NCCN: Continuing Education
This activity has been designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.
This activity is approved for 1.0 contact hour. Approval as a provider refers to recognition of educational activities only and does not imply ANCC Commission on Accreditation approval or endorsement of any product. Accredited status does not imply endorsement by the provider of the education activity (NCCN). Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.
National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-13-010-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/11592; and 4) view/print certificate.
Release date: February 18, 2013; Expiration date: February 18, 2014
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Colon Cancer
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Colon Cancer
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 for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2012, an estimated 103,170 new cases of colon cancer and approximately 40,290 cases of rectal cancer occurred. During the same year, an estimated 51,690 people died of these cancers combined.1 Despite these high numbers, the incidence of colon and rectal cancers per 100,000 people has decreased from 60.5 in 1976 to 46.4 in 2005.2 In addition, mortality from colorectal cancer has decreased by almost 35% from 1990 to 2007,3 likely because of earlier diagnosis through screening and better treatment modalities.
Peritoneal Carcinomatosis: Cytoreductive Surgery and Perioperative Hyperthermic Intraperitoneal Chemotherapy
Approximately 17% of patients with metastatic colorectal cancer have peritoneal carcinomatosis,
The panel discussed the data regarding cytoreductive surgery (ie, peritoneal stripping surgery) and perioperative hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis without extraabdominal metastases. Several surgical series have addressed the role of this procedure in this setting.5-9 In the only randomized controlled trial involving this approach, Verwaal et al10 randomized 105 patients to either standard therapy (5-FU/leucovorin [LV] with or without palliative surgery) or aggressive cytoreductive surgery and HIPEC with mitomycin C; postoperative 5-FU/LV was given to 33 of 47 patients. Overall survival was 12.6 months in the standard arm and 22.3 months in the HIPEC arm (P=.032). However, treatment-related morbidity was high, and the mortality was 8% in the HIPEC group, mostly related to bowel leakage. In addition, long-term survival does not seem to be improved by this treatment as seen in follow-up results.11 Importantly, this trial was performed without oxaliplatin, irinotecan, or molecularly targeted agents. The panel agreed with experts who have argued that the overall survival difference might have been much smaller if these agents were used (ie, the control group would have had better outcomes).12
Other criticisms of the Verwaal trial have been published.12 One important point discussed by the panel is that the trial included patients with peritoneal carcinomatosis of appendiceal origin, a group
The panel noted that the individual components of this approach have not been well studied. In fact, studies in rats have suggested that the hyperthermia component of the treatment is irrelevant.15 Results of a retrospective cohort study also suggest that heat may not affect outcomes from the procedure.6 In addition, the panel expressed concerns about the significant morbidity and mortality associated with this procedure. A 2006 meta-analysis of 2 randomized controlled trials and 12 other studies reported morbidity rates ranging from 23% to 44% and mortality rates ranging from 0% to 12%.9 Although the risks are reportedly decreasing with time (ie, recent studies report 1%–5% mortality rates at centers of excellence12), the benefits of the approach have not been definitively shown. Therefore, the panel reaffirmed their previous recommendation that the treatment of disseminated carcinomatosis of colorectal cancer with cytoreductive surgery and HIPEC should be considered investigational (see footnote “ee,” page 143 [COL-5, -7, -8]). The panel does not endorse this therapy outside of a clinical trial. However, it does recognize the need for randomized clinical trials
Management of the Primary Tumor in the Setting of Unresectable Metastases
The panel discussed results from a recent pooled analysis of patients from 4 randomized trials suggesting that patients may experience some benefit in both overall and progression-free survival from resection of the primary tumor in the setting of unresectable colorectal metastases.16 Other retrospective analyses also have shown a potential benefit to this approach.17,18 On the other hand, the prospective, multicenter phase II NSABP C-10 trial showed that patients with an asymptomatic primary colon tumor and unresectable metastatic disease who received mFOLFOX6 with bevacizumab experienced an acceptable level of morbidity without upfront resection of the primary tumor.19 The median overall survival was 19.9 months. Notably, symptomatic improvement in the primary is often seen with systemic chemotherapy even within the first 1 to 2 weeks. Furthermore, complications from the intact primary lesion are uncommon in these circumstances,20 and its removal delays initiation of systemic chemotherapy. In fact, a recent systematic review concluded that resection of the primary does not reduce complications, nor does it improve overall survival.21 Overall, the panel believes that the risks of surgery outweigh the possible benefits of resection of asymptomatic primary tumors in the setting of unresectable colorectal metastases. Therefore, the panel maintained their recommendation that palliative resection of a synchronous primary lesion should only be considered if the patient has an unequivocal imminent risk of obstruction or acute significant bleeding (see page 143 [COL-5, -7, -8]). The panel acknowledged that relevant
Chemotherapy for Advanced and Metastatic Disease
The current management of disseminated metastatic colon cancer involves various active drugs, either in combination or as single agents, given across a continuum: 5-FU/LV, capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, and regorafenib.22-62 The putative mechanisms of action of these agents are varied and include interference with DNA replication and inhibition of the activities of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptors.63-66 The choice of therapies and their sequence is based on consideration of the goals of therapy, the type and timing of prior therapy, the differing toxicity profiles of the constituent drugs, and the KRAS status of the tumor.
