First-line high-dose chemotherapy for 'poor risk' metastatic non-seminomatous testicular germ cell tumors

Background: With the use of cisplatin-based chemotherapy metastatic testicular cancer has become a model for a highly curable malignant disease. Today 70-80% of patients will achieve long-term survival following 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 outcome of patients with relapse after previous standard-dose chemotherapy and of patients presenting initially with advanced metastatic disease. Patients and methods: The application of upfront high-dose therapy 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 Cancer 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 received dose intensive PEI therapy at 8 consecutive dose levels. Starting 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 escalations were only performed when the previous dose level was considered safe. 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 patients at levels 3-5 received PBSC retransfusion on the second day after each PEI cycle plus G-CSF 5 mu g/kg. From dose level 6 on patients received one initial cycle of standard dose PEI therapy followed by PBSC-separation 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 courses at 3-week intervals. Results: 82 (58%) of the fully evaluable 141 patients at dose levels 1-5 have achieved CR/NED and 32 patients (22%) PR with marker normalization. The early death rate was 8%. The achieved overall and event-free survival rates at two years are 78 and 73% with a projected 5-year overall survival of 74%. Despite preliminary favorable results, this approach can not be considered standard treatment. A randomized US Intergroup study comparing 2 cycles of PEB plus 2 cycles of high-dose chemotherapy to 4 cycles of standard FEB was initiated in early 1996. Conclusion: The application of high-dose chemotherapy with peripheral stem cell transplantation for patients with testicular cancer should only be performed within controlled clinical trials in order to allow both the evaluation of long-term cure rates and of treatment-related late side effects.