A phase I/II study of a stepwise dose-escalated regimen of cisplatin, etoposide and ifosfamide plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced germ cell tumours.

In order to improve the survival of patients with metastatic advanced disease germ cell tumours (according to Indiana University classification), 77 patients were treated by a stepwise dose-escalated combination regimen of platinum (P), etoposide (E) and ifosfamide (I) (PEI) followed by application of granulocyte-macrophage colony-stimulating factor (GM-CSF) (10 micrograms/kg subcutaneously per day at levels 2 and 3) starting the first day after chemotherapy for 10 consecutive days. The maximally tolerated dose was reached at the third dose level with P 30 mg/m2, E 200 mg/m2 and I 1.6 g/m2, all given for 5 days, once every 21 days, for a total of four cycles. Sixty-seven per cent of patients had three or more metastatic sites. Twenty-two per cent of patients had extragonadal primary tumours. 49 (65%) patients achieved complete remission, and 9 additional patients (12%) achieved marker normalisation with unresectable residual disease. After a median follow-up of 27 months, the overall survival is 80%, with 67% of patients remaining free from progression. The dose-limiting toxicities were WHO grades 3/4 mucositis/enteritis in 33% of patients and prolonged thrombocytopenia < 20.000/microliters (> 10 days). Adverse reactions to GM-CSF occurred in 13% of patients. The use of a single haematopoietic growth factor allowed only a moderate increase in dose intensity (factor 1.37). Peripheral blood stem cells will be additionally incorporated into the treatment protocol in order to deliver multiple cycles of an upfront dose-intensified PEI regimen in patients with "poor risk" germ cell tumours with less toxicity.