall survival, although patients were allowed to cross over after progression [280,281].

Patients randomized to FOLFIRI, modified IFL (mIFL), or capecitabine/irinotecan (CAPIRI) showed progression-free survival of 7.6 vs. 5.9 months with FOLFIRI vs. mIFL, and 7.6 vs. 5.8 months with FOLFIRI vs. CAPIRI. CAPIRI also led to the highest rates of grade 3 or greater nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome [282].

FOLFOX and FOLFIRI are first-line treatments for patients with metastatic colorectal cancer, with FOLFIRI preferred when using irinotecan [282].

Oxaliplatin

CAPOX was found comparable to 5-FU and oxaliplatin as an oxaliplatin-based regimen for first-line treatment of metastatic colorectal cancer [274,275]. As second-line treatment following progression on irinotecan and 5-FU/leucovorin, patients randomized to FOLFOX4 or infusional 5-FU/leucovorin showed a median time-to-progression of 4.6 versus 2.7 months [283].

Bevacizumab

Bevacizumab is effective when added to FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer. In a 2009 study of patients with metastatic colorectal cancer, patients randomized to FOLFIRI/bevacizumab showed an overall survival of 28.0 months compared with 19.2 months with mIFL/bevacizumab [284]. In a separate study, patients randomized to IFL/bevacizumab or IFL/placebo showed progression-free survival of 10.6 vs. 6.2 months and overall survival of 20.3 vs. 15.6 months [285].

A trial randomized 1,401 patients with stage IV colorectal cancer to CAPOX or FOLFOX4, and then to bevacizumab or placebo. Patients receiving bevacizumab versus placebo showed progression-free survival of 9.4 vs. 8.0 months and overall survival of 21.3 vs. 19.9 months. Patients in the pooled CAPOX versus FOLFOX4 arms had a progression-free survival of 8.0 vs. 8.5 months. Overall survival had less benefit from bevacizumab than previously reported [286].

In another study, patients who progressed on FOLFIRI were randomized to FOLFOX plus bevacizumab or placebo, and showed a progression-free survival of 7.43 vs. 4.7 months, and overall survival of 12.9 vs. 10.8 months [287]. Based on these studies, bevacizumab was deemed a reasonable addition to FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer.

In a 2012 study, patients progressing on a first-line regimen that included bevacizumab were randomized to a different chemotherapy regimen plus continued bevacizumab or placebo. Participants who continued bevacizumab showed an overall survival of 11.2 months and progression-free survival of 5.7 months, compared with 9.8 months and 4.1 months, respectively, with placebo [288]. These results led to FDA approval of bevacizumab continuation in patients with progression during first-line chemotherapy, allowing patients to continue bevacizumab after switching to a different regimen containing irinotecan or oxaliplatin that may improve the synergistic activity [289].

FOLFOXIRI plus bevacizumab was compared to FOLFIRI plus bevacizumab in patients with untreated metastatic colorectal cancer, who showed a progression-free survival of 12.1 vs. 9.7 months and overall survival of 31.0 vs. 25.8 months. FOLFOXIRI led to significantly more grade 3/4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy [290].

Ziv-Aflibercept

As second-line therapy, 1,226 patients with metastatic colorectal cancer randomized to FOLFIRI plus ziv-aflibercept or placebo showed overall survival of 13.50 vs. 12.06 months and progression-free survival of 6.90 vs. 4.67 months. Both statistically significant outcomes favored ziv-aflibercept, and FOLFIRI plus ziv-aflibercept is an accepted second-line regimen for patients previously treated with FOLFOX [291].

Cetuximab

Tumors with KRAS mutations are cetuximab-insensitive, but adding cetuximab to multiagent chemotherapy improves survival in patients with colorectal cancers lacking KRAS mutation (i.e., KRAS wild type). As discussed, patients with mutant KRAS tumors may experience worse outcomes when cetuximab is combined with bevacizumab. These differences are evident in the clinical trial data.

Patients who progressed on irinotecan regimens randomized to cetuximab plus irinotecan or placebo showed a time-to-progression of 4.2 vs. 1.5 months [292]. A trial of 1,198 patients with stage IV colorectal cancer randomized to FOLFIRI plus cetuximab or placebo found improved progression-free survival but not overall survival with cetuximab. With emerging evidence that cetuximab response is limited to patients with wild-type KRAS tumors, the results were re-analyzed by KRAS status. A significant interactive effect was found for KRAS mutation status and cetuximab treatment response but not progression-free survival, with KRAS wild-type outcomes favoring FOLFIRI and cetuximab [293].

In a 2009 study, patients were randomized to capecitabine/oxaliplatin/bevacizumab plus cetuximab or placebo for metastatic colorectal cancer. The median progression-free survival was 9.4 vs. 10.7 months, and patients with KRAS gene mutation (versus wild-type) receiving cetuximab had progression-free survival of 8.1 vs. 10.5 months. Patients with KRAS tumor mutation receiving cetuximab (as opposed to placebo) showed progression-free survival of 8.1 vs. 12.5 months and overall survival of 17.2 vs. 24.9 months [284].

The benefit of adding cetuximab to first-line combination chemotherapy was studied in patients with KRAS wild-type tumors. The 1,630 patients were randomized into three treatment groups and cetuximab or placebo:

- Arm A: Fluoropyrimidine/oxaliplatin

- Arm B: Fluoropyrimidine/oxaliplatin/cetuximab

- Arm C: Intermittent fluoropyrimidine/oxaliplatin

In patients receiving chemotherapy plus placebo versus cetuximab, the overall survival was 17.9 vs. 17.0 months and progression-free survival was 8.6 vs. 8.6 months. In patients treated continuously (arm A) versus intermittently (arm C), median survival was 15.8 vs. 14.4 months [294,295]. None of these findings were statistically significant.

In a separate study, patients with EGFR-expressing metastatic colorectal cancer were randomized to first-line FOLFOX-4 plus cetuximab or placebo. The participants did not differ in response rate or progression-free survival. However, in patients with KRAS wild-type tumors, the response rate was 61% vs. 37% and progression-free survival was 7.7 vs. 7.2 months. In contrast, patients with KRAS mutant tumors showed progression-free survival of 5.5 vs. 8.6 months [296].

Panitumumab

Panitumumab is approved for use in patients with chemotherapy-refractory metastatic colorectal cancer. In clinical trials, panitumumab as single agent or combination therapy demonstrated improvements in progression-free survival and overall survival comparable to cetuximab [297,298,299].

Regorafenib

The safety and efficacy of regorafenib was evaluated by a single clinical trial of 760 patients with previously treated metastatic colorectal cancer. Participants were randomized to regorafenib or placebo plus best supportive care and showed a median overall survival of 6.4 vs. 5.0 months [300].

Second-Line Chemotherapy

Second-line chemotherapy with irinotecan in patients treated with 5-FU/leucovorin as first-line therapy led to improved overall survival versus infusional 5-FU or supportive care [301]. Conversely, patients who progressed on irinotecan and 5-FU/leucovorin and then received FOLFOX4 or 5-FU/leucovorin showed a median time-to-progression of 4.6 vs. 2.7 months [283].

TREATMENT OF LIVER METASTASES

Approximately 15% to 25% of patients with colorectal cancer will present with liver metastases at diagnosis, and another 25% to 50% will develop metachronous hepatic metastasis after resection of the primary tumor. Only a small proportion of patients with hepatic metastases are candidates for surgical resection, but advances in tumor ablation techniques and regional and systemic chemotherapy administration have now expanded the treatment options [193].

Diagnosis

The diagnostic workup of hepatic metastases should use CT scan to assess hepatic metastases and contrast-enhanced CT of the chest, abdomen, and pelvis to identify extra-hepatic metastases [238]. If intracranial disease is suspected, use of contrast-enhanced MRI of the brain is recommended. If CT shows extra-hepatic metastases potentially amenable to further surgery, a whole-body PET scan may be appropriate. If contrast-enhanced CT suggests pelvic disease, this should be confirmed with pelvic MRI [238].

Surgery

Evidence Based Practice Recommendation

According to the National Comprehensive Cancer Network, hepatic resection is the treatment of choice for resectable liver metastases from colorectal cancer. Complete resection must be feasible based on anatomic grounds and the extent of disease; maintenance of adequate hepatic function is required.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

Advances in chemotherapy have steadily improved survival in patients with colorectal cancer liver metastases, with trials now reporting a median survival of 20 months. However, with chemotherapy alone, five-year survival has been poor historically—less than 1%. This has been modestly improved in trials using FOLFOX and/or FOLFOXIRI, with five-year survival rates of 5% to 10% [279,302]. Despite advances in chemotherapy, liver resection is the best option for achieving long-term survival and may be curative in stage IV disease confined to the liver [303,304]. Resection of liver metastases with clear margins is associated with a 5-year survival rate of 45% and 10-year overall survival rate of 25% [264,305,306,307].

