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Biologic Factors Determine Prognosis in Infants With Stage IV Neuroblastoma: A Prospective Children’s Cancer Group Study

From the Department of Pediatrics, University of Illinois at Chicago College of Medicine, Chicago, IL; Department of Pediatrics, University of California School of Medicine, San Francisco; Departments of Pediatrics, Pathology, and Preventive Medicine, University of Southern California School of Medicine and Children’s Hospital; University of California Los Angeles School of Medicine, Los Angeles; The Children’s Cancer Group, Arcadia, CA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Pediatrics, Vanderbilt University, Nashville, TN; and Denver Pediatric Surgeons, Denver, CO.

Address reprint requests to Mary Lou Schmidt, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA, 91066-6012; email mls3{at}uic.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: A prospective Children’s Cancer Group study, CCG-3881, has been completed to determine if a more accurate prediction of prognosis by biologic features can identify subgroups of infants with stage IV neuroblastoma (NBL) who require differing intensities of treatment.

PATIENTS AND METHODS: One hundred thirty-four infants were registered from June 1989 to August 1995, with a median follow-up of 47.1 months (range, 0 to 88 months). The biologic factors examined were tumor MYCN copy number, Shimada histopathologic classification, serum ferritin, and bone marrow immunocytology (sensitivity, one tumor cell per 10⁵ bone marrow cells). Patients treated on CCG-3881 (n = 116) received four-drug chemotherapy for 9 months (cisplatin, cyclophosphamide, doxorubicin, and etoposide), with surgery and local radiation to residual disease. After January 1991, all subsequent infants with tumor MYCN amplification (n = 18) were transferred after one cycle of therapy to the high-risk CCG-3891 protocol (open January 1991 to April 1996) for more intensive treatment.

RESULTS: The 3-year event-free survival (EFS) and overall survival (mean ± SD) for the 134 infants were 63% ± 5% and 71% ± 5%, respectively. Patients whose tumors were without MYCN amplification had a 93% ± 4% 3-year EFS, whereas those with amplified MYCN had a 10% ± 7% 3-year EFS (P < .0001). Each of the other biologic features studied had prognostic significance in univariate analysis but not after stratifying by MYCN copy number.

CONCLUSION: Infants less than 1 year of age at diagnosis with stage IV NBL have a much improved outcome compared with children 1 year of age. Nonamplified MYCN tumors identify a group of infants with a 93% ± 4% EFS, whereas amplified MYCN copy number clearly identifies patients who are unlikely to survive despite intensive chemotherapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
INFANTS LESS THAN 1 year of age at diagnosis with stage IV neuroblastoma (NBL) have a much better prognosis than older children with stage IV NBL, with a 50% to 75% event-free survival (EFS) compared with a less than 30% EFS for older children.^1-8 Nevertheless, some patients experience rapid disease progression despite intensive therapy. Biologic features, including tumor MYCN gene amplification, Shimada histopathology, serum ferritin, bone marrow immunocytology (BMI), and DNA content have been shown to have prognostic value in NBL.^9-20 The purpose of this study was to identify subgroups of infants with stage IV NBL with significantly different probabilities of survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Population
All infants with Evans stage IV NBL were registered onto Children’s Cancer Group (CCG) trial CCG-3881 (open June 1989 to August 1995).²¹ After 1991, the high-risk NBL protocol, CCG-3891, opened and an amendment was written to CCG-3881 to transfer all infants with tumor MYCN amplification and disseminated disease to CCG-3891 because of these patients’ proven high risk for failure shown in the first 13 such patients treated on CCG-3881. Infants were transferred to CCG-3891 after the first course of chemotherapy when the MYCN determination became available. All patients entered onto either study had an informed consent signed by a parent or guardian and study approval by the appropriate local institutional human research review board.

Biologic Features
From 1989 to 1993, MYCN gene amplification was determined by Southern analysis of gene copy number.¹⁰ After 1993, MYCN gene amplification was determined by the pattern of MYCN protein expression by immunoperoxidase stain¹² combined with a semi-quantitative polymerase chain reaction technique for MYCN gene copy number.¹³ These studies were performed in the centralized CCG Neuroblastoma Reference Laboratory.^10,11 Shimada histopathologic classification was performed centrally by H. Shimada.^14-16 Although only the centrally reviewed Shimada classification was used in the analyses, there was concordance between central and local institutional pathologists’ classification in 51 (77%) of 66 of samples where both reviews were available. A favorable classification was rendered by Shimada for three cases identified as unfavorable by the institutional pathologist, and 12 cases were designated unfavorable by Shimada when the institutional pathologist had identified the cases as favorable. BMI was performed using a mixture of antibodies on bone marrow samples sent at diagnosis to the CCG Neuroblastoma Reference Laboratory by methods previously described.¹⁷ The sensitivity was one tumor cell per 100,000 nucleated cells. Ferritin was measured by radioimmunoassay at the treating institutional laboratory and reported as unfavorable if it was 143 ng/mL and favorable if it was less than 143 ng/mL.⁹

