Tandem High-Dose Therapy in Rapid Sequence for Children With High-Risk Neuroblastoma By Stephan A. Grupp, Julie W. Stern, Nancy Bunin, Cheryl Nancarrow, Amy A. Ross, Mark Mogul, Roberta Adams, Holcombe E. Grier, Jed B. Gorlin, Robert Shamberger, Karen Marcus, Donna Neuberg, Howard J. Weinstein, and Lisa Diller Purpose: Advances in chemotherapy and support- ive care have slowly improved survival rates for pa- tients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high- dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. Patients and Methods: Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control mea- sures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. Results: Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2  10 6 CD34  cells/kg available to support each cycle. Engraftment was rapid; median time to neutro- phil engraftment was 11 days. Four patients who com- pleted the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. Conclusion: A tandem HDT/SCR regimen for high- risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival. J Clin Oncol 18:2567-2575. © 2000 by American Society of Clinical Oncology. M ULTIAGENT CHEMOTHERAPY and combined- modality treatment strategies have improved out- come for pediatric patients with leukemias and localized solid tumors. These strategies have also improved rates of remission induction for patients with high-risk solid tumors, but the impact on long-term disease-free survival is less clear. The hypothesis that further dose escalation may cure more children with malignancies such as high-risk neuro- blastoma 1 has led investigators to explore the use of myeloablative regimens for remission consolidation. Expe- rience with autologous bone marrow transplantation (ABMT) has been variable, with early studies suggesting that ABMT may improve overall survival or lengthen time to progression. 2 Recently, the Children’s Cancer Group (CCG) published the results of study 3891, which found statistically significant improvement in event-free survival (EFS) among patients randomized to consolidation with ABMT compared with those randomized to continuation chemotherapy. 3 The goal in designing ABMT regimens is to use effective drug combinations whose doses can be safely escalated, while ensuring rapid bone marrow reconstitution. Another goal has been to determine which stem-cell product and which tumor-purging strategy minimize tumor cell contamination. Tandem AMBT was tried in children with neuroblas- toma, but toxicity was a problem, especially delay in hematopoietic recovery when bone marrow was used as stem-cell support. 4 To lessen the toxicity of ABMT, many oncologists have moved to using peripheral-blood progen- itor cells (PBPCs) as a stem-cell source (stem-cell rescue [SCR]). Clinical trials involving adult patients with solid tumors have demonstrated rapid hematopoietic recovery with the use of PBPCs. In adult patients, collection of enough stem or progenitor cells for support through tandem transplantation courses has been shown to be a valid approach. 5,6 PBPC support through single transplantation has also been explored in children 7,8 and has resulted in From the Division of Oncology, Department of Pediatrics, Chil- dren’s Hospital of Philadelphia, University of Pennsylvania, School of Medicine, Philadelphia, PA; Diagnostics Division, Nexell Therapeu- tics, Inc, Irvine, CA; Emory University, Atlanta, GA; Primary Chil- dren’s Hospital, University of Utah Health Sciences Center, Salt Lake City, UT; Department of Pediatric Oncology, Dana-Farber Cancer Institute; Departments of Medicine and Surgery, Children’s Hospital; and Division of Pediatric Hematology-Oncology, Massachusetts Gen- eral Hospital, Boston, MA; and Memorial Blood Centers of Minnesota and University of Minnesota, Minneapolis, MN. Submitted January 5, 1999; accepted March 7, 2000. Supported in part by the University of Pennsylvania Cancer Center (S.A.G.); the Benacerraf/Frei Clinical Investigator Award, Dana- Farber Cancer Institute (L.D.); and the Fiftieth Anniversary Program for Scholars in Medicine, Harvard Medical School (L.D.). Address reprint requests to Stephan Grupp, MD, PhD, Children’s Hospital of Philadelphia, 324 S 34th St, Abramson 902, Philadelphia, PA 19104; email grupp@email.chop.edu. © 2000 by American Society of Clinical Oncology. 0732-183X/00/1813-2567 2567 Journal of Clinical Oncology, Vol 18, No 13 (July), 2000: pp 2567-2575 192.131.129.140 Information downloaded from jco.ascopubs.org and provided by at YALE MEDICAL LIBRARY on February 26, 2012 from Copyright © 2000 American Society of Clinical Oncology. All rights reserved.