Age at Diagnosis and Prognosis in Children With Neuroblastoma

Three articles in this issue address the important topic of age at diagnosis as a prognostic factor in children with neuroblastoma (NB). 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. This was heightened by the report in 1966 by Everson and Cole, 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. Prominent among them was the inverse relationship between age at diagnosis and prognosis. A subsequent interesting report by Beckwith and Perrin 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 cooperativegroup patients collected by Breslow and McCann 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. In addition, DNA index seems to have an independent influence on disease outcome, particularly for patients younger than 2 years of age. The histo-cytopathologic pattern described by Shimada et al, 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 shortand 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 al; the other two articles are limited to those patients with metastatic (but not MYCN amplified) disease (George et al and Schmidt et al). 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 al deals with the outcome of treatment of 43 patients with stage 4 nonamplified MYCN disease in patients 12 to 24 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 27 SEPTEMBER 2