This year, the panel discussed data pertaining to new drugs and other changes to the continuum of systemic therapy for patients with advanced or metastatic disease after progression, as discussed in the following sections.
Continuation of Bevacizumab After Progression on Bevacizumab
In the TML trial, patients with good performance status and metastatic colorectal cancer who progressed on regimens containing bevacizumab received second-line therapy consisting of a different chemotherapy regimen with or without bevacizumab.67 This study met its primary end point, with patients continuing on bevacizumab having a modest improvement in overall survival (11.2 vs. 9.8 months; hazard ratio [HR], 0.81; 95% CI, 0.69–0.94; P=.0062).
The continuation of bevacizumab after progression on bevacizumab was also studied in a community oncology setting through a retrospective analysis of 573 patients from the US Oncology iKnowMed electronic medical record system.68 Bevacizumab beyond progression was associated with a longer overall survival (HR, 0.76; 95% CI, 0.61–0.95) and a longer postprogression overall survival (HR, 0.74; 95% CI, 0.60–0.93) on multivariate analysis.
Overall, the panel believes that these data (along with those from the VELOUR trial, discussed later) show that the continuation of VEGF blockade in second-line therapy offers a very modest but statistically significant overall survival benefit. The panel noted that the TML trial excluded patients whose disease progressed quickly or who had a poor performance status, and considered limiting their recommendation similarly. In the end, the panel added the continuation of bevacizumab to the second-line treatment options for the 2013 versions of the NCCN Guidelines for Colon and Rectal Cancers without these patient limitations (see all COL-C figures, pages 144–147, and in the full guidelines, available at NCCN.org). Bevacizumab may be added to any second-line regimen that does not contain an EGFR inhibitor or ziv-aflibercept. The panel recognizes the lack of data suggesting a benefit to bevacizumab with irinotecan alone in this setting, but believes that the option is acceptable, especially in patients for whom a 5-FU– or capecitabine-based regimen failed. This addition to the systemic therapy continuum was made as a category 2A recommendation because it is based on only 1 trial with a modest clinical benefit.
The panel discussed the recent data from the phase III VELOUR trial at their annual panel meeting and again on an interim call after ziv-aflibercept was approved by the FDA. Ziv-aflibercept is a recombinant protein that has part of the human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1.69 It is designed to function as a VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis. The VELOUR trial tested second-line ziv-aflibercept in patients with metastatic colorectal cancer for whom one regimen containing oxaliplatin failed. The trial met its primary end point, with a clinically modest but statistically significant improvement in OS (13.5 months for FOLFIRI/zivaflibercept vs. 12.1 months for FOLFIRI/placebo; HR, 0.82; 95% CI, 0.71–0.94; P=.003).61
Adverse events associated with ziv-aflibercept treatment in the VELOUR trial led to discontinuation in 26.6% of patients compared with 12.1% in the placebo group.61 The most common causes for discontinuation were asthenia/fatigue, infections, diarrhea, hypertension, and venous thromboembolic events.
