Adjuvant chemotherapy duration in stage III colon cancer: One size does not fit all
medwireNews: The optimal duration of adjuvant chemotherapy in patients with stage III colon cancer may depend on the regimen used and the patient’s risk status, indicate the results of the international IDEA collaboration.
These findings were published in The New England Journal of Medicine, while the results of two of the constituent trials – IDEA France and TOSCA – appeared in the Journal of Clinical Oncology.
The idea behind the IDEA (International Duration Evaluation of Adjuvant Therapy) collaboration was to pool together data from six clinical trials to establish the noninferiority of 3 months of FOLFOX (fluorouracil, leucovorin and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjuvant chemotherapy versus a 6-month regimen.
The investigators explain: “Given the cumulative nature of oxaliplatin-mediated neurotoxicity, shorter adjuvant therapy would be beneficial for patients and reduce the use of health care resources if efficacy were maintained.”
Across the six trials, 12,834 patients with resected stage III disease were randomly assigned to receive either 3 or 6 months of oxaliplatin-based therapy, but the choice of FOLFOX or CAPOX was left to the treating physician’s discretion, and overall 60.5% of participants received FOLFOX and 39.5% received CAPOX. The proportions varied widely across trials though, with CAPOX use ranging from 0% in the CALGB/SWOG 80702 trial to 66.5% and 75.1% in the SCOT and ACHIEVE trials, respectively.
After a median follow-up of 41.8 months, the primary endpoint of 3-year disease-free survival (DFS) was achieved by 74.6% of patients in the 3-month group and 75.5% of those in the 6-month group, giving a hazard ratio (HR) of 1.07, the upper limit of which fell outside the prespecified noninferiority threshold.
However, although the noninferiority of the 3-month regimen could not be confirmed in the overall population, there were differences by subgroup. Specifically, the 3-month schedule was found to be noninferior to the 6-month schedule among patients who received CAPOX (HR=0.95), while 6 months of FOLFOX therapy was superior to 3 months (HR=1.16).
And when patients were stratified by risk, those with low-risk disease (defined as T1–T3 or N1 tumors) could receive 3 months of adjuvant therapy without loss of efficacy regardless of the regimen (nonsignificant HR=1.01), whereas 6 months of oxaliplatin-based therapy was superior among those with high-risk colon cancer (T4 and/or N2 tumors; significant HR=1.12).
Unsurprisingly, the 3-month schedule was associated with a lower rate of grade 2 or worse neurotoxicity during and in the month after cessation of treatment for both FOLFOX (16.6 vs 47.7%) and CAPOX (14.2 vs 44.9%). Other toxicities – such as diarrhea, neutropenia, thrombocytopenia, and nausea – also occurred at a “substantially lower” rate in the 3- versus the 6-month group, the researchers report.
Axel Grothey (Mayo Clinic Rochester, Minnesota, USA) and co-investigators conclude: “These data suggest that the choice of treatment regimen, duration of therapy, and characteristics of the patients may be balanced against the substantial risk of increased toxicity of longer oxaliplatin-based therapy, including persistent neurotoxicity.”
But they urge caution in interpreting the subgroup results as “[t]he study design did not call for patients to undergo a secondary randomization to CAPOX or FOLFOX,” and the analysis by risk was exploratory in nature.
For instance, in the overall IDEA France population – which included 2010 participants – the 6-month regimen emerged as superior to the 3-month regimen, with 3-year DFS rates of 76% and 72%, respectively, giving an HR of 1.24. But it is worth noting that 90% of study participants received FOLFOX – specifically, modified FOLFOX6 – as per the treating oncologists’ preferences, and that in subgroup analyses, the 6-month group was favored in all instances except the CAPOX subgroup.
“[T]he low number of patients treated with CAPOX precludes from any robust conclusion,” notes the team led by Thierry André (Hôpital Saint-Antoine, Paris, France). “Nonetheless, this observation is in line with [the] IDEA international collaboration.”
The Italian TOSCA trial was initiated before the IDEA collaboration was launched, and also recruited patients with stage II colon cancer.
The TOSCA results were mostly in accordance with the overall IDEA findings, with regard to the overall and subgroup analyses. But the researchers did observe that stage II patients appeared to benefit significantly from the longer duration, with an HR for relapse-free survival of 1.41 relative to the 3-month schedule, while no such association was seen in patients with stage III disease.
Describing the finding as “unexpected and counterintuitive,” Alberto Sobrero (Ospedale Policlinico San Martino, Genova, Italy) and co-workers wonder how much they can trust this potential differential effect of the treatment duration on stage, and recommend that the results “be interpreted with caution within the context of the combined analyses of IDEA.”
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