Retina specialists examine evolving role of laser therapy in DME treatment
Laser photocoagulation has long been a mainstay in the treatment of diabetic macular edema associated with diabetic retinopathy, but some retina specialists believe adjunctive use of laser may increase durability of commonly used anti-VEGF agents.
Before anti-VEGFs became the go-to treatment for DME, laser therapy was the norm, according to David M. Brown, MD, FACS.
“The treatment before anti-VEGF was all laser,” Brown said. “However, the gains seen in RISE/RIDE (ranibizumab), VISTA/VIVID (aflibercept) and the DRCR protocols (ranibizumab, aflibercept and bevacizumab) are all superior to anything seen with historical laser trials.”
However, in light of the high cost and treatment burden of monthly anti-VEGF injections, there is yet a role for laser treatment in combination with pharmacologic therapies, according to some experts.
Laser treatment may reduce the burden of monthly Lucentis (ranibizumab, Genentech) injections and be combined with intraocular steroids that are poised to enter the market,OSN Retina/Vitreous Board Member Pravin U. Dugel, MD, said.
More focus should be directed at combination therapy because many macular diseases have a multifactorial etiology, according to OSN Retina/Vitreous Board Member Seenu M. Hariprasad, MD.
An upcoming multisite investigator-sponsored trial, TREX-DME, will examine a treat-and-extend protocol using ranibizumab with and without fluorescein-guided navigated laser photocoagulation for DME. Results of the study may confirm or refute previous studies showing anti-VEGF therapy alone is superior to laser treatment, even in combination with anti-VEGF injections, Brown said.
Image: Hariprasad SM
Pattern, subthreshold and guided lasers
Recent innovations in lasers for retinal photocoagulation include pattern scanning, multi-spot delivery and subthreshold treatment. Pattern scanning and multi-spot technology allow targeted treatment of diseased areas, while subthreshold technology minimizes the delivery of laser energy. Subthreshold, pattern scanning and multi-spot delivery all minimize collateral damage to surrounding tissue.
Newer modalities such as eye tracking and computer guidance promise to further enhance the safety and accuracy of laser treatment.
“We now have more precise guidance of laser delivery that can be delivered in a pattern,” making the treatment session simpler and more consistent, according to Sam E. Mansour, MD.
“The concept is to decrease power to such a low level that you can’t even see the laser uptake,” Hariprasad said.
Subthreshold treatment involves significantly reduced laser energy, such that the treated areas or laser burns are invisible, which presents a dilemma, according to David Boyer, MD.
“Subthreshold allows you to treat near the fovea with no apparent damage,” Boyer said. “One of the problems is that you don’t know exactly where you’ve treated because all of your burns are subthreshold. You can’t even see them. The addition of a pattern-type laser to do subthreshold would make it a much more appealing process because you would not go over the same marks. You know where you’ve been.”
The Pascal Synthesis Pattern Scanning Laser (Topcon) was the first pattern scanning laser designed for retinal indications.
Boyer said that while treatment with the Pascal can be plotted with fluorescein angiography or optical coherence tomography, the Pascal is even better suited for panretinal photocoagulation than for focal treatment.
“If you find that grid therapy is all that you need and that focal is not necessarily important, the Pascal is a very good laser,” Boyer said.
While conventional laser therapy may cause atrophic creep, or scarring that diminishes vision, the Pascal reduces the risk for that complication, Dugel said.
Other pattern lasers include the Visulas 532s (Carl Zeiss Meditec).
Navigated retinal photocoagulation began in 2009 when the Navilas laser system (OD-OS) received 510(k) clearance from the U.S. Food and Drug Administration. The Navilas features eye tracking and guidance.
“I think the Navilas is by far the most accurate of all the lasers,” Boyer said. “The Navilas is computer-guided, placing marks only in a predetermined area.”
Treatment with the Navilas can be guided by fluorescein angiography or OCT, enabling surgeons to avoid damaging vital retinal anatomy and not applying treatment to normal areas.
