In two sequential trials, 154 patients were treated with dosages of
ifosfamide, ranging between 8 and 18 g/m2 divided over 4 days, with
mesna uroprotection. The first was a phase II efficacy trial in 125 advanced
sarcoma patients (Antman et al: J Clin Oncol 7:126-131, 1989), while the second was a dose escalation trial involving 29 patients (Elias et al: J Clin Oncol 8:170-178, 1990). In the first trial, patients received 8 to 10 g/m2
ifosfamide either by bolus or continuous infusion. The response rate for the 64 patients receiving bolus administration was 23% compared with 12% for the 60 patients receiving a continuous infusion schedule (P = .09). Of the 154 patients, 144 had
sarcoma and had failed at least one previous regimen. Of these 144, 4% responded completely and 23% had a complete or partial response. The maximum tolerated dose of
ifosfamide was 16 g/m2 in the second trial. Dose-limiting renal toxicity was observed at 18 g/m2
ifosfamide (Elias et al: J Clin Oncol 8:170-178, 1990). The duration of myelosuppression and the frequency and severity of
mucositis and
renal tubular acidosis were dose-dependent. A median of 11 days (range, 8 to 18) of
granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion was not required. Severe central nervous system toxicity (transient
confusion,
hallucinations, and
somnolence) was observed sporadically at both low- and high-dose levels. The first four patients on the standard-dose study did not receive
mesna because it was unavailable; three developed gross
hematuria. In patients who received
mesna,
hematuria was uncommon.
Hematuria in the group as a whole was significantly associated with a lack of uroprotection, but was not associated with prior
cyclophosphamide, pelvic
radiotherapy, age, or bolus versus a continuous infusion schedule. Patients receiving
ifosfamide with
mesna uroprotection can tolerate considerable dose escalation over the usual prescribed doses before nonhematologic toxicity becomes dose-limiting.
Ifosfamide, with its broad activity in solid
tumors, may prove to be an important addition to high-dose
combination-chemotherapy regimens (Elias et al: J Clin Oncol 8:170-178, 1990).