Primary tumor location as a prognostic factor in metastatic colorectal cancer

Abstract

Background: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).

Methods: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.

Results: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.

Conclusions: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.

Figure 1.

Analyses of overall survival by primary tumor location. Panels A, B, and C show Kaplan-Meier estimates of the probability of overall survival by primary tumor location in the PROVETTA (A), NO16966 (B), and AVF2107g (C) studies, respectively. Patients with left-sided tumors (red) had statistically significantly increased OS compared with patients with right-sided tumors (blue) within each study. All statistical tests were two-sided. BV = bevacizumab; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; FOLFOX4 = 5-fluorouracil and folinic acid plus oxaliplatin; HR = hazard ratio; IFL = irinotecan, bolus fluorouracil, and leucovorin; P = placebo; XELOX = capecitabine plus oxaliplatin.

Figure 2.

Subgroup analyses of overall survival by primary tumor location. Panel A shows the effect of primary tumor location on overall survival in the PROVETTA trial, stratified by baseline variables. Panels (B) and (C) show similar stratified analyses for the NO16966 and AVF2107g trials, respectively. The effect of primary tumor location was found to be statistically significant and consistent across the majority of the strata evaluated. Logistic regression analysis. All statistical tests were two-sided. CI = confidence interval; HR = hazard ratio.