Mohamed E. Salem, MD
Assistant Professor of Clinical Medicine
Division of Hematology and Oncology
Lombardi Comprehensive Cancer Center
Georgetown University School of Medicine
Metastatic colorectal cancer (mCRC) has been transformed from a one-drug disease with a median overall survival (mOS) rate of 6 months to one that presents an opportunity for multiagent, multimodality treatment pathways with an overall survival (OS) rate of nearly 3 years. This progress can be attributed to a continually growing understanding of the variable molecular biology of CRCs; the vast improvement in technology offering a way to assess these differences and, to some degree, tailor treatment to them (eg, for EGFR and HER2 inhibition); and increased access to novel, more diverse, and selective therapies.
Currently, the standard first-line treatment for inoperable mCRC is combination chemotherapy with an oxaliplatin- or irinotecan-based fluoropyrimidine- containing regimen (usually FOLFOX, FOLFIRI or FOLFOXIRI), commonly combined with a biological agent—ordinarily either the anti-VEGF inhibitor bevacizumab, or, for patients with RAS
wild-type tumors only, the anti-EGFR inhibitors, cetuximab or panitumumab. Until recently, bevacizumab and cetuximab seemed to have the same efficacy when added to chemotherapy in the frontline treatment of RAS
Impact of Tumor Location
A myriad of data supports the standard practice described above. However, in light of a new retrospective analysis, carried out by Venook and colleagues, this tradition is now being challenged. The potentially practice-changing post factum analysis of the Cancer and Leukemia Group B/ Southwest Oncology Group (CALGB/SWOG 80405) trial, recounted by Alan P. Venook, MD, at the 2016 ASCO Annual Meeting, demonstrated that in patients with mCRC receiving first-line therapy, the anatomic location of the tumor within the colon appears to have an impact not only on patient survival (Figure)
but also on response to biological therapy. The apparent efficacy of bevacizumab and cetuximab differs according to the location of the patient’s tumor (whether in the right or left side of the colon).
Thus, patients with tumors originating in the right side of their colon generally had a much shorter mOS (19.4 months) than patients whose tumors seeded in the left side (33.3 months; HR, 1.60; P
<.001). This was true for KRAS
wild-type and mutant tumors, regardless of cetuximab or bevacizumab-containing therapy (Figure A)
Furthermore, among patients who received cetuximab, mOS was 16.7 months for those with right-sided primary tumors, compared with 36 months for those who had left-sided primaries. Similarly, patients receiving bevacizumab had an mOS of 24.2 months versus 31.4 months, depending on whether their primary was right or left-sided, respectively.1
These results suggest that cetuximab might actually be detrimental to patients with right-sided tumors, making bevacizumab the better option for these patients, regardless of RAS
status. On the other hand, it seems that cetuximab was better for left-sided tumors (Figure B)
Left or Right Side?
As a disconcerting side note, patients with primary tumors that were right-sided RAS-mutated appeared to have a better response to cetuximab than those that were right-sided RAS wild-type (23.3 vs 16.7 months). If this finding is further validated, it throws our whole belief system into question, or in Venook’s words, “if true, we know less about RAS than we think we do”.
Venook concluded that all differences in his reported study are probably due to differences in the underlying biology and that the anatomic location is a perhaps a proxy of these biological differences.