The Current Status of Lasers in Treating Diabetic Retinopathy

MARK S. BLUMENKRANZ, MD

Dramatic advances in the emerging field of pharmacotherapy for the treatment of age-related macular degeneration (AMD), retinal vascular diseases, and diabetic retinopathy (DR) have improved our ability to manage even the most complex cases. As a result, it is appropriate to reflect precisely upon the current standard of care for DR in all its various manifestations. Should we be considering wholesale changes in how we approach this disease, or should we be further improving and refining methods that have been employed for the greater part of the past35 years? Should all patients now receive injections of an intravitreal anti-vascular endothelial growth factor (VEGF) agent or steroid as first-line therapy, or should these drugs be reserved online for the most complex cases? Should patients still receive photocoagulation as first-line therapy or only in those cases where pharmacotherapy is ineffective? Is there even a role for destructive treatments such as laser in the modern era of anti-VEGF and related pharmacotherapies?

All these questions have been posed by thoughtful physicians as they evaluate changing treatment paradigms for DR. However, these questions remain unanswered because the necessary data are not available in their entirety. Based upon the combination of clinical experience and, more importantly in this era of evidence-based medicine, well-controlled, randomized clinical trials, we can obtain the answers. By carefully evaluating the existing evidence, it is possible to pose important therapeutic questions to be evaluated in the light of new existing technologies, not only evaluating efficacy and safety, but also cost-effectiveness. This evidence can then be used to establish preferred practice guidelines that can be widely applied to patient management.

PAST RESULTS

It may be worthwhile to stop and reflect on where we have been and are now as a prelude to where we are headed. If the past is any guide to the future of medical and surgical therapies, then while new technologies arise that change how we think about disease management, these therapies not so often replace older therapies, but rather represent building blocks on which more robust therapies can be established. Examples of this phenomenon include the use of multiple approaches for the treatment of various solid and lymphoproliferative malignancies involving a combination of surgery, radiotherapy, and different chemotherapeutic agents acting on different pathways.

Prior to the late 1960s there was no effective therapy for DR, nor even any consensus that precepts that we now hold to be completely true, such as tight control, made any difference. With the introduction of medical lasers in the mid-1960s and the performance of the first multicenter, prospective, randomized clinical trials in the Diabetic Retinopathy Study, it was proved beyond doubt that photocoagulation therapy was effective in preventing severe vision loss in proliferative DR.¹ The results of the Diabetic Retinopathy Study unequivocally established that the rates of severe vision loss at 3 and 6 years could be reduced from 21.1% to 10.2% and 34.2% to 17.5%, respectively, in patients receiving panretinal photocoagulation compared with those with high-risk characteristics who were observed rather than treated promptly.² Argon laser photocoagulation performed in this study proved itself to be not only superior to observation, but to treatment with an alternative modality, xenon arc photocoagulation, which was felt by many at that time to be superior to the laser without the benefit of a well-controlled, randomized clinical trial evaluating a variety of variables including not only final vision, but also visual field loss.

Subtleties relating to preferred therapy were able to be established, something that could not have been achieved with anything short of a prospective, randomized clinical trial. Following that study, investigators turned their attention to the treatment of diabetic macular edema (DME) in the Early Treatment Diabetic Retinopathy Study (ETDRS), which employed focal and grid photocoagulation. This second study established that, in 2244 patients treated at multiple sites throughout the United States, moderate vision impairment, defined as 3 lines or more of vision loss, could be reduced from 24% to 12% when photocoagulation was performed promptly rather than deferred. These results were apparent as early as 1 year and were stable in excess of 6 years.^3,4

Multiple subgroups were studied, including various permutations of therapy, with and without scatter photocoagulation, as well as with and without aspirin, and important insights were gained into preferred methods of therapy. These results have stood the test of time and, as a consequence, focal and grid photocoagulation for clinically significant DME and scatter photocoagulation for proliferative DR with high-risk characteristics remain the gold standard of care.³ Many of the fundamental axioms that relate to DR treatment, including more subtle changes in photocoagulation therapy, the combination of photocoagulation therapy and pharmacotherapy, or pharmacotherapy alone, are now being explored through the Diabetic Retinopathy Clinical Research Network (DRCRN), a critical and effective collaborative research group that is facilitating the establishment of new standards.