“You can precisely put laser marks specifically over the area where you want to minimize any tissue damage and minimize any collateral damage to the normal retina,” Boyer said.
Fluorescein angiography detects two to three times more microaneurysms than can be identified on clinical examination, Brown said. After pinpointing the site to receive treatment, the navigated laser acquires and maintains that target for the operator.
“You still have to put your foot on the foot pedal, but if the patient moves, it doesn’t fire. If the patient blinks, it doesn’t fire. And it hits exactly in the spot you want,” Boyer said.
Guidance and tracking with the Navilas enable safer laser treatment, Hariprasad said.
“[With the traditional laser], you see this graying of the retina, so you know you got a burn,” Hariprasad said, but using subthreshold treatment, there are no retinal changes.
“Without laser-assisted photodocumentation, you have no way of knowing where you did the laser treatment. That’s a very important concept and a solution that Navilas provides,” he said.
Downsides of the Navilas are longer planning time and higher equipment cost, Brown said.
“To really look at the microaneurysms and to plan your treatment take more time than with regular focal laser,” he said. “And it’s a significant capital expenditure.”
Some lasers, such as Quantel Medical’s SupraScan 577 and Vitra Multispot laser, feature multi-spot and micropulse capabilities and offer a broad range of treatment patterns and precisely controlled energy emission.
The Iridex IQ 577 true yellow laser coupled with the TxCell Scanning Slit Lamp Adapter features precise pattern and MicroPulse delivery of laser energy.
“What I like about it is the consistency of delivering the ultra-low subthreshold laser therapy,” Mansour said. “With the pattern system, the laser treatment is delivered in a more consistent fashion, avoiding untoward late-term sequelae like scar expansion or pigmentary atrophy, which we experienced with continuous wave lasers. There’s a larger margin of safety.”
Retina laser ‘wish list’
Visualization tops Hariprasad’s wish list of capabilities that would make laser photocoagulation safer, more accurate and more efficient.
“When I use a traditional laser, I use a lens that I put on the patient’s eye and the image is inverted,” he said. “It’s upside down, and visualization is through a little slit beam. We need to see better so that we can treat better.”
Live visualization on a large computer display would be beneficial, Hariprasad said.
Mansour echoed Hariprasad’s sentiments about visualizing areas targeted for treatment.
“The ultimate ‘holy grail’ that we’re trying to reach is to be able to look on a computer monitor at the patient’s fundus in wide angle and circle the areas that need treatment, specify the treatment parameters and then put the patient in front of the laser and have the laser deliver the treatment automatically,” Mansour said.
Second on the list is the ability to plan treatment, Hariprasad said.
“That’s one big shortcoming of the previous lasers, that in real time you cannot preplan the treatment,” he said.
Surgeons want the ability to overlay a fluorescein angiogram on a fundus image of the area that is going to receive laser treatment, Hariprasad said.
“The way it works now is, we do a fluorescein angiogram or an OCT in a separate room,” he said. “The tech puts it up on the screen in the room where we do the laser. I look up at the screen to get a mental image of where I need to do laser, then look back in the patient’s eye through that tiny slit beam, and then I conduct my laser treatment. You can imagine the inaccuracy in this traditional way of doing laser.”
Mansour also expressed a desire for the integration of pattern recognition and fundus imaging, saying that the Navilas approach is moving in that direction.
“You’re going to hear more about this in the near future,” Mansour said.
One solution might be to overlay the OCT images on areas being visualized in real time in order to mark areas of retinal thickness and obtain objective retinal topographic information to guide laser treatment, Hariprasad said.
Lastly, most subthreshold lasers do not incorporate documentation of treated areas because of limitations in technology, Hariprasad said.
“In the old days, we would take a pen and paper and draw Xs where we did the laser,” he said. “With the Navilas, you can actually have very good photodocumentation. I can go back to the previous laser appointment and say, ‘This is exactly where the patient had retinal laser treatment performed.’”
