Sequential dose-dense doxorubicin and ifosfamide for advanced soft tissue sarcomas: a Phase II trial by the Spanish...

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.