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Journal of Clinical Oncology, Vol 23, No 34 (December 1), 2005: pp. 8819-8827 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.00.2931 Outcomes of Children With Intermediate-Risk Neuroblastoma After Treatment Stratified by MYCN Status and Tumor Cell PloidyFrom the University of Arizona, Department of Pediatrics and Steele Children’s Research Center, Tucson, AZ; Children’s Oncology Group, University of Florida, Gainesville, FL; Northwestern University, Feinberg School of Medicine, Chicago, IL; the Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Children’s Hospital of Philadelphia and the University of Pennsylvania, School of Medicine, Philadelphia, PA; A.I. DuPont Hospital for Children, Wilmington, DE; Department of Pathology, Hartford Hospital, Hartford, CT; Department of Laboratory Medicine, Hospital for Sick Children; University of Toronto, Toronto, Canada; University of Alabama, Birmingham, AL; Children’s Healthcare of Atlanta; Emory University, Atlanta, GA Address reprint requests to Rochelle Bagatell, MD, Department of Pediatrics, Pediatric Hematology/Oncology, Room 5341, Arizona Health Sciences Center, 1501 N Campbell Ave, Tucson, AZ 85724; e-mail: bagatell{at}peds.arizona.edu; CC: pubs{at}childrensoncologygroup.org
PURPOSE: The goal of Pediatric Oncology Group 9243 was to improve outcomes for children with intermediate-risk neuroblastoma (NB). PATIENTS AND METHODS: Patients were assigned to treatments on the basis of age, tumor MYCN status, and tumor cell ploidy. Children in the less intensive arm A received cyclophosphamide/doxorubicin and surgery. Patients not in complete remission postoperatively were treated with cisplatin/etoposide, cyclophosphamide/doxorubicin, and additional surgery. Patients with less favorable features were assigned to arm B, which consisted of carboplatin, etoposide, ifosfamide, and surgery. Survival rates were determined using an intent-to-treat approach. RESULTS: For arm-A patients, the 6-year event-free survival (EFS) was 86% with an SE of 3%. For arm-B patients, the 6-year EFS was 46% with an SE of 7%. MYCN status was the only statistically significant prognostic variable. Among patients whose tumors were MYCN nonamplified, a trend toward improved EFS was seen in children with hyperdiploid versus diploid tumors. However, many of these children responded well to salvage therapy, and overall survival rates did not differ on the basis of ploidy. Six-year EFS rates for arm B were patients with MYCN nonamplified, hyperdiploid tumors, 86% with an SE of 3%; patients with MYCN nonamplified, diploid tumors, 74% with an SE of 10%; patients with MYCN-amplified, hyperdiploid tumors, 46% with an SE of 15%; and patients with MYCN-amplified, diploid tumors, 22% with an SE of 10%. CONCLUSION: Outcomes for patients with MYCN-nonamplified, hyperdiploid tumors were excellent. Therapy reductions for these patients merit study. A trend toward less favorable outcomes for patients with MYCN-nonamplified, diploid tumors was observed; more children may need to be evaluated before therapy is reduced for this subgroup. For patients with MYCN-amplified tumors, new strategies are needed.
During the last several decades, a body of literature has developed regarding risk-based therapy for children with neuroblastoma (NB). Clinical stage, age, histopathology, and MYCN copy number are important for risk assessment in NB.1-5 Patients with stage I tumors fare well with surgery alone, regardless of risk factors,6-9 but less than 40% of children more than 12 months old with metastatic disease at diagnosis survive, despite multimodality treatment that includes stem-cell transplantation.10 Between these disparate populations are children with NB whose risk of recurrence is intermediate. Intrinsic biologic features of NB tumors are particularly important in treatment planning for these children, because even within a cohort that appears to be similar with respect to age and stage, biologically defined subgroups have had excellent survival rates with less toxic therapy, whereas, others do poorly even with more intensive chemotherapy.11,12 Bowman et al11 described the Pediatric Oncology Group (POG) experience using risk-based therapy for infants younger than 1 year with unresectable or metastatic NB (POG 8743). Although 3-year overall survival (OS) for infants with hyperdiploid tumors was 95% with an SE of 5%, 3-year OS for infants with diploid tumors was 55% with an SE of 15%.The goal of POG 9243 was to improve outcomes of intermediate-risk patients whose tumors had less favorable biologic features. Patients considered to have intermediate-risk NB at the time of the study were infants with metastatic or incompletely resected tumors (stages B, C, D, and DS) and children older than 1 year with localized but unresectable disease (stage B). Patient age and stage, as well as tumor MYCN copy number and cellular DNA content were used to determine treatment intensity. We hypothesized that excellent survival rates could be maintained and toxicity limited with a moderately intensive regimen for infants younger than 1 year, who had hyperdiploid tumors, and older children with MYCN nonamplified stage B tumors. We further hypothesized that augmentation of therapy would improve survival for patients with MYCN-amplified tumors, infants with diploid tumors, and patients with poor responses to initial therapy.
