The findings of the landmark IDEA trial in stage III colorectal cancer, presented at the 2017 ASCO Annual Meeting and subsequently published in The New England Journal of Medicine,1 were upheld by a subsequent analysis by the same group, the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration—this time, in the high-risk stage II subset.2 The results of this recent pooled analysis of the four IDEA studies in patients with stage II disease were presented at the 2019 ASCO Annual Meeting.
These data strongly suggest noninferiority of 3 months of CAPOX vs 6 months but equally suggest inferiority of 3 months of FOLFOX vs 6 months.— Timothy Iveson, MD
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In patients with high-risk stage II colorectal cancer, 3 months of adjuvant capecitabine plus oxaliplatin (CAPOX) were as beneficial as 6 months, with considerably less toxicity. By contrast, 6 months of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) yielded better efficacy than 3 months of FOLFOX, albeit with significantly more toxicity than the shorter duration of treatment, according to Timothy Iveson, MD, of the University Hospital Southampton (England) NHS Foundation Trust.
“We now have good data on both the efficacy and also toxicity of the regimens according to the duration of treatment,” said Dr. Iveson. “That should allow us to recommend both the chemotherapy regimen and the duration of treatment to our patients.”
The results of the primary IDEA analysis triggered a more nuanced algorithm for treating stage III disease. Although the study did not confirm the noninferiority of 3 vs 6 months of adjuvant FOLFOX or CAPOX in the overall population, it did find that 3 months of CAPOX, especially in lower-risk patients, was sufficient.
Turning to Patients With Stage II Disease
Questions were then raised as to whether the results could be extrapolated to stage II disease. In the IDEA Collaboration’s recent prospective, preplanned analysis, the investigators zeroed in on 3,273 patients with high-risk stage II disease drawn from the SCOT, TOSCA, ACHIEVE-2, and HORG trials, of whom 2,019 received CAPOX and 1,254 received FOLFOX.“High risk” was defined as one or more T4 tumors, inadequate nodal harvest, poorly differentiated tumors, obstruction, perforation, or vascular/perineural/lymphatic invasion.
Clinically meaningful inferiority was a hazard ratio of at least 1.2, corresponding to a 3.1% reduction in 5-year disease-free survival with 3 months vs 6 months of treatment. This was different from the upper limit (1.12) in patients with stage III disease.
Regimens Differed
The overall analysis could not demonstrate the noninferiority of 3 vs 6 months of treatment in terms of efficacy—similar to that of the primary IDEA analysis. By regimen, however, CAPOX proved noninferior to FOLFOX, with 5-year disease-free survival rates of 81.7% for 3 months of treatment and 82.0% for 6 months. By contrast, with FOLFOX, these rates were 79.2% vs 86.5%—an
Adjuvant Treatment of Stage II Colorectal Cancer
- The IDEA collaboration conducted a pooled analysis of four trials within the umbrella IDEA trial that included patients with high-risk stage II colorectal cancer.
- By regimen, 3 months of CAPOX is likely as beneficial as 6 months; with FOLFOX, 6 months is better than 3 months.
- FOLFOX for 6 months, however, was associated with a 51% rate of grade 3 to 5 toxicity.
absolute 7.3% difference in favor of a longer treatment duration.
“These data strongly suggest noninferiority of 3 months of CAPOX vs 6 months but equally suggest inferiority of 3 months of FOLFOX vs 6 months,” Dr. Iveson said.
The rates of grade ≥ 2 neuropathy were 36% for 6 months of treatment and 13% for 3 months of treatment; for grade 3 or 4 neuropathy, these rates were 8% and 1%, respectively (P < .0001). Six months of FOLFOX was associated with a 51% rate of grade 3 to 5 adverse events. ■
DISCLOSURE: Dr. Iveson has received honoraria from Lilly and Servier; has served as a consultant/advisor to BMS, Celgene, Roche, and Servier; and has received travel expenses from Bayer and Servier.
REFERENCES
1. Grothey A, Sobrero AF, Shields AF, et al: Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med 378:1177-1188, 2018.
2. Iveson T, Sobrero AF, Yoshino T, et al: Prospective pooled analysis of four randomized trials investigating duration of adjuvant oxaliplatin-based therapy (3 vs 6 months) for patients with high-risk stage II colorectal cancer. 2019 ASCO Annual Meeting. Abstract 3501. Presented June 1, 2019.
