Current trends in chemotherapy for metastatic nonseminomatous testicular germ cell tumors

With the introduction of cisplatin-based chemotherapy, metastatic testicular cancer represents a model for a highly curable malignant disease. Approximately 70-80% of patients achieve a durable remission following chemotherapy +/- secondary surgery of residual tumors. With the development of prognostic classifications based on clinically available parameters, the aims of chemotherapy have been twofold: on the one hand, the reduction of toxicity in patients with 'low-risk' metastatic disease without a concomitant reduction in treatment efficacy and, on the other hand, the improvement of treatment results in patients with 'poor-prognosis' criteria who achieve a long-term cure rate of less than 50% with standard chemotherapy regimens. Despite a number of large randomized studies attempting either to avoid the toxicity of bleomycin or to reduce cisplatin-associated side-effects through the substitution with carboplatin, the combination of cisplatin, etoposide and bleomycin (PEB) given at 3-week intervals still remains the standard treatment for metastatic disease. The role of high-dose chemotherapy with autologous stem cell support is currently being investigated in order to improve the outcome of patients with relapse after previous chemotherapy and of patients initially exhibiting advanced metastatic disease. For patients with relapsed disease receiving high-dose chemotherapy, a prognostic score has recently been developed: cisplatin-refractory disease, beta human gonadotropin values > 1,000 U/l or primary mediastinal germ cell tumors are factors characterizing patients which will profit less from high-dose chemotherapy treatment than patients with chemosensitive disease at relapse. Standard dose salvage regimens only result in a 20% long-term survival rate. In contrast, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. However, the only randomized study comparing high-dose versus conventional-dose therapy in patients with relapsed disease is still ongoing. The investigation of dose-intensive approaches as first-line treatment is currently being studied by several institutions. Despite preliminary favorable results, this approach still cannot be considered standard treatment. A randomized study comparing high-dose chemotherapy with 4 cycles of standard PEB was initiated in the USA in 1996. The evaluation of new drugs in testicular cancer patients with absolute cisplatin-refractory disease has demonstrated that paclitaxel is one of the few agents with antitumor activity in these patients. Paclitaxel has therefore been included in combination regimens--such as cisplatin, ifosfamide and paclitaxel--for the treatment of patients with first and second relapse of testicular cancer. These combinations are used as induction therapy prior to high-dose salvage treatment. Due to the large group of patients with metastatic disease being cured nowadays, the long-term side effects of treatment have become even more important. One of the major risk factors for the development of late toxicities such as oto-, neuro-, nephro-, gonadal and cardiovascular toxicity is the cumulative dose of cisplatin applied during therapy. The development of new treatment strategies, such as the use of adjuvant chemotherapy for stage I disease, the widespread application of high-dose chemotherapy with peripheral stem cell rescue and the use of new cytotoxic agents, makes the evaluation of the late effects of treatment for testicular cancer within controlled clinical trials mandatory.