Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

Abstract

Background: Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations.

Results: The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0-6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response.

Conclusions: Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.

Keywords: High-risk neuroblastoma; MIBG; SIOPEN score.

Annex 1: Consort Diagram

a) Comparison of event-free survival (EFS) of patients on the SIOPEN trial and in the analysis mIBG review data set.

b) Comparison of event-free survival (EFS) of patients on the COG A3973 trial and in the analysis mIBG review data set.

Fig. 1

Definition of scores for the extension of the skeletal involvement with illustrative planar I-123-mIBG scans (arrows) of the various positive scores (left). The mIBG uptake over 12 body segments (right) is scored from 0 to 6 points per segment depending on the disease extension [13]

Fig.2

Schematic overview of therapy on SIOPEN/HR-NBL-1 and COG A3973. Rapid COJEC [cycles given every 10 days; cycles 1 and 5: Vincristine, Carboplatin, Etoposide; cycles 2, 4, 6, and 8: Vincristine, Cisplatin; cycles 3 and 7: Vincristine, Etoposide, Cyclophosphamide]; Optional: TVD [cycles repeat every 3 weeks; Topotecan, Vincristine, Doxorubicin]; Modified N7 [cycles repeat every 3 weeks; cycles 1, 2, 4, and 6: cyclophosphamide, doxorubicin, vincristine; cycles 3 and 5: cisplatin and etoposide] mIBG scan; HDT: high dose therapy [BuMel: Busulfan-Melphalan; CEM: Carboplatin-Etoposide-Melphalan]; XRT, radiotherapy

Fig. 3

Event-free survival (EFS) by SIOPEN at diagnosis (mIBG1). a Histogram of pre-induction mIBG score values at diagnosis; b Relationship between the hazards of an event (logHR) and the baseline score using restricted cubic splines (solid line estimated relationship; dotted line 95% confidence intervals); c EFS according tertiles of the maximum score at diagnosis for SIOPEN/HRNBL1 (events/ patients for score 0–23: 76/131; score 24–48: 95/126; score > 48: 66/84) and COG–A3973 (events/ patients for: score 0–23: 51/92; score 24–48: 48/74; score > 48: 39/50). d EFS with a threshold of ≤3 mIBG positive skeletal spots at diagnosis for SIOPEN/HRNBL1 (events/patients for: score 0–3: 26/52; score > 3: 211/289) and COG–A3973 (events/patients for score 0–3:26/49; score > 3: 112/ 167)

Fig. 4

Event-free survival (EFS) by SIOPEN post-induction (mIBG2). a Histogram of pre-induction mIBG score values at diagnosis; b Relationship between the hazards of an event (logHR) and the baseline score using restricted cubic splines (solid line estimated relationship; dotted line 95% confidence intervals); c EFS according to tertiles of the maximum score at diagnosis for post-induction scores of SIOPEN/HRNBL1 (events/patients for: score 0–23: 177/259; score 24–48: 34/41; score > 48: 6/ 7 and COG–A3973 (events/patients for score 0–23: 74/122; score 24–48: 15/16; score > 48: 2/2). d EFS with a threshold of ≤3 mIBG positive skeletal spots for SIOPEN/HRNBL1 (events/patients for score 0–3: 116/185; score>3: 101/122) and for COG–A3973 (events/patients for score 0–3: 59/102; score > 3: 32/38)

Fig. 5

Event-free survival (EFS) by post-induction mIBG response. a: EFS of patients mIBG skeletal positive at diagnosis; post-induction score 0 vs. >0 for SIOPEN/HR-NBL-1 and COG A3973 trial cohorts. b: EFS of patients mIBG skeletal positive at diagnosis with scores >0 post-induction according to the percent change in SIOPEN mIBG score from diagnosis to post-induction mIBG scans