Hepatic metastases are considered suitable for resection based on the following criteria [193]:

- Limited number of lesions

- Intrahepatic location of lesions

- Lack of major vascular involvement

- Absent or limited extra-hepatic metastases

- Sufficient functional hepatic reserve

Cancer Care Ontario recommends that patients with extra-hepatic metastases limited to the lungs may be suitable for liver resection if all pulmonary metastases are eradicated [305]. Studies of patients with combined liver and lung resection found three-year survival of 36% to 59%, and five-year survival of 9% to 74% [308]. The study showing 74% survival at five years calculated survival from the first metastasectomy instead of the more common second metastasectomy (usually the lungs). Median survival was 42 months when calculated from last metastasectomy [309]. Pooled data from all studies showed five-year survival of 30% [308]. Routine liver resection is not recommended in patients with portal nodal disease or non-pulmonary extra-hepatic metastases [305].

Liver resection is recommended in patients with initially unresectable liver metastases sufficiently downstaged by neoadjuvant chemotherapy. If complete resection has been achieved, adjuvant chemotherapy should be used; neoadjuvant chemotherapy in patients without extra-hepatic metastases led to complete resection in 15% to 36%, and the five-year survival in these patients (33% to 42%) is similar to survival in patients with liver metastases considered resectable without chemotherapy [308]. Consensus is lacking on the best regimen to convert isolated liver metastases from unresectable to resectable [193].

Resection of all lesions, including those with radiographic complete response, is recommended when technically feasible and an adequate functional liver remnant can remain. When a lesion with radiographic complete response is present in an unresectable portion of the liver, surgery may still be an option if all other visible disease can be resected. Adjuvant chemotherapy should also be considered. Closely follow the lesion to allow localized treatment or further resection for in-situ recurrence [305].

Perioperative Chemotherapy

Cancer Care Ontario recommends perioperative chemotherapy for patients with resectable liver metastases and extra-hepatic metastases amenable to resection with clear margins [305]. However, the role of adjuvant chemotherapy in potentially curative liver metastases resection is uncertain. Before FOLFOX and FOLFIRI were introduced, two trials randomized patients after resection of liver metastases to 5-FU/leucovorin or observation. Both studies closed early due to poor accrual, but some data were obtained. Patients randomized to 5-FU/leucovorin or observation had five-year disease-free survival of 33.5% vs. 26.7% and overall survival of 51.1% vs. 41.1% [310]. In patients randomized to post-surgery 5-FU/leucovorin, the progression-free survival was 27.9 months compared with 18.8 months in the observation group [311].

Since the introduction of FOLFOX and FOLFIRI, multiagent chemotherapy has been evaluated as adjuvant therapy following resection of colorectal cancer liver metastases. In one study, patients randomized to 5-FU/leucovorin or FOLFIRI showed disease-free survival of 21.6 vs. 24.7 months; disease-free survival and overall survival were statistically comparable [312].

In another study, patients with up to four resectable liver metastases received perioperative FOLFOX (six cycles before and after surgery) or surgery alone. The progression-free survival was 42.4% vs. 36.2%. Reversible postoperative complications were more frequent after chemotherapy than surgery alone (25% vs. 16%), and there was one fatality after chemotherapy versus two fatalities after surgery [313].

Based on these findings, some physicians feel perioperative therapy is reasonable [193]. However, improved overall survival from resection plus chemotherapy has not been found.

Intra-Arterial Chemotherapy after Liver Resection

Hepatic intra-arterial chemotherapy with floxuridine for liver metastases has shown higher overall response rates but no consistent improvement in survival compared with systemic chemotherapy. In one trial, patients receiving curative liver resection were randomized to combined hepatic intra-arterial floxuridine and dexamethasone plus systemic 5-FU/leucovorin or to systemic 5-FU/leucovorin alone. Combined therapy improved two-year progression-free survival (57% vs. 42%) and overall survival (86% vs. 72%) but not median survival (72.2 vs. 59.3 months) [314].

A meta-analysis of randomized trials of fluoropyrimidine systemic therapy found no survival advantage. Furthermore, hepatic intra-arterial therapy is associated with increased local toxic effects, including liver function abnormalities and fatal biliary sclerosis [315].

Radiofrequency Ablation

Radiofrequency ablation (RFA) has emerged as a safe technique (2% major morbidity and less than 1% mortality rate) that may provide for long-term tumor control [316]. With RFA, high-frequency alternating current is delivered through needle electrodes inserted into the hepatic tumor area. The generated heat induces localized coagulative necrosis and tissue destruction. RFA is performed under imaging guidance, and the patient receives local or general anesthesia [317].

With hepatic colorectal cancer metastases, RFA is indicated as primary treatment in patients medically unfit for surgery; when the number, location, and size of metastases contraindicate resection; for treatment of post-resection recurrence; and as resection adjunct to ablate small-volume colonies in the future remnant liver. The National Institute for Health and Clinical Excellence (NICE) concluded in 2009 that RFA safety and efficacy evidence was sufficient to support its use in patients unfit or unsuitable for hepatic resection and in patients with previous hepatic resection [317].

Other Local Ablation

Cryosurgical ablation is an option for patients with tumors that cannot be resected and for patients who are not candidates for liver resection [318,319]. Other local ablative techniques include embolization and interstitial radiation therapy [320]. Patients with limited pulmonary metastases, or with both pulmonary and hepatic metastases, may also be considered for surgical resection, with five-year survival possible in select patients [321].

TREATMENT-INDUCED TOXICITY AND COMPLICATIONS

Chemotherapy-Induced Bone Marrow Suppression

Neutropenia, thrombocytopenia, and anemia may develop with the chemotherapeutic agents used in colorectal cancer treatment. Management of these short-term complications is temporary drug cessation and supportive treatment until recovery of bone marrow function [164].

Oxaliplatin-Associated Hepatotoxicity

Elevations in serum liver enzymes are common during treatment with oxaliplatin. Rarely, there is evidence of a hepatic veno-occlusive disease that presents with evidence of portal hypertension or persistent abnormalities in liver biochemistry [164].

Chemotherapy-Associated Gastrointestinal Toxicity

Diarrhea, nausea, vomiting, and/or abdominal pain commonly occur with chemotherapeutic agents. Management is symptomatic, with loperamide for diarrhea, antiemetics for nausea and vomiting, and analgesia for pain [164].

Chemotherapy-Associated Alopecia

Alopecia is a short-term adverse effect of certain chemotherapies. This effect will resolve with cessation of treatment, but in the interim, management is largely cosmetic.

Cetuximab-Associated Rash

Acneiform rash is very common in patients being treated with cetuximab. It primarily occurs on the face and upper torso, often improves with continued treatment, and is reversible. This complication is associated with improved chance of treatment response independent of KRAS status [164].

Radiation Therapy-Associated Fecal Incontinence

Loose stool, urgency, and fecal incontinence are common after radiation therapy for rectal cancer [164]. Patients should be prepared for this long-term complication.

Bladder Dysfunction after Rectal Excision

Bladder dysfunction can result from damage to the pelvic nerves during rectal cancer surgery. Symptoms can include urinary urgency, incontinence, and retention. Urinary catheterization may be required to relieve retention [164].

Erectile Dysfunction after Rectal Excision

Erectile dysfunction can also occur due to pelvic nerve damage. In one study of 28 men treated for colorectal cancer, 24 reported experiencing erectile dysfunction after treatment (i.e., chemotherapy, radiation, and/or surgery) [322]. Almost none of the men in the study received adequate care and education related to this complication.

Oxaliplatin-Associated Pulmonary Fibrosis

Pulmonary fibrosis occurs in less than 1% of patients being treated for colorectal cancer [164]. This generally presents as dry cough, dyspnea, basal crepitations, and pulmonary infiltrates on chest x-ray or CT.

Oxaliplatin-Associated Neuropathy

Neurotoxicity is a common adverse effect of oxaliplatin, usually presenting as acute or chronic peripheral neuropathy. The acute form develops in more than 90% of patients, with usual onset during or shortly after the first few infusions. Symptoms include paresthesias and dysesthesias in the hands, feet, and perioral region, and may be exacerbated by cold. It is self-limiting [164].

The chronic form is a cumulative axonal sensory neuropathy and may be dose limiting. The neuropathy is reversible in most patients after halting treatment. No intervention has shown definitive prevention of neurotoxicity.

Adverse Effects of Anti-EGFR Agents

Anti-EGFR agents have a specific adverse effect profile primarily involving skin toxicities. Electrolyte abnormalities also occur with these agents, especially magnesium-wasting syndrome. Cetuximab is associated with an infusion reaction caused by the immunogenicity of the chimeric antibody. The most prominent adverse effects of anti-EGFR agents are skin lesions (e.g., acneiform eruption, paronychial inflammation) and hair abnormalities (including a marked increase in the length of eyelashes). These are sometimes dose-limiting complications that, while not fatal, can greatly interfere with patients' quality of life. The development of skin toxicities (particularly more intense reactions) has actually been associated with better outcomes of cetuximab and panitumumab. Preliminary evidence shows benefit with use of a pre-emptive prophylactic skin treatment regimen of skin moisturizers, sunscreen, topical steroids, and doxycycline [216].

