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Originally published as JCO Early Release 10.1200/JCO.2005.05.005 on August 22 2005 © 2005 American Society of Clinical Oncology.
Age at Diagnosis and Prognosis in Children With NeuroblastomaThe University of Pennsylvania School of Medicine, and The Children's Hospital of Philadelphia, Philadelphia, PA Three articles in this issue address the important topic of age at diagnosis as a prognostic factor in children with neuroblastoma (NB).1-3 Unraveling the puzzle created by the extraordinarily varied natural history of patients with NB has attracted the attention of many pediatric oncologists and other scientists for decades. It has long been observed that infants with NB seemed to fare better than older children, even after minimal therapy.4 This was heightened by the report in 1966 by Everson and Cole,5 who observed 176 patients of all ages with various cancers whose tumors underwent spontaneous regression. Thirty among the 176 (17%) were children with NB. This is a disproportionally high figure considering the minuscule incidence of NB among all humans with malignant diseases. One of the first international conferences devoted to NB in 1967 discussed several biologic features that apparently affected outcome.6 Prominent among them was the inverse relationship between age at diagnosis and prognosis. A subsequent interesting report by Beckwith and Perrin7 described what seemed to be nests of NB cells in the adrenal glands of infants who had died as a result of sudden infant death syndrome. The frequency of this finding was greater than the incidence of NB as detected clinically in their peers of the same age. This gave rise to the concept of NB in situ, suggesting a strong propensity for spontaneous regression of NB dating even from birth. Later, an analysis of a large number of cooperative-group patients collected by Breslow and McCann8 showed that age was not only a strong prognostic factor, but also a continuous variable independent of the validated staging system then in use. In the intervening years many clinical, biologic, and genetic studies have been reported. References to some of these are found in the three articles discussed herein. The most important factor with clear influence on outcome is amplification of the MYCN gene.9 In addition, DNA index seems to have an independent influence on disease outcome, particularly for patients younger than 2 years of age.10 The histo-cytopathologic pattern described by Shimada et al,11 in which age at diagnosis is used for stratification, is also an important variable and was another landmark contribution to prognostication. The current scheme used in cooperative-group studies in the United States, at least to prescribe treatment, thus employs age, stage, MYCN status, and histology to divide patients into treatment groups according to perceived relapse risk. Treatment consequently varies widely, ranging from surgical resection alone to an aggressive and potentially lethal program of surgery, intensive chemotherapy, radiation therapy (including total-body irradiation in some regimens), and stem-cell rescue. Because the range of treatment is so wide, with its short- and long-term effects, the clearest possible definition of what constitutes low risk is of great importance. Fortunately, age younger than 1 year is a strongly favorable factor by itself. Any additional criteria that could be used to increase the so-called safe range beyond the age of 1 year would spare many more patients the rigors of aggressive treatment. This is especially important in young children who are so vulnerable to the deleterious late effects of such therapy. The influence of age in the second year of life is reported for all stages in the article by London et al1; the other two articles are limited to those patients with metastatic (but not MYCN amplified) disease (George et al2 and Schmidt et al3). The article by George et al also addresses DNA index as a predictor of outcome. The goal of all three analyses was to determine at what point the relapse rates distinguish most clearly between the favorable prognosis of the infant and the less favorable outlook of the older child. The Children's Cancer Group report by Schmidt et al3 deals with the outcome of treatment of 43 patients with stage 4 nonamplified MYCN disease in patients 12 to 24 months of age. The event-free survival (EFS) was 74% for the 12- to 18-month age group compared with 31% for those 18 to 24 months of age (P = .008). The authors therefore suggest that patients up to an age of 18 months "may not benefit from intensive therapy." George et al2 used Pediatric Oncology Group data to analyze ploidy and MYCN amplification as prognostic indices in 22 children 12 months and older with stage 4 disease. Patients 12 to 24 months of age with nonamplified MYCN tumors and hyperdiploidy had a survival rate of 72.7% compared with 26.7% for their older counterparts (P = .0092). Superiority again was strongest in the 12- to 18-month age group, in which the EFS was 92.2% v 37.5% in those 19 to 24 months of age (P = .0037). London et al1 revisit the study by Breslow and McCann that showed age to be a continuous independent variable with a lessened impact after 2 years. They pooled data from 3,666 patients of all stages from both the Children's Cancer Group and Pediatric Oncology Group and distributed them among 27 groups. The EFS P values for the various cutoffs between 15 and 22 months were all extremely small. Thus, any age within this range could be used for risk stratification. In addition, they found that the EFS was 92% in nonamplified MYCN stage 4 patients between age 365 and 460 days. These three articles refine attempts to stratify and prescribe the correct intensity of treatment for each patient, the guideline being "enough but not too much." Investigators charged with designing NB clinical trials should use these careful analyses to select a newly expanded low-risk group based on age in patients with nonamplified MYCN tumors. The investigators should then be expected to mount trials using uniform treatment regimens for all stages in the study (given that therapy differences would introduce confounding variables) to test the validity of that age criterion. Such trials must include not only the initial elements of therapy but also uniform retrieval regimens. It will be important to establish that overall survival is not jeopardized by the minimal therapy strategy, should EFS rates prove less satisfactory than those projected by these important and provocative articles. That this is a feasible way to proceed was demonstrated by Wolff et al12 for Wilms' tumor in an early clinical trial of that malignant neoplasm. If confirmed, many more young children so vulnerable to iatrogenic adversities will be spared the rigors of combined-modality therapies. A final observation: these considerations should certainly be extended to patients with stage 4S disease. Spontaneous resolution of NB is the hallmark of that syndrome, which in the current International Neuroblastoma Staging System scheme applies only to infants younger than 1 year of age. Older children are assigned to stage 4. Thus, an infant 364 days old would be managed by careful observation, with minimal therapy added only as dictated by clinical necessity. For an identical infant 24 hours older, the morbid engines of full-scale therapy potentially would be—and have been—set in motion. This is an untenable position given the continuous nature of the age variable established 30 years ago by Breslow and McCann,8 and confirmed by the articles discussed here. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. London WB, Castleberry RP, Matthay KK, et al: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23:6459-6465, 2005
2. George RE, London WB, Cohn S, et al: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: A Pediatric Oncology Group Study. J Clin Oncol 23:6466-6473, 2005
3. Schmidt ML, Lal A, Seeger R, et al: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: A Children's Cancer Group Study. J Clin Oncol 23:6474-6480, 2005 4. Wittenborg MH: Roentgen therapy in neuroblastoma: Review of 73 cases. Radiology 54:670-688, 1950 5. Everson TC, Cole WH. Spontaneous Regression of Cancer. Philadelphia, PA, WB Saunders, 1966 6. Bill HA, Koop CE: The biology of neuroblastoma. J Pediatr Surgery 3:103-193, 1968[CrossRef][Medline] 7. Beckwith JB, Perrin EV: In situ neuroblastoma: A contribution to the natural history of neural crest tumors. Am J Pathol 43:1089-1104, 1963
8. Breslow N, McCann B: Statistical estimation of the prognosis for children with neuroblastoma. Cancer Res 31:2098-2103, 1971
9. 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 10. Look AT, Hayes FA, 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] 11. Shimada H, Chaten J, Newton WAJ, et al: Histologic prognostic factors in neuroblastoma tumors: Definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastoma. J Natl Cancer Inst 73:405-406, 1984 12. Wolff JA, D'Angio GJ, Hartman WA, et al: Long term evaluation of single vs. multiple courses of actinomycin-D therapy of Wilms' tumor. N Engl J Med 209:84-86, 1974
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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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