Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer

Abstract

Purpose: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers.

Patients and methods: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required.

Results: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68).

Conclusion: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

Trial registration: ClinicalTrials.gov NCT00749450 NCT00646607 NCT01308086.

FIG 1.

CONSORT diagram. ACHIEVE2, Adjuvant Chemotherapy for Colon Cancer with High Evidence2; CAPOX, capecitabine and oxaliplatin; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; HORG, Hellenic Oncology Research Group; mITT, modified intention-to-treat; RT, radiation therapy; SCOT, Short Course Oncology Treatment; TOSCA, Three or Six Colon Adjuvant.

FIG 2.

Kaplan-Meier estimates of disease-free survival (DFS) for modified intention-to-treat study population. HR, hazard ratio; NIF, noninferiority.

FIG 3.

Forest plot for preplanned subgroup analyses. CAPOX, capecitabine and oxaliplatin; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; SCOT, Short Course Oncology Treatment.

FIG 4.

(A) Kaplan-Meier estimates of disease-free survival (DFS) among capecitabine and oxaliplatin (CAPOX)–treated patients and (B) Kaplan-Meier estimates of DFS among fluorouracil, leucovorin, and oxaliplatin (FOLFOX)–treated patients. HR, hazard ratio; NIF, noninferiority.

FIG 5.

(A) Kaplan-Meier estimates of disease-free survival (DFS) for patients from Short Course Oncology Treatment (SCOT), Adjuvant Chemotherapy for Colon Cancer with High Evidence2, and Hellenic Oncology Research Group comparing those with one risk factor and those with two or more risk factors. (B) Forest plot for patients with one or two or more high-risk factors and chemotherapy regimen received. CAPOX, capecitabine and oxaliplatin; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; NIF, noninferiority.

FIG A1.

Kaplan-Meier estimates of disease-free survival for patients with T3 disease compared to T4 disease.