Poster Presentation Advances in Neuroblastoma Research Congress 2016

Prognostic Factors in stage 4 neuroblastoma patients treated with Busulphan-Melphalan. Report from the European High Risk Neuroblastoma HR-NBL1/SIOPEN Trial. (#324)

Ruth Ladenstein 1 , Ulrike Poetschger 2 , Martin Elliott 3 , Roberto Luksch 4 , Victoriai Castel 5 , Isaac Yaniv 6 , Vassilios Papadakis 7 , Geneviève Laureys 8 , Josef Malis 9 , Walentyna Balwierz 10 , Ellen Ruud 11 , Henrik Schroeder 12 , Ana Forjaz de Lacerda 13 , Maja Beck-Popovic 14 , Pavel Bician 15 , Miklos Garami 16 , Per Kogner 17 , TobyTo Trahair 18 , Peter Ambros 19 , Keith Holmes 20 , Guenter Schreier 21 , Mark Gaze 22 , AndyAndrew Pearson 23 , DominDomonique Valteau-Couanet 24
  1. St. Anna Kinderkrebsforschung e.V. and St. Anna Kinderspital, Vienna, Austria
  2. St. Anna Kinderkrebsforschung e.V., Vienna, Austria
  3. Leeds Teaching Hospitals NHS Trust, Leeds , UK
  4. Istituto Nazionale Tumori di Milano, Milan, Italy
  5. Hospital La Fe, Valencia, Spain
  6. Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  7. Agia Sofia Children's Hospital, Athens, Greece
  8. University Hospital Gent, Gent, Belgium
  9. University Hospital Motol, Prague, Czech Republic
  10. Jagiellonia University Medical College, Krakow, Poland
  11. Rikshospitalet, Oslo, Norway
  12. Hospital of Aarhus, Skejby, Denmark
  13. Portuguese Institute of Oncology, Lisboa, Portugal
  14. University Hospital Lausanne , Lausanne, Switzerland
  15. University Children's Hospital, Banska Bystrica, Slovakia
  16. Semmelweis University Budapest, Budapest, Hungary
  17. Karolinska Institutet, Stockholm
  18. Sydney Children's Hospital, Randwick, Australia
  19. St. Anna Kinderkrebsforschung e.V., Vienna, Austria
  20. St George Hospital, London, UK
  21. AIT Austrian Institute of Technology, Graz, Austria
  22. University College London, London, UK
  23. Institute of Cancer Research , Sutton, UK
  24. Institut Gustav Roussy, Villejuif, France

Aim: Evaluation of prognostic factors in high risk stage 4 neuroblastoma(HRNBL) patients(pts) treated with busulfan-melphalan(BUMEL) within HR-NBL1/SIOPEN.


Methods: Between 2002-2009 (prior antiGD2 immunotherapy) BUMEL was given to 475pts(275males) in 149 centres/20 countries. Pts<1year(yr) had MYCN amplification(MNA). After induction (COJEC ± 2-4 TVD, ) BUMEL/SCR was given once pts achieved at least PR. Local control aimed at gross surgical resection (achieved in 76%) and for radiotherapy (21Gy) to the primary tumour site. Maintenance was 13cis retinoid acid only. The median age at diagnosis was 3yrs (1month-19yrs). The median observation time is 7.4yrs. Outcomes are reported as 5-yrs EFS rates.

Results: EFS was 0.64±0.12 for age<1yr (17pts), 0.62±0.08 for 1-1.5yrs (42pts), 0.40±0.03 for 1.5-5yrs (317pts) and 0.20±0.04 for pts>5yrs (99pts)(p=0.0001). EFS was better with BUMEL/SCR given ≤240days (421pts) after diagnosis (0.41±0.02) than for 54pts taking longer (0.16±0.05;p<0.0001). Outcome was not different in 221pts randomised for BUMEL (221/475). Pts with TVD have a significantly different EFS (0.41±0.03(214pts) vs.106pts+TVD:0.30±0.05) (p=0.026). CR-pts prior to BUMEL (172pts; 36pts+TVD) had an EFS of 0.45±0.04, whilst EFS was 0.38±0.04 for VGPR-pts (165pts; 36pts+TVD) and 0.31 ±0.04 for PR-pts (138 pts; 34pts+TVD) (p=0.004). Earlier CR of pts without TVD appears superior (0.48±0.04 vs. 0.33±0.08 for CR after TVD(NS). EFS in PR-pts prior BUMEL with ≤3 mIBG avid skeletal spots was better (0.38±0.05) than with more spots (0.13±0.06; p=0.014). Also involvement of only one metastatic compartment results in significantly better EFS (0.50±0.07 vs. 0.37±0.02 for multiple compartments, p=0.037). Severe toxicity rate was 7% (ICU, toxic deaths), the VOD rate 24% (grade 3:4%).

Conclusion: Multivariable analysis (stage 4 patients >1yr and BUMEL ≤240days) reveals as independent unfavourable prognostic factors: age group 5-10yrs (Hazard-Ratio 2.77, p<0.0001), age group 1.5-5yrs (Hazard-Ratio 1.73;p=0.043) and PR prior BUMEL (HR=1.46;p= 0.008). These findings enable guidance to future altered phase II approaches.