Patients were enrolled from March 1992 to February 1996. A coordinating pathologist confirmed the diagnosis of NB in all patients. Staging was based on POG criteria: stage A, localized resected tumors; stage B, localized unresected tumors with negative noncontiguous lymph nodes; stage C, metastasis to noncontiguous lymph nodes; stage D, metastasis beyond lymph nodes; DS, metastasis limited to liver, skin, and bone marrow.7 Infants younger than 1 year with stages B, C, D, and DS disease and children older than 1 year with stage B disease were eligible. The study was approved by the institutional review boards of participating institutions. Written informed consent was obtained from parents/legal guardians of participants.
Biologic Studies
Treatment Plan
Arm A Infants with stages B, C, D, and DS NB whose tumors were MYCN nonamplified and hyperdiploid and children older than 1 year with stage B MYCN nonamplified tumors (regardless of tumor cell ploidy) were assigned to arm A. Arm A induction therapy consisted of five courses of oral cyclophosphamide and intravenous doxorubicin. Patients who achieved complete response (CR) after induction received no further therapy. Patients with progressive disease (PD) or residual metastatic disease after induction crossed to arm B. All other patients underwent second-look surgery. When complete resection was not possible, but more than 50% of the tumor present at the time of surgery was resected, patients were treated with two courses of cisplatin/etoposide and two courses of cyclophosphamide/doxorubicin. Patients with residual disease underwent additional resection. Those with PD after chemotherapy and those with residual disease after third-look surgery crossed over to arm B.
Arm B
Toxicity Monitoring
Study Design and Statistical Analysis
Among 269 patients registered on POG 9243, seven patients were later found to be ineligible and were excluded from this analysis. The remaining 262 children form the basis of this report. Four children could not be assessed for toxicity. Median follow-up time was 7.5 years with a minimum of 4 days and a maximum of 11.3 years. Of the 262 children, 230 children were younger than 1 year (Table 1). More than half of the patients had stage C (30%) or stage D (33%) disease. Tumors from 29 of 249 patients (12%) had MYCN amplification. MYCN status was not determined in 13 patients. DNA index was determined in tumors from 252 patients but could not be determined in 10 patients. Tumors from 208 patients (83%) were hyperdiploid, whereas 44 tumors were diploid (18%). Of the 44 diploid tumors, 18 tumors were MYCN-amplified, 23 tumors were MYCN nonamplified, and in three diploid tumors, MYCN status was unknown. For the entire cohort, the 6-year EFS and OS rates were 79% with an SE of 3% and 88% with an SE of 2%, respectively.
Response to Arm A Therapy Two hundred fourteen patients were assigned to arm A. Eighty-three percent of patients (178 patients) responded to this regimen and received only arm-A therapy. Thirty-five children (16%) initially treated with the arm-A regimen did not respond and went on to receive the arm-B regimen. In 84 children (46%) treated entirely according to arm A, CR was induced after therapy limited to five cycles of cyclophosphamide/doxorubicin. An additional 33 patients obtained CR after resection of residual tumor and treatment with cisplatin/etoposide and cyclophosphamide/doxorubicin. Twenty children required third resections to achieve CR. On the basis of an intent-to-treat analysis, patients initially assigned to arm A had 6-year EFS and OS rates of 86% with an SE of 3% and 95% with an SE of 2% (Table 2 and Fig 2). There was insufficient evidence for a statistically significant difference in OS on the basis of tumor cell ploidy. The number of patients with diploid tumors was small, however, and a trend toward improved EFS for patients with hyperdiploid tumors was observed. Deaths of arm A patients were caused by tumor (three patients), infection (one patient), or other reasons (three patients).
