Cascinu, S., Catalano, V., Cordella, L., Labiance, R., Giordani, P., Baldelli, A.M., . . . Catalano, G. (2002). Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: A randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology, 20, 3478–3483.

Fifty-two patients with advanced colorectal cancer who were treated with a bimonthly oxaliplatin-based regimen were randomized to receive glutathione (GSH) (1,500 mg/m² over a 15-minute infusion period before oxaliplatin) or normal saline solution. Chemotherapy regimen was given as follows: oxaliplatin 100 mg/m² on day 1 concurrent with leucovorin 250 mg/m² followed by 5-FU 1,500 mg/m² per day for two consecutive days every two weeks. GSH was administered at a dose of 1,500 mg/m² in 100 ml of normal saline over 15 minutes immediately before each oxaliplatin administration. The placebo-randomized patients received normal saline. Disease response was assessed after four cycles of therapy. Those with responsive or stable disease received four additional cycles of treatment.

• Fifty-two patients with histologically verified advanced colorectal carcinoma were randomized to receive combination chemotherapy; 26 with and 26 without GSH.
• Patients were excluded if they had established clinical neuropathy, diabetes, alcoholic disease, other neurologic disease or brain involvement.
• Those who received vitamin B1, B6, or B12 supplements also were excluded.

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

• A neurologic examination, including measures of strength and reflexes, assessment of neurologic symptoms, position and vibratory sensation, and neurophysiologic evaluations of sural nerves were conducted at baseline, 4, 8, and 12 cycles of chemotherapy.
• The presence of signs and symptoms of peripheral nervous system involvement and the assessment of position and vibratory sensations also was performed.
• Neurotoxicity was expressed according to National Cancer Institute Common Terminology Criteria for Adverse Events.
• Neurophysiologic evaluation of sensory nerve conduction in the sural nerves was performed by the same examiners who were blinded to the group affiliation.

At baseline, no patients suffered from clinical neuropathy in either arm. At the time of second the neurologic exam (four cycles) seven patients had clinical neuropathy in the GSH arm and 11 in the placebo arm. After eight cycles of chemotherapy, nine patients had clinical neuropathy in the GSH arm compared with 15 patients in the placebo arm with an incidence of moderate to severe (grade 2–4) clinical neurotoxicity present in 11 of 19 assessable patients in the placebo arm, as compared to 2 of 21 assessable patients in GSH arm. No grade 3–4 neurotoxicity was present in GSH arm while grade 3–4 neurotoxicity was reported in five patients in placebo arm. Only 18 patients received 12 cycles of chemotherapy, 10 in the GSH arm and 8 in the placebo arm. Grade 2–3 neurotoxicity was observed in three patients in GSH arm and eight patients in the placebo arm.

The study was performed on patients who had received preliminary date on a small number of patients with no true control group.