Treatment
The CCG-3881 treatment protocol consisted of approximately 9 months of four-drug combination chemotherapy with cisplatin, cyclophosphamide, doxorubicin, and etoposide, as well as surgery to residual disease after induction, followed by local radiation for gross residual disease after delayed surgery.²¹ After January 1991, a total of 18 patients with tumor MYCN amplification were transferred to CCG-3891. CCG-3891 used the same four chemotherapeutic agents in a more dose-intensive induction. Chemotherapy was followed by consolidation therapy, with randomized assignment to either myeloablative therapy with carboplatin, etoposide, and melphalan and total-body irradiation with autologous purged bone marrow transplantation (BMT) or to a chemotherapy consolidation with continuous-infusion cisplatin, etoposide, doxorubicin, and ifosfamide.²¹ Of the 18 infants with stage IV disease transferred to CCG-3891, four were randomly assigned to chemotherapy, three were randomly assigned to autologous BMT (one actually received it), eight were nonrandomly assigned to chemotherapy, and three relapsed or were withdrawn from the study before the first randomization at 8 weeks.

Statistical Analysis
Life-table methods were used to estimate the EFS from time of diagnosis. The log-rank statistic was used to compare the EFS probabilities between subgroups of patients.²² Relative risk analysis was performed using the Cox regression method.²³

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
A total of 134 infants with Evans stage IV NBL were registered onto CCG-3881 and 3891. Table 1 lists biologic data, including serum ferritin for 86% of patients, MYCN for 76% of patients, BMI for 61%, and Shimada histopathology for 68% of patients. All four biologic features were measured in 28% (n = 37) of the patients. At least three of these four features were measured in 71% (n = 95) of the patients; at least two of the four in 93% (n = 124); and at least one of the four in 100% (n = 134). Unfavorable characteristics were seen in approximately one third of the patients; 30% of patients had MYCN amplification, 31% had unfavorable pathology, 33% had elevated ferritin, and 44% had positive BMI.

View larger version (12K): [in this window] [in a new window]   Fig 1. EFS by best eventual surgical resection of the primary tumor for stage IV infants: CR + MR (n = 71; 3-year Peto SE, 0.061), PR (n = 13; 3-year Peto SE, 0.136), and BX (n = 22; 3-year Peto SE, 0.134) (P = .219).

View larger version (13K): [in this window] [in a new window]   Fig 2. (A) EFS and (B) OS outcome for all 134 infants less than 12 months of age with stage IV NBL treated on CCG protocols from June 1989 to April 1996. SE bars represent 3-year probability ± Peto SE.

View larger version (16K): [in this window] [in a new window]   Fig 3. EFS for infants with stage IV NBL by biologic factor. SE bars represent 3-year EFS probability ± Peto SE. (A) EFS by MYCN status: nonamplified (n = 71) v amplified (n = 31) (P < .0001). (B) EFS by Shimada pathologic classification: favorable (n = 63) v unfavorable (n = 28) (P < .0001). (C) EFS by serum ferritin: < 143 ng/mL (n = 77) v 143 ng/mL (n = 38) (P = .0017). (D) EFS by BMI: < 100 tumor cells per 105 nucleated cells (n = 46) v 100 tumor cells per 105 nucleated cells (n = 36) (P = .0076).

View larger version (15K): [in this window] [in a new window]   Fig. 3 (continued)

Toxicity
In CCG-3881, grade 3/4 hematologic toxicity was seen in 68% of patients during induction, 35% during consolidation, and 41% during maintenance. Renal, cardiac, and ototoxicity greater than grade 2 occurred in less than 5% of patients. In CCG-3891, grade 3/4 hematologic toxicity was seen in 71% of patients during induction and 78% during consolidation. Only one patient underwent BMT, and this patient had grade 3/4 toxicity.

