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

• Published in: Clinical and translational radiation oncology Vol. 34; pp. 42 - 50
• Main Authors: Lucas, John Thomas, Wakefield, Daniel Victor, Doubrovin, Michael, Li, Yimei, Santiago, Teresa, Federico, Sara Michele, Merchant, Thomas E., Davidoff, Andrew M., Krasin, Matthew J., Shulkin, Barry L., Santana, Victor M., Lee Furman, Wayne
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.05.2022; Elsevier
• Subjects: Original; ALK; IMRT; MIBG; CPHr; CNS; HR; CBCT; LDH; SIOP; Maint; COG; cphfR; MSF; MR; CCG; CI; MS; Cor; MEC; SIOPEN; CT; MYCN; GD2; BuMel; Met; SIOP, International Society of Pediatric Oncology; ALK, anaplastic lymphomakinase; COG, Children's Oncology Group; cphfR, Cox proportional hazards frailty regression; CNS, Central Nervous System; Maint, Maintenance; MIBG, meta-iodobenzylguanidine; CI, Confidence interval; BuMel, Busulfan-Melphalan; HR, Hazard Ratio; IMRT, Intensity Modulated Radiotherapy; MSF, Metastatic Site Failure; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog, MYCN proto-oncogene; SIOPEN, European SIOP Neuroblastoma Group; CPHr, Cox proportional hazards regression; Cor, Correlation; LDH, lactate dehydrogenase; MS, Metastatic Sites; CCG, Children's Cancer Group; GD2, Disialoganglioside; MR, Magnetic Resonance Imaging; CT, Computed Tomography; Met, Metastasis; MEC, Melphalan-Etoposide-Carboplatin; CBCT, Cone Beam Computed Tomography
• ISSN: 2405-6308; 2405-6308
• DOI: 10.1016/j.ctro.2022.02.009

•We observed an increased hazard for failure at metastatic sites which remain persistently avid on MIBG following systemic therapy.•-Limited response to induction therapy described by Curie and SIOPEN score selects patients at greater risk for poly-metastatic site failure.•-The low proportion of metastatic sites treated with radiotherapy precluded definitive testing of its impact on the hazard for metastatic site failure.•-Patients who are unable to undergo transplant, and/or have extensive disease at diagnosis (lung metastases) may be poor candidates for consolidative metastatic site directed radiotherapy given the high competing risk of failure at a new metastatic site. 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. 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 I­123 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. 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%) non­irradiated and 18 of 30 (60%) irradiated MSs (p = 0.018). Original- MSF occurred in post­induction MIBG-avid MSs in 68 of 81 (84%) non­irradiated and 12 of 14 (85%) radiated MSs (p = 0.867). The median overall and progression-free survival rates were 61 months (95% CI 42.6­Not Reached) and 24.1 months (95% CI 16.5­38.7), respectively. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3­96.8, p < 0.001) and/or maintenance chemotherapy (HR 5.2, 95%CI 1.7­16.2, p = 0.005), and the presence of lung metastases at diagnosis (HR 4.4 95%CI 1.7­11.1, 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. 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.