Preventive effect of a traditional Japanese Kampo medicine, shakuyakukanzoto, against neurotoxicity of FOLFOX plus bevacizumab used for metastatic colorectal cancer management: A single-arm phase II study

Aim: 5-Fluorouracil/folinic acid and oxaliplatin plus bevacizumab (FOLFOX+BV) is a standard chemotherapy regimen for metastatic colorectal cancer (mCRC). This study was aimed at evaluating the preventive effects of shakuyakukanzoto against oxaliplatin-induced neurotoxicity associated with FOLFOX+BV administration. Methods: In this single-arm, open-label, phase II clinical trial, we enrolled patients with previously untreated, histologically confirmed mCRC from six hospitals in Japan who were aged 20years and older and had an Eastern Cooperative Oncology Group performance status of 0-1. The patients received shakuyakukanzoto 2.5g thrice daily, orally, until disease progression and/or unacceptable toxicity was noted. The primary endpoint was the incidence of neurotoxicity following oxaliplatin administration at a dose of 500mg/m(2). Neurotoxicity was evaluated according to the Neurotoxicity Criteria of Debiopharm (DEB-NTC). The trial was registered in the UMIN Clinical Trials Registry of Japan (UMIN000001853). Results: Forty-one non-pretreated mCRC patients were included between April 2009 and September 2013. At an oxaliplatin dose of 500mg/m(2), neurotoxicity of DEB-NTC grade 1-2 developed in 25.0% of patients; no patient had DEB-NTC grade 3 neurotoxicity. The most common grade 3/4 adverse events were neutropenia (34.1%), hypertension (24.4%), and fatigue (9.8%). The response rate of the 38 patients with measurable lesions was 55.2%. The median progression-free and overall survival was 14.9 and 35.2months respectively. Conclusion: Shakuyakukanzoto substantially reduced oxaliplatin-induced neurotoxicity without negatively affecting tumor response or survival in FOLFOX+BV-treated patients with CRC.