The Hidden Legacy: A Systematic Review and Meta-analysis of Second Primary Cancers in Retinoblastoma Survivors
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Abstract
Background: Retinoblastoma (RB) is the most common intraocular malignancy of childhood, with an excellent primary cure rate. However, survivors-particularly those with hereditary forms-face a heightened lifetime risk of second primary malignancies (SPMs). Aim and Objective: This meta-analysis and systematic review aimed to answer a key and understudied question: “What proportion of population developed SPM after RB and how much do heritable genetic signatures and treatment exposures quantitatively impact second malignancy risk in RB survivors?” Methods: A systematic search of databases and grey literature was conducted to identify studies reporting SPM outcomes in RB patients. Eligible studies were cohort or population-based designs involving heritable or non-heritable RB, reporting numerical outcomes or SIRs. Meta-analysis was performed on studies with compatible effect sizes. Statistical tests such as Cox regression, Mann-Whitney U, Kruskal-Wallis, Fisher's exact test, and logistic regression were calculated or extracted for relevant associations. Results: Ten studies met inclusion criteria, with four eligible for meta-analysis. The pooled mean proportion of SPMs was 7.5%. The standardized incidence ratio (SIR) for heritable RB patients was 17.55 (95% CI: 13.10–23.51). Radiation therapy increased the risk of SPM by 3-5 times, and RB1 mutation severity significantly correlated with higher SPM incidence (Mann-Whitney U = 56.0, p = 0.0045; Fisher's OR = 49.0, p = 0.0101). Cox regression showed a 5-fold increased hazard of SPM in hereditary RB (p < 0.00001). The pooled estimate for the mean proportion of SPM population post RB was 0.07(95%CI: -0.05, 0.19). Conclusion: Second primary malignancies are a significant long-term risk in retinoblastoma survivors, especially those with heritable forms and prior radiation therapy by considering the mean proportion of SPM population after RB and arriving at a pooled meta-analytical estimate. Severe RB1 mutations further elevated this risk. Molecular stratification, minimization of radiation exposure, and adoption of long-term follow-up must be incorporated as a future protocol.
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Copyright (c) 2025 Anitha L, Abhishek Babu, Thirumagal Vaishnavi, Sruthi Swaminathan, Jamila Hameed
This work is licensed under a Creative Commons Attribution 4.0 International License.
Creative Commons License All articles published in Annals of Medicine and Medical Sciences are licensed under a Creative Commons Attribution 4.0 International License.
Anitha L, Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Abhishek Babu, Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Thirumagal Vaishnavi, Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Sruthi Swaminathan, Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Jamila Hameed, Department of Ophthalmology, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
Emiratus Professor, Research Mentor, Karuna Medical College, Vilayodi, Chittur, Palakkad, Kerala, 678103, India.
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