Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors
Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors
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DOI：
10.1093/annonc/mdv369
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发表时间：
2015-11-01
影响因子：
50.5
通讯作者：
Gietema, J. A.
中科院分区：
文献类型：
--
作者：
Boer, H.;Proost, J. H.;Gietema, J. A.
背景：顺铂（Platinol，百时美施贵宝公司，美国纽约州纽约市）化疗治疗睾丸癌的成功是以健康组织损伤相关的长期和晚期影响为代价的。我们对化疗后的血清铂 (Pt) 衰减进行了评估和建模，并确定了长期循环 Pt 水平与已知晚期效应之间的关系。患者和方法：在 99 名睾丸癌幸存者中，接受基于顺铂的化疗，在随访期间（治疗后 1-13 年）收集血清和 24 小时尿液样本。为了建立群体药代动力学模型，使用 NONMEM 软件同时分析测量的 Pt 数据以及顺铂剂量、年龄、体重和身高。基于该模型，计算每位患者治疗后 1 至 3 年之间的曲线下面积（Pt AUC1-3 年）。预测的长期 Pt 暴露与肾功能以及化疗后中位 9（3-15）年评估的治疗后期效果相关。结果：两室模型最好地描述了 Pt 的衰变。平均终末 T1/2 为 3.7 年（范围 2.5-5.2）年。 Pt AUC1-3 年与顺铂累积剂量以及治疗前和治疗后 1 年的肌酐清除率相关。与无感觉异常的患者相比，有感觉异常的患者具有较高的 Pt AUC1-3 年（30.9 与 27.0 μg/l 月）（P = 0.021）。患有性腺功能减退、LDL-胆固醇水平升高或高血压的患者也具有较高的Pt AUC1-3年。结论：顺铂治疗前后的肾功能是长期铂暴露的重要决定因素。已知的睾丸癌治疗的长期影响，如感觉异常、性腺功能减退、高胆固醇血症和高血压，与长期循环 Pt 暴露有关。
Background: The success of cisplatin- based ( Platinol, Bristol- Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long- term and late effects related to healthy tissue damage. We assessed and modelled serum platinum ( Pt) decay after chemotherapy and determined relationships between long- term circulating Pt levels and known late effects. Patients and methods: In 99 testicular cancer survivors, treated with cisplatin- based chemotherapy, serum and 24- h urine samples were collected during follow- up ( 1- 13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment ( Pt AUC1- 3 years) was calculated for each patient. Predicted long- term Pt exposure was related to renal function and to late effects of treatment assessed median 9 ( 3- 15) years after chemotherapy. Results: Decay of Pt was best described by a two- compartment model. Mean terminal T1/ 2 was 3.7 ( range 2.5- 5.2) years. Pt AUC1- 3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1- 3 years ( 30.9 versus 27.0 mu g/ l month) compared with those without paraesthesia ( P = 0.021). Patients with hypogonadism, elevated LDL- cholesterol levels or hypertension also had higher Pt AUC1- 3 years. Conclusions: Renal function before and after cisplatin treatment is an important determinant of long- term Pt exposure. Known long- term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long- term circulating Pt exposure.