Response to Arm B Therapy A total of 48 patients were initially assigned to arm B. Nearly all (46 of 48 patients) were younger than 1 year at diagnosis. Eleven patients were assigned to arm B because of MYCN amplification, 15 because of diploidy and 18 because of both diploidy and MYCN amplification. Five patients were treated in arm B despite unknown MYCN status or ploidy. For the intent-to-treat cohort of patients initially assigned to arm B (excluding the 37 patients who crossed over from arm A), 6-year EFS and OS rates were 46% with an SE of 7% and 56% with an SE of 7%, respectively (Table 3). Deaths of patients treated in arm B were attributed to tumor (19 patients), infection (three patients), hemorrhage (one patient), tumor and infection (two patients), or other reasons (one patient).
Prognostic Factors Consistent with prior studies, MYCN amplification was a key prognostic factor in this study. EFS rates were highest among patients whose tumors were MYCN nonamplified and hyperdiploid (Tables 2 and 3; Figs 3A and 3B). The 6-year EFS rate for patients whose tumors had both favorable biologic features (ie, hyperdiploid, MYCN- nonamplified tumors) was 86% with an SE of 3% (n = 191); the 6-year EFS rate for patients whose tumors had both unfavorable biologic features (ie, diploid, MYCN-amplified tumors) was 22% with an SE of 10% (n = 18). EFS for patients with hyperdiploid MYCN-amplified tumors was intermediate; the 6-year EFS rate for this small group (n = 11) was 46% with an SE of 15%. Twenty-three patients’ tumors were MYCN nonamplified but diploid; the 6-year EFS rate in that group was 74% with an SE of 10% (Fig 3A). These patients responded well to salvage therapy, however, and OS curves for patients with MYCN-nonamplified, diploid tumors and patients with MYCN-nonamplified hyperdiploid tumors were virtually overlapping (Fig 3B). There was no statistically significant difference in OS on the basis of ploidy for patients with MYCN-nonamplified tumors (Tables 2 and 3).
EFS and OS rates for POG 9243 were compared with rates for the preceding POG study (POG 8743). Most patients enrolled on both studies had tumors with favorable biologic features. For patients on POG 8743, 6-year EFS and OS rates were 75% with an SE of 3% and 83% with an SE of 3%, respectively. On POG 9243, 6-year EFS and OS rates were 79% with an SE of 3% and 88% with an SE of 2%, respectively. There were no significant differences in overall EFS and OS rates for POG 8743 compared with POG 9243. However, there was a trend toward improved OS on POG 9243 (P = .1416). Among arm B patients with diploid, MYCN-nonamplified tumors, a trend toward higher EFS rates for patients on POG 9243 was observed (P = .0572). In addition, OS rates for POG 9243 patients with MYCN-amplified, diploid tumors were statistically significantly higher than those for the same subgroup of POG 8743 patients, with a 6-year OS of 32% with an SE of 12% versus 9% with an SE of 9%, respectively (P = .0470; Figs 4A and 4B).
Toxicity Myelosuppression was the most commonly reported toxicity (Table 4). Of the 79 patients for whom toxicity could be assessed, 56% of those in arm A and 96% of those in arm B had  grade 3 hematologic toxicity. Incidence of hemorrhage was low, however, with only two patients reported as having grade 3 hemorrhage. There was one toxic death because of hemorrhage. Neutropenia grade 3 was observed in 54% of patients in arm A and 95% of patients in arm B. The rate of grade 3 neutropenia in POG 9243 arm A was lower than in POG 8743 arm A (P < .0001), likely, because of the addition of granulocyte colony-stimulating factor on POG 9243. Bacterial sepsis was documented in 78 patients, 44 of whom were treated on arm B. There were five infection-related toxic deaths and two deaths as a result of bacteremia in the setting of PD. Pulmonary toxicity grade 3 was observed in 23 patients. In 10 patients, pulmonary compromise was related to tumor mass effects. Thirteen patients experienced pulmonary toxicity related to infection (ie, sepsis, pneumonia/pneumonitis, myocarditis, tracheitis). Renal and cardiac toxicity grade 3 occurred in less than 7% of patients. No ototoxicity was reported. Three patients developed secondary leukemias (ie, two acute lymphoblastic leukemia and one acute nonlymphoblastic leukemia).
