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.