Intravitreal Methotrexate for Retinoblastoma Tero Kivelä, MD, FEBO, Sebastian Eskelin, MD, FEBO, Markku Paloheimo, MD  Ophthalmology  Volume 118, Issue 8, Pages 1689-1689.e6 (August 2011) DOI: 10.1016/j.ophtha.2011.02.005 Copyright © 2011 American Academy of Ophthalmology Terms and Conditions

Figure 1 Response of vitreous (A−D), subretinal (E−G), and retinal (A−G) relapses of retinoblastoma (Rb) to intravitreal methotrexate monotherapy (IVMM) in Case 1 (A−D, right eye; E−G, left eye). A large peripapillary Rb and 1 of 3 equatorial foci seeded the vitreous, OD. A large Rb with abundant seeds filled two thirds of the subretinal space, OS. We gave 8 cycles of chemoreduction and consolidated focally. Ten weeks after the last cycle, we managed an equatorial relapse with brachytherapy, OD. At 14 and 16 weeks, we found progressive vitreous seeds in 3 quadrants (A, B; arrowheads) and a marginal relapse (open arrowhead; calcified vitreous deposits and scars from brachytherapy and cryocoagulation are also seen). Sixteen weeks after starting IVMM, active vitreous seeds (C, D; arrowheads) and the marginal relapse (C, D; open arrowhead) had regressed. Response is maintained 29 months after IVMM. The eye fixates and follows. We treated new marginal and subretinal relapses focally 5, 19, 21, and 22 months after chemoreduction, and a peripapillary one with stereotactic radiotherapy at 8 months, OS. At 27 months, a dozen vitreous and several subretinal seeds (E, arrowhead) with adjacent infiltrated retina (open arrowhead) were seen. We started IVMM based on complete response, OD. After 4 weekly injections, the vitreous and subretinal seeds (F, arrowhead) had regressed, but the infiltrated retina (open arrowhead) was unchanged. Two months after switching to twice weekly IVMM; it had responded (G, open arrowhead). At 17 weeks, a major choroidal relapse adjacent to the disk necessitated enucleation. Ophthalmology 2011 118, 1689-1689.e6DOI: (10.1016/j.ophtha.2011.02.005) Copyright © 2011 American Academy of Ophthalmology Terms and Conditions

Figure 2 Response of diffuse subretinal relapse of retinoblastoma (Rb) to intravitreal methotrexate monotherapy (IVMM) in Case 2. A large macular tumor seeded the vitreous and detached two thirds of the retina, OD. Two smaller foci were located close to the disk. A large Rb filled two thirds of the subretinal space and a smaller one was found inferior to the disk, OS. We gave 7 cycles of chemoreduction. After the 4th cycle, we found subretinal seeds (arrowheads) at the ora temporally and inferiorly (A, D; arrowheads), scattered subretinal seeds superiorly and nasally (B−D; arrowheads) and a marginal relapse (A, double arrowhead), OS. Chorioretinal scars (open arrowheads in B−D, F−H) and lipid exudates (C; double open arrowhead) after chemoreduction and focal therapy were also seen. We considered the seeding to be too diffuse for focal therapy. After 8 weeks on IVMM; active subretinal seeds had disappeared (E−H; arrowheads) and the marginal relapse (E, double arrowhead) had responded to concurrent brachytherapy. Response is maintained 14 months after IVMM. Visual acuity is 20/200 with eccentric fixation. The fellow eye does not fixate. Ophthalmology 2011 118, 1689-1689.e6DOI: (10.1016/j.ophtha.2011.02.005) Copyright © 2011 American Academy of Ophthalmology Terms and Conditions

Figure 3 Response of subretinal relapse of retinoblastoma (Rb) to intravitreal methotrexate monotherapy (IVMM) in Case 3. A large Rb nasal to the disk and 2 smaller foci in the midperiphery and equator were found, OD. A large tumor extended to the macula superiorly and seeded the vitreous, OS. A smaller tumor was found at the equator. We gave 6 cycles of chemoreduction and consolidated focally. After the 5th cycle, we cryocoagulated 3 new superotemporal subretinal seeds, OS. A month later, a dozen additional subretinal seeds were scattered supero- and inferotemporally behind the ora (A−C, arrowheads; some scars are also seen, open arrowhead in A, B, D, E). Given the response in Case 2, we started IVMM. Eight weeks later, all subretinal seeds except 1 (E, double arrowhead) had disappeared (D−F), and we cryocoagulated it; note tiny scars in the pars plana (pp) from IVMM injections (E). During the maintenance phase starting at week 19, we found altogether 8 subretinal seeds and cryocoagulated them. Some of them relapsed 3 and 5 months after IVMM and were treated with brachytherapy. Both eyes fixate and follow 9 months after ending IVMM. Ophthalmology 2011 118, 1689-1689.e6DOI: (10.1016/j.ophtha.2011.02.005) Copyright © 2011 American Academy of Ophthalmology Terms and Conditions

Figure 4 Response of a small retinal relapse of retinoblastoma (Rb) to intravitreal methotrexate monotherapy (IVMM) in Case 4, right eye. Familial Rb was diagnosed with 6 foci of Rb up to 2.8 mm in diameter, OD. The largest one was located 1.5 mm from the disk superotemporally, 3 smaller ones superonasally, inferonasally, and superiorly in the posterior pole, and 2 smallest ones anterior to the equator. A 7.5-mm tumor occupied the macula and a small tumor was detected nasally, OS. We managed the 5 smallest foci with transpupillary thermotherapy (TTT) and started chemoreduction. Before the 2nd cycle, we managed with TTT 2 new postequatorial foci, OD. Chemoreduction had to be discontinued after the 3rd cycle because of deteriorating renal function. We consolidated the partly regressed largest tumors in each eye with TTT in 2 sessions 1 month apart and managed similarly 1 relapse, OD (A, B; open arrowhead). A month later, the largest focus had grown to a diameter of 4.5 mm despite TTT (A, B; arrowhead), another 1 showed a marginal relapse (B; double open arrowhead), and 2 new peripheral foci were found, OD. We managed the latter with TTT (C; double open arrowhead). We started IVMM for the unresponsive focus. It had reduced by one half at 4 weeks and slightly more at 8 weeks (C; arrowhead). We noted no further change up to 20 weeks, but at 24 weeks the tumor had regrown to a diameter on 2.8 mm (D; arrowhead). We combined the next 3 monthly injections with TTT given minutes before IVMM to achieve a chemothermotherapy effect. The relapse had stabilized (E; arrowhead) after the first and had responded completely (F; arrowhead) after the third session. The response persists 10 months after IVMM. The eye fixates and follows. We later treated with TTT-IVMM 2 new foci from the fellow eye, which did not regress completely with 2 sessions of TTT only. After 2 chemothermotherapy treatments, both foci showed complete response, which was maintained 8 months after completing IVMM. Ophthalmology 2011 118, 1689-1689.e6DOI: (10.1016/j.ophtha.2011.02.005) Copyright © 2011 American Academy of Ophthalmology Terms and Conditions