NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-013-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/90822; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: October 10, 2021; Expiration date: October 10, 2022
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Jennifer M. Weiss, MD, MS, Panel Vice Chair, has disclosed receiving grant/research support from Exact Sciences.
Samir Gupta, MD, Panel Chair, has disclosed serving as a scientific advisor for Cellmax, Freenome, and Guardant; and receiving grant/research support from Epigenomics and Freenome.
Carol A. Burke, MD, has disclosed serving as a consultant for SLA Pharma and Freenome; and receiving grant/research support from Freenome, Emtora Biosciences, and Janssen Pharmaceuticals.
Susan D. Darlow, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
Mary A. Dwyer, MS, CGC, Director, Guidelines Operations, NCCN, has disclosed that she has no relevant financial relationships.
Mallory Campbell, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.
Overview
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States.1 In 2021, an estimated 104,270 new cases of colon cancer and 45,230 new cases of rectal cancer will occur in the United States. During the same year, it is estimated that 52,980 people will die of colon and rectal cancer.1 Importantly, the incidence of CRC per 100,000 decreased from 60.5 in 1976 to 46.4 in 2005.2 Despite improvements in the overall CRC incidence rate, a retrospective cohort study of the SEER CRC registry found that the incidence of CRC in patients aged <50 years has been increasing.3 The authors estimate that the incidence rates for colon and rectal cancers will increase by 90.0% and 124.2% for patients aged 20 to 34 years, respectively, by 2030.
CRC often occurs sporadically, with approximately 5% to 10% of all CRCs attributed to well-defined hereditary colon cancer syndromes. These well-defined inherited syndromes include Lynch syndrome, adenomatous polyposis syndromes (eg, familial adenomatous polyposis [FAP], attenuated familial adenomatous polyposis [AFAP], MUTYH-associated polyposis), and hamartomatous polyposis syndromes (eg, juvenile polyposis syndrome, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndromes). This article will focus on recent updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal regarding the management of FAP/AFAP, including lower gastrointestinal tract surveillance following surgery and upper gastrointestinal tract surveillance for gastric and duodenal neoplasia.
FAP/AFAP
Classic FAP and AFAP are autosomal dominant conditions characterized by a pathogenic/likely pathogenic (P/LP) germline variant in the APC gene, located on chromosome 5q21.4,5 A truncating mutation of the APC gene is detectable in approximately 80% of patients with FAP.6,7 Approximately 20% to 30% of cases are due to de novo P/LP APC germline mutations, with some cases attributable to mosaicism.8–10
Diagnosis: Classic Versus Attenuated FAP
A clinical diagnosis of classic FAP is suspected with the early onset of at least 100 cumulative adenomas in the large bowel. Individuals with classic FAP can start to develop adenomas in early adolescence, which then progress to hundreds to thousands of colonic adenomas at older ages, if no endoscopic or surgical interventions are performed. If risk-reducing surgery (ie, total abdominal colectomy with ileorectal anastomosis, proctocolectomy with ileal pouch-anal anastomosis, or proctocolectomy with end-ileostomy) is not performed, the lifetime risk for CRC in individuals with classic FAP approaches 100% by age 50 years. Individuals with FAP also have an increased lifetime risk for other cancers, including duodenal/ampullary cancer (1%–10%), thyroid cancer (1%–12%), gastric cancer (0.5%–1.3%), and hepatoblastoma (1%–2%, usually by age 5 years).11–32 Most thyroid cancers seen in FAP are papillary thyroid carcinomas, with the rare cribriform-morular variant considered almost pathognomonic.33 Other possible associated findings of patients with FAP include benign desmoid tumors, which occur more frequently in patients with mutations in the 3′ end of the APC gene (after codon 1444), and congenital hypertrophy of the retinal pigment epithelium (CHRPE), which occurs in patients with mutations in the central portion of the gene (between codons 311 and 1444).34–38 Increasingly, individuals are being diagnosed in the second decade of life through genetic testing for their specific familial P/LP variant or through endoscopic screening of at-risk family members.39
AFAP is a recognized variant of FAP characterized by a later onset of disease and fewer cumulative lifetime adenomas than observed with classic FAP, typically ranging from 10 to <100.4,5 AFAP is due to APC P/LP variants in the 5′ end of the gene, in exon 9, or in the 3′ end of the gene.40 Adenomas associated with AFAP are more prone to occur in the right colon. Phenotypic expression of classic versus attenuated FAP is often variable within families. The onset of CRC is typically delayed by 10 to 20 years compared with patients with FAP,40 but the incidence of cancer increases sharply after the age of 40 years and approaches 70% by age 80 years in absence of endoscopic or surgical intervention. Upper gastrointestinal findings, including gastric and duodenal/ampullary cancer risks, as well as thyroid cancer risks are similar to those observed for classic FAP.
