(ChemotherapyAdvisor) – Adding cetuximab to a modified version of the leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) adjuvant regimen did not improve disease-free survival in patients with resected stage 3 wild-type KRAS colon cancer vs. mFOLFOX6 alone, according to a study in the April 4 issue of JAMA.
The multicenter trial randomized 2,686 patients — 1,863 with wild-type KRAS, 717 patients with mutated KRAS, and 106 patients with indeterminate KRAS — to 12 biweekly cycles of mFOLFOX6 with and without cetuximab. Patient enrollment began February 2004 and was permanently halted on November 25, 2009, after the second planned interim analysis demonstrated a low probability that disease-free survival of the cetuximab group would surpass that of the mFOLFOX6-only group.
Median follow-up was 28 months (range, 0–68 months). “The trial demonstrated no benefit when adding cetuximab,” the investigators noted. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; P=0.08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; P=0.38) in patients with mutated KRAS, respectively. Time-to-recurrence and overall survival were not significantly different between treatment groups.
Patients in the cetuximab group had a higher rate of grade ≥3 adverse events (72.5% vs. 52.3%; P<0.001) and were significantly more likely to fail to complete 12 cycles (33% vs. 23%; P<0.001) than those in the mFOLFOX6 alone group. Those ≥70 years of age had increased toxicity and greater detrimental differences in all outcomes.
The researchers concluded that reasons for lack of benefit of mFOLFOX6 with cetuximab in this setting remain unclear.
An accompanying editorial notes that “the inescapable conclusion is that efficacy in the metastatic setting does not reliably predict efficacy in the adjuvant setting. The role of adjuvant chemotherapy does not involve treating the tumor that the surgeon has removed, but rather attempts to eradicate whatever occult micrometastatic disease may still be present after surgery. If there are no micrometastases, surgery is curative and adjuvant chemotherapy is unnecessary. If micrometastases are present, the long-term health of the patient will depend on whether the chemotherapy can destroy all remaining micrometastases.”