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Abstract

We appreciate the opportunity to respond to the comments of Dr Asensio-Sanchez regarding our article. The use of intravitreal bevacizumab for type 1 retinopathy of prematurity (ROP) has expanded our options and perhaps improved outcomes from this disease. As Dr Asensio-Sanchez points out, our data suggested a trend toward earlier reactivation of ROP with lower doses. In our study, we performed a time-to-event analysis that showed the restricted mean time to reactivation was shorter with very low doses than with low doses of bevacizumab.1Freedman S.F. Hercinovic A. Wallace D.K. et al.Low- and very low-dose bevacizumab for retinopathy of prematurity: reactivations, additional treatments, and 12-month outcomes.Ophthalmology. 2022; 129: 1120-1128Abstract Full Text Full Text PDF Scopus (0) Google Scholar It is true that treatment for reactivation of ROP, and indeed for all clinical management after the initial 4 weeks after initial bevacizumab injection, was left to the investigators.2Wallace D.K. Kraker R.T. Freedman S.F. et al.Assessment of lower doses of intravitreous bevacizumab for retinopathy of prematurity: a phase 1 dosing Study.JAMA Ophthalmol. 2017; 135: 654-656Crossref PubMed Scopus (88) Google Scholar When designing the study, we did not know how effective very low doses would be or when recurrence might occur (if at all), so we intentionally planned to rapidly release infants to treatment at investigator discretion. In addition, the study design included the administration of bevacizumab to the nonstudy eye (if also type 1 ROP), at 1 dose level higher, which was usually twice the dose administered to the study eye. We did not want to give both eyes the study dose, because we did not know if it would be effective. We also avoided giving the fellow eye a dose that was higher than necessary, so as to minimize any crossover effect. We did report the total dose of bevacizumab received by each baby in the study—most received only the initial study-assigned bevacizumab injection and then laser, if needed, as subsequent treatment for either ROP reactivation or persistent avascular retina.3Wallace D.K. Kraker R.T. Freedman S.F. et al.Short-term outcomes after very low-dose intravitreous bevacizumab for retinopathy of prematurity.JAMA Ophthalmol. 2020; 138: 698-701Crossref PubMed Scopus (31) Google Scholar We agree that at very low doses of bevacizumab, accuracy is required both for the preparation of the diluted drug by an experienced pharmacy, as well as during delivery of the drug. In the reported studies, an investigational drug pharmacy prepared diluted bevacizumab such that the injected volume was the same for all doses and was delivered in study-specific syringes (with 0.3 ml capacity) where the 0.010 ml volume could be reliably measured and carefully dispensed.4Wallace D.K. Dean T.W. Hartnett M.E. et al.A dosing study of bevacizumab for retinopathy of prematurity: late recurrences and additional treatments.Ophthalmology. 2018; 125: 1961-1966Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 5Crouch E.R. Kraker R.T. Wallace D.K. et al.Secondary 12-month ocular outcomes of a phase 1 dosing study of bevacizumab for retinopathy of prematurity.JAMA Ophthalmol. 2020; 138: 14-20Crossref PubMed Scopus (7) Google Scholar For our ongoing randomized trial of low-dose intravitreal bevacizumab versus laser, we chose to administer a volume of 0.020 ml to each study eye, similar to what we expect is being done in clinical practice. We do not recommend attempted administration of low-dose bevacizumab of less than 0.25 mg (0.010 ml of undiluted commercially available bevacizumab), unless clinicians have access to reliable pharmacy-assisted dilution, and we do not recommend attempted administration of less than 0.010 ml for intravitreal injection. We completely agree that further study is required to identify the ideal dose of bevacizumab for intravitreal administration for type 1 ROP. Lower doses may offer similar treatment response with lower systemic exposure for these premature infants, as well as possible advantages for retinal development. Re: Freedman et al: Low- and very low-dose bevacizumab for retinopathy of prematurity: reactivations, additional treatments, and 12-month outcomes (Ophthalmology. 2022;129:1120–1128)OphthalmologyPreviewWe read the article by Freedman et al1 with joy and great interest. Traditionally, the accepted treatment for retinopathy of prematurity (ROP) is laser photocoagulation.2 Moreover, photocoagulation takes a longer time and has late complications such as loss of peripheral vision field, strabismus, anisometropia, and high myopia.3 Bevacizumab is increasingly being used for the treatment of patients with ROP. Full-Text PDF