Background: Ifosfamide and cisplatin are frequently combined cytotoxic agents. Both have a dose-response relationship. In view of this it appears attractive to study regimens with a higher dose intensity than usual. One way to increase the dose intensity is to shorten intervals between chemotherapy cycles. As bone marrow toxicity is dose limiting in ifosfamide-cisplatin combinations we started a phase II study with both drugs administered every 2 weeks in combination with G-CSF.
Patients and methods: Patients with advanced non-small-cell lung cancer or malignant melanoma were eligible for the study. The treatment consisted of ifosfamide 2 gram/m2/day days 1-3 combined with mesna, and cisplatin 33 mg/m2/day days 1-3, administered in hypertonic saline (3% NaCl). G-CSF was started on day 4 at a dose of 5 micrograms/kg/day and was continued until day 12. The cycles were to be repeated every 2 weeks for a maximum of 6 cycles.
Results: Thirty-two patients were entered in the study; 30 patients were evaluable for response and toxicity. Neutropenia (grade 4 in 16 patients) and thrombocytopenia (grade 4 in 15 patients) were the most common toxicities. Thrombocytopenia incidence and -duration increased per cycle and was the main cause of treatment delays especially after the third cycle. Only 4 patients were able to complete the planned treatment without any delay or dose reduction and reached the intended dose intensity of 3 gram/m2/week of ifosfamide and 50 mg/m2/week of cisplatin. Non haematologic toxicities were generally mild. Out of 22 evaluable patients with non-small cell lung cancer 6 responded (27%; 95% CI: 10%-48%) while only one out of 8 patients with melanoma responded. The median response duration was 26 weeks (range 16-36 weeks).
Conclusion: The planned high-dose intensity of ifosfamide and cisplatin could be reached only for the first 2-3 cycles. Haematologic toxicity, especially cumulative thrombocytopenia, necessitated treatment delays jeopardizing the dose intensity. The response rate in non-small-cell lung cancer and melanoma was not superior to what can be expected from more conventional regimens.