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 Credit™. 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: JA4008196-0000-20-008-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/88191; 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: July 10, 2020; Expiration date: July 10, 2021
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Rectal Cancer
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Rectal Cancer
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:
Al B. Benson III, MD, Panel Chair, has disclosed that he receives other financial benefit from Bristol-Myers Squibb Company, Genentech, Inc., Novartis Pharmaceuticals Corporation, ARRAY Biopharma, AVBCCC, Bayer, Dava Onc, Guardant Health, Harborside Press, LSK, Merck Sharpe and Dohme, Patient Resource, PrECOG, Springer, and Pfizer Inc.
Alan P. Venook, MD, Panel Vice Chair, has disclosed that he is a scientific advisor for Genentech, Inc.; Halozyme, Inc.; and Roce Laboratories, Inc.
Stacey Cohen, MD, Panel Member, has disclosed that she receives honoraria from Boston Healthcare Associates and consulting fees from Natera.
Jeffrey Meyerhardt, MD, MPH, Panel Member, has disclosed that he receives consulting fees from Cota Healthcare and other financial benefit from Taiho Pharmaceuticals Co., Ltd.
Eric D. Miller, MD, PhD, Panel Member, has disclosed that he has no relevant financial relationships.
Alyse Johnson-Chilla, MS, Guidelines Coordinator, NCCN, has disclosed that she has no relevant financial relationships.
Lisa A. Gurski, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has 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 AstraZeneca; Celgene Corporation; Coherus BioSciences; Genentech, a member of the Roche Group; and TESARO, a GSK Company. This activity is supported in part by an educational grant from Bayer Healthcare Pharmaceuticals. This activity is supported by an independent medical education grant from Bristol-Myers Squibb. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc.
Overview
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2020, an estimated 43,340 new cases of rectal cancer will occur in the United States (25,960 in men; 17,380 in women), and an estimated 53,200 people will die of rectal and colon cancer combined.1 Despite these statistics, the incidence per 100,000 population of colon and rectal cancers decreased from 60.5 in 1976 to 46.4 in 2005.2 In addition, mortality from CRC decreased by almost 35% from 1990 to 2007,3 and is currently reduced by approximately 50% from peak mortality rates.1 These improvements in incidence of and mortality from CRC are thought to be a result of cancer prevention and earlier diagnoses due to screening and of better treatment modalities. More recent data show continued rapid declines in incidence among individuals aged ≥65 years, with a decrease of 3.3% annually from 2011 through 2016.4 Conversely, incidence has increased among those aged <65 years, with a 1% annual increase among those aged 50 to 64 years and a 2% annual increase among those aged <50 years. CRC death rates also showed age-dependent trends, declining by 3% annually for those aged ≥65 years, compared with a 0.6% annual decline for individuals aged 50 to 64 years and a 1.3% annual increase for individuals aged <50 years.4
The determination of an optimal treatment plan for an individual patient with localized rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative vs palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. For patients with distal rectal cancer, in particular, the simultaneous achievement of the goals of cure and of minimal impact on quality of life can be challenging.5 Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis.6–8 For most patients with localized rectal cancer, multimodality therapy that combines chemoradiotherapy (chemoRT), chemotherapy, and surgery is recommended.9
For metastatic CRC (mCRC), the goal of treatment may be curative if the tumor and metastases are resectable or potentially able to be converted to resectable; however, most patients with mCRC have unresectable disease.10 For patients with unresectable metastatic disease, treatment most commonly consists of systemic therapy, with the goal of prolonging quantity and maintaining quality of life. Systemic therapy for mCRC involves various active drugs, either in combination or as single agents. Choice of therapy is based on consideration of the goals of therapy, type and timing of prior therapy, mutational profile of the tumor, and differing efficacy and toxicity profiles of the constituent drugs.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy (TNT) approach for localized rectal cancer; and biomarker-targeted therapy for mCRC, with a focus on new treatment options for patients with BRAF V600E– or HER2 amplification–positive disease.
