Alan P. Venook, MD
In metastatic colorectal cancer, the anatomic location of the tumor within the colon appears to make a difference in overall survival as well as response to pivotal treatments, according to a retrospective analysis of the pivotal CALGB/SWOG 80405 (Alliance) trial.1 “While previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected,” said lead investigator Alan P. Venook, MD, Professor of Medicine at the University of California, San Francisco.
Interestingly, response to bevacizumab (Avastin) and cetuximab (Erbitux) also differed according to right- vs left-sided origin, a finding that could be practice-changing, according to Dr. Venook. “We saw a dramatic difference in patients receiving cetuximab—an almost 20-month differential for left- vs right-sided tumors,” he said in a press briefing in advance of the meeting. (The findings [abstract 3504] will be presented on June 5, 2016, at the 2016 ASCO Annual Meeting.) “This was really a dramatic finding that was surprising to all of us.”
It is now clear that metastatic tumors arising in the right vs left side of the colon are clinically different, according to Dr. Venook. These two parts of the colon are “discreet organs” that arise in different parts of the embryo, he explained.
Dr. Venook said the investigators’ leading hypothesis is that “side is a surrogate marker for biology,” predicting that molecular features, once they are understood from the more than 44,000 biospecimens from the study, will define “different versions of cancer distributed across the colon,” some of which indicate aggressiveness.
The phase III CALGB/SWOG 80405 study was a federally funded trial comparing bevacizumab and cetuximab, given in conjunction with FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) or FOLFIRI (leucovorin, 5-FU, irinotecan), as first-line treatment of metastatic colorectal cancer. The study found no difference between the two agents in overall or progression-free survival.2
Because the location of the primary tumor may affect metastatic colorectal cancer outcomes, the investigators assessed the impact of tumor site on overall and progression-free survival in the study population in 732 patients with left-sided primaries and 293 with right-sided ones (66 with transverse tumors and 26 uncertain were not included). The current analysis was restricted to the 1,137 patients with wild-type KRAS, for whom either agent could be effective.
Left-Sided Tumors Respond Best to Cetuximab
Patients with tumors originating in the right side of the colon had much shorter median overall survival (19.4 months) than patients with left-sided tumors (33.3 months; hazard ratio [HR] = 1.60; P < .001). “The 14 months improved survival in left- vs right-sided primary tumors is striking for patients with metastatic disease,” Dr. Venook commented.
Importantly, the study also showed the relative efficacy of cetuximab and bevacizumab depending on the tumor location. Among patients who received cetuximab, median overall survival was 36 months for patients with left-sided tumors but 16.7 months for patients with right-sided tumors. With bevacizumab, median overall survival was 31.4 months and 24.2 months, respectively.
Although the original analysis of the study found no treatment-related differences in survival, in the latest analysis, bevacizumab led to better outcomes than cetuximab among patients with right-sided tumors, and cetuximab was better for left-sided tumors, Dr. Venook emphasized. Median progression-free survival was also impacted by the site of the tumor: 8.9 months for right-sided tumors vs 11.5 months for left-sided tumors (HR = 1.26; P = .002).
Dr. Venook concluded that cetuximab “appears to add more than bevacizumab to chemotherapy in KRAS wild-type patients with left-sided primaries, while patients with right-sided primaries appear to benefit more from bevacizumab than cetuximab.”
“In the absence of an understanding of the biology, our data argue that patients with right-sided cancer get no benefit from cetuximab,” he commented. “Decisions around how to treat patients are multifaceted, and this [sidedness] is but one factor, but I believe it’s a pretty strong argument against using EGFR [epidermal growth factor receptor] antibodies for right-sided cancers.” ■
Disclosure: The study received funding and support from Bristol-Myers Squibb, Genentech, Imclone, in collaboration with the National Cancer Institute. For full author disclosures, visit asco.abstracts.org.
1. Venook AP, Niedzwiecki D, Innocenti F, et al: Impact of primary tumor location on overall survival and progression-free survival in patients with metastatic colorectal cancer: Analysis of CALGB/SWOG 80405 (Alliance). 2016 ASCO Annual Meeting. Abstract 3504. To be presented June 5, 2016.
2. Venook AP, Niedzwiecki D, Lenz H-J, et al: CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab or cetuximab for patients with KRAS wild-type untreated metastatic adenocarcinoma of the colon or rectum. 2014 ASCO Annual Meeting. Abstract LBA3.
Deborah Schrag, MD, MPH
Deborah Schrag, MD, MPH, Professor of Medicine at Harvard Medical School, Boston, and an oncologist at Dana-Farber Cancer Institute, commented on the findings for The ASCO Post.
She said the inferior survival of patients with right-sided tumors “is almost certainly ...!-->!-->