POST-TREATMENT FOLLOW-UP

Evidence Based Practice Recommendation

The National Comprehensive Cancer Network recommends survivors of colorectal cancer be encouraged to maintain a healthy body weight throughout life; adopt a physically active lifestyle (at least 30 minutes of moderate-intensity activity on most days of the week); consume a healthy diet with emphasis on plant sources; eliminate or limit alcohol consumption to no more than one drink/day for women and two drinks/day for men; and quit smoking.

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

Last Accessed: March 5, 2019

Level of Evidence: 2a (Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.)

After patients with colorectal cancer finish their treatment, they are often discharged from specialist care, with follow-up performed by community-based family physicians or institution-based, nurse-coordinated care. As there is a transfer of responsibilities, it is important to have guidelines for the follow-up of these patients. A treatment plan from the specialist should be sent to the patient's other providers, particularly primary care providers, and it should have clear directions on appropriate follow-up [323].

Postoperative surveillance of colorectal cancer is essential, and the objectives are to assess initial treatment efficacy, detect synchronous or metachronous malignancies, and identify potentially curable recurrent or metastatic cancers [324]. The benefits from routine, periodic assessments following colorectal cancer treatment include earlier identification and management of recurrent disease. Clinical trials have shown a significant survival advantage with more intensive follow-up protocols [324,325].

Several guidelines for surveillance of patients following resection of stage II/III colorectal cancer have been published. Due to minimal available and current data, few surveillance guidelines have been published for patients with stage I or resected metastatic disease [323].

Post-Resection Colon Cancer

Outcomes from several large clinical trials were pooled and analyzed and demonstrated that following resection of the primary tumor, 85% of colon cancer recurrences occur within three years and 95% occur within five years. These results underscored the importance of regular surveillance for a minimum of five years following the resection of stage II and III colon cancer [323]. Accordingly, several professional organizations have published updated practice recommendations for surveillance of patients with resected stage II and III colon cancer. The recommendations by the ASCO, the NCCN, and the joint European Society of Medical Oncology and Japanese Society of Medical Oncology (ESMO/JSMO) are broadly similar but differ on some parameters (Table 12) [323,326].

Table 12: PRACTICE RECOMMENDATIONS FOR RESECTED STAGE II/III COLON CANCER SURVEILLANCE

Parameter

Organization

ASCO

NCCN

ESMO/JSMO

History and physical exam

Every 3 to 6 months for 3 years, then every 6 months until 5 years

Every 3 to 6 months for 2 years, then every 6 months until 5 years

Every 3 to 6 months for 3 years, then every 6 to 12 months in years 4 and 5

Carcinoembryonic antigen (CEA)

Every 3 months for 3 yearsa

Every 3 to 6 months for 2 years, then every 6 months until 5 years

Every 3 to 6 months for 3 years, then every 6 to 12 months in years 4 and 5

Chest CTa

Annually for 3 years

Annually for 5 years

Every 6 to 12 months for first 3 years

Colonoscopyb

At 1 year, then every 5 years, based on previous colonoscopy findings

At 1, 3, and 5 years if negative

At 1 year after surgery, then every 3 to 5 years thereafter

Abdominal CTa

Annually for 3 years

Annually for 5 years, including pelvic scan

Every 6 to 12 months for first 3 years

aFor patients at high risk for recurrence (e.g., lymphatic/venous invasion, poorly differentiated tumor)

bColonoscopy is indicated 3 to 6 months postoperatively if preoperative colonoscopy was not performed due to obstructing lesion. Otherwise, colonoscopy should be done after 1 year. If abnormal, repeat in 1 year; if no advanced adenoma (e.g., villous polyp, polyp

Source: [323,326]

Post-Resection Rectal Cancer

Guidelines for surveillance of patients following resection of stage II/III colon and rectal cancer have been produced by Cancer Care Ontario and endorsed by the ASCO. Many recommendations for patients with stage II/III rectal cancer are the same as those described for patients with colon cancer [327]. A medical history, physical examination, and CEA testing should be performed every six months for five years. In addition to abdominal and chest CT imaging, pelvic CT should be performed every 6 to 12 months for two to three years, then annually until five years from surgery.

Rectosigmoidoscopy should be performed every six months for two to five years in patients who did not receive pelvic radiation [327]. In the absence of complete pre-diagnosis colonoscopy, a colonoscopy should be done as soon as is reasonable after completing adjuvant therapy and within six months of completing primary treatment. New and persistent or worsening symptoms, such as pelvic pain, sciatica, and difficulty urinating or defecating, may indicate rectal cancer recurrence.

Carcinoembryonic Antigen

Measurement of the serum glycoprotein CEA as a tumor marker for colorectal cancer has been used to help guide patient management and follow-up. Serum CEA testing is not valuable in screening for colorectal cancer because of its low sensitivity and specificity [328]. Use of postoperative CEA testing is usually limited to patients who may benefit from further intervention, including:

- Patients with stage II or III colorectal cancer

- Patients who would be candidates for resection of liver metastases

Patient Support after Apparently Curative Resection

The NICE recommends offering follow-up to all patients with primary colorectal cancer undergoing treatment with curative intent [229]. Follow-up should begin at an outpatient clinic visit four to six weeks after potentially curative treatment. Regular surveillance with colonoscopy, CEA testing, and CT of the chest, abdomen, and pelvis, should be provided as indicated by the treating oncology team. Any clinical, radiologic, or biochemical finding suspicious of recurrent disease should initiate further testing [229]. Regular follow-up may be halted when the patient and healthcare professional have discussed and agreed that likely benefits no longer outweigh risks of further tests or when the patient can no longer tolerate further treatments.

Information about Bowel Function

After any treatment, patients should receive specific information on managing the effects of treatment on their bowel function. This could include information on incontinence, diarrhea, difficulty emptying bowels, bloating, excess flatus, diet, and where to go for help in the event of symptoms. Verbal and written information should be clearly understood by the patient and free from jargon. Information about support organizations or Internet resources may be included [229].

Culturally and Linguistically Competent Patient Education

As a result of the evolving demographics in the United States, interaction with patients for whom English is not a native language is inevitable. It is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. 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 is being provided, the use of an interpreter should be considered.

9. CONCLUSION

Several critical needs regarding the care of patients with colorectal cancer have been identified. The high volume of new emerging information on colorectal cancer therapies can overwhelm clinicians who lack the time to adequately review the new information in this rapidly expanding field. However, improved clinician knowledge of the most recent research on new diagnostic and therapy modalities is required in order to improve patient outcomes and reduce side effects.

10. GLOSSARY

Colostomy: Surgery in which the end of the colon is passed through the abdominal wall to make the stoma [247].

Ileostomy: Surgery whereby the end of the ileum is passed through the abdominal wall to make the stoma [247].

Metachronous colorectal tumors: Primary tumors diagnosed more than six months apart [257].

Oncogene: Mutated form of a gene involved in normal cell growth, which can facilitate cancer cell growth. Gene mutations that become oncogenes arise through an inherited trait or environmental exposure to carcinogens [257].

Ostomy pouch: A removable external collection pouch attached to the stoma and worn outside the body for collection of intestinal contents or stool [247].

Ostomy surgery: Surgery of the bowel (also termed bowel diversion) involving removal of a bowel segment with the need to reroute passage of stool from the anus to and through the abdominal wall [247]. The ostomy brings the end of the intestines through an abdominal incision and attaches it to the skin, creating an opening outside the body.

Stoma: Refers to the end of the intestines that exits through the abdominal incision. Stomas range in width from 0.75–2 inches [247].

Synchronous colorectal tumors: Primary tumors diagnosed within six months of each other [257].

Tumor suppressor gene: Gene that produces a tumor suppressor protein that helps control cell growth. Mutations (changes in DNA) in tumor suppressor genes may promote cancer [257].

Works Cited

1. National Cancer Institute. Colorectal Cancer Screening: Health Professional Version. Available at https://www.cancer.gov/types/colorectal/hp/colorectal-screening-pdq. Last accessed February 8, 2019.

2. Imperiale TF, Wagner DR, Lin CY, Larkin GN, Rogge JD, Ransohoff DF. Results of screening colonoscopy among persons 40 to 49 years of age. N Engl J Med. 2002;346(23):1781-1785.

3. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer. N Engl J Med. 1994;331(25):1669-1674.

4. Keum N, Giovannucci EL. Folic acid fortification and colorectal cancer risk. Am J Prev Med. 2014;46(3 Suppl 1):S65-S72.

5. Nielsen A, Munk C, Kjaer SK. Trends in incidence of anal cancer and high-grade anal intraepithelial neoplasia in Denmark, 1978–2008. Int J Cancer. 2012;130(5):1168-1173.

6. World Health Organization, International Agency for Research on Cancer. Cancer Fact Sheets: Colorectal Cancer. Available at http://gco.iarc.fr/today/fact-sheets-cancers. Last accessed February 8, 2019.

7. American Cancer Society. Key Statistics for Colorectal Cancer. Available at https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html. Last accessed February 8, 2019.

8. American Cancer Society. Colorectal Cancer: Preventable, Beatable, Treatable. Available at https://www.cancer.org/content/dam/cancer-org/cancer-control/en/presentations/colorectal-cancer-presentation.pdf. Last accessed February 8, 2019.

9. Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2015. Bethesda, MD: National Cancer Institute; 2018.

10. Howlader N, Mariotto AB, Woloshin S, Schwartz LM. Providing clinicians and patients with actual prognosis: cancer in the context of competing causes of death. J Natl Cancer Inst Monogr. 2014;2014(49):255-264.

11. Siegel R, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30.

12. Laiyemo AO, Doubeni C, Pinsky PF, et al. Race and colorectal cancer disparities: health-care utilization vs. different cancer susceptibilities. J Natl Cancer Inst. 2010;102(8):538-546.

13. Sutton, E, Bellini G, Lee D, Njoh L, Whelan RL. An Update on Young-Onset Colorectal Cancer: An NCDB Analysis. Available at http://meetings.ssat.com/abstracts/2016/Tu1812.cgi. Last accessed February 8, 2019.

14. American Cancer Society. Cancer Facts and Figures, 2018. Atlanta, GA: American Cancer Society; 2018.

15. American Cancer Society. Survival Rates for Colorectal Cancer, by Stage. Available at https://www.cancer.org/cancer/colon- rectal-cancer/detection-diagnosis-staging/survival-rates.html. Last accessed February 8, 2019.

16. National Cancer Institute. Colorectal Cancer Prevention: Health Professional Version. Available at https://www.cancer.gov/ types/colorectal/hp/colorectal-prevention-pdq#link/_1025_toc. Last accessed February 8, 2019.

17. Fedirko V, Tramacere I, Bagnardi V, et al. Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol. 2011;22(9):1958-1972.

18. Cho E, Smith-Warner SA, Ritz J, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med. 2004;140(8):603-613.

19. Haggar FA, Boushey PP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009;22(4):191-197.

20. Zisman AL, Nickolov A, Brand RE, Gorchow A, Roy HK. Associations between the age at diagnosis and location of colorectal cancer and the use of alcohol and tobacco: implications for screening. Arch Intern Med. 2006;166(6):629-634.

21. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P. Smoking and colorectal cancer: a meta-analysis. JAMA. 2008;300(23):2765-2778.

22. Liang PS, Chen TY, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer. 2009;124(10):2406-2415.

23. Ma Y, Yang Y, Wang F, et al. Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One. 2013;8(1):e53916.

24. Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002;3(9):565-574.

25. Jacobs ET, Ahnen DJ, Ashbeck EL, et al. Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. Am J Epidemiol. 2009;169(6):657-666.

26. Gibson TM, Park Y, Robien K, et al. Body mass index and risk of second obesity-associated cancers after colorectal cancer: a pooled analysis of prospective cohort studies. J Clin Oncol. 2014;32(35):4004-4011.

27. Morikawa T, Kuchiba A, Lochhead P, et al. Prospective analysis of body mass index, physical activity, and colorectal cancer risk associated with ß-catenin (CTNNB1) status. Cancer Res. 2013;73(5):1600-1610.

28. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer. 2009;100(4):611-616.

29. Kruk J, Aboul-Enein HY. Physical activity and cancer prevention: updating the evidence. The role of oxidative stress in carcinogenesis. Curr Cancer Ther Rev. 2007;3(2):81-95.

30. Aleksandrova K, Jenab M, Leitzmann M, et al. Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC Cohort. Int J Epidemiol. 2017;46(6):1823-1835.

31. Boyle T, Keegel T, Bull F, Heyworth J, Fritschi L. Physical activity and risks of proximal and distal colon cancers: a systematic review and meta-analysis. J Natl Cancer Inst. 2012;104(20):1548-1561.

32. Rose DP, Boyar AP, Wynder EL. International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer. 1986;58(11):2363-2371.

33. Reddy BS. Dietary fat and its relationship to large bowel cancer. Cancer Res. 1981;41(9 Pt 2):3700-3705.

34. Potter JD, McMichael AJ. Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst. 1986;76(4):557-569.

35. Bingham SA. Diet and large bowel cancer. J R Soc Med. 1990;83(7):420-422.

36. Augustsson K, Skog K, Jägerstad M, Dickman PW, Steineck G. Dietary heterocyclic amines and cancer of the colon, rectum, bladder, and kidney: a population-based study. Lancet. 1999;353(9154):703-707.

37. Forman D. Meat and cancer: a relation in search of a mechanism. Lancet. 1999;353(9154):686-687.

38. Fuchs CS, Giovannucci EL, Colditz GA, et al. Dietary fiber and the risk of colorectal cancer and adenoma in women.N Engl J Med. 1999;340(3):169-176.

39. Kunzmann AT, Coleman HG, Huang WY, Cantwell MM, Kitahara CM, Berndt SI. Fruit and vegetable intakes and risk of colorectal cancer and incident and recurrent adenomas in the PLCO cancer screening trial. Int J Cancer. 2016;138(8): 1851-1861.

40. Jacobs ET, Lanza E, Alberts DS, et al. Fiber, sex, and colorectal adenoma: results of a pooled analysis. Am J Clin Nutr. 2006;83(2):343-349.

41. Koushik A, Hunter DJ, Spiegelman D, et al. Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies.J Natl Cancer Inst. 2007;99(19):1471-1483.

42. Je Y, Jeon JY, Giovannucci EL, Meyerhardt JA. Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int J Cancer. 2013;133(8):1905-1913.

43. Meyerhardt JA, Niedzwiecki D, Hollis D, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007;298(7):754-764.

44. Meyerhardt JA, Sato K, Niedzwiecki D, et al. Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst. 2012;104(22):1702-1711.

45. McCullough ML, Gapstur SM, Shah R, Jacobs EJ, Campbell PT. Association between red and processed meat intake and mortality among colorectal cancer survivors. J Clin Oncol. 2013;31(22):2773-2782.

46. Song M, Nishihara R, Wang M, et al. Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut. 2016;65(2):296-304.

47. Rigas B, Tsioulias GJ. The evolving role of nonsteroidal anti-inflammatory drugs in colon cancer prevention: a cause for optimism. J Pharmacol Exp Ther. 2015;353(1):2-8.

48. Manson JE, Bassuk SS. Vitamin D research and clinical practice: at a crossroads. JAMA. 2015;313(13):1311-1312.

49. Boghossian S, Hawash A. Chemoprevention in colorectal cancer––where we stand and what we have learned from twenty years' experience. Surgeon. 2012;10(1):43-52.

50. Benamouzig R, Uzzan B. Identification and chemoprevention in subjects at moderate risk of colorectal cancer. Best Pract Res Clin Gastroenterol. 2011;25(4-5):631-640.

51. Ng K, Meyerhardt JA, Chan AT, et al. Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst. 2015;107(1):345.

52. Knights KM, Mangoni AA, Miners JO. Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity. Expert Rev Clin Pharmacol. 2010;3(6):769-776.

53. Chan AT, Arber N, Burn J, et al. Aspirin in the chemoprevention of colorectal neoplasia: an overview. Cancer Prev Res (Phila). 2012;5(2):164-178.

54. Flossman E, Rothwell M. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomized and observational studies. Lancet. 2007;369(9573):1603-1613.

55. Burn J, Bishop DT, Mecklin JP, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359(24):2567-2578.

56. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081-2087.

57. Cooper K, Squires H, Carroll C, et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess. 2010;14(32):1-206.

58. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649-658.

59. Liao C, Gao F, Cao Y, Tan A, Li X, Wu D. Meta-analysis of the colon J-pouch vs. transverse coloplasty pouch after anterior resection for rectal cancer. Colorectal Dis. 2009;12(7):624-631.

60. U.S. Preventive Services Task Force. Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/aspirin-to-prevent-cardiovascular-disease-and-cancer. Last accessed February 8, 2019.

61. Rostom A, Dubé C, Lewin G, et al. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):376-389.

62. Thun MJ, Blackard B. Pharmacologic effects of NSAIDs and implications for the risks and benefits of long-term prophylactic use of aspirin to prevent cancer. Recent Results Cancer Res. 2009;181:215-221.

63. Garcia-Albeniz X, Chan AT. Aspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol. 2011;25(4-5): 461-472.

64. Federal Register. Pfizer, Inc. Withdrawal of Approval of Familial Adenomatous Polyposis Indication for CELEBREX. Available at https://www.federalregister.gov/articles/2012/06/08/2012-13900/pfizer-inc-withdrawal-of-approval-of-familial-adenomatous-polyposis-indication-for-celebrex. Last accessed February 8, 2019.

65. BlueCross BlueShield of North Carolina. COX-2 Inhibitors Utilization Management Criteria. Available at https://www.bcbsnc.com/assets/services/public/pdfs/formulary/Cox-2-V485.pdf. Last accessed February 8, 2019.

66. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclooxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332(7553):1302-1308.

67. Ritenbaugh C, Stanford JL, Wu L, et al. Conjugated equine estrogens and colorectal cancer incidence and survival: the Women's Health Initiative randomized clinical trial. Cancer Epidemiol Biomarkers Prev. 2008;17(10):2609-2618.

68. Simon MS, Chlebowski RT, Wactawski-Wende J, et al. Estrogen plus progestin and colorectal cancer incidence and mortality.J Clin Oncol. 2012;30(32):3983-3990.

69. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

70. Bostick RM, Potter JD, McKenzie DR, et al. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study. Cancer Res. 1993;53(18):4230-4237.

71. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294(1):56-65.

72. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. 2004;364(9441):1219-1228.

73. Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005;97 (1-2):179-194.

74. Pritchard RS, Baron JA, Gerhardsson de Verdier M. Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden. Cancer Epidemiol Biomarkers Prev. 1996;5(11):897-900.

75. Morales-Oyarvide V, Meyerhardt JA, Ng K. Vitamin D and physical activity in patients with colorectal cancer: epidemiological evidence and therapeutic implications. Cancer J. 2016;22(3):223-231.

76. Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998;129(7):517-524.

77. Eussen SJ, Vollset SE, Igland J, et al. Plasma folate, related genetic variants, and colorectal cancer risk in EPIC. Cancer Epidemiol Biomarkers Prev. 2010;19(5):1328-1340.

78. Cole BF, Baron JA, Sandler RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351-2359.

79. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med. 1999;340(2):101-107.

80. Grau MV, Baron JA, Sandler RS, et al. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst. 2007;99(2):129-136.

81. Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684-696.

82. Shaukat A, Scouras N, Schünemann HJ. Role of supplemental calcium in the recurrence of colorectal adenomas: a meta-analysis of randomized controlled trials. Am J Gastroenterol. 2005;100(2):390-394.

83. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.

84. Qaseem A, Denberg TD, Hopkins RH Jr. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann Intern Med. 2012;156(5):378-386.

85. Mishra N, Hall J. Identification of patients at risk for hereditary colorectal cancer. Clin Colon Rectal Surg. 2012;25(2):67-82.

86. Imperiale TF, Juluri R, Sherer EA, Glowinski EA, Johnson CS, Morelli MS. A risk index for advanced neoplasia on the second surveillance colonoscopy in patients with previous adenomatous polyps. Gastrointest Endosc. 2014;80(3):471-478.

87. American Society of Colon and Rectal Surgeons. Hereditary Colorectal Cancer. Available at https://www.fascrs.org/patients/disease-condition/hereditary-colorectal-cancer-0. Last accessed February 8, 2019.

88. Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138(6):2044-2058.

89. National Cancer Institute. Genetics of Colorectal Cancer: Health Professional Version. Available at https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq. Last accessed February 8, 2019.

90. Gala M, Chung DC. Hereditary colon cancer syndromes. Semin Oncol. 2011;38(4):490-499.

91. Pollock J, Welsh JS. Clinical cancer genetics: part I: gastrointestinal. Am J Clin Oncol. 2011;34(3):332-336.

92. Murff HJ, Peterson NB, Greevy R, Zheng W. Impact of patient age on family cancer history. Genet Med. 2006;8(7):438-442.

93. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296(12):1479-1487.

94. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2012;143(3):844-857.

95. Jang E, Chung DC. Hereditary colon cancer: Lynch syndrome. Gut Liver. 2010;4(2):151-160.

96. Patel SG, Ahnen DJ. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr Gastroenterol Rep. 2012;14(5):428-438.

97. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014;147(2):502-526.

98. Khan O, Blanco A, Conrad P, et al. Performance of Lynch syndrome predictive models in a multi-center U.S. referral population. Am J Gastroenterol. 2011;106(10):1822-1827.

99. Jasperson KW, Vu TM, Schwab AL, et al. Evaluating Lynch syndrome in very early onset colorectal cancer probands without apparent polyposis. Fam Cancer. 2010;9(2):99-107.

100. Boland CR. Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer. 2005;4(3):211-218.

101. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology. 1999;116(6):1453-1456.

102. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261-268.

103. Kastrinos F, Syngal S. Inherited colorectal cancer syndromes. Cancer J. 2011;17(6):405-415.

104. Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812-823.

105. Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut. 2011;60(7):950-957.

106. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007;44(6):353-362.

107. Renkonen-Sinisalo L, Seppälä TT, Järvinen HJ, Mecklin JP. Subtotal colectomy for colon cancer reduces the need for subsequent surgery in Lynch syndrome. Dis Colon Rectum. 2017;60(8):792-799.

108. Kim TJ, Kim ER, Hong SN, et al. Survival outcome and risk of metachronous colorectal cancer after surgery in Lynch syndrome. Ann Surg Oncol. 2017;24(4):1085-1092.

109. Rodriguez-Bigas MA, Möeslein G. Surgical treatment of hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). Fam Cancer. 2013;12(2):295-300.

110. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.Nat Genet. 1997;17(1):79-83.

111. Anaya DA, Chang GJ, Rodriguez-Bigas MA. Extracolonic manifestations of hereditary colorectal cancer syndromes. Clin Colon Rectal Surg. 2008;21(4):263-272.

112. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. 2008;57(5):704-713.

113. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Last accessed February 8, 2019.

114. Iwama T, Tamura K, Morita T, et al. A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan. Int J Clin Oncol. 2004;9(4):308-316.

115. Libutti SK, Willett CG, Saltz LB. Cancer of the rectum. In: DeVita VT Jr, Lawrence TS, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015: 823-841.

116. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am. 2009;18(4):687-703.

117. Burt R, Neklason DW. Genetic testing for inherited colon cancer. Gastroenterology. 2005;128(6):1696-1716.

118. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 2010;138(2):746-774.

119. Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. New Engl J Med. 2013;369(12):1095-1105.

120. Stracci F, Zorzi M, Grazzini G. Colorectal cancer screening: tests, strategies, and perspectives. Front Public Health. 2014;2:210.

121. Zauber AG, Winawer SJ, O'Brien MJ, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths.N Engl J Med. 2012;366(8):687-696.

122. Shaukat A, Mongin SJ, Geisser MS, et al. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013;369(12):1106-1114.

123. Brenner H, Chang-Claude J, Jansen L, Knebel P, Stock C, Hoffmeister M. Reduced risk of colorectal cancer up to 10 years after screening, surveillance, or diagnostic colonoscopy. Gastroenterology. 2014;146(3):709-717.

124. Løberg M, Kalager M, Holme Ø, Hoff G, Adami HO, Bretthauer M. Long-term colorectal-cancer mortality after adenoma removal. N Engl J Med. 2014;371(9):799-807.

125. Klabunde CN, Cronin KA, Breen N, et al. Trends in colorectal cancer test use among vulnerable populations in the United States. Cancer Epidemiol Biomarkers Prev. 2011;20(8):1611-1621.

126. Oxentenko AS, Goel NK, Pardi DS, et al. Colorectal cancer screening education, prioritization, and self-perceived preparedness among primary care residents: data from a national survey. J Cancer Educ. 2007;22(4):208-218.

127. Hampel H. NCCN increases the emphasis on genetic/familial high-risk assessment in colorectal cancer. J Natl Compr Canc Netw. 2014;12(5 Suppl):829-831.

128. Bressler B, Paszat LF, Chen Z, Rothwell DM, Vinden C, Rabeneck L. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology. 2007;132(1):96-102.

129. Warren JL, Klabunde CN, Mariotto AB, et al. Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med. 2009;150(12):849-857.

130. ASGE Standards of Practice Committee, Fisher DA, Maple JT, et al. Complications of colonoscopy. Gastrointestinal Endosc. 2011;74(4):745-753.

131. Rabeneck L, Paszat LF, Hilsden RJ, et al. Bleeding and perforation after outpatient colonoscopy and their risk factors in usual clinical practice. Gastroenterology. 2008;135(6):1899-1906.

132. Levin TR, Zhao W, Conell C, et al. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med. 2006;145(12):880-886.

133. Johnson DA, Barkun AN, Cohen LB, et al. Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2014;147(4):903-924.

134. Froehlich F, Wietlisbach V, Gonvers JJ, Burnand B, Vader JP. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005;61(3):378-384.

135. Harewood GC, Sharma VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endosc. 2003;58(1):76-79.

136. Rex DK, Imperiale TF, Latinovich DR, Bratcher LL. Impact of bowel preparation on efficiency and cost of colonoscopy.Am J Gastroenterol. 2002;97(7):1696-1700.

137. Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019;156(1):254-272.

138. Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Am J Gastroenterol. 2015;110(1):72-90.

139. Baxter N, Sutradhar R, Forbes SS, Paszat LF, Saskin R, Rabeneck L. Analysis of administrative data finds endoscopist quality measures associated with post-colonoscopy colorectal cancer. Gastroenterology. 2011;140(1):65-72.

140. Shaukat A, Oancea C, Bond JH, Church TR, Allen JI. Variation in detection of adenomas and polyps by colonoscopy and change over time with a performance improvement program. Clin Gastroenterol Hepatol. 2009;7(12):1335-1340.

141. Imperiale TF, Glowinski EA, Juliar BE, Azzouz F, Ransohoff DF. Variation in polyp detection rates at screening colonoscopy. Gastrointest Endosc. 2009;69(7):1288-1295.

142. Pohl H, Robertson DJ. Colorectal cancers detected after colonoscopy frequently result from missed lesions. Clin Gastroenterol Hepatol. 2010;8(10):858-864.

