Results of Two Consecutive Trials of Dose-Intensive Chemotherapy With Doxorubicin and Ifosfamide in Patients With Sarcomas

Abstract

The authors evaluate the efficacy and feasibility of dose-intensive doxorubicin and ifosfamide combination chemotherapy in patients with sarcomas. From January 1995 to April 1996, 33 evaluable patients with either metastatic sarcoma or primary sarcomas with a high-risk for metastases (all except one was previously untreated with chemotherapy) were treated on two consecutive protocols. The median age was 45 years (range, 15-68 years). The first protocol included doxorubicin at 75 mg/m2 given as a 72-hour infusion on days 1 to 3 along with ifosfamide at 2 g/m2/d over 2 hours x 5, days 1 to 5 (protocol AI 75/10). Granulocyte colony-stimulating factor (G-CSF) was used only if indicated according to American Society of Clinical Oncology guidelines. The second protocol included doxorubicin at 90 mg/m2 as a 72-hour continuous infusion and ifosfamide at 2.5 g/m2/d for 4 days (protocol AI 90/10) with prophylactic G-CSF. A median of four cycles were administered (range, 1-6). Three patients achieved a pathologic complete response (CR) and 18 patients achieved a partial response (PR) for a response rate (RR) of 64% (95% confidence interval (CI), 45-80%). Response rate for the subset of patients with soft-tissue sarcomas was 66% (95% CI, 46-82%). Only three patients progressed on therapy. Febrile neutropenia was noted in 31% of cycles at AI 75/10 and in 56% of cycles at AI 90/10. One patient developed reversible grade 3 central nervous system (CNS) toxicity. There was one treatment-related death on AI 90/10 secondary to doxorubicin cardiac toxicity at a cumulative dose of 435 mg/m2. Dose-intensive doxorubicin plus ifosfamide is feasible in appropriately selected patients and appears to be a very active regimen in patients with sarcomas. The authors are currently testing this regimen with G-CSF and thrombopoietin.

Radiographic response to neoadjuvant chemotherapy is a predictor of local control and survival in soft tissue sarcomas

“…15,16 In our study, radiographic response rates were significantly higher using such regimens. Although the rates of tumor response sufficient to alter surgical treatment are still low, progress is being made using newer high-dose combination chemotherapy regimens.…”

Treatment of advanced soft-tissue sarcomas using a combined strategy of high-dose ifosfamide, high-dose doxorubicin and salvage therapies

“…It has successfully accomplished this purpose by demonstrating a response rate of 48% (95% CI: 33 -63%) in 46 patients with advanced soft-tissue sarcomas. Although this observed response rate did not reach the requirement being considered promising as defined by the statistical design, it is in the range of similar response rates (40 -66%) for high-dose combination of ifosfamide and doxorubicin that have been obtained in other phase-II studies (Frustaci et al, 1997;Patel et al, 1998;Reichardt et al, 1998). The most recent trials have yielded less impressive response rates (25 -23%) but were designed such that only one agent was administered at high dose levels (Le Cesne et al, 2000;Worden et al, 2005).…”

“…Following suggestions that these agents may have a doseresponse relationship (O'Bryan et al, 1973;Le Cesne et al, 1995;Cerny et al, 1999), various phase-I and -II trials were performed in which they were administered at high doses, yielding response rates of 40-66% (Frustaci et al, 1997;Patel et al, 1998;Reichardt et al, 1998;Maurel et al, 2004a). In some studies, median overall survival was up to 24 months.…”

Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors

“…The most common side effect of this treatment was febrile neutropenia. 24 In a group of 9 children with malignant vascular tumors, only 3 patients (33%) responded to various chemotherapies (1 CR and 2 PRs). 2 For paclitaxel, an overall response rate of 89% has been reported, and the median duration of response was 5 months.…”