GENETIC STAGING OF UNRESECTABLE OR METASTATIC NEUROBLASTOMA IN INFANTS - A PEDIATRIC-ONCOLOGY-GROUP STUDY

Background: Current staging systems for unresectable or metastatic neu roblastoma do not reliably predict responses to chemotherapy in infant s under 1 year of age. Previous studies have indicated that the DNA co ntent, or ploidy, of malignant neuroblasts can discriminate between go od and poor responders in this group of patients, but the clinical uti lity of ploidy assessment has remained in question. Purpose: We tested , in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in inf ants with unresectable or metastatic tumors and could differentiate be tween those who would respond to our previous standard regimen and tho se who would benefit from an immediate switch to another therapy. Meth ods: One hundred seventy-seven infants were enrolled in this trial, Fi ve of these infants were subsequently excluded (two ineligible, two la cking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with h yperdiploid tumors (DNA index >1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamid e (150 mg/m(2) per day orally or intravenously on days 1-7) and doxoru bicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploi d tumors (DNA index =1.0; worse prognosis in retrospective studies) re ceived cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/2 intravenously on day 3) after an initial course of cyclophospham ide plus doxorubicin, Statistical end points were response and long-te rm survival, In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the p rognostic significance of NMYC gene copy number, tumor stage, and othe r variables commonly measured in this disease, Results: Of the 127 ass essable infants with hyperdiploid tumors, 115 (91%) had complete respo nses-85 after receiving five courses of cyclophosphamide plus doxorubi cin and 30 after receiving further therapy including cisplatin plus te niposide. The 3-year survival estimate for the entire hyperdiploid gro up was 94% (95% confidence interval [CI] = 89%-98%), Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders, T he overall 3-year survival estimate for this group was 55% (95% CI = 3 9%-70%), Prognostic factor analysis indicated that NMYC gene amplifica tion and an elevated serum lactate dehydrogenase level were statistica lly significant markers of higher risk disease within the diploid grou p (two-sided P values of .005 and .003, respectively). Only NMYC was p redictive in the hyperdiploid group (P = .003), Conclusion: Use of a p rognostic staging system based on tumor cell ploidy, augmented with th e NMYC gene copy number and serum level of lactate dehydrogenase, woul d very likely improve the treatment of infants with unresectable or me tastatic neuroblastoma, Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk grou p that may benefit from innovative new therapies.