Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma

John Thomas Lucas Jr; Daniel Victor Wakefield; Michael Doubrovin; Yimei Li; Teresa Santiago; Sara Michele Federico; Thomas E Merchant; Andrew M Davidoff; Matthew J Krasin; Barry L Shulkin; Victor M Santana; Wayne Lee Furman

doi:10.1016/j.ctro.2022.02.009

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma

Clin Transl Radiat Oncol. 2022 Mar 10:34:42-50. doi: 10.1016/j.ctro.2022.02.009. eCollection 2022 May.

Authors

Affiliations

¹ Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.
² Department of Radiation Oncology, University of Tennessee Health Science Center, Memphis, TN, United States.
³ Harvard T.H. Chan School of Public Health, Boston, MA, United States.
⁴ Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, United States.
⁵ Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁶ Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁷ Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁸ Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, United States.

Abstract

Purpose: This retrospective study sought to identify predictors of metastatic site failure (MSF) at new and/or original (present at diagnosis) sites in high-risk neuroblastoma patients.

Methods and materials: Seventy-six high-risk neuroblastoma patients treated on four institutional prospective trials from 1997 to 2014 with induction chemotherapy, surgery, myeloablative chemotherapy, stem-cell rescue, and were eligible for consolidative primary and metastatic site (MS) radiotherapy were eligible for study inclusion. Computed-tomography and I-123 MIBG scans were used to assess disease response and Curie scores at diagnosis, post-induction, post-transplant, and treatment failure. Outcomes were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) and CPH regression (CPHr) were used to identify covariates predictive of MSF at a site identified either at diagnosis or later.

Results: MSF occurred in 42 patients (55%). Consolidative MS RT was applied to 30 MSs in 10 patients. Original-MSF occurred in 146 of 383 (38%) non-irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post-induction MIBG-avid MSs in 68 of 81 (84%) non-irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6-Not Reached) and 24.1 months (95% CI 16.5-38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7-16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7-11.1, p = 0.002) as predictors of new MSF. The new MSF-free survival rate at 3 years was 25% and 87% in patients with and without high-risk factors.

Conclusions: Incremental improvements in systemic therapy influence the patterns and type of metastatic site failure in neuroblastoma. Persistence of MIBG-avidity following induction chemotherapy and transplant at MSs increased the hazard for MSF.

Keywords: ALK, anaplastic lymphomakinase; BuMel, Busulfan-Melphalan; CBCT, Cone Beam Computed Tomography; CCG, Children's Cancer Group; CI, Confidence interval; CNS, Central Nervous System; COG, Children's Oncology Group; CPHr, Cox proportional hazards regression; CT, Computed Tomography; Cor, Correlation; GD2, Disialoganglioside; HR, Hazard Ratio; IMRT, Intensity Modulated Radiotherapy; LDH, lactate dehydrogenase; MEC, Melphalan-Etoposide-Carboplatin; MIBG, meta-iodobenzylguanidine; MR, Magnetic Resonance Imaging; MS, Metastatic Sites; MSF, Metastatic Site Failure; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog, MYCN proto-oncogene; Maint, Maintenance; Met, Metastasis; SIOP, International Society of Pediatric Oncology; SIOPEN, European SIOP Neuroblastoma Group; cphfR, Cox proportional hazards frailty regression.