Palumbo R, Palmeri S, Antimi M, Gatti C, Raffo P, Villani G, Toma S
National Institute for Cancer Research, Genoa, Italy.
Ann Oncol. 1997 Nov;8(11):1159-62. doi: 10.1023/a:1008279426654.
Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.
Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m2/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 micrograms/m2/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.
A total of 159 cycles of therapy were given (median 4 per patient, range 3-6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5-21+ months), and the overall median survival ranged from 6-30+ months (median 13 months).
High-dose ifosfamide is an active regimen in anthracycline-pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.
异环磷酰胺在经预处理的软组织肉瘤（STS）中具有重要活性，近期数据支持该药物存在具有临床意义的剂量 - 反应关系。通过持续输注给药及造血支持，通过降低血液学和非血液学毒性，使剂量强化方案成为可能。高剂量异环磷酰胺给药时的最佳剂量和方案仍有待确定。在先前的一项I期研究中，我们证明了在门诊环境中对晚期实体瘤患者采用持续输注（c.i.）高剂量异环磷酰胺（HDI）方案的可行性。本II期研究的目的是评估这种方案在晚期经预处理的STS患者中的抗肿瘤活性和毒性。
38例晚期和/或转移性STS患者接受了治疗，所有患者均接受过蒽环类药物治疗，部分患者联合或未联合标准剂量异环磷酰胺。异环磷酰胺通过持续输注给药，剂量为3.5 g/m²/天，连续4天，同时在5天内给予等量美司钠进行尿路保护。从第6天至第12天，皮下注射剂量为200微克/m²/天的粒细胞集落刺激因子（G-CSF）。在门诊环境中，每三周重复一个周期。
共进行了159个治疗周期（每位患者中位数为4个周期，范围为3 - 6个周期）。治疗依从性总体令人满意。主要毒性为血液学毒性，有6例发热性中性粒细胞减少发作需要住院并接受静脉抗生素治疗。1例患者在3个周期治疗后发生急性肾衰竭；中枢神经系统毒性较轻。观察到总体缓解率为39%（95%置信区间，26%至55%），其中1例完全缓解，14例部分缓解。除1例缓解患者外，其余所有缓解患者之前均接受过标准剂量异环磷酰胺治疗。中位缓解持续时间为9个月（范围为5 - 21 +个月），总体中位生存期为6 - 30 +个月（中位数为13个月）。
高剂量异环磷酰胺在蒽环类药物预处理的STS中是一种有效的方案。未来的临床试验应旨在评估不同给药方案对临床反应和结局的影响。高剂量异环磷酰胺作为一线化疗以及在STS辅助治疗中的潜在作用需要在随机试验中进行研究。