Combined laser, anti-VEGF
The treatment burden of anti-VEGF monotherapy is large and unsustainable, particularly for patients who are too busy to undergo multiple injections or are noncompliant with treatment plans, Dugel said.
“The treatment burden from monotherapy is enormous,” Dugel said. “In reality, patients are not getting the kind of results that the clinical trials would suggest they should be getting. There’s a big disconnect between clinical trials and real clinical practice.”
Dugel said some studies show the benefits of combined therapy in terms of treatment burden.
“There are a lot of studies [such as the READ studies] that have shown us that if you combine anti-VEGF injections with laser photocoagulation, that the treatment burden is less and that you need fewer injections,” Dugel said. “That seems to be the most sustainable solution until we find something else that would help with that.”
Dugel noted that the Early Treatment Diabetic Retinopathy Study is often misunderstood.
“As far as not improving vision is concerned, there was a clear ceiling effect in that study,” Dugel said. “There were a number of patients who were recruited who had 20/40 vision, so they couldn’t improve by three lines. Mathematically, they couldn’t improve. Of the patients who could improve, I think it was about 40% that actually did improve. So, ultimately, that myth is perpetuated, that laser somehow doesn’t improve vision. It just improves vision in a different time frame than anti-VEGFs. Anti-VEGFs act very quickly, and laser tends to be more sustainable and acts slowly.”
The Diabetic Retinopathy Clinical Research Network Protocol I study implied that monotherapy anti-VEGF outperformed anti-VEGF therapy combined with laser photocoagulation in terms of visual gain, Brown said.
“As a result, focal laser has really diminished in terms of number of procedures, how often it’s used, even the number of patients who even are offered laser because so far we haven’t proven that there is a role for laser in an anti-VEGF era,” he said.
To gather more data on the efficacy of laser treatment, Boyer and Brown, along with Lloyd Clark, MD, and John Payne, MD, of Palmetto Retina Center in West Columbia, S.C., are undertaking the TREX-DME study (treat-and-extend regimen with and without navigated retinal photocoagulation for diabetic macular edema), a multicenter clinical trial sponsored by Genentech.
The TREX-DME study will include 150 patients: 60 patients randomized to a treat-and-extend ranibizumab regimen plus adjunctive navigated laser treatment with the Navilas; 60 patients randomized to undergo the treat-and-extend regimen alone; and 30 patients randomized to monthly ranibizumab injections.
Patients will be followed for 24 months. Investigators will assess change in vision and number of injections.
Ultimately, results of the TREX-DME study may shed new light on the efficacy of laser treatment, at least with the Navilas laser, Brown said.
“If we do this trial and either it doesn’t lead to fewer [ranibizumab] shots or the visual acuity is not as good as the other arm, we’ll know that at least we used the best possible laser,” he said. “Then, if that’s the case, laser is dead. There will be no role for focal laser. Our hypothesis, though, is that treating these leaking microaneurysms is going to, at the very least, decrease the number of injections needed to maintain a dry retina.”
Preliminary results of the TREX-DME study are expected to be released in fall 2014, Brown said.
At the 2013 Euretina meeting in Hamburg, Germany, Marcus Kernt, MD, reported that combined navigated laser treatment with the Navilas and as-needed ranibizumab injections reduced anti-VEGF re-treatment rates by more than 50% while maintaining gains in vision.
At 12 months, 65% of the combination therapy group had required no additional injections after the loading phase. During the same period, 84% of ranibizumab monotherapy patients required additional injections to sustain visual gains, according to an OD-OS news release.
Laser with steroid delivery
Laser treatment may also be combined with implantable steroid delivery devices such as Ozurdex (dexamethasone intravitreal implant, Allergan) and Iluvien (fluocinolone acetonide intravitreal insert, Alimera). The dexamethasone and fluocinolone acetonide implants are up for FDA approval for treatment of DME.
