Risk factors for secondary neoplasms in retinoblastoma survivors: a systematic literature review

Retinoblastoma is the most common intraocular malignancy in children. Although survival has improved with multimodal therapy, survivors remain at risk for subsequent malignant neoplasms (SMNs), often due to prior treatments or genetic predisposition. To identify risk factors associated with SMNs in childhood retinoblastoma survivors.

This systematic review followed PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251026103). A comprehensive search was conducted in PubMed, Embase, and Scopus up to January 2025. Observational studies reporting SMNs risk factors were included. Study selection, data extraction, and quality assessment were independently performed by two reviewers.

Of 1,640 records, five studies met the inclusion criteria. The main risk factors identified were: radiotherapy, especially linked to bone and soft tissue sarcomas; chemotherapy, notably alkylating agents and anthracyclines; germline RB1 mutations and Li-Fraumeni syndrome; bilateral retinoblastoma; and socioeconomic disparities, with increased SMNs incidence in low- and middle-income countries. One study reported a potential protective role of proton therapy.

Radiotherapy, chemotherapy, and genetic predisposition are key risk factors for SMNs in retinoblastoma survivors. Standardized prospective studies are needed to guide prevention strategies and survivor care.

PROSPERO (CRD420251026103).