Gandara D R, Nahhas W A, Adelson M D, Lichtman S M, Podczaski E S, Yanovich S, Homesley H D, Braly P, Ritch P S, Weisberg S R
University of California-Davis, Martinez.
J Clin Oncol. 1995 Feb;13(2):490-6. doi: 10.1200/JCO.1995.13.2.490.
Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy.
Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles.
At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type.
This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.
二乙基二硫代氨基甲酸盐（DDTC）可在动物模型中阻断顺铂诱导的毒性作用，同时不抑制其抗肿瘤效应。在肺癌或卵巢癌患者中，对DDTC的化学保护作用与安慰剂（PB）进行了一项随机、多中心、双盲对照试验。主要终点为肾毒性、耳毒性、神经病变及治疗完成情况。
1990年4月至1992年2月期间，221例小细胞肺癌（SCLC）、非小细胞肺癌（NSCLC）或卵巢癌患者登记入组。顺铂（100 mg/m²）与环磷酰胺（用于卵巢癌）或依托泊苷（用于肺癌）联合使用，每4周静脉注射一次DDTC（1.6 g/m²，持续4小时）或PB，计划进行6个周期。
在中期安全性分析时，可获得来自肺癌和卵巢癌联合人群中195例患者的数据（PB组99例；DDTC组96例）。接受PB治疗的患者中有9%因化疗引起的毒性反应而退出研究，接受DDTC治疗的患者中有23%退出（P = 0.008）。两组的顺铂平均给药剂量强度（DDI）均为23 mg/m²/周。然而，PB组的顺铂累积给药剂量（CDD）平均为379 mg/m²，而DDTC组为247 mg/m²（P = 0.0001）。在中期分析时，接受PB治疗的患者中有28%完成了所有6个周期的治疗，而接受DDTC治疗的患者中只有6%完成（P < 0.001）。虽然两个治疗组的临床听力丧失、神经病变、呕吐和骨髓抑制情况相当，但根据血清肌酐浓度变化确定，接受DDTC治疗的患者肾毒性更大。与DDTC输注相关的毒性反应包括短暂性高血压、潮红和高血糖。DDTC对两种肿瘤类型的缓解率均无影响。
本研究未证明在所测试的DDTC剂量方案下，其对顺铂诱导的毒性有显著的化学保护作用。接受DDTC治疗的患者顺铂累积剂量较低，但由于化疗相关毒性反应，更有可能较早退出治疗。