To confirm the diagnosis of FAP or AFAP, germline testing to evaluate for a P/LP variant in the APC gene is recommended. Single-site testing can be pursued if there is a known familial P/LP pathogenic variant. Multigene panel testing for hereditary polyposis syndromes is recommended in absence of a known P/LP variant. Germline testing is important to differentiate between other etiologies of adenomatous polyposis (eg, MUTYH-associated polyposis, POLE- and POLD1-associated polyposis) for the consideration of extracolonic screening, as well as counseling, risk assessment, and testing of family members.
If there is suspicion for FAP/AFAP, genetic counseling and testing should be suggested. Identifying a P/LP variant allows for screening and testing of at-risk family members. When the familial P/LP variant is known, genetic counseling and testing of asymptomatic, at-risk family members is indicated. If the clinically affected family member is not available for testing, testing of other at-risk family members can be considered. Genetic testing for FAP in at-risk children is recommended to be performed no later than age 10 to 12 years, the age at which polyp surveillance would be initiated. If there is intent to perform hepatoblastoma screening, genetic testing may be considered in infancy. Genetic testing for AFAP in at-risk individuals may be performed by the late teens, the age range during which endoscopic surveillance would be initiated.
Preoperative Lower Gastrointestinal Tract Surveillance for Individuals With a Personal and Family History of Classic FAP/AFAP
Negative Genetic Testing in the Setting of a Known P/LP APC Variant
If an at-risk individual has negative genetic testing for the known familial P/LP variant, then average-risk CRC screening starting at age 45 years is recommended. Screening recommendations should also take into consideration other risk factors for CRC that might modify the approach to CRC screening (see NCCN Guidelines for Colorectal Cancer Screening, available at NCC.org).
Positive Genetic Testing
In a family with classic FAP, if an APC P/LP variant is found, high-quality colonoscopy (preferred option) or flexible sigmoidoscopy every 12 months, beginning at 10 to 15 years of age, is recommended. If adenomas develop, a surgical consultation to discuss timing and options for surgery should be reviewed. Timing of surgery should be individualized to account for genotype, phenotype, and personal considerations. In a family with AFAP, if an APC P/LP variant is found, high-quality colonoscopy should begin in late teens and continue every 1 to 2 years. Sigmoidoscopy is specifically not recommended due to predominance of right-sided polyps in AFAP. Surveillance intervals may be shortened or initiated at earlier ages depending on family history. Features of high-quality colonoscopy include an examination complete to the cecum, a bowel preparation adequate for detection of polyps >5 mm, and careful attention to adenoma detection.41
No Genetic Testing in an Affected Individual With a Family History of FAP/AFAP
Affected individuals with a phenotype consistent with FAP/AFAP may choose not to undergo genetic testing, and the healthcare team should continue to address barriers to and concerns about completing genetic testing. In this situation, these individuals should continue to be managed as if they had positive genetic testing and based on their presenting phenotype (see previous section).
No Genetic Testing in an Unaffected Individual With a Family History of FAP/AFAP
Testing for an APC P/LP variant in a family member exhibiting clinical features of FAP/AFAP is the most informative strategy. In some cases, at-risk individuals who are unaffected (ie, not known to have a phenotype consistent with FAP/AFAP) may elect not to follow recommendations to undergo genetic testing. During a recent meeting to discuss updates to these NCCN Guidelines, the panel consensus was to modify the surveillance intervals for unaffected, at-risk individuals who have not had genetic testing and have had multiple colonoscopic examinations without any adenomas. If genetic testing is not performed in an individual considered to be at risk for classic FAP, this individual should be offered annual high-quality colonoscopy (preferred option) or flexible sigmoidoscopy beginning at 10 to 15 years of age. If no adenomas are found, surveillance intervals may be extended to every 2 years. If multiple surveillance examinations show no adenomas on follow-up, the interval between colonoscopies may be lengthened based on clinical judgements. At-risk individuals in families with phenotypic or genotypic AFAP should be offered high-quality colonoscopy every 2 years beginning in late teens, with lengthened intervals considered if multiple follow-up examinations show no adenomas. Accordingly, the panel recommends that individuals who have not undergone genetic testing should continue to have discussions with their providers about the advantages of genetic testing, which include avoidance of the costs, burden, and potential risks associated with frequent colonoscopy procedures that could be stopped if the familial APC P/LP variant is not detected.
