With the use of
cisplatin-based
combination chemotherapy, metastatic testicular
germ cell tumors can be cured in 70-80% of patients, but patients refractory to
cisplatin-based
chemotherapy continue to have a very poor prognosis. Various chemotherapeutic agents have been evaluated in intensively pretreated or
cisplatin-refractory patients, but as single agents, only orally administered
etoposide,
paclitaxel,
gemcitabine, and, most recently,
oxaliplatin have been shown to be active with selected patients achieving complete remissions. This has for the first time lead to clinical evaluation of
combination chemotherapy regimens such as
gemcitabine-
paclitaxel or
oxaliplatin-
gemcitabine, demonstrating the feasibility of combination
therapy in these heavily pretreated patients. High response rates of up to 45% were observed in particular with the latter combination. Salvage surgery remains a very important treatment option for patients with resectable disease. The molecular mechanisms of
cisplatin resistance have been intensively studied, and several mechanisms have been discussed such as a decreased intracellular concentration of the
drug, increased repair of the
drug-induced damage, or an altered apoptotic response to this damage. This increasing knowledge may now allow design of new therapeutic options. Ongoing studies in refractory
germ cell tumors are evaluating 3-drug regimens such as
gemcitabine-
paclitaxel-
oxaliplatin but also
biologic approaches such as inhibitors of the
epidermal growth factor receptor or the
vascular endothelial growth factor. This research may eventually allow the development of a noncross-resistant multidrug combination regimen that can be evaluated in an earlier line of
therapy.