These results show excellent survival rates after moderately intensive therapy for children with intermediate-risk NB whose tumors have favorable biologic characteristics. They also suggest that augmented therapy for subsets of patients whose tumors have less favorable biologic characteristics may improve survival. POG 9243 was the first study designed for intermediate-risk NB patients in which children (except those > 1 year of age with stage B disease) were stratified a priori on the basis of both tumor cell ploidy and MYCN status. In most cases, MYCN-amplified tumors also were diploid, and tumors without MYCN amplification were hyperdiploid; in only 34 patients were they discordant. While the difference between EFS rates of patients with MYCN-nonamplified diploid tumors versus patients with hyperdiploid tumors did not reach statistical significance at the .05 level, a trend toward improved EFS for the patients with MYCN-nonamplified hyperdiploid tumors was observed. These observations suggest that the use of both features in risk-group stratification for intermediate-risk patients should be considered. It should be noted that definitions of intermediate-risk disease have evolved since the inception of POG 9243. Patients older than 1 year with stage B disease were eligible for POG 9243. Under current stratification schemes, children older than 1 year with International Staging System for Neuroblastoma stage II NB would be considered low risk if their tumors are MYCN nonamplified, and would be considered high risk if their tumors are MYCN amplified. Infants with stage DS NB were eligible for POG 9243, if chemotherapy was considered clinically indicated. Currently, only infants with MYCN nonamplified tumors and either unfavorable Shimada histology or diploidy are classified as having intermediate-risk disease. Children older than 1 year with stage III favorable histology NB whose tumors were not MYCN amplified were not included on POG 9243, but are now considered to have intermediate-risk disease. Data regarding Shimada histology were not collected uniformly as part of the POG 9243 study, and clinical considerations influenced risk designation at the time of this trial, making it impossible to accurately determine the number of patients who were treated as intermediate risk in the POG 9243 era who would now be classified as having either low-risk or high-risk disease. Results presented should be interpreted with an understanding of the evolution of risk stratification schemes in mind.
In POG 9243, as in the preceding POG intermediate-risk NB study,11 survival of patients whose tumors were MYCN nonamplified and hyperdiploid was excellent. The 6-year OS for patients with both favorable features on both studies was
A comparison of cumulative chemotherapy doses on POG 8743, POG 9243, and CCG 3881/3891 was performed (Table 5). The arm-A regimens on both POG studies consisted of considerably less chemotherapy than did the CCG 3881 regimen. Cumulative doses were higher in POG 9243 arm B than on CCG 3881. Reported rates of grades 3 or 4 hematologic toxicity in infants with stage IV disease treated on CCG 3881 were 68% during induction, 35% during consolidation, and 41% during maintenance.12 By comparison, among patients treated in POG 9243 arm A, the overall rate of grade
Although long-term complications of therapy are rare, given the excellent survival of this group, therapy reduction for patients with hyperdiploid, MYCN-nonamplified tumors may be beneficial. In a single-institution experience, patients with non–stage IV MYCN-nonamplified tumors treated with surgery and observation have fared well, and the few patients with recurrent disease have responded well to salvage therapy.19-21 Other investigators have also reported favorable outcomes for children with stages I, II, and IVS NB who did not receive adjuvant therapy.22 Excellent outcomes have been documented in a retrospective CCG analysis of patients with stage II NB and a prospective Italian cooperative group study of patients with localized, resectable NB.23,24 To determine whether these favorable findings can be replicated in a prospective multicenter trial, this strategy is being assessed for children with localized, biologically favorable disease in the Children’s Oncology Group P9641 study for patients with low-risk NB. In contrast, patients who have MYCN-nonamplified, diploid tumors may not necessarily be good candidates for therapy reductions. The 6-year EFS for those treated on POG 8743 was 49.7% with an SE of 10.6% (n = 24). On the basis of evidence of activity in clinical trials,25-27 ifosfamide and etoposide were incorporated into POG 9243 arm B. Carboplatin was added to permit treatment with a platinum-based agent, while reducing the risk of ototoxicity and nephrotoxicity. The 6-year EFS of patients with MYCN-nonamplified, diploid tumors assigned to POG 9243 arm B was 73% with an SE of 12% (n = 15). The difference in EFS for patients on POG 9243 versus POG 8743 did not reach statistical significance (P = .0882). However, a trend toward improved EFS with more intensive therapy was observed. No difference in OS was seen for this subgroup on the two studies, which suggests that salvage therapy for these patients may be effective and that more efficacious retrieval regimens may have been used at the time of later study. Information regarding the nature of salvage regimens used to achieve this outcome is not available, nor is information regarding toxicities experienced by patients who required salvage therapy. Study of a larger number of patients who meet the current criteria for intermediate-risk NB, who have MYCN-nonamplified, diploid tumors, is warranted. Further assessment of this subgroup may be possible when results of the Children’s Oncology Group trial for uniformly treated intermediate-risk patients (A3961) are available. Patients with MYCN amplification with or without diploidy continue to present a therapeutic challenge. We detected a difference between OS of patients with diploid, MYCN-amplified tumors treated according to POG 9243 and that of similar patients treated on POG 8743 (P = .047). However, these results must be interpreted with caution. The POG studies were sequential, and improvements in supportive care may account, at least in part, for improvements in survival. Furthermore, despite the 70% decrease in relative risk of death for patients on POG 9243 compared with POG 8743, EFS and OS for patients with MYCN-amplified, diploid tumors remained poor (22% ± 10%; and 32% ± 12%, respectively). In a study of infants with stage IV MYCN-amplified NB treated per CCG 3881/3891 with cisplatin, cyclophosphamide, doxorubicin, and etoposide, Schmidt et al12 reported a 3-year EFS of 10% with an SE of 7%. Unlike the CCG 3881/3891 study, the POG 9243 study grouped infants with MYCN-amplified or diploid tumors together. However, even with the inclusion of some infants with diploid, MYCN-nonamplified tumors, 6-year EFS for infants on POG 9243 with stage D disease and either MYCN-amplification or diploidy remained poor at 31% with an SE of 9% (n = 26). An alternative therapeutic approach for patients with tumors with unfavorable features is needed. The benefits of strategies such as myeloablative therapies, NB-specific antibodies, differentiating agents, signal transduction inhibitors, demethylating agents, and antiangiogenic agents are being studied. These approaches could be useful for patients with biologically less favorable NB.
The authors indicated no potential conflicts of interest.
Supported in part by the Pediatric Oncology Group Statistics and Data Center Grants No. U10 CA29139 and Children’s Oncology Group Statistics and Data Center Grant No. U10 CA98413-01, the Caitlin Robb Foundation (R.B.), NIH Grant No. CA39771 (G.M.B.), and National Institutes of Health Grants No. CA98543 (A.T.L.) and CA104605 (A.T.L.). Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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19. Kushner BH, Cheung NK, LaQuaglia MP, et al: Survival from locally invasive or widespread neuroblastoma without cytotoxic therapy. J Clin Oncol 14:373-381, 1996 20. Cheung NK, Kushner BH, LaQuaglia MP, et al: Survival from non-stage 4 neuroblastoma without cytotoxic therapy: An analysis of clinical and biological markers. Eur J Cancer 33:2117-2120, 1997 21. Kushner BH, Kramer K, LaQuaglia MP, et al: Curability of recurrent disseminated disease after surgery alone for local-regional neuroblastoma using intensive chemotherapy and anti-G(D2) immunotherapy. J Pediatr Hematol Oncol 25:515-519, 2003[CrossRef][Medline] 22. Evans AE, Silber JH, Shpilsky A, et al: Successful management of low-stage neuroblastoma without adjuvant therapies: A comparison of two decades, 1972 through 1981 and 1982 through 1992, in a single institution. J Clin Oncol 14:2504-2510, 1996[Abstract] 23. Matthay KK, Sather HN, Seeger RC, et al: Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 7:236-244, 1989[Abstract] 24. De Bernardi B, Conte M, Mancini A, et al: Localized resectable neuroblastoma: Results of the second study of the Italian Cooperative Group for Neuroblastoma. J Clin Oncol 13:884-893, 1995[Abstract]
25. 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 26. Pinkerton CR, Zucker JM, Hartmann O, et al: Short duration, high dose, alternating chemotherapy in metastatic neuroblastoma: ENSG 3C induction regimen—The European Neuroblastoma Study Group. Br J Cancer 62:319-323, 1990[Medline] 27. Campbell LA, Seeger RC, Harris RE, et al: Escalating dose of continuous infusion combination chemotherapy for refractory neuroblastoma. J Clin Oncol 11:623-629, 1993[Abstract] Submitted October 28, 2004; accepted September 8, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
