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Importance: The risk of extraocular extension from injecting chemotherapy into eyes with retinoblastoma is minimally understood; however, understanding this risk is important because of the increasing use of intravitreous chemotherapy., Objective: To evaluate the risk of extraocular extension in eyes with retinoblastoma that have received intravitreous chemotherapy injections., Design, Setting, and Participants: This retrospective cohort study was performed in 655 patients at 10 retinoblastoma centers in North and South American, European, Israeli, and Chinese centers. Physicians at the retinoblastoma centers administered more than 120 intravitreous chemotherapy injections in eyes with retinoblastoma from February 1, 1999, through February 28, 2017., Main Outcomes and Measures: Risk of extraocular extension with secondary observational variables, including injection and precautionary techniques., Results: A total of 3553 intravitreous chemotherapy injections (3201 melphalan hydrochloride, 335 topotecan hydrochloride, and 17 methotrexate sodium) were administered to 704 eyes in 655 patients with retinoblastoma (mean [SD] age of patients at the time of the initial injections, 31.6 [11.6] months; 348 male [53.1%]). There were no extraocular tumor events related to prior intravitreous injections. This finding resulted in a calculated proportion of zero extraocular events per eye. According to the rule of 3, the risk is no greater than 0.08% injections. All 10 centers included in this study used at least 2 presumed precautionary injection methods (lowering of intraocular pressure, cryotherapy, ocular surface irrigation, ultrasonic biomicroscopy surveillance of the injection site, and subconjunctival chemotherapy deposition)., Conclusions and Relevance: With use of at least 2 presumed precautionary safety methods, no extraocular extension of tumor events occurred. According to the rule of 3, this finding suggests that the risk is no greater than 0.08% injections.

Importance: Anterior chamber seeding following intraophthalmic artery chemotherapy is rarely reported., Objectives: To describe clinicopathologic observations in eyes in which intraophthalmic artery chemotherapy for retinoblastoma failed and to report anterior chamber involvement., Observations: A retrospective case series of 12 enucleated eyes (11 patients) with retinoblastoma refractory to intraophthalmic artery chemotherapy between March 1, 2010, and October 31, 2013, at University College London Institute of Ophthalmology and the Retinoblastoma Service, Royal London Hospital. Data analysis was conducted from June 1, 2014, to March 1, 2015. The International Classification of Retinoblastoma groups were B in 1 eye (8%), C in 4 eyes (33%), and D in 7 eyes (58%). Systemic chemotherapy with vincristine sulfate, etoposide, and carboplatin had failed in 10 patients (91%) and 6 eyes (50%) received additional local treatments. In 6 eyes (50%) anterior chamber invasion was clinically detectable. On histopathologic examination, 4 eyes (33%) had no viable retinal tumor; the remainder had poorly differentiated tumor (6 eyes [50%]) or moderately differentiated tumor (2 eyes [17%]). Anterior segment involvement occurred in the ciliary body and/or ciliary muscle (7 eyes [58%]), iris (6 eyes [50%]), and cornea (4 eyes [33%])., Conclusions and Relevance: Intraophthalmic artery chemotherapy can fail in eyes with retinoblastoma. In contrast to previous reports on outcomes following intraophthalmic artery chemotherapy, our series shows involvement of the anterior segment of the eye, including the ciliary body, iris, and cornea. Careful case selection and follow-up are advised.

Importance: Disseminated retinoblastoma is usually fatal. Identification of small amounts (minimal dissemination [MD]) of tumor cells in extraocular sites might be a tool for designing appropriate treatments., Objective: To test cone-rod homeobox (CRX) transcription factor as a lineage-specific molecular marker for metastatic retinoblastoma and for evaluation of MD., Design, Setting, and Participants: In a prospective cohort design study, we evaluated CRX messenger RNA (mRNA) by retrotranscription followed by real-time polymerase chain reaction as a diagnostic test in samples obtained from bone marrow, peripheral blood, and cerebrospinal fluid (CSF) at diagnosis, after induction chemotherapy, and during follow-up. The study was conducted from June 30, 2008, to June 30, 2014. Seventeen retinoblastoma primary tumors, 2 retinoblastoma cell lines, and 47 samples of bone marrow from other cancers (controls) were studied. Seventeen patients with metastatic retinoblastoma (9 at diagnosis, 8 at relapse; age range: 18-41 months) were included., Main Outcomes and Measures: Detection of CRX mRNA as a marker for metastatic retinoblastoma and MD in bone marrow and CSF and its correlation with clinical findings., Results: Cone-rod homeobox mRNA was expressed in all tumors (relative expression levels range, 8.1 × 10-5 to 5.6) and cell lines. In control samples, there was no amplification of CRX; only the housekeeping gene (GAPDH) demonstrated amplification. Bone marrow metastatic cells showed expression of CRX mRNA in all 9 children presenting with metastasis at the diagnosis (relative expression levels, 6.0 × 10-5 to 0.67). After induction chemotherapy, no evidence of MD of tumor cells was seen in any of the 8 responding children since only GAPDH showed amplification. In the CSF of children who had a metastatic relapse, CRX mRNA detection was positive in 2 patients in whom no conclusive results were reached by immunocytology for disialoganglioside GD2. Minimal dissemination in the CSF was associated with a clinical relapse in 2 cases. No concomitant MD was evident in the bone marrow in any case., Conclusions and Relevance: These data suggest that CRX mRNA is a novel marker for retinoblastoma at extraocular sites. In this study among patients with bone marrow metastasis, there was a quick, complete, and sustained molecular response after induction chemotherapy. In all patients with secondary metastasis, CSF relapse occurred independently from the bone marrow, suggesting a sanctuary site.

