Trump D L, Grem J L, Tutsch K D, Willson J K, Simon K J, Alberti D, Storer B, Tormey D C
J Clin Oncol. 1987 Aug;5(8):1281-9. doi: 10.1200/JCO.1987.5.8.1281.
Cisplatin (NSC 119875) and carboplatin (NSC 241240) are platinum (II) analogues with very different spectra of toxicity. Cisplatin dose is limited by nausea and vomiting, renal dysfunction, and dose-related peripheral neuropathy, whereas carboplatin is myelosuppressive. There are also clinical and laboratory data that suggest that these drugs may not be completely cross-resistant. Therefore, the following phase I trial of combination therapy with cisplatin and carboplatin was undertaken. Since carboplatin toxicity is enhanced in the presence of renal impairment, carboplatin excretion was also evaluated in selected patients at the maximum tolerated dose. Thirty-three patients received 50 mg/m2 cisplatin and doses of carboplatin between 160 mg/m2 and 400 mg/m2. Sequential 20-minute infusions of carboplatin and then cisplatin were able to be administered at the standard doses of carboplatin (320 and 400 mg/m2) with thrombocytopenia to the degree expected if carboplatin alone had been given. However, 280 mg/m2 carboplatin followed by 25 mg/m2 cisplatin/d X 3 caused unexpectedly severe thrombocytopenia in seven of eight patients (median platelet nadir 45,000/microL; range, 12 to 321,000/microL; nadir was less than 90,000 in seven of eight patients). In three patients treated with 280 mg/m2 carboplatin plus 25 mg/m2/d X 3 cisplatin, pharmacokinetics of carboplatin were compared during consecutive monthly cycles without and with cisplatin. Modestly increased areas under the curve (AUC) for carboplatin (15% and 35%) with cisplatin were seen in the two patients who experienced more pronounced platelet suppression with combination therapy. No other limiting or unusual toxicity was seen with this combination. Responses, primarily in "platinum responsive" tumors, were seen. The combination of cisplatin plus carboplatin is feasible and merits further study.
顺铂（NSC 119875）和卡铂（NSC 241240）是具有截然不同毒性谱的铂（II）类似物。顺铂的剂量受恶心、呕吐、肾功能不全以及剂量相关的周围神经病变限制，而卡铂则具有骨髓抑制作用。也有临床和实验室数据表明这些药物可能并非完全交叉耐药。因此，开展了以下顺铂与卡铂联合治疗的I期试验。由于肾功能损害会增强卡铂的毒性，所以还对选定患者在最大耐受剂量下的卡铂排泄情况进行了评估。33例患者接受了50mg/m²的顺铂以及160mg/m²至400mg/m²的卡铂剂量。卡铂和顺铂依次进行20分钟输注，在卡铂标准剂量（320和400mg/m²）下能够给药，且出现了单独给予卡铂时预期程度的血小板减少。然而，280mg/m²的卡铂随后给予25mg/m²顺铂/天×3天，在8例患者中有7例出现了意外的严重血小板减少（血小板计数最低点中位数为45,000/μL；范围为12至321,000/μL；8例患者中有7例最低点低于90,000）。在3例接受280mg/m²卡铂加25mg/m²/天×3天顺铂治疗的患者中，比较了连续每月周期在未使用和顺铂联合使用时卡铂的药代动力学。在联合治疗中血小板抑制更明显的2例患者中，观察到卡铂的曲线下面积（AUC）适度增加（分别为15%和35%）。该联合治疗未观察到其他限制性或异常毒性。观察到了反应，主要出现在“铂类敏感”肿瘤中。顺铂加卡铂的联合治疗是可行的，值得进一步研究。
