• Ocular Pathology/Oncology

    Improved treatment plans for retinoblastoma (RB) could be established with knowledge of which specific clinical features indicate high risk of metastasis. In this study, researchers compared patient outcomes with clinical features and treatment modalities to understand the varying risks of metastatic mortality.

    Study design

    In an international, multicenter, registry-based retrospective study, 18 RB centers from 13 countries enrolled 1841 patients with advanced intraocular RB of categories cT2 and cT3, as defined by the 8th edition AJCC, with high-risk clinical features of advanced RB stratified into cT2 and cT3 subcategories. Of these patients, 1416 were also included in an analysis according to the new AJCC-Ophthalmic Oncology Task Force (AJCC-OOTF) Size Groups: (1) <50% of globe volume, (2) >50% but <2/3, (3) >2/3, and (4) diffuse infiltrating RB. Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage. The main outcome measure was metastatic death.

    Outcomes

    According to patient-level AJCC clinical subcategories of advanced RB, the 5-year Kaplan-Meier cumulative survival estimates were 98% for cT2a (subretinal fluid), 96% for cT2b (RB seeds), 88% for cT3a (phthisis), 95% for cT3b (anterior chamber involvement), 92% for cT3c (glaucoma), 84% for cT3d (intraocular hemorrhage), and 75% for cT3e (orbital cellulitis). Risk of metastatic mortality increased with increasing cT subcategory. Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c, cT3d, and cT3e with hazard ratios of 4.9, 14.0, and 19.6, respectively. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. The risk of metastatic mortality increased as the treatment shifted from primary enucleation of advanced RB to systemic chemotherapy with or without eye salvage. Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality with systemic chemotherapy with secondary enucleation (hazard ratio (HR) 3.3) and eye salvage (HR 4.9) compared to primary enucleation. The 5-year Kaplan-Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing size group. Demonstrating greater risk of metastatic mortality than Size Group 1, HR was 10.0 and 41.1 in Size Groups 3 and 4, respectively. Advanced age at presentation also conferred a worse prognosis for metastatic disease.

    Limitations

    The limitations of this study include those inherent in retrospective study designs. With multicenter designs, data are impacted by the lack of consensus on diagnosis, documentation, and treatment. For this study, specifically, the researchers lacked data regarding pars plana and ciliary body involvement, did not assess the risk of metastatic death following treatment of recurrent or refractory tumors, and there was a dearth of patients treated by intra-arterial chemotherapy.

    Clinical significance

    As a multicenter, global, registry-based analysis using a uniform staging system, the study included extensive data that are required to resolve debates. The results represent evidence that the AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 and 4 provide a robust stratification of clinical risk for metastatic death, advanced age at presentation correlates with a worse prognosis, and primary enucleation offers the highest survival rates for patients with advanced intraocular RB.