Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials

Abstract

Background: Oxaliplatin-based adjuvant therapy is the standard of care for stage III colon cancer. Adjuvant capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin has not been directly compared; therefore, we aimed to analyse the efficacy and safety of these treatments using individual patient data pooled from four randomised controlled trials. We also assessed post-relapse survival, which has been postulated to be worse in patients receiving adjuvant oxaliplatin.

Methods: Patients with resected stage III colon cancer who were 18 years of age or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from four randomised controlled trials (NSABP C-08, XELOXA, X-ACT, and AVANT; 8734 patients in total) were pooled and analysed. The treatment regimens included in our analyses were: XELOX (oxaliplatin and capecitabine); leucovorin and fluorouracil; capecitabine; FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin); and modified FOLFOX-6 (mFOLFOX-6). Disease-free survival was the primary endpoint for all trials that supplied patients for this analysis. Here, we compared disease-free, relapse-free, and overall survival between the patient groups who received capecitabine with or without oxaliplatin and those who received leucovorin and fluorouracil with or without oxaliplatin. Post-relapse survival was compared between the combined XELOX and FOLFOX groups, and the leucovorin and fluorouracil groups. Post-relapse survival was also compared between the capecitabine with or without oxaliplatin and leucovorin and fluorouracil with or without oxaliplatin groups.

Findings: Disease-free survival did not differ significantly between patients who received leucovorin and fluorouracil versus those who received capecitabine in adjusted analyses (hazard ratio [HR] 1·02 [0·93-1·11; p=0·72]) or in unadjusted analyses (HR 1·01 [95% CI 0·92-1·10; p=0·86]). Relapse-free survival was similar (adjusted HR 1·02 [0·93-1·12; p=0·72] and unadjusted HR 1·01 [95% CI 0·92-1·11; p=0·86]), as was overall survival (adjusted HR 1·04 [95% CI 0·93-1·15; p=0·50] and unadjusted HR 1·02 [0·92-1·14]; p=0·65). For overall survival, a significant interaction between oxaliplatin and fluoropyrimidine was recorded in the multiple Cox regression analysis (p=0·014). Post-relapse survival was similar in adjusted (p=0·23) and unadjusted analyses (p=0·33) for the comparison of XELOX or FOLFOX versus leucovorin and fluorouracil, and was also similar for capecitabine-based regimens versus leucovorin and fluorouracil-based regimens (unadjusted p=0·26).

Interpretation: Combination therapy with oxaliplatin provided consistently improved outcomes without adversely affecting post-relapse survival in the adjuvant treatment of stage III colon cancer, irrespective of whether the fluoropyrimidine backbone was capecitabine or leucovorin and fluorouracil. These data add to the existing evidence that oxaliplatin plus capecitabine or leucovorin and fluorouracil is the standard of care for the adjuvant treatment of stage III colon cancer, and offers physicians flexibility to treat patients according to the patients' overall physical performance and preference.

Funding: Genentech Inc.

Figure 1. Summary description of the composition of pooled analytic groups with respect to the individual clinical trials

(A) The XELOX or FOLFOX versus leucovorin and fluorouracil comparison, (B) the capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin comparison, (C) the XELOX versus capecitabine comparison, and (D) the sensitivity analysis directly comparing XELOX with or without bevacizumab versus FOLFOX with or without bevacizumab. X-ACT=Xeloda in Adjuvant Colon Cancer Therapy. XELOXA=XELOX in Adjuvant Colon Cancer Treatment. NSABP=National Surgical Adjuvant Breast and Bowel Project. XELOX=capecitabine plus oxaliplatin. mFOLFOX-6=modified FOLFOX-6. FOLFOX=leucovorin and fluorouracil plus oxaliplatin. AVANT=Avastin Adjuvant.

Figure 2. Adjusted survival curves

(A) Disease-free survival and (B) overall survival for capecitabine with or without oxaliplatin versus leucovorin and fluorouracil with or without oxaliplatin, adjusted for sex, age, tumour (T) stage, and nodal (N) stage. ±=with or without. HR=hazard ratio. No numbers at risk are presented because this figure displays adjusted survival curves derived from a Cox proportional hazards regression model (rather than Kaplan–Meier survival analysis); hence, those data are not directly used.

Figure 3. Post-relapse survival curves

(A) Unadjusted Kaplan-Meier plot of post-relapse survival in patients receiving adjuvant capecitabine plus oxaliplatin (XELOX) or leucovorin and fluorouracil plus oxaliplatin (FOLFOX) compared with those receiving leucovorin and fluorouracil alone. (B) Adjusted post-relapse survival in patients receiving adjuvant capecitabine plus oxaliplatin (XELOX) or leucovorin and fluorouracil plus oxaliplatin (FOLFOX), compared with those receiving leucovorin and fluorouracil alone (adjusted for sex, age, tumour [T] stage, and nodal [N] stage), generated by the average covariate method. (C) Adjusted post-relapse survival in patients receiving adjuvant capecitabine plus oxaliplatin (XELOX) or leucovorin and fluorouracil plus oxaliplatin (FOLFOX), compared with those receiving leucovorin and fluorouracil alone (adjusted for sex, age, T stage, and N stage), generated by the corrected group prognosis method. (D) Unadjusted Kaplan-Meier plot of post-relapse survival in patients receiving adjuvant capecitabine plus oxaliplatin (XELOX) or leucovorin and fluorouracil plus oxaliplatin (FOLFOX) compared with those receiving leucovorin and fluorouracil alone, by nodal stage. HR=hazard ratio. XELOX=capecitabine plus oxaliplatin. FOLFOX=leucovorin and fluorouracil plus oxaliplatin. N=nodal stage. Please note that figures without numbers at risk display adjusted survival curves derived from a Cox proportional hazards regression model (rather than Kaplan–Meier survival analysis); hence, those data are not directly used.