Cascinu, S., Cordella, L., Del Ferro, E., Fronzoni, M., & Catalana, G. (1995). Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. Journal of Clinical Oncology, 13, 26–32.

Fifty patients with advanced gastric cancer were randomized to receive either 1.5 g/m² GSH in 1 L of normal saline or normal saline 1 L as a placebo infusion given over 15 minutes before cisplatin-based chemotherapy. GSH also was given by intramuscular injection on days 2 and 5. One cycle consisted of nine weekly treatments. Patients who showed responsive or stable disease received an additional six weeks of therapy.

• Fifty patients with advanced gastric cancer; 25 received GSH treatment and 25 received placebo infusions of normal saline.
• Sample size was determined to detect a 40% difference in the occurrence of grade 1–4 (World Health Organization [WHO] scale) neurotoxicity between the two treatment arms.
• Exclusion criteria includes previous chemotherapy, established clinical neuropathy, diabetes, alcoholic disease, brain involvement, or use of vitamins B1, B6, or B12.

The study had a randomized, placebo-controlled clinical trial design.

• Complete neurologic examination (strength, deep tendon reflexes, symptoms of peripheral nervous system involvement, position, and vibratory sensation); neurophysiologic assessment of the medial, ulnar; and sural nerves also were performed.
• Toxicity scores (using the WHO criteria) were evaluated weekly by the same examiner who was blinded to treatment group assignment.

Seven patients in the placebo group were unable to complete the study (six with progressive disease and one from grade 3 neurotoxicity). Only one patient in the GSH group was not able to complete the study. At nine weeks, no patients who received GSH had clinical evidence of neuropathy, compared to16 patients (66%) in the placebo-control group. After 15 weeks, 4 of 24 (17%) patients in the GSH arm showed clinical evidence of neurotoxicity compared to 16 (88%) in the placebo-control group. Most common symptoms included distal parasthesias and numbness in legs, decreased sense of vibration, and reduced or absent deep reflexes. No changes in mean latency and sensory amplitude potentials were noted in the group that received GSH but were significantly affected at 9 and 15 weeks in the control group. No patients reported ototoxicity.

• The study is almost 20 years old.
• Well-described methods and measures recorded higher than expected levels of neurotoxicity in the control arm, but could be from specific attention to the symptom.
• This study did not examine potential delayed toxicity. This could lead to an inaccurate conclusion about the benefits of GSH if it delays rather than prevents toxicity.