Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution
Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution
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DOI：
10.1093/annonc/mdf019
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发表时间：
2002-02-01
影响因子：
50.5
通讯作者：
Ducreux, M
中科院分区：
文献类型：
--
作者：
Elias, D;Bonnay, A;Ducreux, M
目的：本文报告了术中腹腔内加热奥沙利铂的药代动力学（PK）及其耐受性特征。奥沙利铂已被证明具有显着的活性，在晚期结直肠癌，这是第一次出版物关于其腹膜内administration.Methods：20例连续腹膜癌（PC）的胃肠道或唯一的腹膜起源进行了完整的细胞减灭术，然后在手术中腹腔内化疗热疗（IPCH）与奥沙利铂的剂量增加。我们采用开放式手术（皮肤向上提拉）进行IPCH，腹腔内温度为42- 44 ℃，在闭合回路中滴入2 l/m2的5%葡萄糖。流速为2 l/min，持续30 min。患者在IPCH前静脉注射甲酰四氢叶酸（20 mg/m2）和5-氟尿嘧啶（400 mg/m2），以最大限度地发挥奥沙利铂的作用。我们在进行下一个奥沙利铂剂量水平之前，在6个腹膜内奥沙利铂剂量水平（从260到460 mg/m2）中的每一个中治疗至少3名患者。我们用原子吸收分光光度法分析了腹腔、血浆和组织样品。结果：整个过程的平均持续时间为8.4 ± 2.7 h。在所有剂量水平下，奥沙利铂剂量的一半在30分钟内被吸收。曲线下面积（AUC）和最大血药浓度（C-max）随剂量增加而增加。在最高剂量水平（460 mg/m2）下，腹膜奥沙利铂浓度是血浆浓度的25倍。腹膜内给药后的AUC始终劣于静脉注射奥沙利铂（130 mg/m2）后的历史对照AUC。奥沙利铂的瘤内渗透率较高，与腹膜表面的吸收相似，是未浸浴组织的17.8倍。将滴注体积增加至2.5 l/m2而不是2 l/m2，可显著降低奥沙利铂浓度和吸收。有没有死亡，也没有严重的血液，肾脏或神经系统毒性，但我们观察到两个瘘和三个deep diseases.Conclusions：加热腹腔内化疗提供了高的腹膜和肿瘤奥沙利铂浓度有限的全身吸收。我们推荐奥沙利铂剂量为460 mg/m2，溶于2 l/m2的5%葡萄糖中，在42- 44 ℃温度下进行30 min的腹腔化疗-热疗。我们可以通过增加腹腔灌注时间或改变滴注液成分来改善这些结果。
Purpose: This article reports the pharmacokinetics (PK) of heated intra-operative intraperitoneal oxaliplatin and its tolerance profile. Oxaliplatin has demonstrated significant activity in advanced colorectal cancer, and this is the first publication concerning its intraperitoneal administration.Methods: Twenty consecutive patients with peritoneal carcinomatosis (PC) of either gastrointestinal or uniquely peritoneal origin underwent complete cytoreductive surgery followed by intra-operative intraperitoneal chemo-hyperthermia (IPCH) with increasing doses of oxaliplatin. We performed IPCH using an open procedure (skin pulled upwards), at an intraperitoneal temperature of 42-44degreesC, with 2 l/m(2) Of 5% dextrose instillate in a closed circuit. The flow-rate was 2 l/min for 30 min. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before the IPCH to maximize the effect of oxaliplatin. We treated at least three patients at each of the six intraperitoneal oxaliplatin dose levels (from 260 to 460 mg/m(2)) before progressing to the next. We analysed intraperitoneal, plasma and tissue samples with atomic absorption spectrophotometry,Results: The mean duration of the entire procedure was 8.4 +/- 2.7 h. Half the oxaliplatin dose was absorbed in 30 min at all dose levels. Area under the curve (AUC) and maximal plasma concentration (C-max) increased with dose. At the highest dose level (460 mg/m(2)), peritoneal oxaliplatin concentration was 25-fold that in plasma. AUCs following intraperitoneal administration were consistently inferior to historical control AUCs after intravenous oxaliplatin (130 mg/m(2)). Intratumoral oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 17.8-fold higher than that in non-bathed tissues. Increasing instillate volume to 2.5 l/m(2) instead of 2 l/m(2) dramatically decreased oxaliplatin concentration and absorption. There were no deaths, nor severe haematological, renal or neurological toxicity, but we observed two fistulas and three deep abscesses.Conclusions: Heated intraperitoneal chemotherapy gives high peritoneal and tumour oxaliplatin concentrations with limited systemic absorption. We recommend an oxaliplatin dose of 460 mg/m(2) in 2 l/m(2) of 5% dextrose for intraperitoneal chemo-hyperthermia, at a temperature of 42-44degreesC over 30 min. We may be able to improve these results by increasing the intraperitoneal perfusion duration or by modifying the instillate composition.