Colorectal Cancer ____________________________________________________________________________
Patients randomized to FOLFIRI, modified IFL (mIFL), or capecitabine/irinotecan (CAPIRI) showed progression-free survival of 7.6 vs. 5.9 months with FOLFIRI vs. mIFL, and 7.6 vs. 5.8 months with FOLFIRI vs. CAPIRI. CAPIRI also led to the highest rates of grade 3 or greater nausea, vomiting, diarrhea, dehydration, and hand-foot syndrome [303]. FOLFOX and FOLFIRI are first-line treatments for patients with metastatic colorectal cancer, with FOLFIRI preferred when using irinotecan [303]. Oxaliplatin CAPOX was found comparable to 5-FU and oxaliplatin as an oxaliplatin-based regimen for first-line treatment of meta- static colorectal cancer [295; 296]. As second-line treatment following progression on irinotecan and 5-FU/leucovorin, patients randomized to FOLFOX4 or infusional 5-FU/leu- covorin showed a median time-to-progression of 4.6 versus 2.7 months [304]. Bevacizumab Bevacizumab is effective when added to FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer. In a 2009 study of patients with metastatic colorectal cancer, patients randomized to FOLFIRI/bevacizumab showed an overall sur- vival of 28.0 months compared with 19.2 months with mIFL/ bevacizumab [305] . In a separate study, patients randomized to IFL/bevacizumab or IFL/placebo showed progression-free survival of 10.6 vs. 6.2 months and overall survival of 20.3 vs. 15.6 months [306]. A trial randomized 1,401 patients with stage IV colorectal cancer to CAPOX or FOLFOX4, and then to bevacizumab or placebo. Patients receiving bevacizumab versus placebo showed progression-free survival of 9.4 vs. 8.0 months and overall survival of 21.3 vs. 19.9 months. Patients in the pooled CAPOX versus FOLFOX4 arms had a progression-free survival of 8.0 vs. 8.5 months. Overall survival had less benefit from bevacizumab than previously reported [307]. In another study, patients who progressed on FOLFIRI were randomized to FOLFOX plus bevacizumab or placebo, and showed a progression-free survival of 7.43 vs. 4.7 months, and overall survival of 12.9 vs. 10.8 months [308] . Based on these studies, bevacizumab was deemed a reasonable addition to FOLFIRI or FOLFOX as first-line treatment of metastatic colorectal cancer. In a 2012 study, patients progressing on a first-line regimen that included bevacizumab were randomized to a different che- motherapy regimen plus continued bevacizumab or placebo. Participants who continued bevacizumab showed an overall survival of 11.2 months and progression-free survival of 5.7 months, compared with 9.8 months and 4.1 months, respec- tively, with placebo [309] . These results led to FDA approval of bevacizumab continuation in patients with progression
during first-line chemotherapy, allowing patients to continue bevacizumab after switching to a different regimen contain- ing irinotecan or oxaliplatin that may improve the synergistic activity [310]. FOLFOXIRI plus bevacizumab was compared to FOLFIRI plus bevacizumab in patients with untreated metastatic colorectal cancer, who showed a progression-free survival of 12.1 vs. 9.7 months and overall survival of 31.0 vs. 25.8 months. FOLF- OXIRI led to significantly more grade 3/4 toxicities, including neutropenia, stomatitis, and peripheral neuropathy [311]. Ziv-Aflibercept As second-line therapy, 1,226 patients with metastatic colorec- tal cancer randomized to FOLFIRI plus ziv-aflibercept or placebo showed overall survival of 13.50 vs. 12.06 months and progression-free survival of 6.90 vs. 4.67 months. Both statistically significant outcomes favored ziv-aflibercept, and FOLFIRI plus ziv-aflibercept is an accepted second-line regimen for patients previously treated with FOLFOX [312]. Cetuximab Tumors with KRAS mutations are cetuximab-insensitive, but adding cetuximab to multiagent chemotherapy improves survival in patients with colorectal cancers lacking KRAS mutation (i.e., KRAS wild type). As discussed, patients with mutant KRAS tumors may experience worse outcomes when cetuximab is combined with bevacizumab. These differences are evident in the clinical trial data. Patients who progressed on irinotecan regimens randomized to cetuximab plus irinotecan or placebo showed a time-to-pro- gression of 4.2 vs. 1.5 months [313]. A trial of 1,198 patients with stage IV colorectal cancer randomized to FOLFIRI plus cetuximab or placebo found improved progression-free sur- vival but not overall survival with cetuximab. With emerging evidence that cetuximab response is limited to patients with wild-type KRAS tumors, the results were re-analyzed by KRAS status. A significant interactive effect was found for KRAS mutation status and cetuximab treatment response but not progression-free survival, with KRAS wild-type outcomes favoring FOLFIRI and cetuximab [314]. In a 2009 study, patients were randomized to capecitabine/ oxaliplatin/bevacizumab plus cetuximab or placebo for meta- static colorectal cancer. The median progression-free survival was 9.4 vs. 10.7 months, and patients with KRAS gene muta- tion (versus wild-type) receiving cetuximab had progression-free survival of 8.1 vs. 10.5 months. Patients with KRAS tumor mutation receiving cetuximab (as opposed to placebo) showed progression-free survival of 8.1 vs. 12.5 months and overall survival of 17.2 vs. 24.9 months [305]. The benefit of adding cetuximab to first-line combination chemotherapy was studied in patients with KRAS wild-type tumors. The 1,630 patients were randomized into three treat- ment groups and cetuximab or placebo:
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