No Familial P/LP Variant Found
In some families with clinical phenotypes of classic FAP/AFAP, P/LP variants in the APC gene are not identified. The frequency of detection of APC P/LP variants is currently approximately 70% to 90%.42 As newer technologies have become available, updated genetic testing to identify an APC P/LP variant is recommended. An emerging approach to evaluation in some families is to test for mosaicism by comparing multiple adenomatous polyps from the same affected individual for APC P/LP variants. In addition, multigene panel testing for other causes of adenomatous polyposis in an affected individual/family member is recommended.
Postoperative Gastrointestinal Tract Surveillance in FAP/AFAP
In general, it is recommended that patients with FAP consider colectomy in late adolescence or early adulthood. Timing of surgery should be individualized to account for genotype, phenotype, and personal considerations. As recommendations for surgical management have not changed, this article mainly focuses on postsurgical surveillance.
Surgical Options in FAP and AFAP
Three different surgical options are available for individuals with classic FAP or AFAP: total proctocolectomy with ileal pouch-anal anastomosis (TPC/IPAA) (recommended for FAP), total abdominal colectomy with ileorectal anastomosis (TAC/IRA) (recommended for AFAP), and TPC with permanent end ileostomy (TPC/EI).43 The prime factors to consider when choosing an operation for FAP and AFAP are the personal and familial phenotype, including the rectal polyp burden (ie, distribution, size and number) and whether colon or rectal cancer is present at diagnosis. Timing of surgery depends on the genotype, severity of the familial phenotype (including risk for desmoid disease), the extent of polyposis at diagnosis, individual considerations, and local practices and expertise. Postsurgical surveillance should be followed as outlined in the following sections. If surgery is delayed, then annual colonoscopy is recommended.
Postoperative CRC Surveillance
Patients with FAP and a retained rectum following TAC/IRA should undergo endoscopic rectal examination every 6 to 12 months, with the frequency of examinations guided by polyp burden. After a TPC/IPAA, the ileal pouch and rectal cuff should be evaluated endoscopically annually, with consideration for shorter interval follow-up based on polyp burden, large flat polyps with villous histology, or high-grade dysplasia. If the patient had a proctocolectomy with EI, consider careful visualization and stoma inspection by ileoscopy annually to evaluate for polyps or malignancy, although the panel notes that evidence to support this recommendation is limited. Chemoprevention should only be considered in select patients as an adjunct to standard endoscopic or surgical treatment, with a full discussion of the risks, benefits, and alternatives. Optimally, it should be supervised by experts in chemoprevention and FAP, and enrollment in a clinical trial should be encouraged.
Duodenal Surveillance
A major component of surveillance in patients with FAP or AFAP relates to the upper gastrointestinal tract. Duodenal adenomatous polyposis develops in >90% of patients with FAP, and duodenal cancer occurs in up to 10%24–32 of patients and usually those aged >40 years. Duodenal adenomas may be classified as Spigelman stage 0–IV, based on endoscopic and histologic criteria.44 The cumulative lifetime risk of developing severe duodenal polyposis (stage IV) has been estimated to be approximately 35%,45 and the risk for duodenal cancer increases dramatically with Spigelman stage IV disease; however stage IV polyposis does not always precede a diagnosis of duodenal cancer.32
Upper gastrointestinal tract surveillance should be performed with upper endoscopy that includes complete visualization of the ampulla of Vater. A side-viewing duodenoscope or distal cap attachment to a standard upper endoscope (cap-assisted endoscopy) improves complete visualization of the ampulla.46 The panel recommends that surveillance begin at approximately 20 to 25 years of age, or younger if there is a family history of significant duodenal polyposis burden or duodenal cancer. At the time of endoscopy, the number, size, and appearance of polyps found in the duodenum and stomach should be documented. When neoplasia at the ampulla of Vater is suspected, biopsy of the suspicious appearing area should be performed prior to attempted endoscopic resection.
