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Journal of Clinical Oncology, Vol 24, No 18 (June 20), 2006: pp. 2891-2896 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6986 High-Risk Neuroblastoma Treated With Tandem Autologous Peripheral-Blood Stem Cell–Supported Transplantation: Long-Term Survival Update
From the Departments of Pediatric Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Departments of Medicine, Radiation Oncology, and Surgery, Children's Hospital Boston, Boston, MA; Division of Oncology, Primary Children's Medical Center, Salt Lake City, UT; and the Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA Address reprint requests to Rani George MD, PhD, MRCP, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Dana 322, 44 Binney St, Boston, MA 02115; e-mail: rani_george{at}dfci.harvard.edu
PURPOSE: To provide an update on long-term survival of patients with high-risk neuroblastoma treated with tandem cycles of myeloablative therapy and peripheral-blood stem-cell rescue (PBSCR). PATIENTS AND METHODS: Ninety-seven patients with high-risk neuroblastoma were treated between 1994 and 2002. Patients underwent induction therapy with five cycles of standard agents, resection of the primary tumor and local radiation, and two consecutive courses of myeloablative therapy (including total-body irradiation) with PBSCR. RESULTS: Fifty-one patients have experienced relapse or died. Median follow-up time among the 46 patients who remain alive without progression is 5.6 years (range, 15.1 months to 9.9 years). Progression-free survival (PFS) rate at 5 years from diagnosis was 47% (95% CI, 36% to 56%), and PFS rate at 7 years was 45% (95% CI, 34% to 55%). Overall survival rate was 60% (95% CI, 48% to 69%) and 53% (95% CI, 40% to 64%) at 5 and 7 years, respectively. The 5- and 7- year PFS rates from time of first transplantation for 82 patients who completed both transplants were 54% (95% CI, 42% to 64%) and 52% (95% CI, 40% to 63%), respectively. Five patients died from treatment-related toxicity after tandem transplantation. Relapse occurred in 37 (42%) of 89 patients, mainly within 3 years of transplantation and primarily in diffuse osseous sites. No primary CNS relapse or secondary leukemia was seen. One patient developed synovial cell sarcoma 8 years after therapy. CONCLUSION: High-dose therapy with tandem autologous stem-cell rescue is effective for treating high-risk neuroblastoma, with encouraging long-term survival. CNS relapse and secondary malignancies are rare after this therapy.
Over the last decade, intensification of consolidation therapy with autologous stem-cell rescue after myeloablative doses of chemotherapy with or without total-body irradiation (TBI) has contributed to the improved survival of children with high-risk neuroblastoma.1-5 However, long-term cure rates remain low, presumably because of the emergence of resistant clones or persistence of minimal residual disease. Additionally, relapse in the CNS has emerged as a problem after some treatment regimens because more intensive treatment has resulted in better control of disease and longer progression-free intervals.6,7 We report here the long-term results of a limited-institution, single-arm trial of induction chemotherapy and local control measures (surgery and local radiation), followed by rapid-sequence tandem high-dose (myeloablative) treatments (HDT) with peripheral-blood stem-cell rescue (PBSCR). The rationale and details of this study have been described elsewhere.8,9 In designing this trial, we initially investigated the feasibility and toxicity of intensification of consolidation therapy using tandem transplantation. This protocol had the following three important characteristics: collection of peripheral-blood stem cells (PBSCs) early in therapy, presumably before significant genetic damage in hematopoietic stem and progenitor cells had occurred from the induction chemotherapy cycles; use of separate non–cross-reactive regimens for each myeloablative treatment; and rapid progression from the first to the second HDT/PBSCR. In the pilot study, this regimen was found to be tolerable, with early results suggesting a low toxic death rate. In the initial 39 patients who were enrolled, 26 remained relapse free, with a 3-year PFS rate of 58% (90% CI, 40% to 72%).8 We report here the long-term survival of an expanded group of patients treated with the same regimen.
Patient Selection and Evaluation Patients with high-risk neuroblastoma who had received no prior therapy or who had received only one course of chemotherapy (for intermediate-risk disease that was later reclassified) were offered this therapeutic protocol. These patients included those more than 1 year of age with International Neuroblastoma Staging System10 stage 4 disease or stage 3 disease with MYCN amplification.11 Beginning in 1999, the inclusion criteria were expanded to include infants less than 12 months of age with stage 3, 4, or 4s disease and MYCN amplification, and children more than 12 months of age with stage 3 disease and unfavorable Shimada histology12 (1999 to 2002 only). Patients were consecutively enrolled onto this trial from 1994 to 1998; from 1999 to 2002, patients were treated "as per" the same regimen after the study had achieved its goal of determining feasibility. Children were treated at the following four centers: Dana-Farber Cancer Institute and Children’s Hospital Boston, Children’s Hospital of Philadelphia, Emory Children’s Center, Atlanta, and Primary Children’s Medical Center, Utah. Institutional review board approval for treatment on this study at each of the four centers was obtained. Parental informed consent was obtained both for treatment on and as per the trial.
