North Central Cancer Treatment Group/Alliance trial N08CA—the use of glutathione for prevention of paclitaxel/carboplatin‐induced peripheral neuropathy: A phase 3 randomized, double‐blind, placebo‐controlled study

Abstract

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy. Methods 185 patients undergoing treatment with paclitaxel and carboplatin were accrued between 12/04/2009 and 12/19/2011. Patients were randomized to receive either placebo (n=91) or 1.5 g/m2 glutathione (n=94) over 15 minutes immediately prior to chemotherapy. CIPN was assessed using the EORTC-CIPN20 sensory subscale and the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Results There were no statistically significant differences between the two study arms with regard to 1) peripheral neurotoxicity, assessed utilizing both EORTC-QLQ-CIPN20 (p=0.21) and CTCAE scales (p=0.449 for grade 2+ neurotoxicity; p=0.039 for time to development of grade 2+ neuropathy, in favor of the placebo); 2) the degree of the paclitaxel acute pain syndrome (p=0.30 for patients who received every 3–4 week paclitaxel vs. p=0.002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (p=0.63); or 4) apparent toxicities. Subgroup analysis did not reveal any evidence of benefit in any particular subgroup. Conclusion This study does not support the use of glutathione for the prevention of paclitaxel/carboplatin-induced CIPN.

Chemotherapy-induced peripheral neuropathy after neoadjuvant or adjuvant treatment of breast cancer: a prospective cohort study

“…The participants in our study were followed for 6 months after the diagnosis of CIPN, and a longer follow-up will allow the comparison with studies with longer follow-up [42]. Previous studies addressed the effect of interventions to prevent CIPN [43][44][45], but no such exposures were observed in our cohort.…”

Therapeutic opportunities for targeting cold pain pathways

“…Few human studies have specifically examined analgesic efficacy in paclitaxel-induced cold allodynia. Randomised controlled trials assessing the effect of gabapentin, lamotrigine and glutathione found a lack of efficacy in chemotherapy-induced peripheral neuropathy (CIPN) [139][140][141]. However, these studies did not specifically investigate cooling-related symptoms.…”

Chemotherapy-Induced Peripheral Neuropathy

“…[218][219][220][221][222][223][224] In a large randomized, double-blind, placebo-controlled trial to investigate the ability of glutathione to reverse the neuropathy associated with paclitaxel/carboplatin combination treatment; however, glutathione did not prevent CIPN. 225 Several small-clinical trials also demonstrated that vitamin E might have efficacy to decrease the incidence or severity of CIPN following paclitaxel or cisplatin treatment [226][227][228][229] ; however, a phase III clinical trial failed to reproduce the beneficial effects of the putative antioxidant. 230 There are some concerns about further development of antioxidant therapies to treat CIPN, since the production of ROS and RNS has been shown to be essential for the anticancer effects of chemotherapeutics.…”