During the recent meeting to discuss updates to these NCCN Guidelines, the panel expanded upon the details for the management of duodenal findings. The updated guidelines highlight how to determine a modified Spigelman score. Factors used in this calculation include the number of polyps, size of polyps, polyp histology, and degree of dysplasia, with each factor assigned a score of 0 to 3 points based on specific criteria (see FAP-B 1 of 2, page 1126). This final aggregated Spigelman score across the 4 categories (total score ranges from 0 to 12) corresponds to a Spigelman stage, ultimately indicating the appropriate recommended interval for endoscopic duodenal surveillance. These duodenal surveillance interval recommendations provided by the panel are intended to provide clinicians with more clear guidance based on patient-specific findings and clinical judgement. Additionally, if an individual has undergone endoscopic or surgical treatment to downstage their duodenal polyp disease, they should continue surveillance based on their highest previous Spigelman stage.
During a recent meeting to discuss updates to these guidelines, the panel discussed that the final surveillance interval should depend on assessment of the combination of both duodenal and gastric findings. The panel recommends that individuals be managed based on the findings that require the closest surveillance. For example, if gastric findings require closer monitoring than the duodenal findings, surveillance intervals for upper endoscopy should be based on the gastric findings, or vice versa. Referral to an expert center for management by endoscopists with expertise in FAP/AFAP should be considered for patients with advanced duodenal polyposis as defined by Spigelman stage, or high-risk gastric polyps such as those ≥20 mm, with mounds of polyps, or containing histology with adenomatous features or high-grade dysplasia. The panel recommends endoscopic ultrasound for large ampullary lesions or large duodenal polyps with features concerning for malignancy before endoscopic or surgical resection, endoscopic retrograde cholangiopancreatography at the time of endoscopic papillectomy to assess for evidence of extension of adenoma into the biliary or pancreatic ducts, and prophylactic pancreatic duct stent placement and rectal indomethacin during papillectomy to reduce the risk for postprocedural pancreatitis.
The appropriate period for follow-up upper endoscopy relates to the burden of polyps, varying from every 3 to 5 years if no polyps are found to every 3 to 6 months for Spigelman stage IV polyposis. Surgical evaluation and counseling are recommended for invasive carcinoma, high-grade dysplasia, or dense polyposis that cannot be managed endoscopically. If surgery is deferred, surveillance endoscopy every 3 to 6 months is recommended. Endoscopic treatment options, when feasible, include endoscopic ampullectomy in addition to excision or ablation of resectable large or villous adenomatous polyps to potentially avert surgery. Potentially higher risk adenomas involving the ampulla of Vater, including adenomas ≥1 cm or adenomas extending into the ampulla of Vater, should be referred to an expert center for evaluation and management. A pilot trial reported that a combination of sulindac and low-dose erlotinib may reduce duodenal polyp burden in patients with FAP, and a larger clinical trial is ongoing.47 Patients with advanced duodenal polyp burden should be referred for expert centers for evaluation and management, and consideration for any clinical trials that are available. The panel recommends that individuals considered for surgical management of duodenal findings may have their small bowel evaluated with capsule endoscopy or CT/MRI enterography prior to surgery to identify large lesions that might modify the surgical approach. Although individuals may be considered for complete small bowel imaging surveillance, the panel notes that evidence of its utility is limited. Shorter intervals for endoscopic surveillance, regardless of Spigelman stage, may be considered based on personal or family history of massive gastric polyposis, multiple gastric adenomas, large ampullary adenoma (>10 mm), family or personal history of gastric/duodenal cancer, or advancing age. During the recent meeting to discuss updates to these guidelines, the panel agreed that providing basic principles and guidance for duodenal and ampullary findings are appropriate in this context given concerns and controversies regarding upper gastrointestinal tract neoplasia in patients with FAP or AFAP. It is recommended that clinicians refer to American Society for Gastrointestinal Endoscopy guidelines for specific polypectomy management.48
Gastric Surveillance
Fundic gland polyps (FGPs) of the stomach also occur in most patients with FAP or AFAP and often are too numerous to count. In FAP/AFAP, FGPs usually have biallelic inactivation of the APC gene, and often display foci of low-grade dysplasia or microadenomatous changes of the foveolar epithelium.49 However, high-grade dysplasia or malignant progression in FGPs is uncommon and the lifetime risk for gastric cancer in patients with FAP/AFAP in Western countries is reported to be in the range of 0.5% to 1.3%.19,23,50 The risk of gastric cancer in patients with FAP or AFAP may be increased in patients from geographic areas with a high prevalence of gastric cancer. Additionally, recent data suggest that gastric cancer risk may be elevated in the setting of certain endoscopic findings, including carpeting of FGPs, solitary polyps >10 to 20 mm, mounds of polyps, and proximal gastric white mucosal patches.51–53 High-risk histologic features include tubular adenomas, polyps with high-grade dysplasia, and pyloric gland adenomas.54 In light of this, the panel recommends that the need for specialized surveillance or surgery may be considered in the presence of described high-risk histologic features or high-risk lesions that cannot be removed endoscopically,55 preferably at a center of expertise. Note that the presence of FGPs with low-grade dysplasia alone in the absence of high-risk features does not require specialized surveillance.
