Robins H I, Cohen J D, Schmitt C L, Tutsch K D, Feierabend C, Arzoomanian R Z, Alberti D, d'Oleire F, Longo W, Heiss C
University of Wisconsin Comprehensive Cancer Center, Madison 53792.
J Clin Oncol. 1993 Sep;11(9):1787-94. doi: 10.1200/JCO.1993.11.9.1787.
To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial.
Thirty assessable patients with cancer refractory to conventional therapy were treated. During induction therapy, patients received WBH alone in week 1, WBH plus carboplatin in week 2, and carboplatin alone in week 5. Carboplatin dose was escalated (three patients per group) as follows: 100, 150, 200, 250, 300, 350, 400, 480, and 575 mg/m2; three additional patients were entered at 480 mg/m2. Carboplatin was administered at target temperature.
Comparisons of the mean/median WBC and platelet nadirs for carboplatin alone and carboplatin plus WBH demonstrated no enhancing effect by WBH. Toxicities including nausea and/or vomiting, as well as myelosuppression, were within acceptable limits, allowing for escalation to a dose of 575 mg/m2; three of three patients at this dose level experienced grade 4 myelosuppression with no associated infection or bleeding. No renal toxicity was observed. Analysis of platinum in plasma ultrafiltrate and urine showed only slight effects of WBH on the pharmacokinetics and renal excretion of platinum. Responses included the following: lung--minor response (200 mg/m2); gastrointestinal neuroendocrine--complete response (CR) (400 mg/m2); pancreatic--partial response (PR) (480 mg/m2); small bowel--PR (575 mg/m2); ovarian--CR, two patients (575 mg/m2), with marker data suggesting WBH enhancement of carboplatin cytotoxicity. Another three patients experienced clinical improvement after WBH plus carboplatin, but progression with carboplatin alone (lung, 400 mg/m2; gastrointestinal neuroendocrine, 480 mg/m2; melanoma, 480 mg/m2).
We conclude that carboplatin with WBH is well tolerated even at conventional carboplatin doses. Clinical results are consistent with preclinical predictions of an increased therapeutic index for this combination, which encourages future clinical studies.
在一项I期临床试验中评估卡铂联合41.8摄氏度全身热疗（WBH）60分钟的生物学相互作用和毒性。
对30例对传统治疗难治的癌症患者进行了治疗。在诱导治疗期间，患者第1周单独接受WBH，第2周接受WBH加卡铂，第5周单独接受卡铂。卡铂剂量如下逐步递增（每组3例患者）：100、150、200、250、300、350、400、480和575mg/m²；另外3例患者接受480mg/m²的剂量。卡铂在目标温度下给药。
单独使用卡铂和卡铂加WBH时白细胞和血小板最低点的平均/中位数比较显示，WBH没有增强作用。包括恶心和/或呕吐以及骨髓抑制在内的毒性在可接受范围内，允许将剂量递增至575mg/m²；该剂量水平的3例患者中有3例出现4级骨髓抑制，无相关感染或出血。未观察到肾毒性。血浆超滤物和尿液中铂的分析表明，WBH对铂的药代动力学和肾排泄仅有轻微影响。反应如下：肺癌——微小反应（200mg/m²）；胃肠道神经内分泌癌——完全缓解（CR）（400mg/m²）；胰腺癌——部分缓解（PR）（480mg/m²）；小肠癌——PR（575mg/m²）；卵巢癌——CR，2例患者（575mg/m²），标志物数据表明WBH增强了卡铂的细胞毒性。另外3例患者在接受WBH加卡铂治疗后病情改善，但单独使用卡铂时病情进展（肺癌，400mg/m²；胃肠道神经内分泌癌，480mg/m²；黑色素瘤，480mg/m²）。
我们得出结论，即使在传统卡铂剂量下，卡铂联合WBH的耐受性也良好。临床结果与该联合治疗提高治疗指数的临床前预测一致，这鼓励了未来的临床研究。