Treatments
Statistical Analysis Descriptive statistical analysis was performed to assess patient characteristics. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and CIs were calculated using Greenwood’s formula.13 PFS was defined as the time from diagnosis and from date of first transplantation to progression or relapse of primary tumor or death, whichever occurred first. Patients who were alive without relapse were censored at the time last known alive and relapse free (April 2005). OS was defined as the time from diagnosis or first transplantation to death. Secondary malignancies were not counted as events.
Patient Characteristics Ninety-seven patients with high-risk neuroblastoma were treated according to this protocol. Patient characteristics are listed in Table 1. The median age at diagnosis was 35 months (range, 6 months to 18 years). There was one patient who was less than 12 months of age at diagnosis, and 14 patients were between 12 and 18 months of age. Eighty-seven patients (90%) had stage 4 disease. MYCN amplification was observed in 53% of the tumors analyzed. Of the 10 patients with stage 3 disease, six had tumor MYCN amplification.
Six of the 97 patients developed progressive disease during induction and did not receive myeloablative therapy. Additionally, two patients did not receive high-dose therapy because of parental wishes. Eighty-two (93%) of the remaining 89 patients underwent two courses of myeloablative therapy. Seven patients received only one course either because of toxicity (three patients) or parental choice (four patients). Five children died of toxicity during tandem transplantation, and one child died 3 months after HDT/PBSCR from unknown causes but had no evidence of disease near the time of death. Causes of toxicity-related deaths included veno-occlusive disease (n = 1), sepsis (n = 1), and viral infections with Epstein-Barr virus and cytomegalovirus (n = 3).
Risk of Relapse and Survival Analysis
Thirty-seven (42%) of 89 patients who underwent one or two transplantations had relapse of disease after consolidation. Twenty-eight (75%) of the 37 patients who experienced relapse have died of disease. There were no late toxic deaths; all deaths after 3 months from transplantation were from progressive disease. There was no difference in survival (OS and PFS) between patients whose stem cells were selected for CD34 positivity and patients whose cells were not (P = .33 and P = .58, respectively). Neither MYCN amplification nor stage influenced PFS (P = .3 and P = .72, respectively) or OS (P = .81 and P = .44, respectively). Among patients with stage 4 disease, there was a marginally significant difference in PFS between children  18 months of age and children more than 18 months of age (P = .08). Survival comparisons between patients in the two age groups with MYCN-nonamplified tumors were unfeasible because almost all of the patients (13 of 14 patients) 18 months of age with stage 4 disease had MYCN-amplified tumors.
Patterns of Relapse and Development of Secondary Malignancies The majority of relapses occurred at metastatic sites and included bone (n = 27), bone marrow (n = 13), liver (n = 2), and lung (n = 1; patients had multiple sites of relapse). Isolated local relapse was rare and occurred in only three patients. One patient had an isolated lymph node relapse out of the radiation field. Of the 31 patients who experienced metastatic relapse, nine experienced relapse in the primary site as well. No relapses primary to the CNS were seen. Secondary cancers were rare in this group of patients. One patient developed a synovial cell sarcoma 8 years after initial diagnosis of neuroblastoma. Another patient developed myelodysplasia with clonal trisomy 8 and with normal peripheral-blood counts 5.6 years after diagnosis. Overt secondary leukemia was not seen in these patients.
