Delta tocotrienol as a supplement to FOLFOXIRI in first-line treatment of metastatic colorectal cancer. A randomized, double-blind, placebo-controlled phase II study

PurposeTriplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether & delta;-tocotrienol, a vitamin E analogue, with possible neuroprotective and anti-inflammatory effects, reduces the toxicity of triplet chemotherapy, we conducted a randomized, double-blind, placebo-controlled trial in mCRC patients receiving first-line 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI).Material and MethodsSeventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either & delta;-tocotrienol or placebo at the Department of Oncology, Vejle Hospital, Denmark. Eligibility criteria were adenocarcinoma in the colon or rectum, age 18-75 years and ECOG performance status 0-1. FOLFOXIRI was given in eight cycles followed by four cycles of 5-fluorouracil. & delta;-tocotrienol 300 mg or placebo x 3 daily was added during chemotherapy and for a maximum of two years. The primary endpoint was time to hospitalization or death during treatment with chemotherapy.ResultsMedian time to first hospitalization or death was 3.7 months in the placebo group (95% CI 1.93-not reached (NR)), and was NR in the & delta;-tocotrienol group (95% CI 1.87-NR) with a hazard ratio of 0.70 (95% CI 0.36-1.36). Grade 3-4 toxicities were uncommon in both groups, except for neutropenia, which occurred in 19 patients (58%) in the placebo group and 17 patients (50%) in the & delta;-tocotrienol group. There were no grade 3 or 4 peripheral sensory neuropathy. In the placebo group, 24 patients (71%) had oxaliplatin dose reductions compared to 17 patients (47%) in the & delta;-tocotrienol group (p = 0.047).ConclusionThe addition of & delta;-tocotrienol to FOLFOXIRI did not statistically significant prolong the time to first hospitalization or death compared to FOLFOXIRI plus placebo. Toxicity was manageable and not statistically different. There was a statistically significant difference in dose reductions of oxaliplatin pointing to a possible neuroprotective effect of & delta;-tocotrienol.