Masuda N, Fukuoka M, Kudoh S, Matsui K, Kusunoki Y, Takada M, Nakagawa K, Hirashima T, Tsukada H, Yana T
Department of Internal Medicine, Osaka Prefectural Habikino Hospital, Japan.
J Clin Oncol. 1994 Sep;12(9):1833-41. doi: 10.1200/JCO.1994.12.9.1833.
We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination.
Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached.
The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively.
The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.
由于伊立替康（CPT - 11，一种拓扑异构酶I抑制剂）和依托泊苷（一种拓扑异构酶II抑制剂）都有重叠的中性粒细胞毒性，我们开展了一项伊立替康联合依托泊苷及重组人粒细胞集落刺激因子（rhG - CSF）支持治疗的I期试验。目的是确定晚期肺癌患者中CPT - 11与固定剂量依托泊苷联合使用的最大耐受剂量，以及该联合方案的剂量限制性毒性。
25例III期或IV期肺癌患者，其中15例（60%）曾接受过化疗，每4周接受一次治疗，使用CPT - 11（第1、8和15天静脉输注90分钟）加依托泊苷（第1至3天静脉输注80 mg/m²）。此外，除CPT - 11给药日外，从第4天至第21天给予rhG - CSF（2微克/千克/天）。CPT - 11的起始剂量为60 mg/m²，以10 mg/m²的增量递增，直至达到最大耐受剂量。
CPT - 11的最大耐受剂量为90 mg/m²，因为在此剂量水平的第一个治疗周期中，三名患者中有两名出现3至4级白细胞减少或3至4级腹泻。腹泻和白细胞减少是剂量限制性毒性，而血小板减少只是一个中度问题。CPT - 11的消除呈双相性，平均±标准差β半衰期为18.17±9.09小时。7 - 乙基 - 10 - 羟基喜树碱（SN - 38；CPT - 11的主要代谢产物）的平均终末半衰期为43.40±37.84小时。21例可评估患者中有1例完全缓解（5%）和8例部分缓解（38%），总缓解率为43%。小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）的缓解率分别为58%（12例患者中的7例）和22%（9例患者中的2例）。
CPT - 11与依托泊苷联合rhG - CSF支持治疗似乎对肺癌，尤其是SCLC有效，且毒性可接受。对于既往未治疗患者，II期研究的推荐剂量为CPT - 11 80 mg/m²（第1、8和15天）、依托泊苷80 mg/m²（第1至3天）加rhG - CSF 2微克/千克（第4至21天，CPT - 11给药日除外）。此外，70 mg/m²的CPT - 11似乎是接受该方案的既往治疗患者的合适剂量。