We reviewed the treatment outcomes for a large cohort of patients with high-risk neuroblastoma who were uniformly treated with a single induction regimen followed by consolidation with either one (n = 7) or two (n = 82) courses of myeloablative therapy. With a median follow-up of 5.3 years, the PFS rate from diagnosis of patients treated with this regimen was 47% (95% CI, 36% to 56%) at 5 years. Patterns of relapse included diffuse disease, primarily bony; diffuse and local disease; and rarely, local disease only. We have seen no primary CNS relapses. Secondary malignancies included a synovial cell sarcoma and myelodysplasia with trisomy 8. There were no cases of overt secondary leukemia. Myeloablative therapy became the standard of care in the United States after the Children’s Cancer Group compared the outcome of 189 patients randomly assigned to receive myeloablative chemotherapy with autologous bone marrow transplantation with the outcome of 190 patients who were randomly assigned to receive chemotherapy alone (3-year PFS rate ± SE: 34% ± 4% v 22% ± 4%, respectively; P = .034).4 If one myeloablative course increases survival rates, could tandem transplantation improve on the outcome? The earliest work attempting to answer this question used a double harvest/double graft approach with purged bone marrow support, with an OS rate of 32% at 5 years in a high-risk group of patients.14 In an analysis of 546 patients with advanced neuroblastoma from the European Bone Marrow Transplantation Solid Tumor Registry, a 5-year PFS rate of 24% was reported for 436 patients who underwent a single procedure compared with 33% for 110 patients who underwent double mega-therapy (P = .05).3 In another study in which 17 high-risk neuroblastoma patients were treated with triple-tandem cycles of high-dose therapy with PBSCR and local irradiation, the 3-year PFS rate was 57%.15 In the present report, patients who underwent double high-dose therapy had a 3-year PFS rate from time of first transplantation of 61%, and 5- and 7-year PFS rates of 54% and 52%, respectively. Whether or not this is significantly better than single myeloablative therapy regimens will require a larger, phase III randomized study. The Children’s Oncology Group has designed a phase III study, which is currently under development, to test the effect of tandem HDT/PBSCR on PFS in patients with high-risk neuroblastoma. Our treatment regimen contains many features that might have influenced outcome. For example, induction therapy was novel in that it incorporated newer agents (carboplatin and ifosfamide) into a standard backbone of anthracycline, cisplatin, and cyclophosphamide, building on the experience of the Pediatric Oncology Group.16,17 Isolated local relapse was rare in our cohort, perhaps because of aggressive surgical debulking as well as the use of local irradiation in addition to TBI.18-20 The use of PBSC as opposed to the use of bone marrow as a source of support after myeloablative therapy may have contributed to improved survival. Similar to other reports,21 we have reported significantly faster hematopoietic recovery associated with higher number of hematopoietic cells infused with PBSCT, which is an effect that was seen in both HDT/PBSCR.8 PBSC may also be cleaner, with less chance of reinfusing tumor cells.9 Other potential explanations for our observed outcomes include bias as a result of patient selection (all patients were cared for at major urban tertiary care centers) and limited sample size. The absence of CNS relapse in itself could also have contributed to the improved survival rate in our cohort. With improved survival in metastatic neuroblastoma, the incidence of CNS relapse has increased.6,22 In a retrospective analysis of 251 patients with neuroblastoma, none of whom had CNS disease at diagnosis, 4.3% were found to develop CNS relapse.6 Development of CNS disease was associated with lumbar puncture in the presence of known bone marrow involvement, suggesting that circulating or epidural microscopic tumor cells may have seeded the craniospinal axis.6 Lumbar puncture at diagnosis was not performed as a part of our study, which may, in part, explain the absence of CNS relapse in this group. In addition, the CNS relapses mentioned in the earlier referenced study6 could have been a result of the non-TBI regimens that were used in these patients. In another retrospective analysis of 434 children with stage 4 disease, 5.3% had the CNS as the site of first recurrence, which occurred in the first 18 months after diagnosis.22 Some of these patients were treated with regimens that included TBI. The estimated risk of CNS recurrence was 8% at 3 years, with no significant change in risk over a 15-year period of follow-up. In this study too, a significant risk factor for CNS recurrence was lumbar puncture at diagnosis, in addition to ages 2 to 3 years and MYCN gene amplification. Our follow-up has been over 5 years, allowing sufficient time for CNS recurrence to occur. Thus far, no evidence of CNS relapse has been documented. Growth