Progression and Death
Forty-five patients (34%) developed progressive disease, 30 of 116 treated on CCG-3881 and 15 of 18 treated on CCG-3891. Eight of the 30 patients treated on CCG-3881 who progressed were retreated with chemotherapy with or without surgery and are surviving disease-free (median follow-up, 34 months). Six of these patients were known to have nonamplified MYCN and/or favorable Shimada histology, whereas, for the other two patients, MYCN status and Shimada histology were missing. No patient who had a tumor with known MYCN amplification or unfavorable Shimada histopathology and who progressed survived. There were 41 deaths among the 134 infants, including 25 patients treated on CCG-3881 and 16 patients treated on CCG-3891. There were four toxic deaths in patients who never showed progressive disease, including three patients treated on CCG-3881, two of whom died of infection and one of whom died of other causes, and one patient treated on CCG-3891 who died of infection. Twenty-six of 31 patients with amplified MYCN status treated on CCG-3881 (n = 11) or CCG-3891 (n = 15) died of progressive disease. An additional 13 patients treated on CCG-3881 died of progressive disease; the tumor MYCN status was unknown in 12 of these cases. In the one patient who died of progressive disease and whose tumor was MYCN-nonamplified, Shimada histopathology was also favorable.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Recent CCG studies have identified a number of potentially important prognostic factors and biologic characteristics for children with NBL.^9,15,21 These include MYCN copy number, the Shimada histopathologic classification, serum ferritin levels, and BMI at diagnosis. Previously, these factors have been examined primarily in the advanced stages of NBL (stages III and IV) in children greater than 1 year of age, but the prognostic significance of all these biologic variables for infant stage IV disease has not been adequately evaluated.

Before the study of biologic characteristics of NBL tumors, many investigators recognized that the progression-free survival rate of 50% to 80% for infants less than 1 year of age with stage IV NBL was more favorable than for older children.^1-7 In CCG-371, 43 infants with stage IV disease received combined modality treatment with cyclophosphamide, vincristine, dacarbazine ± doxorubicin, teniposide, and cisplatin, which resulted in a 5-year disease-free survival of 49%. Twenty-four infants treated at the Dana-Farber Cancer Institute/Boston Children’s Hospital (Boston, MA) from 1970 to 1988 with multiagent chemotherapy had a 5-year actuarial survival rate of 75%.³ Treatment with 4 months of cyclophosphamide and doxorubicin at St Jude Children’s Research Hospital (Memphis, TN) of 44 infants with disseminated NBL, including 12 stage IV-S patients, resulted in an 80% survival.⁴ In a recent report from the Pediatric Oncology Group, 62 stage D patients received five courses of cyclophosphamide and doxorubicin, with or without cisplatin, and had a 60% 5-year actuarial survival rate.⁶ In none of these previous reports were biologic factors studied to define prognostic subgroups of infants who would be at high risk for relapse.

Lampert et al²⁴ noted that infants with disseminated NBL whose tumors showed hyperdiploidy, nonamplification of MYCN, normal chromosome 1p, and high serum and tumor levels of cellular matrix protein CD44 had an excellent prognosis. All patients with MYCN amplification progressed. It was not shown whether the additional analysis of ploidy or CD44 was prognostic independent of MYCN status.

The aim of CCG-3881 was to refine the prognostic classification of more favorable NBL by combining the clinical variables of stage and age with the biologic variables, including MYCN gene status, Shimada histopathology, serum ferritin, and BMI. The results of the treatment of infants with stage IV NBL on CCG-3881 and CCG-3891 show that MYCN copy number is the most important predictor of prognosis in this group. Patients with MYCN-amplified tumors had a 3-year EFS of 10% compared with a 93% 3-year EFS for patients with nonamplified MYCN tumors. Despite the fact that 24% of the patients did not have MYCN copy number measured, the overall EFS for the patients with unknown MYCN copy number was not significantly different from that of patients who had known MYCN copy number. Because MYCN remained so highly prognostic in the later time period (after the protocol change in January 1991) when little MYCN data was missing, we suspect that other variables must play, at most, a subordinate role to MYCN amplification for prediction of EFS in patients with stage IV disease. Of the 41 patients who died, only one patient had documented nonamplified MYCN copy number; whereas 28 patients had amplified MYCN tumors, and 12 had tumors with unknown MYCN copy number. After stratification by tumor MYCN copy number, no other biologic feature examined (histopathology, ferritin, or BMI) or clinical feature (surgical resection, age 0 to 3 months v > 3 months, or chemotherapy regimen) altered prognosis. This is consistent with two previous reports that assessed ploidy, CD44 values and/or clinical features, and MYCN copy number. In these, MYCN copy number retained significance independent of all variables or was only analyzed in a minimum number of cases.^20,24

