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.

Risk stratification of high‐risk metastatic neuroblastoma: A report from the HR‐NBL‐1/SIOPEN study

“…MNA was determined by FISH, array comparative genomic hybridisation or multiplex ligation‐dependent probe amplification . Marrow involvement was based on morphology and/or immunostaining of bilateral aspirates and trephines, and bone involvement was based on 123 I‐mIBG scintigraphy or 99 Tc bone scan for mIBG non‐avid tumours. These investigations were mandatory for all patients.…”

“…The presence of tumour segmental chromosomal abnormalities (SCA) and pattern of metaiodobenzylguanidine (mIBG) uptake (particularly in patients with MNA tumours) also have prognostic impact. The extent of mIBG‐avid disease (assessed using semi‐quantitative scoring) at diagnosis and after induction chemotherapy correlates with outcome . Finally, molecular quantification of neuroblastoma mRNAs in blood or bone marrow (BM) samples at diagnosis also appears prognostic in HR‐NBL patients .…”

“…The extent of mIBG-avid disease (assessed using semi-quantitative scoring) at diagnosis and after induction chemotherapy correlates with outcome. 8,9 Finally, molecular quantification of neuroblastoma mRNAs in blood or bone marrow (BM) samples at diagnosis also appears prognostic in HR-NBL patients. 10 Despite their promising value in prognostication, the independent value of these various factors has not yet been determined in a combined multi-variable analysis.…”

The challenge of defining “ultra‐high‐risk” neuroblastoma

“…This latter approach has been successfully adopted for the treatment of other malignancies, most notably in childhood acute lymphoblastic leukemia (ALL) by assessing MRD at the end of induction . It remains unclear whether our understanding of NBL biology will ultimately improve to the point that a deterministic approach at diagnosis alone will be possible, or whether outcome at a later time—such as response based on the International Neuroblastoma Response Criteria (INRC), Curie/SIOPEN score, or RT‐PCR—will remain of additional prognostic importance. Ultimately, if it were possible to prospectively identify at diagnosis a group with very poor survival, it might be argued that these patients should no longer be treated with current, highly toxic therapies with little or no chance of long‐term benefit.…”

“…Assessment of the extent of disease at diagnosis and following induction chemotherapy is also of prognostic importance in HR‐NBL. Semiquantitative evaluation of mIBG (meta‐iodobenzylguanadine) scintigraphy, such as Curie and SIOPEN scores, is useful for response evaluation and prognostication . Quantification of tumor‐derived mRNA in blood and bone marrow at diagnosis (and during therapy) has been shown to correlate with outcome in patients with HR‐NBL .…”