Implications of MYCN amplification in patients with stage 4 neuroblastoma who undergo intensive chemotherapy.
OBJECTIVE
This study aims to clarify the implications of MYCN amplification in patients with high-risk neuroblastomas treated with 2 different regimens of induction chemotherapy established by the Japan Study Group for Advanced Neuroblastoma.


METHODS
Between 1985 and 2003 in Japan, 392 patients with stage 4 neuroblastomas who were older than 12 months were treated with 2 regimens of induction chemotherapy (the combination of cyclophosphamide [CTX], cisplatin [CDDP], pirarubicin, and vincristine or etoposide). Regimen 91A3 or 98A3 (A3) (CTX 2400 mg/m2, CDDP 125 mg/m2) was a higher dose combination of CTX and CDDP than regimen 85A1 or 91A1 (A1) (CTX 1200 mg/m2, CDDP 90 mg/m2). The 392 cases were classified into 3 groups (A, 1 copy; B, 2-9 copies; C, more than 10 copies) based on the MYCN amplification status by a Southern blot analysis.


RESULTS
The 5-year overall survival rate (5-YS) was 41.1% for all 392 cases. Regarding the MYCN amplification status, the 5-YS was 46.6% for A group (n = 227), 22.7% for B group (n = 26), and 36.0% for C group (n = 139). A fluorescence in situ hybridization analysis showed the presence of the cells with more than 10 copies in cases with 2 to 9 copies based on the Southern blot findings. Of the 227 patients in a group, the 5-YS was 46.7% for the 70 cases treated by A3 and 47.0% for 154 cases treated by A1 (nonsignificant). The 5-YS of the 210 patients with stem cell transplantation (SCT) (51.%) was significantly better than that of the 127 patients without SCT (41.1%) (P < .05).


CONCLUSIONS
Regarding the MYCN amplification status, the tumor aggressiveness might thus be different between 2 and 9 copies and a single copy of MYCN. In neuroblastomas with 2 and 9 copies of MYCN based on a Southern blot analysis, the MYCN amplification status should be analyzed using the fluorescence in situ hybridization method. Induction chemotherapy followed by SCT according to the Japan Study Group for Advanced Neuroblastoma protocol improved the outcome of neuroblastomas with MYCN amplification; however, obtaining a further improvement in the long-term survival of stage 4 neuroblastomas may therefore require the development of an even more effective treatment modality.
Suita
Sachiyo
S
Department of Pediatric Surgery, Kyushu University, Fukuoka 812-8582, Japan. suita@pedsurg.med.kyushu-u.ac.jp
Tajiri
Tatsuro
T
Kaneko
Michio
M
Hirai
Misako
M
Mugishima
Hideo
H
Sugimoto
Toru
T
Tsuchida
Yoshiaki
Y
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D005784:Gene Amplification; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D020360:Neoadjuvant Therapy; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D033581:Stem Cell Transplantation; D016019:Survival Analysis
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins