Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer

Abstract

IMPORTANCE Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. OBJECTIVE To determine if the addition of cetuximab vsbevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS Patients (≥18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. INTERVENTIONS Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. MAIN OUTCOMES AND MEASURES The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. RESULTS Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0–110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77–1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab-chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84–1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). CONCLUSIONS AND RELEVANCE Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00265850

Retrospective Analyses of Systemic Chemotherapy and Cytoreductive Surgery for Patients with Ovarian Metastases from Colorectal Cancer: A Single-Center Experience

“…Because the RR in patients with ex-ova metastases in our study was almost equivalent to the RRs reported in recent clinical trials using molecular-targeting agents [1,2], our data also reinforces the fact that ovarian metastases are less responsive to CTx, even when using active molecular targeting agents. Ovarian metastases from other primary sites, such as gastric cancer, are also reported to be less responsive to systemic CTx [13].…”

“…Treatment strategies for metastatic colorectal cancer (mCRC) have markedly progressed in recent years due to the development of effective combination chemotherapy (CTx) regimens that include cytotoxic drugs (e.g., fluoropyrimidine, oxaliplatin, and irinotecan) and molecular targeting agents (e.g., bevacizumab, cetuximab, and panitumumab) [1][2][3]. Recently, median overall survival (OS) has reached almost 30 months in a clinical trial setting for mCRC.…”

Eastern Canadian Colorectal Cancer Consensus Conference 2017

“…Initial management of unresectable metastatic crc involves a combination of systemic chemotherapy (fluorouracil-leucovorin with either irinotecan or oxaliplatin) and mAb therapies targeting either vascular endothelial growth factor receptor or egfr. The reported os for advanced crc with those treatments ranges from 24 months to 32 months 75,76 .…”

Non‐V600E BRAF mutations and EGFR signaling pathway in colorectal cancer

“…The incidence of BRAF V600E MT is 5–10% and the prognosis of patients treated by standard chemotherapy remains extremely poor with median progression‐free survival (PFS) after standard first and second line chemotherapies being around 6 and 3 months, respectively . Current pivotal phase III clinical trials, such as FIRE‐3, CALGB80405 and TRIBE, have demonstrated that the overall survival (OS) in patients with wild‐type (WT) RAS mCRC is over 30.0 months, as compared to an OS of approximately 20.0 months in patients with mCRC whose tumors harbor a RAS MT and 13.4 months in patients with mCRC whose tumors harbor a BRAF V600E MT. Based on current knowledge, to maximize the effect of chemotherapy during the initial treatment, combination treatment with bevacizumab and chemotherapy is the preferred regimen for patients with right‐sided colorectal cancer (RCC) harboring WT RAS or patients with both left‐sided colorectal cancer (LCC) and RCC harboring MT RAS or MT BRAF , and combination treatment with an anti‐EGFR antibody and chemotherapy is considered for patients with LCC and both WT RAS and BRAF .…”