Importance: Recurrent or persistent vitreous seeds following treatment of retinoblastoma poses difficult management and often leads to enucleation., Objective: To describe the technique and evaluate the efficacy and complications of intravitreal melphalan for vitreous seeding from retinoblastoma., Design, Setting, and Participants: This retrospective noncomparative analysis was conducted at a tertiary referral center. The study included 11 consecutive eyes of 11 patients with viable persistent or recurrent vitreous seeds following treatment of retinoblastoma., Interventions: All eyes received intravitreal melphalan injection (20-30 µg) by transconjunctival pars plana route with concomitant triple-freeze cryotherapy at the injection site during needle withdrawal for prevention of extraocular seeding. Each patient was offered planned 6 monthly cycles., Main Outcomes and Measures: Vitreous seed control and complications of therapy., Results: The mean patient age at vitreous injection was 37 months (median, 27 months; range, 16-82 months). Viable vitreous seeds involved 2 (n = 1), 3 (n = 4), or 4 (n = 6) quadrants. The solid intraretinal retinoblastoma and subretinal seeds showed regression in all eyes following intravenous chemotherapy (n = 6) or intra-arterial chemotherapy (n = 5). There were a total of 55 injections, with a mean number per patient of 5 (median, 6; range, 2-6). Fewer than 6 injections (n = 5) were delivered owing to complete vitreous seed control and parental desire to avoid more injections. By a mean of 9 months' follow-up (median, 9 months; range, 6-16 months), therapeutic success with complete vitreous seed regression was achieved in all 11 cases (100%). Globe salvage was attained in all cases (100%). Further vitreous seed development did not occur in any case. Complications included focal retinal pigment epithelial mottling near the site of chemotherapy injection (2 eyes) and nonaxial posterior lens opacity (2 eyes). There was no case of extraocular tumor extension, hypotony, or phthisis bulbi., Conclusions and Relevance: These preliminary short-term results suggest that intravitreal melphalan injection for persistent or recurrent vitreous retinoblastoma seeding can provide tumor control with minimal toxicity and complications.

Importance: Different staging systems for extraocular retinoblastoma have been published, but to date they have not been validated in large cohorts., Objective: To review 533 patients (and pathology slides) with retinoblastoma included in 4 protocols (January 1, 1988, to December 31, 2009) who received uniform treatment., Design and Setting: Retrospective review in a hospital setting. A critical analysis for detecting inconsistencies and omissions was performed., Participants: Patients were reclassified according to the modified St Jude Children's Research Hospital staging system, Grabowski-Abramson staging system, International Retinoblastoma Staging System (IRSS), and American Joint Committee on Cancer TNM staging system., Main Outcome and Measure: The main outcome measure was disease-free survival (DFS), considering only extraocular relapse as an event., Results: In the IRSS and the St Jude system, higher stages correlated with poorer DFS. For intraocular disease, only the TNM system and the IRSS included pathological definitions, and all systems except for the IRSS included substages without differences in DFS. Omissions of factors significantly associated with lower DFS included scleral invasion by the TNM system and massive choroidal invasion by the Grabowski-Abramson system. The St Jude system omits postlaminar optic nerve involvement, but this omission did not correlate significantly with lower DFS because these patients received intensive therapy. No differences in DFS were observed among substages for metastatic disease except for the presence of central nervous system involvement. All staging systems had inconsistencies in definitions of extent of disease. No system provides guidelines for imaging., Conclusions and Relevance: Only the IRSS and the St Jude system allowed for grouping of patients with increasing risk of extraocular relapse. For lower stages, only the IRSS considers all unequivocal pathological prognostic factors. For higher stages, all systems had redundant information, resulting in an excess of substages.