Ziv-aflibercept has only shown activity when given in conjunction with FOLFIRI in FOLFIRI-naïve patients. No data suggest activity of FOLFIRI plus ziv-aflibercept in patients who experienced disease progression on FOLFIRI plus bevacizumab, or vice versa, and no data suggest activity of single-agent ziv-aflibercept. Thus, the panel added ziv-aflibercept as a second-line treatment option in combination with FOLFIRI or irinotecan only after progression on therapy not containing irinotecan (see all COL-C figures, 144–147, and in the full guidelines, available at NCCN.org). This addition to the systemic therapy continuum was made as a category 2A recommendation because currently only 1 trial has been performed, the observed benefit was quite modest, and toxicities were considerable.
The panel discussed the recent data from the phase III CORRECT trial at the annual panel meeting and again on an interim call after regorafenib was approved by the FDA. Regorafenib is a small molecule inhibitor of multiple kinases (including VEGF receptors, fibroblast growth factor receptors, platelet-derived growth factor [PDGF] receptors, BRAF, KIT, and RET) that are involved with various processes, including tumor growth and angiogenesis.70 In the CORRECT trial, 760 patients who progressed on standard therapy were randomized to best supportive care with placebo or regorafenib.42,71 The trial met its primary end point of overall survival (6.4 months for regorafenib vs. 5.0 months for placebo; HR, 0.77; 95% CI, 0.64–0.94; P=.005). Progression-free survival was also significantly but modestly improved (1.9 vs. 1.7 months; HR, 0.49; 95% CI, 0.42–0.58; P<.000001).
The most common grade 3 or higher adverse events in the regorafenib arm of the CORRECT trial were hand-foot skin reactions (17%), fatigue (10%), hypertension (7%), diarrhea (7%), and rash/desquamation (6%).42,71 Severe and fatal liver toxicity occurred in 0.3% of 1100 patients treated with regorafenib across all trials.70
Regorafenib has only shown activity in patients who have experienced progression on all standard therapies. Therefore, the panel decided to add regorafenib as an additional line of therapy for patients with metastatic colorectal cancer refractory to chemotherapy (see all COL-C figures, 144–147, and in the full guidelines, available at NCCN.org). For patients with mutant KRAS, regorafenib can be used in the third-line setting; patients with wild-type KRAS can receive regorafenib as a third or fourth line of therapy. This addition to the systemic therapy continuum was made as a category 2A recommendation because it is based on only 1 trial with a modest clinical benefit, and toxicities associated with regorafenib are significant.
Summary of Changes to the 2013 NCCN Guidelines for Colon Cancer
In summary, the panel discussed many pertinent issues this year. Some recommendations were reviewed in detail and not changed (denoted by purple text in algorithms):
The panel reaffirmed their previous recommendation that the treatment of disseminated carcinomatosis of colorectal cancer with cytoreductive surgery and HIPEC should only occur on a clinical trial, because the risks are high and the benefits unproven.
The panel maintained their recommendation that palliative resection of a synchronous primary lesion in the setting of unresectable metastases should only be considered if the patient has an unequivocal, imminent risk of obstruction or acute significant bleeding.
Other discussions resulted in changes to the 2013 recommendations:
The panel added the continuation of bevacizumab with a different chemotherapy backbone to the second-line treatment options for patients with advanced or metastatic disease who progressed on regimens containing bevacizumab.
The panel added ziv-aflibercept as a second-line treatment option in combination with FOLFIRI or irinotecan for patients with advanced or metastatic disease who progressed on therapy not containing irinotecan.
The panel added regorafenib as an additional line of therapy for patients with advanced or metastatic colorectal cancer refractory to all standard systemic therapy options.
EDITOR: Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network, has disclosed that she has no relevant financial relationships.
CE AUTHORS: Nicole Harrold, BS, Manager, Continuing Education and Grants, has disclosed that she has no relevant financial relationships. Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships. James Prazak, RPh, Director, Continuing Education and Grants, has disclosed the following relationships with commercial interests: Bristol-Myers Squibb Company: Pension; Pfizer, Inc: Stockholder; United Healthcare Group: Stockholder; Johnson & Johnson: Stockholder. Deborah Moonan, RN, BSN, Manager, Supporter Outreach, has disclosed the following relationships with commercial interests: AstraZeneca: former employee/stockholder. Deborah A. Freedman-Cass, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.
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SouglakosJAndroulakisNSyrigosK. FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG). Br J Cancer2006;94:798–805.
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