143. Simmons DT, Harewood GC, Baron TH, et al. Impact of endoscopist withdrawal speed on polyp yield: implications for optimal colonoscopy withdrawal time. Aliment Pharmacol Ther. 2006;24(6):965-971.

144. Lim G, Viney SK, Chapman BA, Frizelle FA, Gearry RB. A prospective study of endoscopist-blinded colonoscopy withdrawal times and polyp detection rates in a tertiary hospital. N Z Med J. 2012;125(1356):52-59.

145. Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med. 2006;355(24):2533-2541.

146. National Institute of Diabetes and Digestive and Kidney Diseases. Virtual Colonoscopy. Available at https://www.niddk.nih.gov/health-information/diagnostic-tests/virtual-colonoscopy. Last accessed February 8, 2019.

147. Zalis ME, Blake MA, Cai W, et al. Diagnostic accuracy of laxative-free computed tomographic colonography for detection of adenomatous polyps in asymptomatic adults: a prospective evaluation. Ann Intern Med. 2012;156(10):692-702.

148. Kimberly JR, Phillips KC, Santago P, et al. Extracolonic findings at virtual colonoscopy: an important consideration in asymptomatic colorectal cancer screening. J Gen Intern Med. 2009;24(1):69-73.

149. Pickhardt PJ, Hanson ME, Vanness DJ, et al. Unsuspected extracolonic findings at screening CT colonography: clinical and economic impact. Radiology. 2008;249(1):151-159.

150. National Institute of Diabetes and Digestive and Kidney Diseases. Flexible Sigmoidoscopy. Available at https://www.niddk.nih.gov/health-information/diagnostic-tests/flexible-sigmoidoscopy. Last accessed February 8, 2019.

151. Levin TR, Palitz A, Grossman S, et al. Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy. JAMA. 1999;281(17):1611-1617.

152. Rex DK, Johnson DA, Anderson JC, et al. American College of Gastroenterology guidelines for colorectal cancer screening, 2009 [corrected]. Am J Gastroenterol. 2009;104(6):1613.

153. National Colorectal Cancer Roundtable. Clinician's Reference: Fecal Occult Blood Testing (FOBT) for Colorectal Cancer Screening. Available at http://nccrt.org/wp-content/uploads/FOBTCliniciansReferenceFinal.pdf. Last accessed February 8, 2019.

154. Levi Z, Rozen P, Hazazi R, et al. A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med. 2007;146(4):244-255.

155. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370:1287-1297.

156. Hewitson P, Glasziou P, Irwig L, Towler B, Watson E. Screening for colorectal cancer using the faecal occult blood test, Hemoccult. Cochrane Database Syst Rev. 2007;24(1):CD001216.

157. Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008;58(3):130-160.

158. Cairns SR, Scholefield JH, Steele RJ, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59(5):666-690.

159. Singh H, Turner D, Xue L, Targownik LE, Bernstein CN. Risk of developing colorectal cancer following a negative colonoscopy examination. JAMA. 2006;295(20):2366-2373.

160. Robertson DJ, Lieberman DA, Winawer SJ, et al. Interval cancer after total colonoscopy: results from a pooled analysis of eight studies. Gastroenterology. 2008;134(4 Suppl 1):A111-A112.

161. U.S. Preventive Services Task Force. Colorectal Cancer: Screening. Available at https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/colorectal-cancer-screening. Last accessed January 7, 2022.

162. Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42(1):124-139.

163. Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27(9):1423-1431.

164. BMJ Best Practice. Colorectal Cancer. Available at https://bestpractice.bmj.com/topics/en-us/258. Last accessed February 8, 2019.

165. Saclarides TJ, Szeluga D, Staren ED. Neuroendocrine cancers of the colon and rectum: results of a ten-year experience. Dis Colon Rectum. 1994;37(7):635-642.

166. Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001;96(10):2992-3003.

167. Burt RW. Familial risk and colorectal cancer. Gastroenterol Clin North Am. 1996;25(4):793-803.

168. Kang H, O'Connell JB, Leonardi MJ, Maggard MA, Mcgory ML, Ko CY. Rare tumors of the colon and rectum: a national review. Int J Colorectal Dis. 2007;22(2):183-189.

169. Arnold CN, Goel A, Blum HE, Boland CR. Molecular pathogenesis of colorectal cancer. Cancer. 2005;104(10):2035-2047.

170. Wu K, Keum N, Nishihara R, Giovannucci EL. Cancers of the colon and rectum. In: Thun MJ, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D (eds). Cancer Epidemiology and Prevention. 4th ed. New York, NY: Oxford University Press; 2018: 681-706.

171. Manne U, Shanmugam C, Katkoori VR, Bumpers HL, Grizzle WE. Development and progression of colorectal neoplasia. Cancer Biomark. 2010;9(1-6):235-265.

172. Shah NB, Lindor NM. Lower gastrointestinal tract cancer predisposition syndromes. Hematol Oncol Clin North Am. 2010;24(6):1229-1252.

173. Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut. 2011;60(1):116-129.

174. De Jong AE, Morreau H, Van Puijenbroek M, et al. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology. 2004;126(1):42-48.

175. Grizzle WE, Srivastava S, Manne U. The biology of incipient, pre-invasive or intraepithelial neoplasia. Cancer Biomark. 2011;9 (1-6):21-39.

176. Reeves HL, Narla G, Ogunbiyi O, et al. Kruppel-like factor 6 (KLF6) is a tumor-suppressor gene frequently inactivated in colorectal cancer. Gastroenterology. 2004;126(4):1090-1103.

177. Gonsalves WI, Mahoney MR, Sargent DJ, et al. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance No. 147. J Natl Cancer Inst. 2014;106(7):dju106.

178. Sideris M, Papagrigoriadis S. Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer. Anticancer Res. 2014;34(5):2061-2068.

179. Monson JRT, Weiser MR, Buie WD, et al. Practice parameters for the management of rectal cancer (revised). Dis Colon Rectum. 2013;56(5):535-550.

180. Chang GJ, Kaiser AM, Mills S, et al. Practice parameters for the management of colon cancer. Dis Colon Rectum. 2012;55:831-843.

181. Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer. 2006;42(2):216-227.

182. Kanellos D, Kitsios G, Kanellos I, et al. Anemia as a symptom of right colon cancer. Tech Coloproctol. 2004;8(Suppl 1):s62-s64.

183. du Toit J, Hamilton W, Barraclough K. Risk in primary care of colorectal cancer from new onset rectal bleeding: 10 year prospective study. BMJ. 2006;333(7558):69-70.

184. Fisher SE, Daniels LR. The clinical presentation of colorectal cancer. In: Brown G (ed). Colorectal Cancer: Contemporary Issues in Cancer Imaging. Cambridge: Cambridge University Press; 2008: 1-14.

185. Halligan S, Wooldrage K, Dadswell E, et al. Computed tomographic colonography versus barium enema for diagnosis of colorectal cancer or large polyps in symptomatic patients (SIGGAR): a multicentre randomised trial. Lancet. 2013;381(9873):1185-1193.

186. Atkin W, Dadswell E, Wooldrage K, et al. Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial. Lancet. 2013;381(9873):1194-1202.

187. ASGE Standards of Practice Committee, Fisher DA, Shergill AK, et al. Role of endoscopy in the staging and management of colorectal cancer. Gastrointest Endosc. 2013;78(1):8-12.

188. Ganeshan A, Upponi S, Uberoi R, D'Costa H, Picking C, Bungay H. Minimal-preparation CT colon in detection of colonic cancer, the Oxford experience. Age Ageing. 2007;36(1):48-52.

189. Kealey SM, Dodd JD, MacEneaney PM, Gibney RG, Malone DE. Minimal preparation computed tomography instead of barium enema/colonoscopy for suspected colon cancer in frail elderly patients: an outcome analysis study. Clin Radiol. 2004;59(1):44-52.

190. Al-Sukhni E, Milot L, Fruitman M, et al. Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol. 2012;19(7):2212-2223.

191. Zhang C, Chen Y, Xue H, et al. Diagnostic value of FDG-PET in recurrent colorectal carcinoma: a meta-analysis. Int J Cancer. 2009;124(1):167-173.

192. Kennedy E, Vella E, MacDonald DB, Wong CS, McLeod R. Optimization of preoperative assessment in patients diagnosed with rectal cancer. Clin Oncol (R Coll Radiol). 2015;27(4):225-245.

193. National Cancer Institute. Colon Cancer Treatment: Health Professional Version. Available at https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq. Last accessed February 8, 2019.

194. Amin MB, Edge SB, Greene F, et al. (eds). AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2018.

195. American Joint Committee on Cancer. Cancer Staging System. Available at https://cancerstaging.org/references-tools/Pages/ What-is-Cancer-Staging.aspx. Last accessed February 8, 2019.

196. American Cancer Society. Colorectal Cancer Stages. Available at https://www.cancer.org/cancer/colon-rectal-cancer/detection-diagnosis-staging/staged.html. Last accessed February 8, 2019.

