Purpose: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB).Design: International, multicenter, registry-based retrospective case series.Participants: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.Methods: Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied.Main Outcome Measures: Metastasis-related 5-and 10-year survival data after initial tumor staging were estimated with the KaplaneMeier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait.Results: Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n ¼ 92) from diagnosis to metastasis was 9.50 months. The 5-year KaplaneMeier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97e99) for cT1b and cT2a, 96% (95% CI, 95e97) for cT2b, 89% (95% CI, 88e90) for cT3 tumors, and 45% (95% CI, 31e59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55e25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86e183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease.Conclusions: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.

Purpose: To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB).Design: International, multicenter, registry-based retrospective case series.Participants: A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.Methods: International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included.Main Outcome Measures: Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC).Results: Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2-and 5-year KaplaneMeier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of local treatment failure in categories cT1b (hazard ratio [HR], 3.5; P ¼ 0.004), cT2a (HR, 15.1; P < 0.001), cT2b (HR, 16.4; P < 0.001), and cT3 (HR, 45.0; P < 0.001) compared with category cT1a. Use of plaque brachytherapy and IAC improved local tumor control in categories cT1a (P ¼ 0.031) and cT1b (P < 0.001).Conclusions: Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB.

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AimTo investigate whether the American Joint Committee on Cancer (AJCC) clinical category cT2b needs to be subclassified by the type and distribution of retinoblastoma (RB) seeding.MethodsMulticentre, international registry-based data were collected from RB centres enrolled between January 2001 and December 2013. 1054 RB eyes with vitreous or subretinal seeds from 18 ophthalmic oncology centres, in 13 countries within six continents were analysed. Local treatment failure was defined as the use of secondary enucleation or external beam radiation therapy (EBRT) and was estimated with the Kaplan-Meier method.ResultsClinical category cT2b included 1054 eyes. Median age at presentation was 16.0 months. Of these, 428 (40.6%) eyes were salvaged, and 430 (40.8%) were treated with primary and 196 (18.6%) with secondary enucleation. Of the 592 eyes that had complete data for globe salvage analysis, the distribution of seeds was focal in 143 (24.2%) and diffuse in 449 (75.8%). The 5-year Kaplan-Meier cumulative globe-salvage (without EBRT) was 78% and 49% for eyes with focal and diffuse RB seeding, respectively. Cox proportional hazards regression analysis confirmed a higher local treatment failure risk with diffuse seeds as compared with focal seeds (hazard rate: 2.8; p<0.001). There was insufficient evidence to prove or disprove an association between vitreous seed type and local treatment failure risk(p=0.06).ConclusionThis international, multicentre, registry-based analysis of RB eyes affirmed that eyes with diffuse intraocular distribution of RB seeds at diagnosis had a higher risk of local treatment failure when compared with focal seeds. Subclassification of AJCC RB category cT2b into focal vs diffuse seeds will improve prognostication for eye salvage.