The As-Needed Treatment Strategy for Choroidal Neovascularization: A Feedback-Based Treatment System

HOROIDAL NEOVASCULARIZATION (CNV) SECONDary to age-related macular degeneration (AMD) causes decreased visual acuity (VA) through a variety of mechanisms including intraretinal edema, subretinal fluid (SRF), hemorrhage, fibrosis and scarring, and disruption of the photoreceptors. Treatment of CNV secondary to AMD with monthly injections of ranibizumab (Genentech Inc, South San Francisco, California, USA), an antibody fragment that avidly binds to vascular endothelial growth factor (VEGF), causes decreased exudation and a cessation of growth of the CNV, with a concomitant stabilization or improvement in VA. 1,2 Although a dosing frequency of once a month proved effective, the optimal dosing schedule is not known. Optimal, meaning most desirable, inevitably is defined in relation to a specific viewpoint. Given the personal and societal burden of monthly lifelong treatment, the testing of alternate strategies to decrease treatment frequency was a logical first step. In the highly influential Prospective Optical coherence tomography (OCT) imaging of patients with Neovascular AMD Treated with intraOcular ranibizumab (PrONTO) Study, 3,4 Rosenfeld and associates gave monthly dosing for 3 consecutive doses. Patients were then evaluated at monthly intervals using OCT for signs of accumulation offluid (SRF or cystoid macular edema) within the macula. VEGF is one of the most powerful agents in causing increased permeability; accumulating fluid within the macula potentially serves as an intraocular indicator for local VEGF levels. Patients were given reinjection if they demonstrated OCT signs of a fluid accumulation. Leakage seen during fluorescein angiography (FA), which was done at quarterly intervals, served as another criterion to administer intravitreal injection of ranibizumab. Mimicry may be the highest form of flattery, but mimicry aids in the comparison of scientific studies (Table). Bashshur and associates 5,6 modeled a study of intravitreal bevacizumab (Genentech Inc) after the PrONTO Study in exquisite detail. After up to 3 consecutive doses of 2.5 mg bevacizumab given at monthly intervals, patients were given reinjection if they showed accumulation of fluid by OCT examination or if they had leakage during FA at quarterly intervals. Similar to the PrONTO Study, reinjection was given to the majority of patients on the basis of OCT findings. However, there was a significant difference in the OCT-based criteria. Whereas the PrONTO Study mandated reinjection if there was any persistent fluid, reinjection occurred in the Bashshur study if the patient met 1 of 3 different fluid-related criteria: recurrence of SRF or cystic maculopathy on OCT in a previously dry lesion, increase in central retinal thickness by more than 100 m from the lowest recorded value, or decrease of 5 letters from highest recorded best-corrected VA associated with increased leakage on FA or OCT. Note that there is no provision to reinject a patient on the basis of only persistent fluid. Thus it is possible that a patient could have persistent fluid, or even subtly increasing fluid, but not get a reinjection unless there was a 5-letter decrease in acuity. Although there are unavoidable differences in studies that limit direct comparison of results, it is tempting to do so. The results of both studies are broadly comparable. The striking similarity was the 3-line responder rate (that is, the proportion of patients experiencing a 3-line or more improvement in acuity) was 43% in both groups. The mean change in VA appeared to be somewhat different, but the PrONTO Study reported the VA only on patients completing the study. This reported mean VA did not include a patient who developed a submacular hemorrhage, lost 31 letters of acuity, and dropped out of the study.