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Location of primary tumor predicts colorectal cancer survival outcomes
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Patients with metastatic colorectal cancer who had a left-sided primary tumor achieved prolonged OS and PFS compared with patients who had a right-sided primary tumor, according to results of a retrospective analysis scheduled for presentation at the ASCO Annual Meeting.
“There are a few small retrospective analyses that have suggested recently that patients with right-sided cancer have a poorer prognosis, but these are very uncertain because of the nature of the studies and the small numbers,” Alan P. Venook, MD, professor of medicine at University of California, San Francisco, said during a press briefing. “But, we have learned over time as we have understood the genetics of cancer that tumor mutations such as RAS and BRAF can predict whether agents work or not, and these are not randomly distributed throughout the colon. We’ve identified multiple colon cancer subtypes based on genetic patterns. Colon cancer is not just one uniform disease, there are multiple variants of the disease located in different parts of the colon.”
Alan P. Venook
Results of the CALGB/SWOG 80504 study showed no difference in OS or PFS with the addition of bevacizumab (Avastin, Genentech) or cetuximab (Erbitux, Eli Lilly) to first-line FOLFOX or FOLFIRI chemotherapy in patients with metastatic colorectal cancer.
Venook and colleagues evaluated data from 1,025 patients (median age, 59 years) with KRAS wild-type disease from CALGB/SWOG 80504 to determine the effects of tumor location on survival outcomes. Of these patients, 293 had a right-sided primary tumor — defined as location in the cecum to hepatic flexure — and 732 patients had a left-sided primary tumor, or a tumor in the splenic flexure to rectum.
“These are discreet organs that arise differentially in the embryo,” Venook said. “It shouldn’t surprise us, then, that these may be different tissues, because they arise from different parts of the embryo.”
Patients with left-sided primary tumors achieved a median OS of 33.3 months, which was significantly longer than the 19.4-month median OS in the right-sided primary tumor cohort (HR for right- vs. left-sided tumors = 1.6; 95% CI, 1.37-1.86).
Left-sided primary tumors were associated with prolonged OS regardless of whether patients received cetuximab (36 months vs. 16.7 months; HR = 1.98; 95% CI, 1.6-2.46) or bevacizumab (31.4 months vs. 24.2 months; HR = 1.29; 95% CI, 1.05-1.6).
“The nearly 20-month difference with cetuximab was really a dramatic finding that was surprising to all of us given our belief beforehand that this really was not likely to make a big difference,” Venook said.
These data appeared comparable with those from the FIRE-3 trial, a smaller, retrospective trial (n = 167) that showed longer median OS among patient with left-sided tumors (38.7 months vs. 16.1 months; P < .001).
Patients in CALGB/SWOG 80504 with left-sided primary tumors also achieved longer median PFS in the overall cohort (11.5 months vs. 8.9 months; HR = 1.26; 95% CI, 1.09-1.45), and in the cetuximab arm (11.9 months vs. 7.7 months; HR = 1.53; 95% CI, 1.25-1.88) and bevacizumab arm (11.1 months vs. 9.6 months; HR = 1.03; 95% CI, 0.48-1.26).
Based on these results, tumor location can help select appropriate treatment options.
Among patients with right-sided tumors, those who received bevacizumab achieved longer OS than those assigned cetuximab (24.2 months vs. 16.7 months).
However, cetuximab was associated with better OS outcomes than bevacizumab in the right-sided primary tumor cohort (36 months vs. 31.4 months).
Venook and colleagues also evaluated data from an additional 213 patients in CALGB/SWOG 80504 who harbored KRAS mutations. Patients with KRAS mutations were originally included in the trial prior to knowledge that cetuximab only benefitted patients with KRAS wild-type disease.
In this cohort, patients with left-sided primary tumors also achieved longer OS (30.3 months vs. 23.1 months; HR = 1.28; 95% CI, 0.95-1.73).
Additional molecular analyses are underway to determine if tumor location is a biomarker for a biological explanation of the difference in treatment outcomes, Venook said.
“Until we have sorted that out, colon cancer originating on the right side should be treated differently than colon cancer on the left side,” Venook said. “Although this is retrospective, these data and other findings at ASCO and in press suggest patients with right-sided primary colon cancer get little to no benefit from cetuximab.” – by Alexandra Todak
Reference:
Venook AP, et al. Abstract 3504. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: The study was funded in part by Bristol-Myers Squibb, ImClone and Genentech. Venook reports royalties from UpToDate and travel expenses and research funding from Bayer, Bristol-Myers Squibb, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Halozyme, Merck Serono and Onyx. Please see the abstract for a list of the researchers’ relevant financial disclosures.
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Julie M. Vose, MD, MBA, FASCO
This study really points out that very large, federally funded studies such as this one can help us to differentiate some of the issues that we need to understand how to treat our patients very specifically in a personalized way. Without these large, federally funded trials we would not be able to understand this information. It definitely is going to help us generate hypotheses for future studies to hopefully take advantage of this information.
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