Definition of the Rectum
There are a number of different anatomic definitions available in the literature that can be used to differentiate the colon from the rectum and the rectum from the anus. Accuracy of this definition is important, because the recommended treatment modalities for localized colon, rectal, and anal cancer differ significantly. Specifically, accurate differentiation between upper rectal and sigmoid colon tumors can be particularly difficult. Because radiotherapy (RT) is rarely recommended for localized colon tumors but is an integral part of the treatment of many rectal cancers, proper identification of a tumor as originating from the colon or rectum can substantially impact treatment decisions.
An NCI guideline published in 2000 defined the rectum as ≤12 cm from the anal verge as determined by rigid proctoscopy.11 This definition was based on a study showing differences in local recurrence rates for lesions located >12 cm from the anal verge (9.6%) compared with those located in the mid- or low-rectum (30.1% and 30.7%, respectively).12 Although this definition has been commonly used in the medical community, this definition is fundamentally imprecise in that it fails to account for differences in body habitus (ie, a measured distance of 12 cm from the anal verge would yield very different anatomic features in a patient who is 4 feet tall compared with one who is 7 feet tall). Furthermore, the panel considers MRI to be a superior tool compared with rigid proctoscopy for determining the anatomic landmarks that truly distinguish the colon from the rectum.
Based on these discussions, the NCCN Guidelines have defined the rectum as lying below a virtual line from the sacral promontory to the upper edge of the symphysis as determined by MRI (Figure 1). The rectum ends at the superior border of the functional anal canal, defined as the palpable upper border of the anal sphincter and puborectalis muscles of the anorectal ring. The rectum can be further divided into the upper-, mid, and lower-rectum based on the location of the anterior peritoneal reflection as determined by MRI or CT.13,14 The upper-rectum occurs above the anterior peritoneal reflection, the midrectum at the anterior peritoneal reflection, and the lower-rectum below. Because the anterior and posterior aspects of the peritoneal reflection often are not at the same level, this definition of the rectum clarifies its relation to the peritoneal cavity.
Definition of rectum, used with permission of Mayo Foundation for Medical Education and Research. All rights reserved.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 7; 10.6004/jnccn.2020.0032
Panel members have also remarked that the 2019 publication of an international, expert-based Delphi Consensus provides an alternative, accurate definition of the rectum. This publication defines the rectum as the point of sigmoid take-off where the mesocolon elongates as the ventral and horizontal course of the sigmoid on axial and sagittal views, respectively, on cross-sectional imaging.15 Although this definition is not currently incorporated into the NCCN Guidelines for Rectal Cancer, it may be considered by the panel in the future.
TNT for Localized Rectal Cancer
Several small trials have tested the utility of a course of chemotherapy preceding chemoRT and resection without the expectation of using chemotherapy postoperatively.16–21 This approach is referred to as a TNT approach. In the Spanish GCR-3 randomized phase II trial, patients were randomized to receive CAPEOX either before chemoRT or after surgery.18,22 Similar pathologic complete response (CR) rates were seen, and induction chemotherapy appeared to be less toxic and better tolerated. Another phase II trial randomized patients to chemoRT and surgery with or without FOLFOX induction therapy.20 There were no differences between the clinical outcomes, but the group receiving induction therapy experienced higher toxicity. The phase II AVACROSS study assessed the safety and efficacy of adding bevacizumab to induction therapy with CAPEOX prior to capecitabine/bevacizumab-chemoRT and surgery.21 The regimen was well tolerated with a pathologic CR rate of 36%. A pooled analysis of 2 phase II trials, EXPERT and EXPERT-C, assessed the safety and efficacy of neoadjuvant chemotherapy followed by chemoRT and surgery.23 Of the 269 patients who were included, 91.1% completed chemotherapy, 88.1% completed chemoRT, and 89.2% underwent curative surgery. Rates of 5-year progression-free survival (PFS) and overall survival (OS) were 66.4% and 73.3%, respectively.
