Monday, June 5, 2023
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The American Society of Retina Specialists (ASRS) 2005 Annual Meeting was held in Montreal, Canada. Much of the buzz surrounding the meeting centered on the developing research and results of the anti-vascular endothelial growth factor (anti-VEGF) agents for the treatment of occult and minimally classic exudative age-related macular degeneration (AMD). Other therapeutic approaches were also discussed, as was some of the newer instrumentation involved in retinal surgery. The highlights of the meeting are reviewed in this article.
The most compelling, well-substantiated information presented at ASRS were the year-1 data on the anti-VEGF agent ranibizumab, used for minimally classic and occult lesions of exudative "wet" AMD.[1] The MARINA study of ranibizumab was a phase 3, multicenter, randomized, double-masked, sham injection-controlled study in which 716 participants were randomized in a 1:1:1 ratio to receive intravitreal injections of 0.5 mg of ranibizumab, 0.3 mg of ranibizumab, or a sham injection every month for 2 years. Although photodynamic therapy (PDT) could be performed if the lesions converted to classic lesions or more than 20 letters were confirmed lost on 2 consecutive visits, only 1 patient who received ranibizumab required PDT. Indeed, 95% (452/478) of patients receiving ranibizumab at 12 months met their primary end point of a less than 15-letter loss compared with 62% (148/238) of sham-therapy patients. Moreover, 25% to 34% (0.3- to 0.5-mg dose) of patients receiving ranibizumab gained 15 or more letters, compared with 5% of the sham group.
In terms of side effects, there were no culture-positive cases of endophthalmitis in the MARINA study. There were 3 cases of culture-negative endophthalmitis, 3 cases of uveitis, 2 retinal tears, 2 with vitreous hemorrhage, and 1 with lens damage. Cerebrovascular accidents occurred, with 1 in the sham group, 1 in the 0.3 mg group, and 3 in the 0.5 mg group. Still, there were no clear statistically significant systemic safety issues with ranibizumab and no observed increase in hypertension. Overall, patients treated with ranibizumab gained 7 letters and the sham group lost 10.5 letters -- and there seemed to be a trend of improved outcome with the higher-dose group. Based on these results, ranibizumab is expected to be evaluated by the US Food and Drug Administration (FDA) for the treatment of choroidal neovascularization (CNV) secondary to AMD.
Dr. Philip Rosenfeld reported on the off-label use of bevacizumab, a complete monoclonal antibody against the isoforms A of VEGF that is an FDA-approved treatment of colorectal cancer. (Ranibizumab is derived from the Fab fragment of bevacizumab.) Dr. Rosenfeld reported promising results from a pilot study of a few patients receiving an intravitreal injection (1.25 mg of the commercially available product) and an open-label prospective study of 18 patients with exudative AMD receiving the drug intravenously.[2,3] Patients enrolled in the intravenous study had subfoveal lesions with a central macular thickness of greater than 300 microns (pegaptanib was not available at the time). The mean visual acuity of the study eye was 20/80. They were infused at baseline, week 2, and at the final week 4 as needed. There was an improvement of 7 letters by week 1 and 13 letters by week 24, with an associated improvement of macular thickness by optical coherence tomography. Overall, no bevacizumab-treated patient lost a single letter, and only 6 required more than the 2-3 initial infusions. It is thought that retreatment could be indicated by increased retinal thickness alone.
While these findings appear promising, studies must proceed with caution as there are several adverse effects associated with bevacizumab. Systemic administration has been associated with hypertension, delayed wound healing, thromboembolic disease, and spontaneous intestinal perforation with patients with gastrointestinal malignancies. The presenters stressed that much further investigation needs to be performed because the efficacy and safety of bevacizumab use has not been established. In the study, 10 of the 18 patients required medication for hypertension.
The FOCUS trial[4] is a single masked randomized phase 1/2 trial comparing PDT with combination treatment of intravitreal ranibizumab and verteporfin therapy, for subfoveal predominantly classic lesions secondary to AMD. Patients could have received prior PDT. The primary end point was the proportion of patients losing less than 15 letters of vision at month 12 compared with baseline. The study included 162 patients randomized 2:1 to PDT with intravitreal medicine compared with sham injection. The initial protocol of intravitreal therapy administered at day 7 post-PDT was modified because of onset of uveitis -- intravitreal therapy was held for 1 month after PDT was administered. Twelve patients developed severe uveitis when combination treatment occurred within the same month, and no uveitis occurred subsequent to protocol modification.