failure, hypothyroidism, and lack of pubertal progress have been observed among the survivors of this protocol. A subset of these patients who have undergone neuropsychological testing showed a lack of morbidity, with excellent neurocognitive functioning.23 A comprehensive analysis is underway to report on the late effects of this treatment regimen. Treatment-related myelodysplasia and leukemia have been reported to occur between 7 months and more than 16 years (median, 2 years) after neuroblastoma diagnosis in patients treated with dose-intensive therapy.24 In our series of patients, only one patient developed myelodysplasia (almost 6 years after diagnosis). This patient had a clonal trisomy 8, which is a genetic abnormality that is not uncommon in post-therapy–related myelodysplasia.25 With the alkylator dose-intensity contained in this regimen, more incidents of treatment-related myelodysplasia/leukemia would have been expected. Explanations for the lack of secondary leukemia in our patients may include the collection of PBSC early in induction therapy and the use of TBI as part of HDT2, thus ablating leukemogenic hematopoietic precursors. Secondary malignancies are not uncommon in long-term survivors of neuroblastoma. In a study of 544 neuroblastoma patients with an average follow-up time of 15 years, 12 (2.2%) developed secondary malignancies compared with the 1.19% expected from general population rates.26 The most frequent secondary solid tumors were thyroid and breast cancers27,28 attributed to external radiotherapy and occurring between 2 and 21 years after neuroblastoma diagnosis. One patient in our series developed a synovial cell sarcoma 8 years after treatment for neuroblastoma. Because all of the patients described in our study received diagnostic metaiodobenzylguanidine (MIBG), local radiation to the primary tumor, or TBI as part of high-dose therapy, the future occurrence of secondary malignancies is expected. Induction response, in particular MIBG response, has been correlated in other studies with improved outcome.29 Unfortunately, we had little data on induction response rates in this cohort, with only limited information on MIBG response at end of induction. During the long time period during which patients were cared for with this regimen, the standards of scanning changed; early patients had no MIBG scans, some later patients had131I-MIBG scans, and more recent patients underwent modern123I-MIBG scanning. Longer follow-up on this small number of more recent patients may be informative. Other risk factors such as MYCN gene status and stage did not predict outcome, but the sample size is limited. Deaths from neuroblastoma have usually been early events; less than 5% occurred more than 3 years from diagnosis, and less than 1% occurred after 5 years.30,31 Late recurrences have also been rare, with most of the relapses of neuroblastoma typically occurring within 2 years after therapy.32 With advances in treatment, an increase in the incidence of late recurrences may be seen.32,33 In our study, late relapses continue to be rare; the largest proportion of patients (68%; 25 of 37 patients) who experienced relapse did so less than 2 years from first transplantation. Only one patient has experienced relapse 5 years or later after diagnosis, with 29 patients at risk. It is still possible that patients may experienced relapse because it has been reported that relapses have been observed as late as 7 years after megatherapy.33 Therefore, longer follow-up of patients in this series will determine whether this regimen merely arrests the disease until recurrence at some later point or holds the promise of long-term cure. The results of a prospective randomized trial now in development by the Children’s Oncology Group comparing single with tandem consolidations may clarify the role that intensification of consolidation has in contributing to long-term outcomes. In conclusion, despite the improved long-term survival rates seen in patients treated with tandem myeloablative therapy, more than 50% of children with high-risk disease still are not cured. One of the methods for further improvement in survival may be the tailoring of treatment according to response after induction.5,30 In fact, to more effectively improve induction, up-front topotecan and cyclophos-phamide are being incorporated in a future Children’s Oncology Group study for newly diagnosed high-risk neuroblastoma patients. Eradication of minimal residual disease may also contribute to better long-term survival through the use of postconsolidation therapy with differentiating agents, targeted antibody therapies, and biologic response modifiers. Finally, detection of molecular aberrations by high-throughput approaches needs to be prioritized in an effort to identify new therapeutic targets.
The authors indicated no potential conflicts of interest.
We thank the physicians, nurses, and clinical research associates of all participating hospitals for their excellent clinical care of these patients and their data management and reporting.
