Second malignant neoplasms after neuroblastoma treatment: a single center experience

Treatment intensification in patients with intermediateand high-risk neuroblastoma (NB) has led to improved survival rates. However, NB survivors face a high risk of long-term side effects associated with intensified therapy, with second malignant neoplasms (SMN) being the most serious and occurring in 1.2% of cases. Our study included 176 cancer survivors who had been treated for intermediateand high-risk NB at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. Specific treatment was carried out according to the modified GPOH NB-2004 protocol from January 2012 to December 2019. High-dose preparative chemotherapy regimens included carboplatin/etoposide/melphalan (CEM) (until June 2013) and treosulfan/melphalan (TreoMel) (from July 2013). Starting from July 2014, high-risk NB patients with metabolically active residual tumors received 131I-metaiodobenzylguanidine (131I-MIBG) therapy after induction chemotherapy. Thirty-six (20%) patients enrolled in our study developed disease relapse. Treatment for relapsed NB depended on the initial risk group, the extent of previous therapy and the type of relapse. The median follow-up time from the date of diagnosis of NB to the date of last follow-up for the patients included in the study was 76 months (range 37–152 months). The final analysis was performed on 31 December 2023. All the patients diagnosed with a second malignancy underwent molecular genetic testing for germline and somatic gene variants at the Laboratory of Molecular Biology and the Laboratory of Molecular Oncology of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. High-throughput sequencing of DNA isolated from tumor tissues was used for the detection of somatic variants (Genetic Characteristics of Pediatric Solid Tumors panel (Pediatric Oncopanel v.4.2)) and whole-genome sequencing of DNA isolated from the patients’ peripheral blood was utilized for the detection of germline mutations in genes associated with tumor predisposition syndromes. Three (1.7%) out of 176 patients developed SMNs: papillary thyroid carcinoma (n = 2) and secondary acute myeloid leukemia (n = 1). At the diagnosis of NB, they had been aged 39, 52, and 55 months. Two of them had been initially stratified to the high-risk group, and one case had been allocated to the intermediate-risk group (and subsequently developed a combined relapse). The two patients from the high-risk group received high-dose chemotherapy as a part of frontline treatment, while the patient with intermediate-risk NB was given high-dose chemotherapy at the time of relapse. 131I-MIBG-therapy as a component of frontline therapy and cranial radiotherapy at relapse were performed in one case. The time from the date of NB diagnosis to the development of second malignancy was 66.5, 76.5, and 56.6 months. The cumulative incidence of SMN in the patients diagnosed with intermediateand high-risk NB after 5, 6, and 7 years was 0.73% (95% confidence interval (CI) 0.01–5.07), 1.64% (95% CI 0.41–6.44), and 2.75% (95% CI 0.88–8.42), respectively. Our molecular genetic analysis revealed the presence of somatic genetic variants in the tumor tissue samples, however, no germline mutations were found in the regions of interest. Second malignancies are rare but serious complications of NB treatment. It is important to closely follow-up surviving patients after treatment for NB, and a follow-up care program should be based on the extent of the prior treatment.