As of January 2007, more than 1600 patients have been randomized to treatment in a variety of studies, including a new study comparing grid photocoagulation to modified ETDRS standard photocoagulation, the results of which were recently published.⁵ In this study, direct and grid photocoagulation as generally employed in the ETDRS study were compared to a mild macular grid without focal treatment in patients with DME. In both arms, somewhat lighter burns were employed than traditionally used in the earlier ETDRS studies. The results at 5, 8, and 12 months suggested that while the treatment still remains highly effective, the modified ETDRS protocol, which includes not only the application of grid laser to the macula but also focal treatment to microaneurysms and other focal leak sites, was more effective in terms of reduction of edema and retinal volume as calculated by optical coherence tomography measurements.⁵ In addition to comparing subtle variations and various photocoagulation regimens for DR, the aggregate results indicated that treatment of DR with photocoagulation remained a highly effective form of therapy, with 82% of patients achieving stabilization improvement of vision, 27% to 32% gaining 1 to 3 lines of improvement, and 14% gaining 2 lines of more of improvement.

RECENT RESULTS

One of the most compelling and potentially underweighted benefits of photocoagulation as evidenced by the results from the different trials is the long-term stability of vision results with this form of therapy. In many cases, patients require no further treatment, or certainly relatively infrequent treatment over many years or decades.⁶ These results have become apparent with very long periods of follow-up. A second benefit, which has become apparent with over 3 decades of trial data and long-term follow-up of clinical cases is the relatively favorable complication profile associated with laser compared to other therapies. While patients may experience some discomfort, especially during panretinal photocoagulation, and there may be some associated microscotoma from focal treatment or field loss or nyctolopia with panretinal photocoagulation, for the most part these long-term consequences appear to be well tolerated by patients, and not progressive in nature. New forms of therapy need to be compared with photocoagulation in regard to long-term safety profiles. Finally, patients and particularly public health planners and policymakers will need to evaluate the cost-effectiveness of new forms of therapy compared with photocoagulation. Photocoagulation has a relatively long-term durability, and while capital equipment is required, there are not a great number of consumable supplies necessary on an ongoing basis.⁷

Looking forward, the future appears particularly bright with regard to 2 emerging areas. The first is the development of new photocoagulation methods and types of photocoagulators that may improve treatment efficacy while reducing undesirable side effects. The second is the use of multimodality therapy, specifically the combination of photocoagulation with pharmacotherapy, to achieve better outcomes than could be achieved with either modality alone.

A variety of new lasers and new laser techniques has been introduced in the past 10 years that appear to provide theoretical advantages in the treatment of DR.⁸ One such advance is the use of short-pulse durations. This work has been pioneered by Roider and colleagues. They demonstrated that if a train of microsecond pulses is applied to the same spot, retinal damage can be localized to specific layers, typically the retinal pigment epithelium, if a low duty factor is applied, minimizing heat accumulation. Higher duty cycles can to lead to significant heat accumulation and retinal damage, comparable to continuous wave lasers. Further research has centered around the use of even shorter duration pulses in the range of 200 ns (nanoseconds), in which case the burns obtained are clinically unapparent to the observer, but are demonstrable by immediate special imaging techniques such as fluorescein angiography and are later visible opthalmoscopically as selective atrophy of the pigment epithelium.⁹ In some instances, pigment epithelial renewal and/or sliding may occur to cover these defects. Small clinical trials employing short duty cycle pulses have demonstrated clinical efficacy in the treatment of DME, comparable to conventional continuous wave thermal photocoagulation effects, although these results need to be further corroborated by larger prospective, randomized clinical trials.¹⁰

A second recent innovation in photocoagulation has been the introduction of a patterned scanning laser(PASCAL, OptiMedica, Santa Clara, CA) for the treatment of various retinal conditions, including DR. Using this approach, multiple applications can be made nearly simultaneously using a scanner. Between 4 and 56 applications can be made in under one-half second using pulse durations in the range of 10 to 30 ms rather than the traditional durations of 100 to 200 ms. In doing so, the burns appear to be somewhat smaller both in axial and lateral dimension, with consequent reduction in pain from choroidal heating and possibly fewer nerve fiber bundle defects.¹¹

These preliminary results, based on preclinical studies as well as initial clinical experiences, will need to be further evaluated by additional prospective clinical trials. However, these different methods of photocoagulation, including short duration and scanning, offer the promise of reduction in some complications of conventional photocoagulation, including pain, long treatment sessions, and visual field loss. However, it seems clear that laser photocoagulation for the treatment of DME results in significant improvements in patients' vision-related quality of life as determined by standardized measures. In a recent study, multivariate models revealed that the improvement of the National Eye Institute Vision Field Quality (NEI-VFQ) scores was significant in subjects younger than 65 who received more laser burns and had worse vision-related quality of life prior to treatment as expressed by baseline NEI-VFQ scores.⁷