197. National Cancer Institute. Rectal Cancer Treatment: Health Professional Version. Available at https://www.cancer.gov/types/colorectal/hp/rectal-treatment-pdq. Last accessed February 8, 2019.

198. Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol. 2009;27(7):1130-1136.

199. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247-257.

200. Quasar Collaborative Group, Gray R, Barnwell J. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370(9604):2020-2029.

201. Kawakami H, Zaanan A, Sinicrope FA. MSI testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16(7):30.

202. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29(6):610-618.

203. Ogino S, Kawasaki T, Kirkner GJ, Ohnishi M, Fuchs CS. 18q loss of heterozygosity in microsatellite stable colorectal cancer is correlated with CpG island methylator phenotype-negative (CIMP-0) and inversely with CIMP-low and CIMP-high. BMC Cancer. 2007;7:72.

204. Hugen N, van de Velde CJ, de Wilt JH, Nagtegaal ID. Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol. 2014;25(3):651-657.

205. Chua TC, Saxena A, Chu F, Zhao J, Morris DL. Predictors of cure after hepatic resection of colorectal liver metastases: an analysis of actual 5- and 10-year survivors. J Surg Oncol. 2011;103(8):796-800.

206. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309-318.

207. Aggarwal C, Meropo NJ, Punt CJ, et al. Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann Oncol. 2013;24(2):420-428.

208. Donadon M, Lleo A, Di Tommaso L, et al. The shifting paradigm of prognostic factors of colorectal liver metastases: from tumor-center to host immune-centered factors. Front Oncol. 2018;8:181.

209. Van der Jeught K, Xu HC, Li YJ, Lu XB, Ji G. Drug resistance and new therapies in colorectal cancer. World J Gastroenterol. 2018;24(34):3834-3848.

210. Angiogenesis Foundation. Update on Antiangiogenic Therapy for Metastatic Colorectal Cancer. Available at http://www.angio.org/pdf/CRC2013ePub.pdf. Last accessed February 8, 2019.

211. Gezen C, Kement M, Altuntas YE, et al. Results after multivisceral resections of locally advanced colorectal cancers: an analysis on clinical and pathological t4 tumors. World J Surg Oncol. 2012;10:39.

212. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Colon Cancer. Available at https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Last accessed February 8, 2019.

213. National Cancer Institute. Drugs Approved for Colon and Rectal Cancer. Available at https://www.cancer.gov/about-cancer/treatment/drugs/colorectal. Last accessed February 8, 2019.

214. Lexicomp Online. Available at http://online.lexi.com. Last accessed February 8, 2019.

215. The Angiogenesis Foundation. Treatments: Angiogenesis Inhibitors for Cancer. Available at https://angio.org/learn/treatments. Last accessed February 8, 2019.

216. Woo J, Palmisiano N, Tester W, Leighton JC Jr. Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer. Cancer. 2013;119(11):1941-1950.

217. Knijn N, Tol J, Punt CJ. Current issues in the targeted therapy of advanced colorectal cancer. Discov Med. 2010;9(47):328-336.

218. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532-536.

219. Kim TW, Elme A, Kusic Z, et al. A phase 3 trial evaluating panitumumab plus best supportive care vs. best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016;115(10):1206-1214.

220. Peeters M, Oliner KS, Price TJ, et al. Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 2015;21(24):5469-5479.

221. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Rectal Cancer. Available at https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Last accessed February 8, 2019.

222. Hines RB, Barrett A, Twumasi-Ankrah P, et al. Predictors of guideline treatment nonadherence and the impact on survival in patients with colorectal cancer. J Natl Compr Canc Netw. 2015;13(1):51-60.

223. Panettiere FJ, Goodman PJ, Costanzi JJ, et al. Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group study. J Clin Oncol. 1988;6(6):947-954.

224. Franklin ME Jr, Rosenthal D, Abrego-Medina D, et al. Prospective comparison of open vs. laparoscopic colon surgery for carcinoma: five-year results. Dis Colon Rectum. 1996;39(10 Suppl):S35-S46.

225. Weeks JC, Nelson H, Gelber S, et al. Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs. open colectomy for colon cancer: a randomized trial. JAMA. 2002;287(3):321-328.

226. Jayarajah U, Samarasekera AM, Samarasekera DN. A study of postoperative anxiety and depression among patients with intestinal stomas. Sri Lanka J Surg. 2016;34(2):6-10.

227. Liao C, Qin Y. Factors associated with stoma quality of life among stoma patients. Int J Nurs Sci. 2014;1(2):196-201.

228. Farrell M. Smeltzer and Bares Textbook of Medical-Surgical Nursing. 4th ed. Netherlands: Wolters Kluwer Health; 2016.

229. National Institute for Health and Clinical Excellence. Colorectal Cancer: Diagnosis and Management. Available at https:// www.nice.org.uk/guidance/cg131/chapter/1-Recommendations#ongoing-care-and-support. Last accessed February 8, 2019.

230. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol. 2004;22(10):1797-1806.

231. Benson AB III, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol. 2004;22(16):3408-3419.

232. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109-3116.

233. Martin LK, Bekaii-Saab T. Optimizing neoadjuvant therapy for rectal cancer with oxaliplatin. J Natl Compr Canc Netw. 2013;11(3):298-307.

234. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926-1933.

235. Roh MS, Colangelo LH, O'Connell MJ, et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol. 2009;27(31):5124-5130.

236. Willett CG, Badizadegan K, Ancukiewicz M, Shellito PC. Prognostic factors in stage T3N0 rectal cancer: do all patients require postoperative pelvic irradiation and chemotherapy? Dis Colon Rectum. 1999;42(2):167-173.

237. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740.

238. National Institute for Health and Clinical Excellence. Colorectal Cancer: Diagnosis and Management. Available at https://www.nice.org.uk/guidance/cg131/resources. Last accessed February 8, 2019.

239. Seitz U, Bohnacker S, Seewald S, et al. Is endoscopic polypectomy an adequate therapy for malignant colorectal adenomas? Presentation of 114 patients and review of the literature. Dis Colon Rectum. 2004;47(11):1789-1796.

240. Peng J, Chen W, Venook AP, et al. Long-term outcome of early-stage rectal cancer undergoing standard resection and local excision. Clin Colorectal Cancer. 2011;10(1):37-41.

241. Stitzenberg KB, Sanoff HK, Penn DC, Meyers MO, Tepper JF. Practice patterns and long-term survival for early-stage rectal cancer. J Clin Oncol. 2013;31(34):4276-4282.

242. Nash GM, Weiser MR, Guillem JG, et al. Long-term survival after transanal excision of T1 rectal cancer. Dis Colon Rectum. 2009;52(4):577-582.

243. Brown CJ, Fenech DS, McLeod RS. Reconstructive techniques after rectal resection for rectal cancer. Cochrane Database Syst Rev. 2008;(2):CD006040.

244. Maurer CA, Renzulli P, Kull C, et al. The impact of the introduction of total mesorectal excision on local recurrence rate and survival in rectal cancer: long-term results. Ann Surg Oncol. 2011;18(7):1899-1906.

245. Baxter NN, Garcia-Aguilar J. Organ preservation for rectal cancer. J Clin Oncol. 2007;25(8):1014-1020.

246. Fujita S, Akasu T, Mizusawa J, et al. Postoperative morbidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): results from a multicentre, randomised controlled, noninferiority trial. Lancet Oncol. 2012;13(6):616-621.

247. National Institute of Diabetes and Digestive and Kidney Diseases. Ostomy Surgery of the Bowel. Available at https://www.niddk.nih.gov/health-information/digestive-diseases/ostomy-surgery-bowel. Last accessed February 8, 2019.

248. Wong R, Berry S, Spithoff K, et al. Preoperative or Postoperative Therapy for the Management of Patients with Stage II or III Rectal Cancer. Available at https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/31891. Last accessed February 8, 2019.

249. Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009;373(9666): 811-820.

250. Valentini V, Beets-Tan R, Borras JM, et al. Evidence and research in rectal cancer. Radiother Oncol. 2008;87(3):449-474.

251. Abraha I, Aristei C, Palumbo I, et al. Pre-operative radiotherapy and curative surgery for the management of localized rectal carcinoma. Cochrane Database Syst Rev. 2018;(10):CD002102.

252. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114-1123.

253. Weiser MR, Quah HM, Shia J, et al. Sphincter preservation in low rectal cancer is facilitated by preoperative chemoradiation and intersphincteric dissection. Ann Surg. 2009;249(2):236-242.

254. De Caluwé L, Van Nieuwenhove Y, Ceelen WP. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev. 2013;2:CD006041.

255. Jakobsen A, Ploen J, Vuong T, Appelt A, Lindebjerg J, Rafaelsen SR. Dose-effect relationship in chemoradiotherapy for locally advanced rectal cancer: a randomized trial comparing two radiation doses. Int J Radiat Oncol Biol Phys. 2012;84(4):949-954.

256. Benson AB III, Venook AP, Bekaii-Saab T, et al. Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014;12(7):1028-1059.

257. National Cancer Institute. NCI Dictionary of Cancer Terms. Available at https://www.cancer.gov/publications/dictionaries/ cancer-terms. Last accessed February 8, 2019.

