N-MYC GENE AMPLIFICATION IS A MAJOR PROGNOSTIC FACTOR IN LOCALIZED NEUROBLASTOMA - RESULTS OF THE FRENCH NBL 90 STUDY

Purpose: To assess the relevance of N-Myc gene amplification (NMA) as a prognostic factor in localized neuroblastoma (NB) and to evaluate wh ether less intensive adjuvant treatment is advisable in infants withou t NMA. Patients and Methods: Assessment of NBs included clinical and i maging data to allow tumor-node-metastasis (TNM) staging, biologic det erminations (N-Myc gene analysis), and standard histology and work-up to eliminate metastatic spread (metaiodobenzylguanidine [MIBG] scintig raphy and extensive bone marrow staging). Resectability was defined ac cording to imaging findings. Chemotherapy wets indicated in children o lder than 1 year at diagnosis who had postoperative residual disease o r lymph node (LN) involvement, in infants with NMA, or as primary trea tment in children with an unresectable NB, including dumbbell tumors. Radiotherapy was recommended in children older than 1 who presented wi th persistent gross residual disease at the end of therapy. Results: B etween 1990 and 1994, 316 consecutive children who presented with a lo calized NE were registered in the NBL 90 study. The median age was 12 months, and 42 patients had dumbbell tumors (13%). NMA was found in 22 of 225 assessable children (10%) and correlated with adverse prognost ic indicators such as age older than 1 year, an abdominal primary tumo r, a large tumor (T3), and unresectability. Among 186 children who had primary excision, five died of surgery-related complications. Primary chemotherapy was given to 130 patients, which allowed removal of the tumor in all but four. The 5-year overall survival (OS) and event-free survival (EFS) rates were, respectively, 91% and 84% with a median fo llow-up time of 36 months. The outcome of infants and older children w as similar (P = .2). EFS of patients with resectable tumors wets sligh tly better than with unresectable primary tumors (EFS, 89% v 78%; P = .02). In dumbbell NBs, neurologic recovery was achieved in 74% of case s that presented with symptoms, and initial laminectomy was avoided in 75% of children. In a univariate analysis, large rumors, high neuron- specific enolase (NSE) and lactate dehydrogenase (LDH) levels, positiv e LNs, macroscopic residue, and NMA adversely influenced outcome. In t he multivariate analysis, NMA was the most powerful unfavorable predic tive indicator: OS and EFS rates for these children were 36% and 32%, compared with 98% and 90% in nonamplified tumors (P < .001). Conclusio n: Our data confirm the overall good prognosis of localized NBs, even when unresectable. NMA is the most relevant adverse prognostic factor in localized NBs, and more intensive treatment should be investigated in these patients. Prospective studies of other biologic factors are w arranted to tailor therapy more accurately. The EFS of children who un derwent primary surgery was excellent, and further justifies eliminati on of adjuvant treatment provided they have no NMA. Despite the elimin ation of postoperative therapy, infants with non-NMA tumors have an ex cellent outcome, which suggests that initial chemotherapy can be furth er reduced in case of unresectable NBs. (C) 1997 by Americon Sociefy o f Clinical Oncology.