“It’s not just a matter of having access to all of the anti-VEGFs, which we do. It’s not just a matter of having access to all of the lasers, which I hope we will as new lasers come out. I’d also like to have access to both of the steroid delivery devices, Ozurdex and Iluvien,” Dugel said. “Ultimately, the way that I think we’ll treat diabetic macular edema is by having access to all of these different modalities, and we’ll individualize treatment based on the patient’s need.”
Unlike anti-VEGFs, intraocular steroids target inflammation, an overlooked component of DME, Dugel said.
“We do know that diabetic macular edema is a multifactorial disease, that it’s not just leakage, that there’s also inflammation involved, particularly for chronic diabetic macular edema or severe diabetic macular edema that’s diffuse. There are good studies that show that steroid delivery devices may have a very important role there,” he said.
The implants require different treatment protocols because they are distinct agents with different elution rates, Dugel said.
“Not all steroids are the same. These two devices aren’t the same. They have a different [pharmacokinetic profile]. They have a different elution rate. The Ozurdex device has an initial elution that’s high and then a gradual decline. The Ozurdex device may work for anywhere from 3 to 4 months. Then there’s the Iluvien device, which is a near-zero-order kinetic that may work for 3 years,” Dugel said. – by Matt Hasson
For more information:
In a treat-and-extend approach to managing DME, do you prefer to integrate laser photocoagulation early or late in the course of treatment?
Use laser early for non-center or recalcitrant DME
Multiple clinical trials have shown benefit of anti-VEGF agents for management of center-involving DME. Therefore, my first-line treatment for DME involving the fovea would be a series of intravitreal anti-VEGF injections. However, for non-center involving DME that meets the definition of clinically significant DME, my first-line treatment would be laser photocoagulation. Laser would be also considered for DME that is refractory to anti-VEGF therapy.
In cases in which there are microaneurysms that appear to be obvious sources of edema, such as those surrounded by a ring of hard exudates with retinal thickening, earlier laser treatment aimed at those microaneurysms could be considered. In cases in which there appears to be associated vitreomacular traction or taut posterior hyaloid contributing to DME, vitrectomy would be considered if refractory to anti-VEGF therapy.
While anti-VEGF therapies have revolutionized our management of DME, we are fortunate to have multiple potential treatment modalities for DME, and the treatment should be tailored to the patient.
Judy E. Kim, MD, is an OSN Retina/Vitreous Board Member. Disclosure: Kim has attended an advisory board for ThromboGenics.
Use laser later for unresponsive cases
Most cases of clinically significant DME have center-involving thickening and decreased visual acuity. In such cases, anti-VEGF therapy has become first-line treatment because studies show better visual outcomes with anti-VEGF therapy compared with laser photocoagulation. These outcomes have been demonstrated with continuous, frequent, fixed injection and as-needed injection protocols.
The degree of visual acuity improvement and mean number of injections per year are about the same whether or not laser photocoagulation is performed early in the course or deferred until after several months of anti-VEGF treatment. The DRCR.net Protocol I trial showed that the mean number of injections decreases over time with or without laser, so many patients do not seem to need frequent or even ongoing anti-VEGF injections for DME after the first year or two of treatment.
Retina specialists frequently use a treat-and-extend approach with anti-VEGF therapy for DME, although most of what is published with this style of treatment is with wet AMD. Regardless, the trend for needing fewer anti-VEGF injections over time is likely to be present with the treat-and-extend approach in DME and the as-needed approach. It seems logical to consider laser photocoagulation later in the course of anti-VEGF therapy for cases that do respond adequately to anti-VEGF therapy alone or for cases that require very frequent anti-VEGF therapy over time to keep DME under control.
Furthermore, treating DME with laser early on when there is moderate or severe edema may result in laser spots that are larger or heavier than desired and, in such cases, may result in excessive photocoagulation damage in the macula.
Carl D. Regillo, MD, is an OSN Retina/Vitreous Board Member. Disclosure: Regillo has received research grant support from and is a consultant for Allergan, Genentech and Regeneron.