Thierry André, MD, and colleagues reported the prospective pooled analysis of six phase III trials in the IDEA collaboration in The Lancet Oncology. The analysis showed that noninferiority in overall survival for 3 vs 6 months of adjuvant chemotherapy was not established in patients with stage III colon cancer, and the absolute difference in 5-year overall survival between approaches was 0.4%.
As noted by the investigators, the previous IDEA analysis did not show noninferiority for the primary endpoint of 3-year disease-free survival for 3 months vs 6 months of adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). However, 6 months of treatment did not provide additional benefit in patients receiving CAPOX, with noninferiority being shown, whereas 6 months of FOLFOX was associated with a moderate but significant improvement vs 3 months.
Thierry André, MD
The analysis included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients were recruited between June 2007 and December 2015 in 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials who started any treatment (modified intention-to-treat population).
Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant FOLFOX every 2 weeks or CAPOX every 3 weeks, as chosen by the treating physician. FOLFOX regimens consisted of infusional leucovorin at 200 mg/m² for FOLFOX4 (400 mg/m² for FOLFOX6), bolus fluorouracil at 400 mg/m² (400 mg/m²), infusional fluorouracil at 600 mg/m² (2,400 mg/m²), and infusional oxaliplatin at 85 mg/m² (85 mg/m²). The CAPOX regimen consisted of infusional oxaliplatin at 130 mg/m² and oral capecitabine at 1,000 mg/m² twice daily.
The primary endpoint was disease-free survival, with overall survival being the prespecified secondary endpoint. The noninferiority margin for overall survival was set as a hazard ratio (HR) of 1.11. Preplanned subgroup analyses included analysis by regimen and by risk group. Noninferiority was demonstrated if the one-sided false discovery rate adjusted (FDRadj) P value was < .025. The cutoff date for the final overall survival analysis was in January 2020.
The analysis included 12,835 patients in the modified intention-to-treat population, with 5,064 (39.5%) receiving CAPOX, 7,771 (60.5%) receiving FOLFOX, and 6,425 receiving 3-month and 6,410 receiving 6-month regimens. Overall median follow-up was 72.3 months (interquartile range = 72.2–72.5 months). A total of 2,584 patients died (20.1%).
Among all patients, 5-year overall survival was 82.4% (95% confidence interval [CI] = 81.4%–83.3%) with 3 months of therapy vs 82.8% (95% CI = 81.8%–83.8%) with 6 months of therapy (HR = 1.02, 95% CI = 0.95–1.11; noninferiority FDRadj P = .058; superiority for 6 months FDRadj P = .64). The absolute difference in 5-year overall survival was −0.4%.
Among patients receiving CAPOX, 5-year overall survival was 82.1% (95% CI = 80.5%–83.6%) in the 3-month group vs 81.2% (95% CI = 79.2%–82.9%) in the 6-month group (HR = 0.96, 95% CI = 0.85–1.08; noninferiority FDRadj P = .033; superiority for 6 months FDRadj P = .62). The absolute difference in 5-year overall survival was +0.9%.
Among patients receiving FOLFOX, 5-year overall survival was 82.6% (95% CI = 81.3%–83.8%) in the 3-month group vs 83.8% (95% CI = 82.6%–85.0%) in the 6-month group (HR = 1.07, 95% CI = 0.97–1.18; noninferiority FDRadj P =.34; superiority for 6 months FDRadj P = .38). The absolute difference in 5-year overall survival was −1.2%.
Among 7,507 patients with low-risk disease (T1, T2, or T3 and N1), 5-year overall survival was 89.6% vs 88.9% (HR = 0.95, 95% CI = 0.84–1.08; noninferiority FDRadj P =.033; superiority of 6 months FDRadj P = .58). Among 5,273 patients with high-risk disease (T4, N2, or both), 5-year overall survival was 72.0% vs 74.1% (HR = 1.08, 95% CI = 0.98–1.19; noninferiority FDRadj P = .39; superiority of 6 months FDRadj P = .29). In total, 5-year overall survival was 89.3% in the low-risk group and 73.1% in the high-risk group.
Updated Disease-Free Survival
The hazard ratio for 5-year disease free survival for the 3-month vs 6-month groups among all patients was 1.08 (95% CI = 1.02–1.15; noninferiority FDRadj P= .25; superiority for 6 months FDRadj P = .044). Among patients receiving CAPOX, the hazard ratio was 0.98 (95% CI = 0.88–1.08; noninferiority FDRadj P = .027; superiority FDRadj P = .67). Among those receiving FOLFOX, the hazard ratio was 1.16 (95% CI = 1.07–1.26; noninferiority FDRadj P = .80; superiority for 6 months FDRadj P = .0061). The P value for interaction between regimen and duration was .011. For low-risk vs high-risk patients, 5-year disease-free survival was 78.5% vs 57.7%.
Data on adverse events were not recorded beyond the initial primary analysis. As noted by the investigators, analysis at that time showed that grade ≥ 2 neurotoxicity during active therapy and in the first month after stopping study treatment occurred in 16.0% of patients in the 3-month group vs 44.5% of those in the 6-month group.
The investigators concluded, “Noninferiority of 3 months vs 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0.4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.”
Qian Shi, PhD, of the Department of Health Science Research, Mayo Clinic, Rochester, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit thelancet.com.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.