Landmark clinical trials in the treatment of diabetic macular edema (DME) and diabetic retinopathy (DR) have provided invaluable and durable treatment guidance over the decades for these visually significant pathologies. However, the ability to personalize therapy to an individual’s clinical appearance is an attractive treatment strategy. For example, the “treat and extend” model for anti-VEGF delivery provides durable treatment for DME without sacrificing efficacy by utilizing the patient’s structural and functional response to determine treatment intervals.

The advent of ultrawidefield fluorescein angiography (UWFA) further encouraged this line of personalized evaluations, because it facilitated visualization of areas of peripheral nonperfusion in patients with DR and DME. Given that ischemic retina is believed to express inflammatory cytokines and VEGF to a high degree, could targeted retinal photocoagulation (TRP) applied to areas of nonperfusion, rather than the standard 360° panretinal photocoagulation (PRP), reduce complications of proliferative retinopathy while maximizing nonablated peripheral retina? Also, could there be any benefit for TRP treatment of DME, via the proposed mechanism of suppressing VEGF and inflammatory cytokines through peripheral ablation? This article will review attempts to answer these questions.

IMAGE STANDARDIZATION

The first challenge in meaningfully addressing these questions was standardizing and appropriately quantifying areas of nonperfusion on ultrawidefield fluorescein angiograms. The difficulty derives from projecting a 3-dimensional retina as a 2-dimensional image. The result is a nonlinear artifactual enlargement of the peripheral surface area relative to the posterior pole. In short, the periphery appears larger than reality. Thanks to the mathematical work of the Doheny Image Reading Center, accurate conversion of pixels to square millimeters on both posterior and peripheral imaging is now possible. Thus, reading centers can look at an Optos image, for example, and obtain a host of accurate surface area measurements. Common metrics include nonperfusion area (NPA), total retinal area, ischemic index (NPA over total retinal area), and total retinal vascular bed area (RVBA), which is the vessel area measurement after binarization and segmentation.¹ It was first established that eyes with DME have a greater dilation and elongation of vasculature compared with healthy controls.² Also, increasing ischemic index was associated with increasing DR severity.³ Interestingly, however, there was no correlation between NPA and severity of DME.²

EFFECTS OF TARGETED RETINAL PHOTOCOAGULATION ON DIABETIC MACULAR EDEMA

Patients with a high ischemic index on UWFA demonstrate increased levels of VEGF and other cytokines in aqueous humor samples.⁴ Thus, selectively ablating areas of nonperfused retina, which produce cytokines in greater number, may diminish the need for prolonged, repeat anti-VEGF therapy. This hypothesis was put to the test in the 3-year prospective randomized DAVE trial.⁵ This study randomized 40 patients with center-involved DME 1:1 to receive TRP with pro re nata (PRN) anti-VEGF therapy for DME, while the other half received only PRN anti-VEGF treatment. Both groups received 4 monthly loading doses of ranibizumab (Lucentis; Genentech) followed by PRN retreatment. In the TRP combination therapy arm, laser was performed at week 1 to areas of retinal capillary nonperfusion with possible retreatment at months 6, 18, and 25. At 3 years, the mean number of ranibizumab injections was 27.1 in the TRP plus anti-VEGF group and 24.4 in the anti-VEGF–only group, indicating that there was no benefit of TRP for reducing the DME treatment burden. A post hoc analysis evaluating cytokine expression levels in these patients at 1 year demonstrated no significant difference in mean VEGF levels between the groups at month 12 (P=.06), providing further rationale as to why TRP did not lower injection volume.⁶

Prior studies that demonstrated some value of TRP to areas of nonperfused retina include the RaScaL study and a study by Takamura et al. The caveat is that both studies were inadequately designed to answer this specific question. RaScaL was a 30-eye pilot study that compared ranibizumab plus TRP to treatment with triamcinolone and focal laser.⁷ The study concluded that patients in the ranibizumab plus TRP group had lower recurrences of DME at 6 months relative to patients receiving triamcinolone and focal laser. However, given the multiple treatments employed across the 2 arms, the role of TRP alone in this treatment paradigm is unclear. Takamura et al performed a randomized controlled trial of 52 patients receiving either intravitreal bevacizumab (Avastin; Genentech) (IVB) plus TRP or bevacizumab alone.⁸ All patients received focal laser prior to randomization. Two months after treatment, patients in the IVB-TRP group had lower retinal thickness and improved outcomes relative to the bevacizumab-only group. One major confounding variable is that two-thirds of all patients previously had received PRP. Thus, while this study suggests that peripheral nonperfusion contributes to DME pathogenesis, the true value of TRP in addition to anti-VEGF is difficult to discern. Therefore, although the proposed pathogenesis of VEGF production from peripheral nonperfused retina is cogent, the aggregate data do not currently support the role of TRP for the reduction of DME.

TRP VERSUS PRP

Panretinal laser photocoagulation remains the gold-standard therapy for the treatment of proliferative diabetic retinopathy (PDR), but treatment is associated with diminished visual field, reduced color vision, reduced contrast sensitivity, and possible development of macular edema.⁹ Targeted retinal photocoagulation has been suggested as an alternative that might have fewer adverse effects. However, the Diabetic Retinopathy Clinical Research Network (DRCRnet) found with Protocol S that even patients enrolled in the anti-VEGF arm for the treatment of PDR had progressive visual field loss that progressed through 5 years of the study with comparable differences to traditional PRP.¹⁰ This finding was attributed to progressive nonperfusion. Thus, while TRP may have short-term visual field benefits relative to PRP, the long-term picture of progressive nonperfusion may nullify any meaningful changes.

Regarding macular edema development, studies have demonstrated the safety of full-field, single-session PRP. The DRCRnet’s Protocol F study concluded that there were no clinically significant differences in rates of macular edema after PRP completed in 1 session vs 4 sessions.¹¹ Extrapolating this to TRP, there is not likely to be a difference in macular edema rates between TRP and PRP.

Nevertheless, TRP demonstrates efficacy with regression of diabetic neovascularization.¹² In one study, TRP was found to be noninferior to PRP in controlling fluorescein leakage, but this finding was confounded by the fact that both arms were cotreated with anti-VEGF therapy.¹³ Certainly, cotreatment for diabetic neovascularization with anti-VEGF and PRP may be more efficacious in high-risk PDR, as was seen in the PROTEUS study, which found treatment with ranibizumab and PRP to be more effective than PRP monotherapy for neovascular regression in high-risk PDR participants over 12 months.¹⁴ However, it is not clear that TRP plus anti-VEGF is as effective or reduces complications in the treatment of PDR over traditional PRP plus anti-VEGF in these high-risk individuals.

CONCLUSION

Employing TRP in the treatment of DME has not yet been shown to reduce anti-VEGF treatment burden. Similarly, TRP in PDR does not seem to offer any clear advantages over standard PRP in both neovascularization regression rates and adverse effects mitigation. Nevertheless, the meaningful work in cytokine analysis and UWFA imaging metrics contributes to the evolving understanding of DME and PDR pathogenesis. RP

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