Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group

Purpose: This randomized multicenter study was designed to compare the acti vity of a high-dose doxorubicin-containing chemotherapy regimen with a conv entional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). Patients and Methods: Between 1992 and 1995, 314 patients were randomized t o receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m( 2) on day 1) and ifosfamide (5 g/m(2) on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m2 on day 1), the same ifosfamide dos e, and recombinant human granulocyte-macrophage colony-stimulating factor ( rhGM-CSF; sargramostim, 250 mu g/m(2) on days 3 to 16); all courses were re peated every 3 weeks. Results: The median age of the 294 eligible patients was 50 years. They rec eived a median of five chemotherapy cycles. The median dose and relative do xorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg a nd 99% in arm B, respectively. Thirty-eight percent and 23% of patients pre sented with leiomyosarcomas and liver metastases, respectively. Objective r esponses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P =.65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) war significantly longer in the intensive arm (P =.03). The median du ration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall surviva l (P =.98) between the two therapeutic arms, Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% o f patients in arm A, respectively, and in 90% and 16.6% in arm B, respectiv ely. Grade 3/4 thrombocytopenia was more frequent in arm B. Conclusion: The use of rhGM-CSF allowed safe escalation of chemotherapy dos es. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS . The low complete response rate, the high incidence of leiomyosarcomas, an d liver metastases may in part explain these results. However, the lengthen ing of the PFS in the intensive arm, because of the quality of stable disea se and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS. (C) 20 00 by American Society of Clinical Oncology.