Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children's Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1

Abstract

A semiquantitative ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children's Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of ¹²³I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited ¹²³I-MIBG-avid, International Neuroblastoma Staging System stage 4 neuroblastoma. ¹²³I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0-3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Keywords: Curie score; MIBG; neuroblastoma.

FIGURE 1.

(A) Anatomic regions for CS and SIOPEN score. Body is divided into 9 (CS) or 12 (SIOPEN score) skeletal regions, with CS adding 10th (soft-tissue) region. (B) Example of CS of individual patient: diffuse uptake (CS, 3) is noted in head, cervical-thoracic spine, lumbar-sacral spine, pelvis, proximal arms, proximal lower extremities, distal lower extremities, and chest (CS, 2). There is one ¹²³I-MIBG–avid soft-tissue site, involving < 50% abdomen (CS, 1). Total CS = 25.

FIGURE 2.

CONSORT (consolidated standards of reporting trials) diagram: CS analysis of SIOPEN/HR-NBL1.

FIGURE 3.

Schematic overview of SIOPEN/HR-NBL1 (2) and COG A3973 (22) therapy. Biotherapy = isotretinoin ± anti-GD2 chimeric antibody; BMT = bone marrow transplant; BuMel = busulfan-melphalan; CEM = carboplatin-etoposide-melphalan; XRT = radiotherapy.

FIGURE 4.

Distribution of CSs at (A) diagnosis, and (B) after induction.

FIGURE 5.

EFS by CS at diagnosis, using optimal cut point of 12: time to event starting from date of corresponding ¹²³I-MIBG scan.

FIGURE 6.

EFS by postinduction CS, using optimal cut point of 2: time to event starting from date of corresponding ¹²³I-MIBG scan.