Journal of Oncology Navigation & Survivorship. 2018;9:196-197.
The National Comprehensive Cancer Network (NCCN) has overhauled its guidelines for the management of colon and rectal cancers. The updated guidelines were presented at the NCCN 23rd Annual Conference.
“One of the most important questions right now in rectal cancer is watch and wait,” said Christopher G. Willett, MD, Professor and Chair, Department of Radiation Oncology, Duke University, Durham, NC. “The classical management for resectable stage II and stage III rectal cancer is radiation therapy and chemotherapy.”
Based on the patient’s response, careful follow-up with MRI and endoscopy every 3 months can be chosen. “The preliminary data suggest that in a percentage of those patients, they do well,” said Dr Willett. “They don’t need a radical resection.”
The exact wording of the guidelines is, “In those patients who achieve a complete clinical response with no evidence of residual disease on digital rectal examination, rectal MRI, and direct endoscopic evaluation, a ‘watch and wait’ nonoperative management approach may be considered in centers with experienced multidisciplinary teams. The degree to which risk of local and/or distant failure may be increased relative to standard surgical resection has not yet been adequately characterized. Decisions for non-operative management should involve a careful discussion with the patient of his/her risk tolerance.”
Shortened Course of Adjuvant Therapy
In the adjuvant treatment of localized colon cancer, “I believe that we have the first important changes since 2004,” said Axel Grothey, MD, Chair, Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ. The previous standard for adjuvant treatment of stage III colon cancer was 6 months of therapy with FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CapeOx (capecitabine and oxaliplatin); the latest guideline reflects recent data that a shorter course of CapeOx works just as well as a 6-month course, particularly in the low-risk population.
The shorter adjuvant regimen is based on data from the IDEA study, which compared 3 months of FOLFOX or CapeOx with 6 months in 12,834 patients with stage III colon cancer. The primary outcome of disease-free survival at 3 years was 74.6% with the 3-month regimen and 75.5% with the 6-month regimen, which met the criterion for noninferiority. When stratified by regimen and risk group, however, 3 months of CapeOx was noninferior to 6 months in patients with T1-3 N1 disease but was not proven to be noninferior to 6 months in those with higher-risk disease (T4 and/or N2). In contrast, 3 months of FOLFOX was not proven to be noninferior to 6 months of FOLFOX in patients with T1-3 N1 disease and was actually inferior to 6 months of FOLFOX in the higher-risk group. Nevertheless, the guideline writers considered 3 months of FOLFOX as one of the preferred regimens in low-risk stage III disease because of its lower toxicity profile compared with 6 months of FOLFOX. In particular, neurotoxicity occurred in 17% of patients on the shorter FOLFOX regimen compared with 48% in those on the longer regimen. Three months of CapeOx was also associated with less neurotoxicity than 6 months of CapeOx (15% vs 45%).
The new guidance for adjuvant treatment of stage III colon cancer is therefore:
- For patients with pathologic stages T1-3 N1, the preferred treatments are CapeOx for 3 months or FOLFOX for 3 to 6 months.
- For patients with pathologic stages T4 N1-2 and any TN2 disease, the preferred treatments are CapeOx for 3 to 6 months or FOLFOX for 6 months.
Advanced Colon Cancer
In patients with suspected or proven metastatic synchronous adenocarcinoma, the new guideline recommends that tumor gene status for RAS and BRAF and determination of tumor mismatch repair deficiency or microsatellite instability status be performed up front, said Alan P. Venook, MD, Professor of Medical Oncology and Translational Research, University of California, San Francisco.
Several options are recommended, but none preferred, as initial chemotherapy for patients with advanced/metastatic disease who are deemed appropriate for intensive therapy. FOLFOXIRI (FOLFOX plus irinotecan) plus bevacizumab is a “superior treatment to all the others in terms of chemotherapy-driven effectiveness,” particularly in patients with BRAF-mutant disease, based on overall survival data from the TRIBE study, he said.
In patients with RAS wild-type metastatic colorectal cancer, overall survival was better with FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus cetuximab as first-line treatment compared with FOLFIRI plus bevacizumab.
Sidedness is a factor in the early use of epidermal growth factor receptor (EGFR) antibodies in that cetuximab seems to be preferentially effective in patients with a primary tumor on the left side of the colon. “Clearly, the EGFR antibodies do not benefit patients with right side cancer, independent of their RAS status,” said Dr Venook. Sidedness is not a factor in later use of EGFR antibodies.
BRAF-mutant colon cancer is an especially aggressive form of the disease for which immunotherapy (nivolumab or pembrolizumab) is now listed as an option in the guideline following irinotecan-based therapy for patients who are BRAF V600 mutation positive and have mismatch repair deficiency or microsatellite instability high disease.