Takahashi M, Yoshizawa H, Tanaka H, Tanaka J, Kagamu H, Ito K, Shimbo T, Chou D, Wakabayashi M, Suzuki E, Sakai K, Arakawa M, Gejyo F
Department of Medicine (II), Niigata University Medical School, Niigata, Japan.
Bone Marrow Transplant. 2000 Jan;25(1):5-11. doi: 10.1038/sj.bmt.1702088.
A phase I dose-escalation study of multicyclic, ifosfamide, carboplatin, and etoposide (ICE) with sequential reinfusion of peripheral blood stem cells (PBSCs) was conducted to determine the maximum-tolerated dose (MTD) of ICE. Twenty-four patients with SCLC (LD: 6, ED: 18) were treated with ifosfamide (3000-9000 mg/m2, 24-h infusion), carboplatin (300-400 mg/m2), and etoposide (300 mg/m2) followed by subcutaneous filgrastim (75 microg/day) from day 4 to the day of PBSC collection. PBSC were harvested when the WBC count reached >/=5 x 109/l. The leukapheresis product was cryopreserved and reinfused on day 4 of the next cycle, which was started 48 h after the last PBSC collection. The ifosfamide dose was escalated as follows: 3000 mg/m2 (level 1), 5000 mg/m2 (level 2), 7000 mg/m2 (level 3), 9000 mg/m2 (level 4). Patients with LD were treated with concurrent radiotherapy at 1.5 Gy twice daily for the initial 3 weeks to a total dose of 45 Gy and MTD, defined separately. Patients were evaluated for hematologic and non-hematologic toxicity, actual dose intensities, as well as response to therapy. The maximum-tolerated dose (MTD) was defined as the dose level at which more than 5 days of grade 4 myelo- suppression or non-hematologic toxicity greater than grade 3 developed in two thirds of the patients. For ED cases, MTD was level 4 and the recommended dose of ifosfamide was 7000 mg/m2. For LD cases, the recommended dose of ifosfamide was 5000 mg/m2. The dose limiting toxicity of multicyclic ICE was hemato- logic toxicity and CNS toxicity which manifested as ataxia. Tumor responses were seen in all patients, with 14 patients showing a complete response. The actual total dose-intensity at the recommended dose level was 2.2 and 1.74, for ED and LD, respectively, compared with previously reported ICE regimens. PBSC support for dose-intensive ICE regimen permitted dose escalation of ifosfamide with a mean interval of 16-17 days. We conclude that this regimen is well tolerated, with acceptable hematological and non-hematological toxicity. Bone Marrow Transplantation (2000) 25, 5-11.
开展了一项多周期异环磷酰胺、卡铂和依托泊苷（ICE）联合序贯回输外周血干细胞（PBSC）的I期剂量递增研究，以确定ICE的最大耐受剂量（MTD）。24例小细胞肺癌患者（局限期：6例，广泛期：18例）接受异环磷酰胺（3000 - 9000 mg/m²，持续24小时输注）、卡铂（300 - 400 mg/m²）和依托泊苷（300 mg/m²）治疗，从第4天至采集PBSC当天皮下注射非格司亭（75 μg/天）。当白细胞计数≥5×10⁹/L时采集PBSC。采集的白细胞分离产物进行冷冻保存，并在下一周期的第4天回输，下一周期在最后一次采集PBSC后48小时开始。异环磷酰胺剂量递增如下：3000 mg/m²（1级）、5000 mg/m²（2级）、7000 mg/m²（3级）、9000 mg/m²（4级）。局限期患者在最初3周每天两次接受1.5 Gy的同步放疗，总剂量为45 Gy，MTD单独定义。对患者进行血液学和非血液学毒性、实际剂量强度以及治疗反应评估。最大耐受剂量（MTD）定义为三分之二的患者出现超过5天的4级骨髓抑制或大于3级的非血液学毒性的剂量水平。对于广泛期病例，MTD为4级，异环磷酰胺的推荐剂量为7000 mg/m²。对于局限期病例，异环磷酰胺的推荐剂量为5000 mg/m²。多周期ICE的剂量限制性毒性为血液学毒性和表现为共济失调的中枢神经系统毒性。所有患者均出现肿瘤反应，14例患者完全缓解。与先前报道的ICE方案相比，在推荐剂量水平下，广泛期和局限期的实际总剂量强度分别为2.2和1.74。PBSC支持剂量密集型ICE方案允许异环磷酰胺剂量递增，平均间隔为16 - 17天。我们得出结论，该方案耐受性良好，血液学和非血液学毒性均可接受。《骨髓移植》（2000年）25卷，5 - 11页 。