A single-institution retrospective cohort analysis of patients with T3/4 or node-positive rectal cancer compared the outcomes after either a traditional approach of neoadjuvant chemoRT then resection with planned adjuvant chemotherapy (n=320), or a TNT approach of induction chemotherapy then chemoRT before resection (n=308).24 Patients in the TNT group received a greater percentage of the planned chemotherapy dose than those in the adjuvant chemotherapy group. CR rates were 36% and 21% in the TNT and adjuvant chemotherapy groups, respectively.
The NCCN panel discussed possible benefits of using chemotherapy first, including the early prevention or eradication of micrometastases, higher rates of pathologic CR, minimizing the length of time patients need an ileostomy, facilitating resection, and avoiding the need to compromise chemotherapy delivery because of bone marrow suppression or postsurgical complications. One potential downside to this approach is the possibility of overtreating low-risk stage II rectal cancer. The panel continues to monitor the literature supporting a TNT approach to the treatment of rectal cancer, and this approach is currently reflected within the guideline recommendations (see REC-5, page 808).
Biomarker-Targeted Therapy for mCRC
As the role of targeted therapy for treatment of advanced or mCRC has become increasingly prominent, the NCCN Guidelines for Rectal Cancer have expanded its recommendations regarding biomarker testing. Currently, determination of tumor gene status for KRAS/NRAS and BRAF V600E mutations, as well as HER2 amplifications, is recommended for patients with mCRC. HER2 testing is not indicated in cases in which the tumor has a known RAS or RAF mutation. Determination of mismatch repair (MMR) or microsatellite instability (MSI) status is also recommended in all patients with newly diagnosed colon or rectal cancer (see REC-7, page 809). The “Principles of Pathologic Review” section (REC-B in the complete version of these guidelines, available at NCCN.org) has been updated to provide additional information on biomarker testing recommendations. Biomarker testing may be performed for individual genes or as part of a next-generation sequencing (NGS) panel, although the NCCN panel does not recommend any specific testing methodology over the other. However, NGS panels do have the advantage of being able to detect rare and actionable genetic alterations, such as NTRK fusions.
Although EGFR-targeted monoclonal antibodies (cetuximab or panitumumab) have been included in the guidelines for RAS wild-type mCRC for more than a decade, the number of biomarker-targeted therapies recommended for mCRC has substantially expanded in recent versions, now including checkpoint inhibitors (pembrolizumab, nivolumab ± ipilimumab) for dMMR/MSI-high disease, as well as BRAF-, HER2-, and TRK-targeted therapy options. BRAF- and HER2-targeted therapies are discussed in more detail in following sections.
NTRK gene fusions are relatively rare in CRC, with recent studies estimating that approximately 0.2% to 1.0% of CRCs carry these fusions.25,26 NTRK fusions are most likely to be found in cancers that are KRAS, NRAS, and BRAF wild-type but MMR-deficient.27 Two targeted therapies, larotrectinib and entrectinib, have been FDA-approved for the treatment of patients with metastatic, unresectable solid tumors that have an NTRK gene fusion and no satisfactory alternative treatment options, regardless of the location of the primary tumor.28,29 These therapies were studied using pooled analyses of phase I and II trials, which included small numbers of patients with NTRK gene fusion–positive CRC (4 patients for larotrectinib, 4 for entrectinib).30,31 Based on these data, but taking into account the rarity of NTRK gene fusions in mCRC as well as concerns from some panel members regarding the CRC-specific efficacy outcomes, the panel decided to include the recommendation for larotrectinib or entrectinib in patients with NTRK gene fusion–positive disease as a footnote for subsequent therapy options throughout the systemic therapy pages of the guidelines (see REC-F 2 of 13 and REC-F 7 of 13, pages 810 and 811).
BRAF V600E–Targeted Therapies
Approximately 5% to 9% of CRCs are characterized by a specific mutation in the BRAF gene (V600E).32,33 BRAF mutations are, for all practical purposes, limited to tumors that do not have KRAS exon 2 mutations.32–34 The NCCN panel currently recommends encorafenib with either cetuximab or panitumumab for patients with mCRC that harbors the BRAF V600E mutation.
