Originally published as JCO Early Release 10.1200/JCO.2003.09.035 on October 20 2003

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Long-Term Results of First-Line Sequential High-Dose Etoposide, Ifosfamide, and Cisplatin Chemotherapy Plus Autologous Stem Cell Support for Patients With Advanced Metastatic Germ Cell Cancer: An Extended Phase I/II Study of the German Testicular Cancer Study Group

From the Department of Hematology/Oncology, University of Halle, Halle; Department of Internal Medicine, Div. of Hematology/Oncology, University of Tuebingen, Tuebingen; Department of Oncology/Hematology, Klinikum Oldenburg, Oldenburg; Department of Oncology, Westdeutsches Tumorzentrum Essen, Essen; Department of Hematology and Oncology, Hannover Medical School, Hannover; Department of Oncology, Katharinenhospital, Stuttgart; Department of Hematology/Oncology, Charite, Berlin; Department of Hematology/Oncology, University of Marburg, Marburg; Department of Hematology/Oncology, University of Hamburg, Hamburg; Department of Medicine/Hematology and Oncology, University of Muenster, Muenster; Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany.

Address reprint requests to H.-J. Schmoll, MD, Department of Hematology/Oncology; University of Halle-Wittenberg, Ernst-Grube-Str. 40, 06120 Halle, Germany; e-mail: hans-joachim.schmoll{at}medizin.uni-halle.de.

Purpose: Patients with disseminated germ cell cancer and poor prognosis (International Germ Cell Cancer Collaborative Group [IGCCCG] classification) achieve only a 45% to 50% long-term survival by standard chemotherapy. First-line high-dose chemotherapy might be able to improve the result. This analysis reports toxicity and long-term results of a large phase I/II study of sequential high-dose etoposide, ifosfamide, and cisplatin (VIP) in patients with advanced germ cell tumors.

Patients and Methods: Between July 1993 and November 1999, 221 patients with either Indiana "advanced disease" (n = 39) or IGCCCG "poor prognosis" criteria (n = 182) received one cycle of VIP followed by three to four sequential cycles of high-dose VIP chemotherapy plus stem cell support, every 3 weeks, at six consecutive dose levels.

Results: Dose limiting toxicity occurred at level 8 (100 mg/m² cisplatinum, 1750 mg/m² etoposide, 12 g/m² ifosfamide) with grade 4 mucositis (three of eight patients), grade 3 CNS toxicity (one of eight patients), grade 4 renal toxicity (one of eight patients), and prolonged granulocytopenia (one of eight patients). After 4-year median follow-up, progression-free survival and disease-specific survival rates in the poor prognosis subgroup were 69% and 79% at 2 years and 68% and 73% at 5 years, with 76% for gonadal/retroperitoneal versus 67% for mediastinal primaries. Severe toxicity included treatment related death (4%), treatment-related acute myeloid leukemia (1%), long-term impared renal function (3%), chronic renal failure (1%), and persistant grade 2–3 neuropathy (5%).

Conclusion: Repetitive cycles of high-dose VIP with peripheral stem cell support can be successfully applied in a multicenter setting. Dose level 6 with cisplatin 100 mg/m², etoposide 1500 mg/m², and ifosfamide 10 g/m² is recommended for further investigation in randomized trials. An ongoing randomized trial within the European Organization for Research and Treatment of Cancer evaluates this protocol against four cycles of standard cisplatin, etoposide, and bleomycin.

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