Maurel Joan, Fra Joaquín, López-Pousa Antonio, García del Muro Xavier, Balañá Carmen, Casado Antonio, Martín Javier, Martínez-Trufero Javier, de las Peñas Ramón, Buesa José M
Department of Medical Oncology, Hospital Clínic, Barcelona, Spain.
Cancer. 2004 Apr 1;100(7):1498-506. doi: 10.1002/cncr.20115.
Combinations of high-dose ifosfamide (IF; 10-12 g/m2) plus doxorubicin (DX; 50-90 mg/m2) have been administered to patients with advanced soft tissue sarcoma (ASTS) in an attempt to improve therapeutic efficacy. Although these combination regimens appear to yield higher response rates than do standard-dose regimens, they also are associated with significant hematologic toxicity, despite the administration of hematopoietic growth factor support. As a potentially less toxic alternative, the authors designed a sequential, dose-dense schedule of DX and IF and explored its feasibility and toxicity, as well as patient compliance with the schedule, in a Phase II trial.
Chemotherapy-naive patients with unresectable locally advanced or metastatic ASTS were to receive DX at 30 mg/m2 per day for 3 consecutive days once every 2 weeks for 3 cycles followed by IF at 12.5 g/m2 delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles. Granulocyte-colony-stimulating factor was administered subcutaneously for 7 days beginning 24 hours after the completion of each DX or IF cycle. Additional IF cycles were allowed if an objective response was achieved.
Sixty patients were enrolled in the trial. Three were ineligible, 9 had locally advanced disease, and 48 had metastatic disease. At the completion of therapy, the mean dose intensities for DX and IF were 40 mg/m2 per week and 3.87 g/m2 per week, respectively. Sixty-six percent of patients completed the regimen projected by the protocol. Grade 3 or 4 granulocytopenia, febrile neutropenia, and stomatitis occurred in 46%, 24%, and 27% of patients, respectively. Twenty of 53 assessable patients (38%; 95% confidence interval [CI], 25-51%) achieved objective responses, with a median time to progression of 24 weeks (95% CI, 18-30 weeks).
Sequential administration of dose-dense DX and high-dose IF is feasible and exhibits an acceptable hematologic toxicity profile and a level of activity that is within the range described for schedules that combine high-dose IF with an anthracycline.
已对晚期软组织肉瘤（ASTS）患者给予大剂量异环磷酰胺（IF；10 - 12 g/m²）联合多柔比星（DX；50 - 90 mg/m²）的方案，以试图提高治疗效果。尽管这些联合方案似乎比标准剂量方案产生更高的缓解率，但尽管给予了造血生长因子支持，它们仍与显著的血液学毒性相关。作为一种潜在毒性较小的替代方案，作者设计了一种DX和IF的序贯、剂量密集给药方案，并在一项II期试验中探索了其可行性、毒性以及患者对该方案的依从性。
未接受过化疗的不可切除的局部晚期或转移性ASTS患者，每2周连续3天每天接受30 mg/m²的DX，共3个周期，随后每3周连续5天持续输注12.5 g/m²的IF，共3个周期。在每个DX或IF周期完成后24小时开始皮下注射粒细胞集落刺激因子，持续7天。如果获得客观缓解，则允许进行额外的IF周期。
60例患者入组该试验。3例不符合条件，9例为局部晚期疾病，48例为转移性疾病。治疗结束时，DX和IF的平均剂量强度分别为每周40 mg/m²和每周3.87 g/m²。66%的患者完成了方案预计的疗程。3或4级粒细胞减少、发热性中性粒细胞减少和口腔炎分别发生在46%、24%和27%的患者中。53例可评估患者中有20例（38%；95%置信区间[CI]，25 - 51%）获得客观缓解，中位进展时间为24周（95%CI，18 - 30周）。
序贯给予剂量密集的DX和大剂量IF是可行的，表现出可接受的血液学毒性特征，且活性水平在将大剂量IF与蒽环类药物联合的方案所描述的范围内。
