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, and George J. Bosl A B S T R A C T 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. J Clin Oncol 25:247-256. © 2007 by American Society of Clinical Oncology INTRODUCTION A collaborative effort led to the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk criteria, 1 which allowed met- astatic germ cell tumors (GCT) to be classified as favorable, intermediate, and poor risk according to pretreatment clinical features. The proportion of pa- tients with favorable-, intermediate-, and poor-risk features who achieve a long-standing complete re- sponse (CR) to chemotherapy is approximately 90%, 75%, and 40%, respectively. 1 Efforts are focused on directing treatment according to risk classification. High-dose chemotherapy (HDCT) was stud- ied in single-arm phase II trials as first-line therapy for patients with poor-prognostic features according to risk models developed before IGCCCG created the criteria. 2-5 The relative tolerability and improve- ment in relapse-free survival and overall survival (OS) compared with historical controls treated with conventional-dose programs suggested that this was a promising approach. Retrospective studies showed that the rate of serum tumor marker decline is a post-treatment predictor of treatment outcome. 6-8 Most patients with a prolonged rate of decline for these markers From the Genitourinary Oncology Service, Division of Solid Tumor Oncol- ogy, Department of Medicine, and Department of Biostatistics and Epide- miology, Memorial Sloan-Kettering Cancer Center; Department of Medi- cine, 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, Sacra- mento, CA; and Indiana University, Indianapolis, IN. Submitted December 22, 2005; accepted June 15, 2006. 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 con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: motzerr@ mskcc.org. © 2007 by American Society of Clinical Oncology 0732-183X/07/2503-247/$20.00 DOI: 10.1200/JCO.2005.05.4528 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 25  NUMBER 3  JANUARY 20 2007 247 Downloaded from jco.ascopubs.org on March 13, 2016. For personal use only. No other uses without permission. Copyright © 2007 American Society of Clinical Oncology. All rights reserved.