High-Dose Chemotherapy in Poor-Risk Germ-Cell Tumors
High-Dose Chemotherapy in Poor-Risk Germ-Cell Tumors
In his comprehensive article, Dr. Srinivas highlights the accomplishments made in the studies of high-dose chemotherapy for patients with advanced germ-cell tumors.
Prior to the advent of high-dose chemotherapy for germ-cell tumors in the mid-1980s, all patients with persistent disease following salvage therapy with cisplatin (Platinol) plus ifosfamide (Ifex) died of the illness. The rare exception was the patient with a solitary metastatic site who was managed successfully by surgical salvage.
As third-line therapy, treatment with high-dose carboplatin (Paraplatin)-containing regimens plus hematopoietic progenitor-cell support resulted in long-term survival in 20% of patients with resistant, progressive germ-cell tumors.[1-3] In the setting of heavy prior therapy, toxicity was severe, resulting in treatment-related deaths in 10% to 20% of patients in the early studies. These studies used bone marrow as the source of blood-cell precursors and lacked hematologic growth factors.
Since then, investigational efforts have focused on reducing toxicity and improving treatment outcome. The use of risk-directed therapy and hematologic growth factors as well as the substitution of peripheral bloodderived stem cells for bone marrow have reduced toxicity and allowed delivery of a more intensive therapeutic regimen.
The purpose of risk-directed treatment is to increase the proportion of patients who derive therapeutic benefit and to reduce toxicity, either by excluding patients from futile therapy or by reducing cumulative toxicity through the early introduction of high-dose chemotherapy. Patients with nonseminoma arising from a mediastinal primary site, germ-cell tumors showing little or no sensitivity to cisplatin-containing chemotherapy (absolute refractory), and very high levels of serum human chorionic gonadotropin prior to treatment are associated with a poor response to high-dose chemotherapy.
In general, patients with these features should be spared the toxicity of high-dose chemotherapy and instead be considered for clinical trials of a new agent or novel strategy, or for surgical salvage. In contrast, patients who are considered responsive to high-dose chemotherapy include those with a gonadal primary site, low tumor burden, and sensitivity to prior cisplatin-containing chemotherapy.
Benefits of Early Intervention
The advantages of early interventionie, high-dose chemotherapy given to less heavily pretreated patients predicted to be resistant to cisplatin therapyinclude improved tolerability through the reduction of cumulative toxicities and more timely administration after cytoreduction. High-dose chemotherapy can be considered a standard treatment approach for patients with gonadal primary germ-cell tumors and an incomplete response to first-line therapy, as these patients rarely achieve long-term survival on cisplatin/ifosfamide salvage therapy.
Early intervention with high-dose chemotherapy shows promise but remains an investigational approach in first-line therapy for poor-risk germ-cell tumors and in second-line therapy for relapsed patients. Phase II trials of high-dose chemotherapy in both of these settings have shown relatively high response rates compared to historical controls given cisplatin-containing therapy alone, and have led to randomized trials.
Two studies in Europe are addressing the role of high-dose chemotherapy in relapsed patients and in previously untreated patients with poor-risk features. In the United States, an intergroup trial of four cycles of BEP (bleomycin [Blenoxane], etoposide, Platinol) vs two cycles of BEP plus two cycles of high-dose chemotherapy is ongoing in previously untreated patients with intermediate- and poor-risk features.
Multiple Large Doses of Chemotherapy
The Norton-Simon model predicts that multiple, rapidly recycled applications of chemotherapy are more likely to eradicate residual cancer cells than either single applications or multiple applications with long intervals between cycles. Therefore, to maximize the dose intensity of chemotherapy, multiple large doses may be administered in as short an interval as feasible.
At our center, patients with poor prognostic features requiring salvage therapy were treated on a clinical trial of repetitive cycles of dose-intensified therapy consisting of paclitaxel (Taxol), ifosfamide, carboplatin, and etoposide with autologous stem-cell rescue. Of the 37 patients treated with this regimen, 21 (57%) achieved a complete response and 13 (35%) remain in durable complete response with follow-up greater than 18 months. Treatment was relatively well tolerated and the durable complete response rate was substantial in patients with unfavorable prognostic features for achieving a durable complete response to conventional-dose salvage regimens. An ongoing study is addressing the optimal dosing of carboplatin in the high-dose range, based on renal function.
High-dose chemotherapy represents curative standard therapy in metastatic testicular germ-cell tumors following an incomplete response to first-line therapy or relapse/incomplete response to ifosfamide-containing salvage therapy. The role of high-dose chemotherapy in the treatment of patients with first relapse and in first-line therapy for poor-risk germ-cell tumors is being addressed in randomized trials. Studies of tumor biology, clinical trials of intensive initial chemotherapy for patients with poor-risk features, novel treatment strategies of dose intensification, and the development of new agents remain priorities of ongoing research.
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2. Motzer RJ, Mazumdar M, Bosl GJ, et al: High-dose carboplatin, etoposide, and cyclophosphamide for patients with refractory germ cell tumors: Treatment results and prognostic factors for survival and toxicity. J Clin Oncol 14:1098-1105, 1996.
3. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 117:124-128, 1992.
4. Motzer RJ, Gulati SC, Tong WP, et al: Phase I trial with pharmacokinetic analyses of high-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in patients with refractory germ cell tumors. Cancer Res 53:3730-3735, 1993.
5. Motzer RJ, Mazumdar M, Bajorin DF, et al: High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for poor-risk germ cell tumors. J Clin Oncol 14:2546-2552, 1997.
6. Motzer RJ, Mazumdar M, Sheinfeld J, et al: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18:1173-1180, 2000.