258. Dragovich T, Tsikitis VL. Colon Cancer Medication. Available at https://emedicine.medscape.com/article/277496-medication. Last accessed February 8, 2019.

259. Cagir B, Trostle DR. Rectal Cancer Medication. Available at https://emedicine.medscape.com/article/281237-medication. Last accessed February 8, 2019.

260. Wang JH, King TM, Chang MC, Hsu CW. Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis. World J Gastroenterol. 2012;18(38):5427-5433.

261. Saif MW, Relias V, Syrigos K, Gunturu KS. Incidence and management of ziv-aflibercept related toxicities in colorectal cancer. World J Clin Oncol. 2014;5(5):1028-1035.

262. Matin K. Colon Cancer Treatment Protocols. Available at https://emedicine.medscape.com/article/2005487-overview. Last accessed February 8, 2019.

263. Poston GJ, Adam R, Alberts S, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol. 2005;23(28):7125-7134.

264. Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759-766.

265. Rodriguez-Bigas MA, Herrera L, Petrelli NJ. Surgery for recurrent rectal adenocarcinoma in the presence of hydronephrosis.Am J Surg. 1992;164(1):18-21.

266. Vermaas M, Ferenschild FT, Verhoef C, et al. Total pelvic exenteration for primary locally advanced and locally recurrent rectal cancer. Eur J Surg Oncol. 2007;33(4):452-458.

267. Ogunbiyi OA, McKenna K, Birnbaum EH, Fleshman JW, Kodner IJ. Aggressive surgical management of recurrent rectal cancer— is it worthwhile? Dis Colon Rectum. 1997;40(2):150-155.

268. Weiser MR, Landmann RG, Wong WD, et al. Surgical salvage of recurrent rectal cancer after transanal excision. Dis Colon Rectum. 2005;48(6):1169-1175.

269. Scheithauer W, Rosen H, Kornek GV, Sebesta C, Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ. 1993;306(6880):752-755.

270. Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol. 1995;13(6):1303-1311.

271. Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Relation between tumour response to first-line chemotherapy and survival in advanced colorectal cancer: a meta-analysis. Meta-Analysis Group in Cancer. Lancet. 2000;356(9227):373-378.

272. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19(21):4097-4106.

273. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19(8):2282-2292.

274. Díaz-Rubio E, Tabernero J, Gómez-España A, et al. Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol. 2007;25(27):4224-4230.

275. Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol. 2007;25(27):4217-4223.

276. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905-914.

277. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938-2947.

278. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355(9209):1041-1047.

279. Sanoff HK, Sargent DJ, Campbell ME, et al. Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741. J Clin Oncol. 2008;26(35):5721-5727.

280. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237.

281. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005;23(22):4866-4875.

282. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.

283. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol. 2003;21(11):2059-2069.

284. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-572.

285. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.

286. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013-2019.

287. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200.J Clin Oncol. 2005;23(16 Suppl):S2.

288. Arnold D, Andre T, Bennouna J, et al. Bevacizumab plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (metastatic colorectal cancer) previously treated with bevacizumab plus CT: results of a randomized phase III intergroup study (TML study). J Clin Oncol. 2012;30(18 Suppl):CRA3503.

289. National Cancer Institute. Bevacizumab. Available at https://www.cancer.gov/about-cancer/treatment/drugs/bevacizumab. Last accessed February 8, 2019.

290. Loupakis F, Cremolini C, Masi G, et al. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer.N Engl J Med. 2014;371(17):1609-1618.

291. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506.

292. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.

293. Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.N Engl J Med. 2009;360(14):1408-1417.

294. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103-2114.

295. Adams RA, Meade AM, Seymour MT, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.Lancet Oncol. 2011;12(7):642-653.

296. Bokemeyer C, Van Cutsem E, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466-1475.

297. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-1664.

298. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697-4705.

299. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(31):4706-4713.

300. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.

301. Cunningham D, Pyrhönen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352(9138):1413-1418.

302. Masi G, Vasile E, Loupakis F, et al. Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis. J Natl Cancer Inst. 2011;103(1):21-30.

303. Scheele J, Stangl R, Altendorf-Hofmann A. Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history. Br J Surg. 1990;77(11):1241-1246.

304. Stangl R, Altendorf-Hofmann A, Charnley RM, Scheele J. Factors influencing the natural history of colorectal liver metastases. Lancet. 1994;343(8910):1405-1410.

305. Gallinger S, Biagi JJ, Fletcher GG, et al. Liver Resection for Colorectal Metastases: Evidence-Based Series No. 17-7. Available at https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/2236. Last accessed February 8, 2019.

306. Shah SA, Bromberg R, Coates A, et al. Survival after liver resection for metastatic colorectal carcinoma in a large population.J Am Coll Surg. 2007;205(5):676-683.

307. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818-827.

308. Quan D, Gallinger S, Nhan C, et al. The role of liver resection for colorectal cancer metastases in an era of multimodality treatment: a systematic review. Surgery. 2012;151(6):860-870.

309. Shah SA, Haddad R, Al-Sukhni W, et al. Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma.J Am Coll Surg. 2006;202(3):468-475.

310. Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24(31):4976-4982.

311. Mitry E, Fields AL, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J Clin Oncol. 2008;26(30):4906-4911.

312. Ychou M, Hohenberger W, Thezenas S, et al. A randomized phase III study comparing adjuvant 5-fluorouracil/folinic acid with FOLFIRI in patients following complete resection of liver metastases from colorectal cancer. Ann Oncol. 2009;20(12):1964-1970.

313. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007-1016.

314. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med. 1999;341(27):2039-2048.

315. Mocellin S, Pilati P, Lise M, Nitti D. Meta-analysis of hepatic arterial infusion for unresectable liver metastases from colorectal cancer: the end of an era? J Clin Oncol. 2007;25(35):5649-5654.

316. Pawlik TM, Izzo F, Cohen DS, Morris JS, Curley SA. Combined resection and radiofrequency ablation for advanced hepatic malignancies: results in 172 patients. Ann Surg Oncol. 2003;10(9):1059-1069.

317. National Institute for Health and Care Excellence. Radiofrequency Ablation for Colorectal Liver Metastases. Available at https://www.nice.org.uk/guidance/ipg327. Last accessed February 8, 2019.

318. Ravikumar TS, Kaleya R, Kishinevsky A. Surgical ablative therapy of liver tumors. PPO Updates. 2000;14:1-12.

319. Bageacu S, Kaczmarek D, Lacroix M, Dubois J, Forest J, Porcheron J. Cryosurgery for resectable and unresectable hepatic metastases from colorectal cancer. Eur J Surg Oncol. 2007;33(5):590-596.

320. Ravikumar TS. Interstitial therapies for liver tumors. Surg Oncol Clin N Am. 1996;5(2):365-377.

321. Headrick JR, Miller DL, Nagorney DM, et al. Surgical treatment of hepatic and pulmonary metastases from colon cancer.Ann Thorac Surg. 2001;71(3):975-979.

322. Dowswell G, Ismail T, Greenfield S, Clifford S, Hancock B, Wilson S. Men's experience of erectile dysfunction after treatment for colorectal cancer: qualitative interview study. BMJ. 2011;343:d5824.

323. Meyerhardt JA, Mangu PB, Flynn PJ, et al. Follow-up care, surveillance protocol, and secondary prevention measures for survivors of colorectal cancer: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol. 2013;31(35):4465-4470.

324. Pfister DG, Benson AB 3rd, Somerfield MR. Clinical practice. Surveillance strategies after curative treatment of colorectal cancer. N Engl J Med. 2004;350(23):2375-2382.

325. Li Destri G, Di Cataldo A, Puleo S. Colorectal cancer follow-up: useful or useless? Surg Oncol. 2006;15(1):1-12.

326. Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi64-vi72.

327. Earle C, Annis R, Sussman J, Haynes AE, Vafaei A. Follow-Up Care, Surveillance Protocol, and Secondary Prevention Measures for Survivors of Colorectal Cancer: Evidence-Based Series 26-2. Available at http://www.southlakeregional.org/doc.aspx?id=900. Last accessed February 8, 2019.

328. Abir F, Alva S, Longo WE, Audiso R, Virgo KS, Johnson FE. The postoperative surveillance of patients with colon cancer and rectal cancer. Am J Surg. 2006;192(1):100-108.

329. Qaseem A, Crandell CJ, Mustafa RA, Hicks LA, Wilt TJ. Screening for colorectal cancer in asymptomatic average-risk adults: a guidance statement From the American College of Physicians. Ann Intern Med. 2019;171(9):643-654.

Evidence-Based Practice Recommendations Citations

1. Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 4.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Last accessed March 5, 2019.

2. Provenzale D, Gupta S, Ahnen DJ, et al. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 1.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Last accessed March 5, 2019.

3. Provenzale D, Gupta S, Ahnen DJ, et al. NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 1.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Last accessed March 5, 2019.

4. Benson AB III, Venook AP, Al-Hawary MM, et al. NCCN Clinical Practice Guidelines in Oncology: Rectal Cancer. Version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Last accessed March 5, 2019.