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Phase III Randomized Trial of Conventional-Dose Chemotherapy With or Without High-Dose Chemotherapy and Autologous Hematopoietic Stem-Cell Rescue As First-Line Treatment for Patients With Poor-Prognosis Metastatic Germ Cell Tumors

Robert J. Motzer, Craig J. Nichols, Kim A. Margolin, Jennifer Bacik, Paul G. Richardson, Nicholas J. Vogelzang, Dean F. Bajorin, Primo N. Lara, Jr, Lawrence Einhorn, Madhu Mazumdar, George J. Bosl

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, and Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center; Department of Medicine, Joan and Sanford I. Weill Medical College, Cornell University, New York, NY; Oregon Health Science Center, Portland, OR; City of Hope National Medical Center, Duarte, CA; Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, University of Chicago, Chicago, IL; University of California-Davis Cancer Center, Sacramento, CA; and Indiana University, Indianapolis, IN

Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: motzerr{at}mskcc.org

PURPOSE: To investigate the role of high-dose chemotherapy (HDCT) as first-line treatment in patients with metastatic germ cell tumor (GCT) and poor-prognostic clinical features. Serum tumor marker decline during chemotherapy was assessed prospectively as a predictor of treatment outcome.

PATIENTS AND METHODS: In this randomized phase III trial, previously untreated patients with intermediate- or poor-risk GCT received either four cycles of standard bleomycin, etoposide, and cisplatin (BEP alone), or two cycles of BEP followed by two cycles of HDCT containing carboplatin and then by hematopoietic stem-cell rescue (BEP + HDCT). Serum tumor markers alpha-fetoprotein and human chorionic gonadotrophin were correlated with treatment outcome as a secondary end point.

RESULTS: Two hundred nineteen patients were randomly assigned: 108 to BEP + HDCT and 111 to BEP alone. The 1-year durable complete response rate was 52% after BEP + HDCT and 48% after BEP alone (P = .53). Patients with slow serum tumor marker decline (alpha-fetoprotein and/or human chorionic gonadotrophin) during the first two cycles of chemotherapy had a shorter progression-free survival and overall survival compared with patients with satisfactory marker decline (P = .02 and P = .03, respectively). Among 67 patients with unsatisfactory marker decline, the 1-year durable complete response proportion was 61% for patients who received HDCT versus 34% for patients receiving BEP alone (P = .03).

CONCLUSION: The routine inclusion of HDCT in first-line treatment for GCT patients with metastases and a poor predicted outcome to chemotherapy did not improve treatment outcome. Frequent serum marker determinations to estimate marker decline during the first two cycles of BEP chemotherapy provide a clinically useful estimate of outcome.

Supported by Grants No. CA-05826, CA-23318, CA-66636, CA-2115, and CA-49883 from the National Institutes of Health.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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