A second changing treatment paradigm for DR may include multimodality therapy. Recent study results indicate that a variety of different steroids and anti-VEGF agents may be of significant benefit in the treatment of DR and especially DME. Injection of conventional intravitreal triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) has been shown to be of benefit in small studies as has a nonbioerodable device eluting fluocinolone acetonide (Medidur, Alimera, Alpharetta, GA) and a bioerodable polymer eluting dexamethasone (Posurdex, Allergan, Irvine, CA).^12,13 In a large, well-controlled, randomized clinical trial, the sustained-release formulation of dexamethasone and a biodegradable copolymer of lactic acid and glycolic acid, improved visual acuity (VA) and reduced OCT thickness in patients with persistent DME. In this study, 24% of patients receiving a 350 μg dose and 35% of patients receiving a 700 μg dose achieved 10 letters or more of VA improvement by day 90.¹⁴ This compares with approximately 14% of patients receiving modified ETDRS photocoagulation treatment in the DRCRN study comparing ETDRS treatment with modified macular grid.⁵

However, the reduced apparent effectiveness of photocoagulation compared with this form of pharmacotherapy is to some extent counterbalanced by features of photocoagulation that may be superior to pharmacotherapy, including longer treatment effect and fewer complications. For fluocinolone, the incidence of glaucoma and cataracts is significant, ranging as high as 49% and 100%, respectively, at least for the highest doses, and in the range of 25% to 33% for intraocular pressure elevation and 50% to 70% in the case of cataract for triamcinolone. Conversely, pharmacotherapy appears to be superior to conventional ETDRS photocoagulation, at least over the short term, for the rapid reversal for diffuse forms of macular edema where focal photocoagulation appears to be most problematic, perhaps because of nonuniformity of uptake related to retinal thickening.

An argument can be made that each of the therapies could be combined into multimodality therapy, emphasizing the strengths of the particular modality and de-emphasizing potential weaknesses. As an example, for patients who have the combination of diffuse macular edema as well as focal leakage, initial thinning of the retina could be achieved with the use of a relatively short-acting low-dose steroid, which would have the benefit of thinning the retina down at least temporarily while minimizing the likelihood of development of secondary complications such as cataracts or glaucoma. Immediately upon thinning of the retina, patients could then undergo focal and/or grid photocoagulation according to modified ETDRS guidelines, thereby achieving longer-term regression of retinopathy by addressing zones of reduced perfusion, focal leakage, or impaired transport, better addressed by photocoagulation on a long-term basis than acute pharmacotherapy. Aside from the steroid-sparing benefits of photocoagulation, the relative cost of providing therapy for large populations could be reduced by fewer intravitreal drug injections. Although VEGF inhibitors appear to provide superior performance in terms of fewer complications compared with steroids, the relative efficacy of these agents compared with steroids or photocoagulation at this point remains unknown, but will be subjected to clinical evaluation.

CONCLUSION

There has been a resurgence of interest in new and more effective ways to treat DR. It seems clear that treatment paradigms will change in the future. The availability of new photocoagulators and photocoagulation treatments are likely to play a role, as will pharmacotherapy. The combination of these 2 modalities, and even possibly vitrectomy in some cases, is likely to yield better outcomes both in terms of overall efficacy and reduced complications. RP

REFERENCES

1. Little, HL, Zweng HC, Peabody RR. Argon laser slit-lamp retinal photocoagulation. Trans Am Acad Ophthalmol Otolaryngol. 1970;74:85-97.
2. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology. 1978;85:82-106.
3. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early treatment diabetic retinopathy study report number 2 Ophthalmology. 1987;94:761-774.
4. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol. 1985;103:1796-1806.
5. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Comparison of the modified early treatment diabetic retinopathy study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.
6. Chew EY, Ferris III, FL, Csaky KG, et al. The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy. The early treatment diabetic retinopathy follow-up study. Ophthalmology. 2003;110:1683-1689.
7. Tranos PG, Tropouzis F, Stangos NT, et al. Effect of laser photocoagulation treatment for diabetic macular edema on patient's vision-related quality of life. Current Eye Res. 2004;29:41-49.
8. Palanker D, Blumenkranz MS, Weiter JJ. Retinal laser therapy: biophysical basis and applications. In: Ryan SJ, ed. Retina. St. Louis, MO: Mosby; 2005.
9. Roider J, Hillenkamp F, Flotte T, Birngruber R. Microphotocoagulation: selective effects of repetitive short laser pulses. Proc Natl Acad Sci U S A. 1993;90:8643-8647
10. Luttrull, JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol. 2005;89:74-80.
11. Blumenkranz MS, Yellachich D, Andersen DE, et al. Semiautomated patterned scanning laser for retinal photocoagulation. Retina. 2006;26:370-376.
12. Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology. 2004;111:218-224.
13. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41:3569-3575.
14. Kuppermann BD, Blumenkranz MS, Haller JA, et al. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007;125:309-317.