Paclitaxel-based chemotherapy for patients with refractory or relapsed nonseminomatous germ cell tumors

Germ cell tumors have been the paradigm for successful solid tumor therapy. With multimodality treatment including surgery and/or chemotherapy and/or radiation therapy 75% of all patients with germ cell tumors will be cured of their malignancy. However, in patients who have primary refractory or relapsed disease, the cure rate is less than 20%. Treatment strategies in this patient population have included: (1) dose intense therapies such as alternating sequential chemotherapy with multiple active regimens given in short intervals, (2) dose dense therapy with high-dose chemotherapy and stem cell support, (3) new agents, and (4) salvage surgery. Prognostic stratification of patients in a salvage setting can help to determine which therapeutic modalities may provide the greatest opportunity for success. The evaluation of new agents has historically occurred in the salvage setting followed by the development of combinations and then advancement to nonsalvage therapy. The introduction of paclitaxel, with its novel mechanism of action and preclinical activity, resulted in its evaluation as a single agent in patients with refractory or relapsed nonseminomatous germ cell tumors. As a single agent, paclitaxel has an overall response rate of 13.3% in a heavily pretreated salvage population. The preclinical evaluation of the combination of paclitaxel and cisplatin allowed for the most appropriate sequencing and dosing of the two agents. In addition, preclinical evaluation suggests that these agents are synergistic as well as active in cisplatin-refractory disease. The combination of paclitaxel and cisplatin was evaluated clinically and demonstrated an overall response rate of 30%. Doxorubicin is an active agent in germ cell tumors and has nonoverlapping toxicity with pactitaxel and cisplatin. The majority of patients treated in a community setting have not had prior exposure to this agent. Therefore, the regime of doxorubicin, paclitaxel, and cisplatin (ATP) was developed and in a small number of patients was utilized in the salvage setting with a 25% response rate. A pilot study with ATP therapy for patients with nonseminomatous germ cell tumors who have disease progression during induction therapy or first and second salvage regimens and who have received a total of more than six courses of prior chemotherapy is ongoing.