The first BRAF V600E–targeted therapy regimen that was recommended in the NCCN Guidelines for Rectal Cancer was a combination of irinotecan, vemurafenib, and cetuximab or panitumumab. This combination was tested in the phase II SWOG S1406 trial of patients with BRAF V600E–mutated mCRC.35 Ninety-nine patients with BRAF-mutant, RAS wild-type tumors who received 1 or 2 prior regimens were randomized to irinotecan and cetuximab with or without vemurafenib. An abstract presenting results of this trial at the 2017 ASCO Annual Meeting reported that the primary endpoint of median PFS was improved in the vemurafenib arm (4.4 vs 2.0 months; hazard ratio [HR], 0.42; 95% CI, 0.26–0.66; P<.001).35 However, the NCCN panel voted to remove the recommendation for the vemurafenib combination from the guidelines in the version 1.2020 update based on the availability of new BRAF V600E–targeted regimens with more mature data and/or lower toxicity.
Another previously recommended regimen for BRAF V600E–mutated mCRC is a combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib and either cetuximab or panitumumab. A phase I study investigated the combination of dabrafenib + panitumumab, trametinib + panitumumab, or a combination of all 3 therapies in 142 patients with BRAF V600E mutation–positive mCRC.36 Response rates were 10%, 21%, and 0% for dabrafenib + panitumumab, dabrafenib + trametinib + panitumumab, and trametinib + panitumumab, respectively. The most common grade 3 or 4 adverse events noted for the dabrafenib, trametinib, and panitumumab combination were diarrhea (7%), nausea (2%), and dermatitis acneform (10%). Seventy percent of patients treated with the triplet therapy had a grade 3 or 4 adverse event.36 The NCCN panel voted to remove this regimen from the guidelines during the version 2.2020 update, again based on the availability of a BRAF V600E–targeted option with more mature data and/or lower toxicity.
A combination of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib with cetuximab has been investigated in the randomized, phase III BEACON trial for metastatic, BRAF V600E mutation–positive CRC.37,38 The safety lead-in of the BEACON trial showed promising efficacy results, with an overall response rate (ORR) of 48% (95% CI, 29.4%–67.5%) among the 29 patients included in the efficacy analysis. Among the 30 treated patients in the safety lead-in, the most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase levels (10%), increased aspartate aminotransferase levels (10%), and urinary tract infections (10%).38 Subsequently, the randomized portion of the BEACON trial reported similarly encouraging results, including a positive OS result.39 Within this portion of the study, 665 patients were randomized to receive either the triplet combination, an encorafenib and cetuximab doublet, or a control regimen of cetuximab plus either irinotecan or FOLFIRI. Confirmed ORR was 26% (95% CI, 18%–35%) for the triplet compared with 2% (95% CI, 0%–7%) for control (P<.0001). After a median follow-up of 7.8 months, median OS was 9 months for the triplet regimen compared with 5.4 months for control (HR, 0.52; 95% CI, 0.39–0.70; P<.0001). Median OS for the doublet regimen was 8.4 months. Adverse events were as expected based on previous studies. Grade ≥3 adverse events occurred in 58% of patients on the triplet regimen, 50% on the doublet, and 61% on the control arm.39 Based on these results, the NCCN panel added both the doublet and triplet regimens as options for patients with BRAF V600E mutation–positive CRC in the version 1.2020 update of the guidelines.
Updated results of BEACON were then presented at ASCO’s 2020 Gastrointestinal Cancers Symposium.40 After a median follow-up of 12.8 months, median OS was 5.9 months, 9.3 months, and 9.3 months for the control, doublet, and triplet arms, respectively. ORRs were 2%, 20%, and 27%, respectively, and grade ≥3 adverse event rates continued to be higher in the triplet arm than in the doublet arm. The triplet including binimetinib did not lead to additional improvements in OS or ORR over the doublet, but had higher rates of grade ≥3 adverse events. Results of quality of life (QoL) assessments were also reported in this presentation. They showed that the doublet and triplet regimens led to a similarly longer maintenance of QoL compared with control. Based on this report, the panel removed the triplet option in the version 2.2020 update of the guidelines. Thus, the panel concluded that only the doublet regimen of encorafenib with either cetuximab or panitumumab should be recommended for patients with BRAF V600E–mutated mCRC at that time.