Other Cancers and Desmoid Disease
Patients with FAP/AFAP also have elevated risk for developing other extracolonic cancers that may warrant surveillance.56 Several studies suggest that patients with FAP or AFAP have an increased lifetime risk for developing thyroid cancer compared with the general population, with incidence ranging from approximately 1% to 12%.12,16,17,21,22 The mean age at diagnosis of thyroid cancer in these patients ranges from 29 to 33 years.17,22 Thyroid cancers in patients with FAP or AFAP are most commonly papillary (cribriform-morular variant) and occur predominantly in women.15,17,21,56 The benefit of regular surveillance for thyroid cancer is uncertain, physical examinations do not detect most thyroid cancers, and more studies may be necessary to develop optimal management.15,18 Currently the panel recommends thyroid ultrasound starting in the late teenage years, and consider repeating every 2 to 5 years if no nodules are identified. Shorter intervals may be considered in individuals with a family history of thyroid cancer or with concerning features on prior thyroid ultrasound examinations.57
Classic FAP/AFAP is also associated with an increased risk for intra-abdominal desmoid tumors, most of which present within 5 years of colectomy or other intra-abdominal surgery. Given the relationship between surgery and development of desmoid tumors, it is important to know the location of the APC P/LP variant when determining timing of surgery, especially in individuals at higher risk, such as those with mutations in codons 1444–1580.58 Because significant morbidity and mortality may be associated with advanced desmoid tumors, early diagnosis may be of benefit.59 Although data to support screening and treatment are limited,60,61 annual abdominal palpation during physical examination is advised. If family history of symptomatic desmoids is present, the panel recommends consideration of abdominal CT with contrast or MRI with and without contrast no less frequently than annually. Abdominal imaging is warranted if suggestive abdominal symptoms are present, such as new, unexplained abdominal pain. For small bowel polyps and cancer, adding small bowel visualization to CT or MRI for desmoids as outlined earlier can be considered, especially if the patient has a personal history of advanced duodenal polyposis.
The risk for hepatoblastoma is increased in young children with FAP compared with those without FAP.36 Although the absolute risk is approximately 1.5%, given the potential lethality of the disease (25% mortality), surveillance by liver palpation, abdominal ultrasound, and serum alpha-fetoprotein every 3 to 6 months during the first 5 years of life may be considered.
Medulloblastoma accounts for most of the brain tumors found in patients with FAP, predominantly in women aged <20 years.62 Patients should be educated regarding signs and symptoms of neurologic cancer and the importance of prompt reporting of abnormal symptoms to their providers. The incidence of pancreatic cancer in FAP is not well defined and is likely very low. Giardiello et al16 reported 4 cases in a retrospective analysis of 1,391 FAP-related subjects. More studies are needed to elucidate the potential risk and benefit of surveillance for brain and pancreatic cancers, and should be individualized based on family history.
Summary
This article discuses recent updates to the 2021 version of the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal. Specifically, several recommendations were made by the panel to update and highlight the importance of duodenal neoplasia management in individuals with FAP/AFAP. These include a more detailed description of the calculation used to arrive at a Spigelman stage, thus further guiding clinicians in determining the appropriate recommended surveillance for this disease. The panel stressed that upper gastrointestinal surveillance intervals depend on evaluation of both gastric and duodenal findings. Evidence and opinions supporting the best strategies for upper and lower gastrointestinal surveillance continue to evolve, and have potential to optimize outcomes for patients with FAP or AFAP.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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