Supported in part by the Fred Lovejoy Resident Research Award (R.E.G.), Grant No. NIH R21 CA110516, and funds from the Sanford and WW Smith Trusts (S.A.G.). Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Philip T, Zucker JM, Bernard JL, et al: Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: Is cure possible in a small subgroup? J Clin Oncol 9:1037-1044, 1991[Abstract] 2. Kushner BH, O'Reilly RJ, Mandell LR, et al: Myeloablative combination chemotherapy without total body irradiation for neuroblastoma. J Clin Oncol 9:274-279, 1991[Abstract] 3. Ladenstein R, Philip T, Lasset C, et al: Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: A report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 16:953-965, 1998[Abstract] 4. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid: Children's Cancer Group. N Engl J Med 341:1165-1173, 1999 5. Frappaz D, Michon J, Coze C, et al: LMCE3 treatment strategy: Results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 18:468-476, 2000 6. Kramer K, Kushner B, Heller G, et al: Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center Experience and A Literature Review. Cancer 91:1510-1519, 2001[CrossRef][Medline] 7. Choi HS, Koh SH, Park ES, et al: CNS recurrence following CD34+ peripheral blood stem cell transplantation in stage 4 neuroblastoma. Pediatr Blood Cancer 45:68-71, 2005[CrossRef][Medline] 8. Grupp SA, Stern JW, Bunin N, et al: Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 18:2567-2575, 2000 9. Grupp SA, Stern JW, Bunin N, et al: Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol 35:696-700, 2000[CrossRef][Medline] 10. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-1477, 1993 11. Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224:1121-1124, 1984 12. Shimada H, Chatten J, Newton WA Jr, et al: Histopathologic prognostic factors in neuroblastic tumors: Definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 73:405-416, 1984[Medline] 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[Medline] 14. Philip T, Ladenstein R, Zucker JM, et al: Double megatherapy and autologous bone marrow transplantation for advanced neuroblastoma: The LMCE2 study. Br J Cancer 67:119-127, 1993[Medline] 15. Kletzel M, Katzenstein HM, Haut PR, et al: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: Results of the Chicago Pilot II Study. J Clin Oncol 20:2284-2292, 2002 16. Castleberry RP, Cantor AB, Green AA, et al: Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 12:1616-1620, 1994 17. Kretschmar CS, Kletzel M, Murray K, et al: Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: A Pediatric Oncology Group study. J Clin Oncol 22:4119-4126, 2004 18. Marcus KJ, Shamberger R, Litman H, et al: Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem cell transplants. J Pediatr Hematol Oncol 25:934-940, 2003[CrossRef][Medline] 19. Haas-Kogan DA, Swift PS, Selch M, et al: Impact of radiotherapy for high-risk neuroblastoma: A Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56:28-39, 2003[CrossRef][Medline] 20. von Allmen D, Grupp S, Diller L, et al: Aggressive surgical therapy and radiotherapy for patients with high-risk neuroblastoma treated with rapid sequence tandem transplant. J Pediatr Surg 40:936-941, 2005[CrossRef][Medline] 21. Sirohi B, Powles R, Kulkarni S, et al: Reassessing autotransplantation for acute myeloid leukaemia in first remission: A matched pair analysis of autologous marrow vs. peripheral blood stem cells. Bone Marrow Transplant 33:1209-1214, 2004[CrossRef][Medline] 22. Matthay KK, Brisse H, Couanet D, et al: Central nervous system metastases in neuroblastoma: Radiologic, clinical, and biologic features in 23 patients. Cancer 98:155-165, 2003[CrossRef][Medline] 23. Carpentieri SC, Diller LR: Neuropsychological resiliency after treatment for advanced stage neuroblastoma. Bone Marrow Transplant 35:1117-1122, 2005[CrossRef][Medline] 24. Kushner BH, Cheung NK, Kramer K, et al: Neuroblastoma and treatment-related myelody-splasia/leukemia: The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 16:3880-3889, 1998 25. Andersen MK, Larson RA, Mauritzson N, et al: Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: Report from an international workshop. Genes Chromosomes Cancer 33:395-400, 2002[CrossRef][Medline] 26. Rubino C, Adjadj E, Guerin S, et al: Long-term risk of second malignant neoplasms after neuroblastoma in childhood: Role of treatment. Int J Cancer 107:791-796, 2003[CrossRef][Medline] 27. Tucker MA, Jones PH, Boice JD Jr, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer: The Late Effects Study Group. Cancer Res 51:2885-2888, 1991 28. de Vathaire F, Hawkins M, Campbell S, et al: Second malignant neoplasms after a first cancer in childhood: Temporal pattern of risk according to type of treatment. Br J Cancer 79:1884-1893, 1999[CrossRef][Medline] 29. Matthay KK, Edeline V, Lumbroso J, et al: Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol 21:2486-2491, 2003 30. Bowman LC, Hancock ML, Santana VM, et al: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: The St Jude Children's Research Hospital experience, 1962 to 1988. J Clin Oncol 9:1599-1608, 1991[Abstract] 31. Cotterill SJ, Pearson AD, Pritchard J, et al: Clinical prognostic factors in 1277 patients with neuroblastoma: Results of the European Neuroblastoma Study Group ‘Survey’ 1982-1992. Eur J Cancer 36:901-908, 2000[CrossRef][Medline] 32. Stram DO, Matthay KK, O'Leary M, et al: Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chem-otherapy for metastatic neuroblastoma: A report of two concurrent Children's Cancer Group studies. J Clin Oncol 14:2417-2426, 1996[Abstract] 33. Berthold F, Hero B: Neuroblastoma: Current drug therapy recommendations as part of the total treatment approach. Drugs 59:1261-1277, 2000[CrossRef][Medline] Submitted January 15, 2006; accepted March 10, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