Results are awaited of this combination targeted therapy in the first-line setting for patients with BRAF V600E–mutated mCRC, and therefore the panel does not currently recommend this as initial treatment. However, because these cancers may progress rapidly beyond the first line, this therapy must be considered early in the clinical course of these patients. The panel expressed no preference between cetuximab or panitumumab for use with encorafenib, although some panel members mentioned that they might preferentially use one agent over the other based on institutional practice, differences in the dosing schedule, and/or the possibility of infusion site reactions.
HER2-Targeted Therapies
HER2 is a member of the same family of signaling kinase receptors as EGFR and has been successfully targeted in breast cancer in both the advanced and adjuvant settings. HER2 is rarely amplified/overexpressed in CRC (∼3% overall), but the prevalence is higher in RAS/BRAF wild-type tumors (reported at 5%–14%).41–43 Two regimens are recommended by the panel as options for subsequent treatment of mCRC with HER2 amplifications: trastuzumab plus either pertuzumab or lapatinib (see REC-F 2 of 13, page 810). Several biosimilars are now available in the US market, including 5 biosimilars for trastuzumab. Trastuzumab-anns, -dkst, -qyyp, -dttb, and -pkrb are not FDA-approved for CRC, but have been approved for other cancer types (breast and gastric).44–48 The panel added a note that FDA-approved biosimilars may be substituted for trastuzumab wherever the therapy is recommended within these guidelines (see REC-F 7 of 13, page 811). Results of clinical trials supporting each of these regimens are detailed below.
A combination regimen of the HER2 inhibitors trastuzumab and pertuzumab was studied in a subset analysis of MyPathway, a phase IIa multiple basket study.49 This subset included 57 patients with previously treated, HER2-amplified mCRC who were treated with the combination of pertuzumab and trastuzumab. ORR was 32% (95% CI, 20%–45%), with 1 CR and 17 partial responses; 37% of patients treated with trastuzumab + pertuzumab had grade 3 or 4 adverse events, with hypokalemia and abdominal pain the most common.49
The combination of trastuzumab plus the dual HER2/EGFR inhibitor lapatinib was studied in the multicenter phase II HERACLES trial.41 This trial included 27 patients with previously treated, HER2-positive tumors that were treated with trastuzumab and lapatinib. ORR was 30% (95% CI, 14%–50%), with 1 patient experiencing CR, 7 experiencing partial responses, and 12 with stable disease; 22% of patients treated with trastuzumab + lapatinib had grade 3 adverse events, including fatigue (n=4), skin rash (n=1), and increased bilirubin (n=1).41
HER2-targeted therapies were first included as a category 2B recommendation in the NCCN Guidelines for Rectal Cancer in the version 2.2019 update of the guidelines; however, this was recently updated to a category 2A recommendation as the data matured and panel consensus on the utility of these regimens strengthened.
Conclusions
Recent medical advances have improved treatment of patients with rectal cancer through an improved ability to distinguish rectal cancer from colon or anal cancers, new treatment approaches for localized rectal cancer, and targeted therapy options for mCRC. An updated definition of the rectum, using improved imaging techniques, allows physicians to more accurately distinguish rectal cancer from colon or anal, yielding more appropriate treatment. Likewise, the TNT approach for treating localized rectal cancer allows higher CR rates, minimizes the length of time patients need an ileostomy, facilitates resection, and improves the completion rates of chemotherapy. For mCRC, new biomarker testing recommendations can inform the use of targeted therapies for HER2 amplifications and BRAF V600E mutations, among other genetic alterations.
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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.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
