Venlafaxine showed clinical activity against oxaliplatin induced acute neurosensory toxicity, reports the French EFFOX trial in the Annuals of Oncology.

Oxaliplatin is a third-generation platinum based cytotoxic agent that is widely used in colorectal cancer, metastatic disease and adjuvant treatment. Neurotoxicity is the most severe and dose-limiting cumulative toxicity that results from oxaliplatin therapy. The pathogenesis of the acute neuropathy is believed to be due to a channelopathy that involves the voltage-gated sodium channels. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has shown therapeutic effects for the management of chronic and neuropathic pain. It has also been shown at therapeutically relevant concentrations to block sodium channels in guinea pig myocytes.

In the EFFOX trial, JP Durand and colleagues, from the Université Paris Descartes, evaluated the efficacy of venlafaxine for the prevention and relief of acute oxaliplatin neurotoxicity. Between October 2005 and May 2008, 48 patients with oxaliplatin-induced acute neurotoxicity from six hospitals in France were randomised into a double-blind study to receive either venlafaxine 50 mg one hour prior to oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale.

Results show that according to the NRS scale 31.3% of patients in the venlafaxine arm experienced 100% pain relief versus 5.3% in the placebo arm (P=0.03). Similarly there were more responder patients experiencing relief greater than 50% in the venlafaxine arm than the placebo arm, 68.8% versus 26.3% (P=0.02). The toxicity profile of venlafaxine was acceptable, write the authors, with no grade 3-4 adverse events, although grade 1-2 emesis was observed more frequently under venlafaxine.

"This phase III trial confirms the clinical activity of venlafaxine for the symptom management of oxaliplatin-induced acute neurotoxicity," write the authors, adding that the study reached its primary end point despite the failure to reach the targeted accrual of patients.

"Although these results, due to the small sample size require further prospective studies, they may have immediate applications to the management of cancer patients under oxaliplatin-based chemotherapy," they add.

One potential explanation for the efficacy of venlafaxine, suggest the authors, is a protective effect against oxaliplatin-induced oxidative stress.

Article: J Durand G Deplanque, V Montheil et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Annals of Oncology doi: 10.1093/annonc/mdr045