Phase I/II randomized study of proton beam with anti-VEGF for exudative age-related macular degeneration: long-term results



To determine if treatment of exudative age-related macular degeneration (eAMD) using proton beam therapy (PBT) combined with intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is safe and effective long term.


Thirty eyes with newly diagnosed eAMD were enrolled in a phase I/II prospective, sham-controlled double-masked university study. Eyes were randomized 1:1:1–24 GyE, 16 GyE or sham radiation, and treated with three initial monthly intravitreal ranibizumab or bevacizumab. Subsequent anti-VEGF reinjection was based on monthly optical coherence tomography and examination for 2 years and standard of care thereafter.


A total of 23 eyes completed 2-year study follow-up, of which 16 maintained monthly follow-up. Mean best-correct visual acuity (BCVA) at 2 years was similar among treatment groups (p > 0.05). The 24 GyE group required fewer anti-VEGF injections when compared with the sham group at 2 years (4.67 ± 1.9 vs 9.67 ± 3.5; p = 0.017). Extended follow-up (mean 4 years) available in 22 eyes showed persistent reduced need for anti-VEGF therapy among eyes treated with 24 GyE compared with sham radiation (2.0 ± 1.6 vs 4.84 ± 2.4 per year, p = 0.008). New and increasing geographic atrophy (GA), noted in some eyes in all treatment groups, resulted in decreased mean BCVA from baseline for the 24 GyE group on extended follow-up (p = 0.009). Possible mild radiation retinopathy noted in 15% of eyes was not visually significant.


Initial treatment combining PBT (24 GyE) with intravitreal anti-VEGF therapy appears to decrease the need for anti-VEGF reinjection in eyes with newly diagnosed eAMD. Radiation retinopathy risk was low and does not appear visually significant. Long-term vision was limited by GA development especially in the 24 GyE group.

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Fig. 1: Mean best-corrected visual acuity of study groups at baseline and follow-up.
Fig. 2: Mean number of anti-VEGF injections in study eye during follow-up.
Fig. 3: Change in choroidal neovascular membrane size and leakage on fluorescein angiography at baseline and at 2 years follow-up among study groups.


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The study was supported in part by the Strategic Opportunities Support Award, Clinical and Translational Science Institute, University of California San Francisco.

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All authors met criteria for authorship by making substantial contributions to conception or design of work, acquisition, analysis, or interpretation of data, or in drafting or revising paper critically for important intellectual content. All authors approved the final version of this work.

Correspondence to Susanna S. Park.

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Conflict of interest

SSP has received research support via employer from Allergan and Roche/Novartis for contracted clinical research exploring anti-VEGF drugs for treatment of retinal disorders including exudative AMD. None of the other authors have any conflict of interest to disclose.


Contracted research with Allergan and Roche Novartis via employer (SSP) investigating anti-VEGF therapy for retinal disorders, including macular degeneration. No other conflicting relationship exists for any of the remaining authors.

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Mukkamala, L.K., Mishra, K., Daftari, I. et al. Phase I/II randomized study of proton beam with anti-VEGF for exudative age-related macular degeneration: long-term results. Eye (2020).

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