Can tocotrienol reduce time to the first serious adverse event during treatment with FOLFOXIRI for colorectal cancer?

Abstract

Background: Improvement of treatment for metastatic colorectal cancer is still needed. We designed a double blinded randomized study to introduce triple drug chemotherapy ‐ 5‐fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) as first‐line treatment for metastatic colorectal cancer. The triplet might be more effective than doublet chemotherapy, but the use is limited by increased risk of serious adverse events (SAE). Tocotrienol ‐ a vitamin E analogue ‐ has neuroprotective and anti‐inflammatory effects and may reduce toxicity. To investigate whether tocotrienol reduces toxicity of FOLFOXIRI, we randomized between addition of tocotrienol or placebo. The primary endpoint was 'time to first SAE' defined as a medical incident during treatment that leads to hospitalization or dead. Methods: Patients with unresectable metastatic colorectal cancer were included for first‐line treatment if 18‐75 years, performance status (PS) 0‐1 and adequate organ function. FOLFOXIRI was given in 8 cycles followed by 4 cycles of 5‐fluorouracil. During and in up to 2 years, tocotrienol 300 mg x 3 daily or placebo was added. Results: We included 70 patients and age (median 64 years, range 41‐75), PS (69% PS=0) and sex (39% female) was well balanced between the two arms. Median time to first SAE in the placebo arm was 3.7 months (95% CI 1.9‐not reached (NR)), and in the tocotrienol arm the median was NR (95% CI 1.9‐NR) with a hazard ratio of 0.70 (p=0.29, 95% CI 0.36‐1.36). The proportion of patients who had a SAE within seven months from treatment start was 53% vs. 43% for placebo and tocotrienol, respectively. Median PFS was 10.0months in the placebo arm (95% CI 7.4‐10.9) vs 9.7 months in the tocotrienol arm (95% CI 7.6‐12.1) with a hazard ratio of 1.24 (p=0.43). Response rate was 61% and 50% for placebo vs. tocotrienol (p=0.49). Preliminary data shows a two‐year survival rate of 51% (tocotrienol) and 54% (placebo), p=0.92 Conclusions: This single center study of FOLFOXIRI combined with placebo or tocotrienol as first‐line treatment of unresectable metastatic colorectal cancer showed a HR of 0.70 for postponing time to SAE but the difference was not statistically different. No differences in early efficacy outcomes were seen.