Background: Colorectal cancer is one of the most common malignancies in the United
States, with a large proportion of patients presenting with metastatic disease or developing a recurrence.
Systemic chemotherapy is the mainstay of therapy in this setting. There is a clear benefit in the
addition of bevacizumab or cetuximab (for rat sarcoma [RAS] wild type tumors) to oxaliplatin- and
irinotecan-based regimens which can be considered for first-line therapy. However, many significant
questions remain as to which agent reflects best practice.
Objective: Our review aimed to elucidate the benefit of adding bevacizumab and cetuximab to initial
therapy for metastatic colorectal cancer based on primary tumor location and a variety of other disease-
and patient-related factors, addressing the paucity of evidence that currently exists in this area
and contributing to current literature and clinical practices.
Methods: The primary endpoints of the study were first Progression-Free Survival (PFS) and Overall
Survival (OS). Secondary endpoints included best response to first- and second-line therapies, Treatment-
Related Adverse Events (TRAEs), second PFS, cost of therapy, and an assessment of other patient-
and disease-related factors affecting PFS and OS.
Results: While there were trends towards improved OS in patients with left-sided primary tumors
(n=57) compared to those with right-sided disease (n=23), there were no significant differences between
the two groups in either primary endpoint. While no differences were found for patients with
left- or right- sided tumors stratified by add-on agent, these analyses were limited by the small number
of patients receiving cetuximab with first-line therapy (n=4). However, the bevacizumab cohort
(n=76) was sizable enough to provide ample data and produce clinically relevant results. Add-on therapy
with bevacizumab in our study achieved impressive survival outcomes in both left-sided (median
first PFS = 13 months, 95% CI 11-15 months; median OS = 37 months, 95% CI 21-53 months) and
right-sided (median first PFS = 13 months, 95% CI 9-17 months; median OS = 37 months, 95% CI
22-52 months) disease.
Conclusion: These results raised questions regarding the true significance of primary tumor location
when selecting bevacizumab or cetuximab for first-line therapy, particularly the current thought of using
cetuximab for left-sided tumors. While the superiority of bevacizumab over cetuximab in rightsided
disease remained evident upon comparison of our analysis with historical controls, survival outcomes
with the agent in our analysis appeared to be similar to that of cetuximab in CRYSTAL, FIRE-
3, and CALGB/SWOG 80405 in left-sided disease. Further study is required to determine if bevacizumab
truly does produce similar outcomes to cetuximab in left-sided primary tumors.