Hexamethylmelamine and Low or Moderate Dose Cisplatin With or Without Pyridoxine for Treatment of Advanced Ovarian Carcinoma: A Study of the Eastern Cooperative Oncology Group

Abstract

A total of 248 analyzable patients with Stages III-IV ovarian epithelial cancer (114 with and 134 without prior chemotherapy) were randomized to one of four cisplatin (DDP)-hexamethylmelamine (HMM) regimens. In each, HMM, 200 mg/m2 was given orally daily on days 8-21 of each 21-day cycle. DDP was given i.v. on Day 1 at a dose of 37.5 mg/m2 (regimens A and B) or 75 mg/m2 (regimens C and D). In addition, since pyridoxine administration has been reported to reduce the neurotoxicity of HMM, that agent was given at a dose of 300 mg/m2 orally on Days 1-21 in regimens B and D. Randomization was stratified for performance status (0-1, 2-3) and largest tumor diameter at entry (greater than 2- less than or equal to 10 cm, greater than 10 cm) for previously untreated patients, and for performance status and time from initial diagnosis to entry on study (less than or equal to 1 year, greater than 1 year) for previously treated patients. The overall response rate (PR + CR) was 54%, with 25% of patients achieving a complete response. The 61% response rate with the higher dose DDP regimens was significantly greater than the 47% response rate with the lower dose regimens (p = 0.031). Multivariate analysis identified higher DDP dose, age less than 60 years, no prior chemotherapy, small tumor bulk and favorable tumor grade as significant prognosticators for response. The overall median response duration was 8.3 months (range 1-70 months). Prior chemotherapy, pyridoxine administration, recent diagnosis, and large tumor size were identified by multivariate analysis as factors adversely affecting response duration. Patients treated with the higher dose DDP regimens had more severe nausea, vomiting, and neurotoxicity. This study demonstrates that the combination of DDP + HMM is an effective regimen for advanced ovarian carcinoma that yields response rates comparable to other more complex regimens, and that there is a dose-response relationship for DDP in ovarian cancer. Although pyridoxine administration significantly reduced neurotoxicity, its adverse effect on response duration suggests that the agent should not be administered with DDP or HMM. The mechanism by which pyridoxine may unfavorably affect response duration deserves further investigation.

A pilot clinical trial assessing the efficacy and safety of supplementation with a B complex vitamin to reduce the incidence of chemotherapy induced peripheral neuropathy in patients diagnosed with a malignancy

“…The dose for this trial is also lower than the vitamin B6 administered in the Wiernik, et al [78] trial, which was 300 mg of vitamin B6 per day for 21 days after chemotherapy treatment. Although no toxicity from vitamin B6 was noted in Wiernik's trial, and CIPN was reduced, the dose of vitamin B6 was found to adversely affect response duration [78].…”

“…Vitamin B6 was found to reduce CIPN [dose 100 mg of vitamin B6, pyridoxine hydrochloride, three times daily from days 1-21 of chemotherapy administration; equivalent to 300 mg/day]. However, it was also found to adversely affect response duration [78]. In 2010, Garg and Ackland found that vitamin B6 in cell culture examination was found to decrease CIPN associated with oxaliplatin administration, in the FOLFOX combination, without interfering with the anti-tumour activity [27].…”

“…Interactions with chemotherapeutic agents still require further investigation with studies showing beneficial effects when administered in conjunction with cisplatin [72]. However, considering that B6 has affected dose response when given in high doses, further studies assessing dose still need to be completed [78].…”

“…In relation to chemotherapy, two studies have been conducted with vitamin B6 and CIPN and positive results have been published [27,78].…”

“…Wiernik, et al [78] conducted a clinical trial on low or moderate dose cisplatin and hexamethylmelamine in advanced ovarian carcinoma patients. Vitamin B6 was found to reduce CIPN [dose 100 mg of vitamin B6, pyridoxine hydrochloride, three times daily from days 1-21 of chemotherapy administration; equivalent to 300 mg/day].…”