FROM THE 2016 ASCO ANNUAL MEETING
In this election year, the focus on left vs. right has even reached the discussion of colon cancer. In a retrospective analysis of data from the CALGB/SWOG 80405 trial of FOLFIRI or FOLFOX chemotherapy in combination with cetuximab or with bevacizumab as first-line treatment for metastatic colorectal cancer, patients with primary tumors that arose on the left side of the colon (descending and sigmoid colon and rectum; n = 732) survived significantly longer than did patients whose tumors originated on the right side (n = 293), comprising the cecum and ascending colon. And the metastatic disease responded differently to the two biologic agents.
The main cohort of the trial involved only patients with tumors with KRAS wild type gene. Patients were randomly assigned to receive cetuximab or bevacizumab in an open-label fashion. The choice of the FOLFIRI or FOLFOX regimen was at the physician’s discretion.
Although there was no significant difference in overall survival between the two treatment arms, “when we looked at patients whose tumors started on the left side, they had a median overall survival of 33 months compared to 19 months if the cancer began on the right side,” Dr. Alan Venook, professor of medicine at the University of California, San Francisco, said in a presscast leading up to the annual meeting of the American Society of Clinical Oncology.
“This is statistically significant with a hazard ratio [HR] of 1.60 describing the magnitude of difference in these outcomes,” he said.
For patients who received cetuximab, the difference in median overall survival approached 20 months. Patients with left-sided tumors had a median survival of 36.0 months vs. 16.7 months for right-sided tumors (HR = 1.987; 95% CI 1.60-2.46; P less than .001).
“This is really a dramatic finding that I think really was surprising to most of us or all of us given our understanding or belief beforehand that this really was not likely to make a big difference,” Dr. Venook said. The results for cetuximab are in line with a smaller European study, FIRE-3, that found a 22.6 month longer median overall survival for tumors on the left vs. the right.
Although not as large a benefit as seen with cetuximab, patients who received bevacizumab also did better if their tumors arose on the left side (n = 356) than if they arose on the right (n = 150): 31.4 months vs. 24.2 months, respectively (HR = 1.297; 95% CI 1.05-1.60; P = .017).
Including the few tumors found in the transverse colon did not change any of the results, so they were eliminated from analysis.
Agent, side matter for PFS
Data for progression-free survival (PFS) showed differential effects for the two biologic agents, depending on the side of the primary tumor. “We see that bevacizumab seemed to be more helpful on the right side … and cetuximab more helpful on the left side,” Dr. Venook said.
Considering both progression-free and overall survival, bevacizumab was superior to cetuximab (P = .03) for right-sided primaries, and cetuximab was superior for left-sided primaries (P = .04). These results showed a clear interaction of sidedness and the biologic agent used, with a P(interaction) = .003.
Practice implications and biologic explanations
“The 14 months’ improved survival in left vs. right side primary tumors is really striking for patients who present with metastatic disease,” Dr. Venook said. “Cetuximab added to first-line chemotherapy is associated with more favorable outcomes in patients with left-sided primary and appears to add more than bevacizumab to chemotherapy in these patients with left-sided primaries. Patients with right-sided primaries appear to benefit more from bevacizumab.”
He said he believes that the side is a surrogate marker for some biological explanation, and molecular analyses of tumor tissues are now in progress. “Until we have sorted that out, colon cancer originating on the right side should be treated differently than colon cancer on the left side,” he recommended. “And although this is retrospective, these data and other findings [presented at ASCO] and in press suggest that patients with right-sided primary metastatic colon cancer should get little to no benefit from cetuximab.”
He noted that the left and right colon segments arise from different embryonic tissues, the left coming from the hindgut and the right from the midgut. Therefore, based on the behavior of the tumors from this and previous studies as well as the tissues of origin of the gut segments, the left and right colon may have different biologies.
Session moderator Dr. Julie Vose, ASCO president and chief of the oncology/hematology division at the University of Nebraska Medical Center in Omaha, emphasized the role of the federal government in studies of this kind. “I think this study really points out how very large federally funded studies such as this one can really help us to differentiate some of the issues that we need to understand to treat our patients very specifically in a personalized way,” she said. And besides yielding information from the trial at hand, “it definitely is going to help us to generate hypotheses for future studies to hopefully take advantage of this information.”
