title: Intensified chemotherapy increases the survival rates in patients with stage 4 neuroblastoma with MYCN amplification.
abstract: OBJECTIVE
  Patients with high-risk neuroblastoma who have multiple copies of MYCN fare much worse than do those without MYCN amplification; however, it has not been clarified whether intensified chemotherapy with or without blood stem cell transplantation can alter the extremely poor prognosis of patients with amplified MYCN.
  
  
  RESULTS
  Between 1985 and 1999, 301 patients older than age 12 months with stage 4 neuroblastoma were treated. From January 1985 to February 1991, 80 patients with stage 4 neuroblastoma with and without MYCN amplification uniformly received induction chemotherapy with regimen A(1) (cyclophosphamide 1,200 mg/m(2) and vincristine 1.5 mg/m(2) on day 1, tetra-hydropyranyl [THP]-Adriamycin 40 mg/m(2) on day 3, and cisplatin 90 mg/m(2) on day 5). Among 22 patients with MYCN amplification, nine (40.9%) achieved a complete remission and seven (31.8%) underwent stem cell transplantation. Of 58 patients without MYCN amplification, 43 (74.1%) achieved a complete remission and 14 (24.1%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 23.2% for stage 4 patients with MYCN amplification and 33.3% for those without MYCN amplification (P = 0.029); the 5-year overall survival rates were 32.8% for stage 4 patients with MYCN amplification and 42.8% for those without MYCN amplification (P > 0.05). From March 1991 to June 1998, patients with stage 4 neuroblastoma who had 10 or more copies of MYCN were treated with regimen A(3) (cyclophosphamide 1,200 mg/m(2) per day on days 1 and 2, THP-Adriamycin 40 mg/m(2) on day 3, etoposide 100 mg/m(2) per day on days 1 to 5, and cisplatin 25 mg/m(2) per day on days 1 to 5); those with fewer than 10 copies of MYCN received regimen new A (cyclophosphamide 1,200 mg/m on day 1, THP-Adriamycin 40 mg/m on day 3, etoposide 100 mg/m per day on days 1 to 5, and cisplatin 90 mg/m on day 5), which is similar in intensity to regimen A. Among 88 patients with MYCN amplification, 63 (71.6%) achieved a complete remission and 63 (71.68%) underwent stem cell transplantation. Of 133 patients without MYCN amplification, 93 (69.9%) achieved a complete remission and 71 (53.4%) underwent stem cell transplantation. The 5-year relapse-free survival rates were 36.0% for stage 4 patients with MYCN amplification and 32.2% for those without MYCN amplification (P > 0.05), the 5-year overall survival rates were 34.0% for stage 4 patients with MYCN amplification and 38.9% for those without MYCN amplification (P > 0.05). The difference in relapse-free survival rates was significantly different (P = 0.003) between patients with MYCN-amplified tumor treated before (regimen A(1)) versus after 1991 (regimen A(3)).
  
  
  CONCLUSIONS
  With the use of the more intensive induction regimen A plus blood stem cell transplantation for MYCN-amplified patients, survival curves for those with or without MYCN amplification now appear similar. Higher doses of chemotherapy may ameliorate the effect of MYCN amplification in patients with high-risk neuroblastoma.
authors.affiliation: Study Group of Japan for Treatment of Advanced Neuroblastoma, and Department of Pediatric Surgery, University of Tsukuba, Tsukuba, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Kaneko
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsuchida
authors.forename: Hideo
authors.initials: H
authors.lastname: Mugishima
authors.forename: Naomi
authors.initials: N
authors.lastname: Ohnuma
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Keisei
authors.initials: K
authors.lastname: Kawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Iwafuchi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sawada
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Suita
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007564:Japan / Q000453:epidemiology; D015993:Life Tables; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction; D015996:Survival Rate; D019172:Transplantation Conditioning; D016896:Treatment Outcome
chemical_list: D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; C027260:pirarubicin; D002945:Cisplatin