Genetic characteristics have recently been reported as having prognostic significance. The Pediatric Oncology Group has demonstrated the prognostic significance of the DNA content of NBL for infants.^18-20 In their most recent study of 172 infants < 1 year of age with unresectable NBL, 56 had stage D disease.²⁰ Thirty-three tumors showed hyperdiploidy, and 23 showed diploid DNA content. For the entire group of infants with unresectable NBL, hyperdiploidy was associated with a 94% 3-year OS, and diploid DNA content was associated with a 55% OS. In this study, MYCN amplification was strongly associated with diploid DNA content (odds ratio of 4.6, P < .01), and after stratification, MYCN copy number retained prognostic significance for both hyperdiploid and diploid tumors. (This report did not examine the statistical significance of diploid DNA content for nonamplified MYCN tumors in stage IV infants.)

Current intergroup studies in the United States (which are investigating MYCN copy number, Shimada histopathology, and DNA content for all infants < 12 months of age) expect a yearly accrual of 50 infants with stage IV NBL, two out of three of whom are expected to have tumors with single-copy MYCN. Our data, in which only 7% of patients with nonamplified MYCN tumors relapsed (two to three per year among expected accrual), suggest that future studies may take as long as 10 years to decide whether or not other prognostic variables (such as DNA content) are predictive in this subset of infants (assuming a relative risk of 3).

Our data indicate a poor outcome (10% 3-year EFS, 12% OS) for infants with MYCN amplification. On the other hand, the Bowman et al²⁰ study found that, among 16 infants with MYCN-amplified tumors, an estimated 37.5% of such patients were still alive after 3 years. Although this figure applies to all stages of infants, in our own experience MYCN amplification among infants is extremely rare in stages other than stage IV. Therefore, a pooled estimate (from the Bowman and the current report) of survival for amplified stage IV infants is 21%, which evidently is within sampling variation of the estimate from either study. Thus, there is no strong evidence that the survival of MYCN-amplified stage IV patients was different for the Bowman et al²⁰ study compared with the current one. Again, our data suggest that it will require lengthy observation to determine whether any other prognostic variable (such as DNA content) is predictive of favorable outcome among infants with MYCN-amplified stage IV NBL.

In conclusion, the current study clearly shows that new approaches are required for infants less than 12 months of age with stage IV MYCN-amplified NBL in an effort to improve their current dismal prognosis. Possible approaches might include myeloablative consolidation therapy without total-body irradiation, immunotherapy, retinoids, targeted radiotherapy, or novel agents such as antiangiogenic compounds. On the other hand, chemotherapy and radiation may perhaps be safely decreased for infants with nonamplified MYCN stage IV tumors. This approach is being tested in the current intergroup study, which decreases total length of therapy for these patients relative to that given in previous CCG protocols.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Participating Principal Investigators: Children’s Cancer Group

	ACKNOWLEDGMENTS

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Kretschmar CS, Frantz CN, Rosen EM, et al: Improved prognosis for infants with stage IV neuroblastoma. J Clin Oncol 2:799-803, 1984[Abstract]

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12. Seeger RC, Wada R, Brodeur GM, et al: Expression of N-myc by neuroblastomas with one or multiple copies of the oncogene. Clin Biol Res 271:41-49, 1988

13. Crabbe DC, Peters J, Seeger RC, et al: Rapid detection of MYCN gene amplification in neuroblastomas using the polymerase chain reaction. Diagn Mol Pathol 1:229-234, 1992[Medline]

14. Shimada H, Chatten J, Newton WA, 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

15. Chatten J, Shimada H, Sather HN, et al: Prognostic value of histopathology in advanced neuroblastoma: A report from the Childrens Cancer Study Group. Hum Pathol 19:1187-1198, 1988[Medline]

16. Shimada H, Stram DO, Chatten J, et al: Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst 87:1470-1476, 1995[Abstract/Free Full Text]

17. Moss TJ, Reynolds CP, Sather HN, et al: Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma. N Engl J Med 324:219-226, 1991[Abstract]

18. Look AT, Hayes A, Nitschke R, et al: Cellular DNA content as a predictor of response to chemotherapy in infants with unresectable neuroblastoma. N Engl J Med 311:231-235, 1984[Abstract]

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Submitted October 14, 1998; accepted November 19, 1999.

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