FIRST-LINE HIGH-DOSE CHEMOTHERAPY FOR POOR-RISK METASTATIC NONSEMINOMATOUS TESTICULAR GERM-CELL TUMORS

Background: With the use of cisplatin-based chemotherapy metastatic te sticular cancer has become a model for a highly curable malignant dise ase. Today 70-80% of patients will achieve long-term survival followin g FEB therapy (cisplatin, etoposide, bleomycin). The role of high-dose chemotherapy with autologous stem cell support is being investigated in patients with metastatic germ cell cancer in order to improve the o utcome of patients with relapse after previous standard-dose chemother apy and of patients presenting initially with advanced metastatic dise ase. Patients and methods: The application of upfront high-dose therap y may not only be better tolerated compared to its use in the salvage situation but may also achieve a rapid initial cell kill prior to the development of cytostatic drug resistance. The German Testicular Cance r Study Group has developed a sequential high-dose combination regimen of cisplatin, etoposide and ifosfamide (HD-PEI) given with G-CSF and PBSC support for 4 cycles every three weeks. Within this ongoing study patients with 'advanced disease' testicular germ cell tumors have rec eived dose intensive PEI therapy at 8 consecutive dose levels. Startin g from a nearly standard dose PEI therapy (125 mg/m(2) cisplatin, 600 mg/m(2) etoposide and 6 g/m(2) ifosfamide, given in total from days 1- 5) the doses of etoposide and ifosfamide were escalated. Dose escalati ons were only performed when the previous dose level was considered sa fe. The first 73 patients were treated on dose levels 1-3 without PBSC support, receiving GM-CSF 10 mu g/kg s.c. per day. The next 68 patien ts at levels 3-5 received PBSC retransfusion on the second day after e ach PEI cycle plus G-CSF 5 mu g/kg. From dose level 6 on patients rece ived one initial cycle of standard dose PEI therapy followed by PBSC-s eparation and 3-4 high-dose PEI cycles. The dose-limiting toxicity is reached at dose level 8 with cisplatin 100 mg/m(2), etoposide 1.75 g/m (2) and ifosfamide 12 g/m(2) per cycle given for 3-4 consecutive cours es at 3-week intervals. Results: 82 (58%) of the fully evaluable 141 p atients at dose levels 1-5 have achieved CR/NED and 32 patients (22%) PR with marker normalization. The early death rate was 8%. The achieve d overall and event-free survival rates at two years are 78 and 73% wi th a projected 5-year overall survival of 74%. Despite preliminary fav orable results, this approach can not be considered standard treatment . A randomized US Intergroup study comparing 2 cycles of PEB plus 2 cy cles of high-dose chemotherapy to 4 cycles of standard FEB was initiat ed in early 1996. Conclusion: The application of high-dose chemotherap y with peripheral stem cell transplantation for patients with testicul ar cancer should only be performed within controlled clinical trials i n order to allow both the evaluation of long-term cure rates and of tr eatment-related late side effects.