Recent advances in management of patients with platinum-refractory testicular germ cell tumors

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.