Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study

Abstract

The regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) (AID) for previously untreated inoperable or metastatic sarcoma has acceptable toxicity with significant activity. Twenty patients received 79 courses of DOX (60-75 mg/m2) with or without DTIC (900 mg/m2) by continuous infusion over 72 hours with escalating doses of IFF and mesna uroprotection. Nineteen patients were evaluable for toxicity. Myelosuppression was dose-limiting. The maximum tolerated dose was DOX at 60 mg/m2, DTIC at 900 mg/m2, and IFF at 7500 mg/m2 per course. Of the 79 courses analyzed, 33 (42%) resulted in wbc counts less than 1000/microliter; 14 (18%) were complicated by fever and neutropenia, and three by sepsis. There were no toxic deaths. Relative platelet sparing was observed and nadirs were brief. In contrast to bolus-dose DTIC divided over 5 days, DTIC by continuous infusion did not add significantly to gastrointestinal toxicity. Nausea and vomiting was well controlled by antiemetics. Mucositis occurred sporadically. Unlike our phase II study of IFF alone, no CNS or renal toxicity was observed. No cardiac toxicity was encountered, although only four patients have received greater than 450 mg/m2 of cumulative DOX. One episode of DOX extravasation occurred despite a long iv line that extended to the axilla. No serious tissue damage was observed, perhaps due to the dilute solutions of DOX used. Partial responses were seen in eight of 18 evaluable patients (44%) and in six of 11 patients at or near the phase II level. Two additional patients with minimal response have continued tumor regression. The median number of courses before partial response was four (range, one to five). The median duration of response has not been reached (3+ to 10+ months). An inoperable primary has been rendered surgically resectable in one patient. Activity in previously untreated sarcomas should be further evaluated in a randomized phase III study against a standard DOX-containing combination.