New drugs to prevent oxaliplatin-induced peripheral neuropathy: A double-blind, randomized study.

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Background: Postoperative adjuvant chemotherapy for colorectal cancer reduces postoperative recurrence; however, it often causes undesirable adverse events. Oxaliplatin, the mainstay of postoperative adjuvant chemotherapy is particularly likely to cause chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSR) that may make it difficult to continue treatment. Various agents have been tested for prevention or treatment of CIPN caused by oxaliplatin, but none have proven effective. Reactive oxygen species contribute oxaliplatin-induced PN; therefore, super oxide dismutase (SOD) could potentially suppress them, but its very short serum half-life has made clinical application difficult. We developed a lecithinized human copper/zinc SOD (Cu/Zn-SOD) (PC-SOD) in which four phosphatidylcholine derivative molecules are bound covalently to each SOD dimer. Compared with SOD, PC-SOD enhanced stability in plasma and stronger tissue affinity, and exerts therapeutic effects in animal models of several diseases, including CIPN. Methods: This double-blind, randomized study included 90 patients with stage II/III colorectal cancer. All patients were slated to receive 12 cycles of mFOLFOX6. In each cycle, patients received PC-SOD or a placebo immediately before oxaliplatin. The primary endpoint of this study was the number of cycles before NCI-CTCAE Grade 2 (G2) CIPN occurred. One of the secondary endpoints was the number of cycles before DEB-NTC G2 PN occurred. Results: Forty-three patients received PC-SOD. No serious adverse events were observed that could be related to PC-SOD. The incidence of neutropenia, diarrhea, stomatitis, and malaise were lower in the study group, but the differences were not significant. Additionally, 3 patients (7.0%) in the study group and 11 (23.4%) in the placebo group had HSR. Although there was no difference in the number of cycles between the two groups until NCI-CTCAE G2 PN occurred, the study group had a significantly greater number of cycles before DEB-NTC G2 PN compared to the placebo group (P=0.08). The study group had a significantly greater number of cycles before NCI-CTC G1 PN (P=0.01) and HSR (P=0.03) compared to the placebo group. The number of cycles before HSR or NCI-CTCAE G2 PN occurred was greater in the study group , but the difference was not significant. The average total oxaliplatin dose was higher in the study group but the difference was not statistically significant. Conclusions: The primary endpoint did not occur; however, the study group had a significantly greater number of cycles before DEB-NTC G2 PN. Notably, the study group also had a significantly greater number of cycles before HSR. These results show that PC-SOD may suppress HSR as well as PN, both of which limit administration of oxaliplatin. Thus, this drug is expected to improve not only patient quality of life, but also the prognosis of patients. Clinical trial information: 2031210466.