Dose finding of ifosfamide administered with a chronic two-week continuous infusion

Purpose: Ifosfamide (IFO) is an active drug in several malignancies. A short-term 3- to 7-day (A) continuous infusion (c.i.) has been used in different tumor types. The 14-day c.i. (B) has been investigated in advanced breast cancer and in soft tissue sarcoma patients at a fixed daily dose. The tolerance and response rate (RR) of therapies A and B has been considered encouraging. Aim: To study the 14-day c.i. IFO schedule, every 28 days, with a dose-finding approach. Methods: From January 1998 to December 2001, 34 pretreated patients with advanced malignancy and disease progression were treated with c.i. IFO (and the same dose of mesna) from 400 to 1,000 mg/m2/24 h for 2 consecutive weeks every 28 days. An elastomeric pumping device via an Infuse-a-Port® or a Groshong® catheter was used. Results: A total of 159 cycles were evaluable for toxicity and results. No toxic deaths occurred. Three patients (8.8%) had a severe acute allergic cutaneous reaction with various grade 3–4 toxicities requiring hospitalization and therapy was stopped at day 6 of the first cycle, 7 and 12 of the second cycle respectively. In the other 31 patients, grade 4 neutropenia occurred in 6 (19.3%) and it represented the main toxicity. There was a positive relationship between the IFO dose step and neutropenia (p = 0.001). A positive relationship was observed between the RR and the received total IFO dose (g) (p < 0.004). Twelve patients out of 31 had progressive disease (PD) (38.7%), 8 had partial remission (PR) (25.8%), and 11 maintained a steady state (35.5%). Six of the 12 patients (50%) with PD and 2 of the 8 PRs (25%) had bone metastases. Conclusions: IFO c.i. is generally well tolerated, but acute untoward allergic reactions can occur. In chemotherapy-pretreated patients the recommended daily dose of continuously infused IFO for 14 days every 4 weeks is 900 mg/m2/day, together with mesna at the same dose schedule.