Overall, 90.5% of combination patients in the FOCUS trial lost less than 15 letters of vision, compared with 68% with PDT alone. In addition, 24% of patients gained 3 lines of vision compared with 5% of PDT alone. Severe vision loss occurred in 1% of patients with intravitreal therapy compared with the PDT-alone arm. At 3 months, only 16% of combination patients required additional PDT compared with 80% in the PDT-alone arm. At month 12, there was an astounding reduction of a mean of only 0.3 additional PDT treatments required in the combination arm to 2.4 PDT treatments in the PDT-arm alone. A lyophylized version of the drug was used in this phase 1/2 trial.
Quan Nguyen, MD,[5] presented a successful outcome in a pilot study on the use of intravenous bevacizumab in CNV due to pathologic myopia refractory to other treatment. Of course, the use of bevacizumab is subject to the same safety warnings as discussed above. He suggested that VEGF likely plays a role in choroidal neovascular membranes secondary to ocular histoplasmosis and uveitis. He also announced a trial of intravenous bevacizumab currently recruiting for CNV membrane in non-AMD, where its safety will be followed by a team of specialists.
The combination of intravitreal triamcinolone acetonide and verteporfin was used by a majority of surveyed retina specialists, potentially resulting in the less frequent use of PDT. Gregory R. Blaha, MD, PhD,[6] discussed profound choroidal hypoperfusion that occurred after simultaneous PDT and intravitreal triamcinolone acetonide therapy. In the discussion session that followed the presentation, the use of intravitreal triamcinolone acetonide without immediate simultaneous PDT therapy was suggested as a possible solution to diminish the risk of choroidal hypoperfusion.
Ingrid Scott, MD,[7] presented the first data comparing outcomes, retrospectively, of patients who received 1000 (82 eyes) vs 5000 (242 eyes) centistoke silicone oil after retinal detachment surgery from 1995-2000. She commented that surgeons at her institution tended to favor 5000 centistoke because of better filling with less efflux of silicone oil from the eye during suturing of sclerotomy sites. There were no significant differences in recurrent retinal detachment, cornea abnormalities, or visual outcomes.
The issue of the development and evaluation of new medicines was addressed by William Rich, MD,[8] who urged a more active role for retina physicians. Noting that there is a scant role for physicians uninfluenced by industry outside reviewing agencies, Dr. Rich argued that unbiased physicians must be part of a future that will make value-based judgments on medical practice and technologies. Dr. Mark Blumenkranz[9] suggested a matrix model for medical value practice evaluation where specific matrix addresses identify the intersection of cost, tolerability, and efficacy.
Paul Tornabe, MD,[10] offered some simple ways to improve the operative room experience for the retina surgeon. He suggested using a Keeler wireless indirect ophthalmoscope, decreasing the number of additions to the operating microscope only to those absolutely needed for a particular case, and a Tegaderm drape. His typical vitrectomy setup consisted of 2 superior 20-gauge transconjunctival sclerotomies, a 23-gauge self-retaining infusion cannula, and a 25-gauge torpedo when bimanual surgery is needed. He stressed the need to hold the conjunctiva and sclera together when making transconjunctival sclerotomies, and noted that he usually places his torpedo light superiorly if it clears the lid and inferiorly if it does not. Looking to the future, there may be need for the development of a side-port infusion cannula to prevent infusion-related forces from damaging the posterior pole in a gas-filled eye. Finally, he usually closes his 20-gauge scleral wound with a vicryl suture and conjunctiva with bipolar cautery.
There is a high risk of medical emergencies in retina clinics. Ingrid Zimmer Haller, MD,[11] reviewed optimal ways to deal with them. Ideally, a clinic should have telephone access, an automatic defibrillator, glucose, oxygen, blood pressure cuff, stethoscope, pocket mask or equivalent, automatic epinephrine injectors, and an emergency treatment plan. But the first important step is to call the emergency services promptly. In addition, Dr. Haller stressed that automatic epinephrine injectors are relatively inexpensive, and a few should be purchased every 6 months because of expiration dates and the likely need for frequent administration.
Dr. Jerzy Nawrocki[12] commented on the diverse features available on a new intraoperative microscope that utilizes slit-lamp illumination (OMS-800 OFFISS). He noted that it allows true bimanual intraoperative surgery without the need for intraocular illumination and even can be used in scleral buckling. The downsides include the need for change of microscope height when switching to the viewing system and the lack of a vertical slit-lamp feature.
The uses and mechanics of 25-gauge instruments continued to find a broader interested audience. New explored techniques included beveled sclerotomy incisions and inserting a light pipe prior to sclerotomy cannula removal to improve sclerotomy closures.
Supported by an independent educational grant from Genentech.
