title: Results of induction chemotherapy in children older than 18 months with stage-4 neuroblastoma treated with an adaptive-to-response modified N7 protocol (mN7).
abstract: OBJECTIVE
  We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol.
  
  
  METHODS
  From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs.
  
  
  RESULTS
  After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, (123)I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival.
  
  
  CONCLUSIONS
  mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival.
authors.affiliation: Department of Oncology, Hospital Sant Joan de Déu, Barcelona, Passeig Sant Joan de Déu, 2, Esplugues de Llobregat, 08950, Barcelona, Spain, Jmora@hsjdbcn.org.
authors.forename: J
authors.initials: J
authors.lastname: Mora
authors.forename: O
authors.initials: O
authors.lastname: Cruz
authors.forename: C
authors.initials: C
authors.lastname: Lavarino
authors.forename: J
authors.initials: J
authors.lastname: Rios
authors.forename: M
authors.initials: M
authors.lastname: Vancells
authors.forename: A
authors.initials: A
authors.lastname: Parareda
authors.forename: H
authors.initials: H
authors.lastname: Salvador
authors.forename: M
authors.initials: M
authors.lastname: Suñol
authors.forename: R
authors.initials: R
authors.lastname: Carrasco
authors.forename: A
authors.initials: A
authors.lastname: Guillen
authors.forename: S
authors.initials: S
authors.lastname: Mañé
authors.forename: C
authors.initials: C
authors.lastname: de Torres
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001853:Bone Marrow / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D016190:Carboplatin / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D015331:Cohort Studies; D060830:Consolidation Chemotherapy / Q000379:methods*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007167:Immunotherapy; D060828:Induction Chemotherapy / Q000379:methods*; D007223:Infant; D015474:Isotretinoin / Q000008:administration & dosage; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D019635:Neurosurgical Procedures; D010865:Pilot Projects; D011446:Prospective Studies; D011878:Radiotherapy; D013852:Thiotepa / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D014750:Vincristine; D005047:Etoposide; D019772:Topotecan; D004317:Doxorubicin; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin; D015474:Isotretinoin; D002945:Cisplatin