Gabriel A. Brooks, MPH, MD

Gabriel A. Brooks, MPH, MD, Associate Professor of Medicine, Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, was invited to discuss the results of the ACCENT/IDEA database analysis of early treatment discontinuation in stage III colon cancer. Although the results confirm the benefit of a full course of adjuvant chemotherapy, they also give reassurance that stopping oxaliplatin for reasons of toxicity may not compromise clinical outcomes, he said.

Dr. Brooks emphasized the importance of avoiding peripheral sensory neuropathy when possible. Many patients with grade 2 neuropathy can have worsening to grade 3 over time, and cumulative neuropathy can persist for months or even years in some. After 12 cycles of FOLFOX [fluorouracil, leucovorin, oxaliplatin], up to 25% of patients develop grade 3 neuropathy, and about 20% report residual symptoms at 18 months.

For this reason, there is high interest in deintensification of oxaliplatin. The IDEA trial compared 3 vs 6 months of adjuvant fluoropyrimidine and oxaliplatin, concluding that 3 months with both agents is not noninferior to 6 months of therapy.¹ “But while 6 months of therapy was shown to be superior, the benefit of the additional time on treatment was very small,” Dr. Brooks noted.

“What was not small was the difference in grade 3 or 4 neuropathy, which occurred in 2.5% of patients who received 3 months of adjuvant chemotherapy with oxaliplatin but in 15.9% of patients randomly assigned to 6 months…. The IDEA trial also showed that 3 months of CAPOX [capecitabine, oxaliplatin] was noninferior to 6 months of that regimen, so we do have some evidence to support a 3-month regimen,” he said.

“The key takeaways [of the analysis] were that early treatment discontinuation is prognostic for worse disease-free and overall survival. Early treatment discontinuation was associated with frailty, older age, worse performance status, and side effects that are consistent with treatment. We do not know, as Dr. Gallois pointed out, whether early treatment discontinuation is causally associated with the worst outcomes, or mostly a prognostic association, or some mix of the two, which is likely,” he commented.

Early oxaliplatin discontinuation, on the other hand, was not prognostic for 3-year disease-free or 5-year overall survival, he noted. As seen with early discontinuation of chemotherapy regimens, early discontinuation of oxaliplatin alone was associated with oxaliplatin side effects (ie, “not surprisingly” neuropathy).

“The inference here is that discontinuation of oxaliplatin after 3 months of adjuvant therapy did not negatively impact disease-free or overall survival. This...should give us confidence that many patients do not benefit from the additional 3 months of oxaliplatin-containing therapy, even if there may be some who benefit from 3 additional months of adjuvant chemotherapy with the fluoropyrimidine component,” Dr. Brooks said.

“The study supports the finding from the IDEA trial: for many patients, 3 months of oxaliplatin-containing chemotherapy is sufficient,” Dr. Brooks concluded. “Is it time to deintensify oxaliplatin to improve patient outcomes? My answer is a resounding ‘yes.’”

“The benefits of oxaliplatin are less than are often assumed in multiple settings, but the harms are well described,” he said. “We are probably overly aggressive in our use of oxaliplatin. I think we should use oxaliplatin cautiously and sparingly beyond the third month of adjuvant therapy for colon cancer.” 

DISCLOSURE: Dr. Brooks has served as a consultant or advisor to CareCentrix, Ipsen, and UnitedHealthcare.

REFERENCE

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.