MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy

Abstract

Purpose: Previous pilot data suggested that venlafaxine could prevent acute and chronic oxaliplatin-related neuropathy. The purpose of this randomized, placebo-controlled, double-blinded pilot study was to obtain additional data to support conducting a phase III trial to test the use of venlafaxine to prevent oxaliplatin neurotoxicity.

Methods: Fifty patients, scheduled to undergo oxaliplatin-based therapy (FOLFOX) for stages II-III (67%) or stage IV (33%) colon cancer, were randomized to receive venlafaxine extended release (37.5 mg) or placebo, twice daily, through their last dose of oxaliplatin and then titrated off. Neurotoxicity was evaluated via several patient- and physician-reported measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20) instrument.

Results: Baseline patient characteristics were equivalent for the two arms, with a median age of 60 years. There was a trend toward benefit for the venlafaxine arm, when evaluated by the oxaliplatin-specific neuropathy scale and by acute neuropathy measures of throat discomfort and discomfort swallowing cold liquids, the latter only for the first two oxaliplatin doses. These trends were outweighed by a lack of any such trends in all other measurements including the following: (1) the CIPN20 sensory subscale (P = 0.55, primary endpoint), physician-completed NCI CTCAE assessment, or cumulative administered oxaliplatin doses (median 716 vs 631 mg for placebo and venlafaxine, respectively, P = 0.34).

Conclusions: The present study neither supports the use of venlafaxine for preventing oxaliplatin-induced neuropathy in clinical practice nor the initiation of a phase III trial to investigate venlafaxine in this setting.

Trial registration: ClinicalTrials.gov NCT01611155.

Keywords: Chemotherapy-induced neuropathy prevention; Venlafaxine.

Fig. 1

CONSORT diagram. SAE serious adverse event

Fig. 2

Acute symptoms over time regarding sensitivity to touching cold items (a), discomfort swallowing cold liquids (b), throat discomfort (c), and muscle cramps (d). Data collected via the Oxaliplatin Acute Symptom Questionnaire; higher scores represent more symptoms

Fig. 3

Peripheral sensory neuropathy changes over time for the two study arms, as measured by the sensory scale of the EORTC QLQCIPN20 instrument, during chemotherapy (a) and following the cessation of chemotherapy (b); higher scores represent fewer symptoms

Fig. 4

Changes over time for individual questions from the EORTC QLQ-CIPN20 instrument: Do you have tingling fingers or hands? (a); Do you have tingling toes or feet? (b); Do you have numbness in your fingers or hands? (c); Do you have numbness in your toes or feet? (d); Do you have shooting or burning pains in your fingers or hands (e); Do you have shooting or burning pains in your toes or feet? (f). Higher scores represent fewer symptoms

Fig. 5

Time to grade 2 or worse chemotherapy-induced peripheral neuropathy measured by the NCI-CTCAE criteria (a) and the oxaliplatin-specific neuropathy instrument (b)

Fig. 6

Oxaliplatin use in each study arm as measured by the following: percentage of patients continuing to use oxaliplatin over time (a), percentage of patients using full doses of oxaliplatin over time (b), and mean oxaliplatin dose over time (c). In each situation, the denominators are the numbers of evaluable patients who started each study arm