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PDT: Its future may be in combination treatments
Recent studies have suggested that photodynamic therapy may not be the most effective treatment for patients with neovascular age-related macular degeneration. Neovascular AMD is characterized by the development of choroidal neovascularization, in which new blood vessels grow from the choroidal circulation into the subretinal pigment epithelial (sub-RPE) and subretinal spaces. Since the late 1990s, PDT has been used to treat patients with neovascular AMD. PDT utilizes the photoactive drug verteporfin, which is activated by laser and results in the production of free-radical oxygen intermediates, leading to vascular thrombosis in the treatment area. Clinical trials have demonstrated that PDT leads to less vision loss compared to the natural history of subfoveal CNV associated with AMD. However, patients and physicians have wanted more out of the treatment, and many clinicians have added the use of intravitreal triamcinolone to standard PDT treatment with positive results.
Newer treatment strategies are a departure from the mechanisms of PDT and target one of the neovascular growth factors believed to be important in the development of CNV, vascular endothelial growth factor (VEGF). Results of recent phase 3 clinical trials suggest that some of the anti-VEGF agents may lead to visual improvement, raising the bar of our expectations for patients with subfoveal CNV. However, current anti-VEGF treatments require intravitreal injections every 4 to 6 weeks, with uncertain endpoints.
Because the mechanism of anti-VEGF agents, intraocular steroids and PDT are unique, combining the treatments may result in an additive effect, leading to improved visual acuity and reduced dependence on repeat treatments.
PDT monotherapy results signal need for new treatments
The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation demonstrated a benefit of PDT over the natural history for predominantly classic subfoveal CNV. Despite effective treatment, patients continue to lose vision on average, though significantly less than without treatment. In the TAP and TAP extension studies, verteporfin was found to be well tolerated with few systemic or ocular side effects. For minimally classic or occult with no classic CNV lesions, PDT treatment is controversial. The Verteporfin in Photodynamic Therapy (VIP) Trial showed a benefit of PDT treatment over the natural history for occult with no classic CNV lesions at year 2, but not at the 1-year follow-up. Subgroup analysis suggested that this benefit extended to patients with lower levels of VA ( <20/50) and/or smaller lesions ( <4 Macular Photocoagulation Study [MPS] disc areas). Limited reports from the Verteporfin in Occult CNV (VIO) Trial bring into question the conclusions of the VIP Trial because the primary endpoints of this more recent trial were not met at 1 or 2 years following enrollment. A full report of the VIO Trial will be forthcoming. The role of PDT in minimally classic CNV lesions is also unsettled, with suggestion from the TAP and Verteporfin in Minimally Classic CNV (VIM) trials that smaller minimally classic CNV lesions ( <4 MPS disc areas) may benefit from treatment over the natural history. To date, more than 500,000 patients have been treated with verteporfin, and it appears to be safe with few systemic side effects. However, between 1% and 4% of patients treated with verteporfin may experience immediate severe vision decrease following treatment.
Pegaptanib: The first out of the blocks
Pegaptanib was the first anti-VEGF agent approved for the treatment of neovascular AMD. The VEGF Inhibition Study In Ocular Neovascularization (VISION) trials, which compared pegaptanib and usual care, concluded that pegaptanib was better than usual care in the treatment of all angiographic subtypes of subfoveal CNV. However, pegaptanib treatment rarely leads to significant visual improvement, and on average patients lose VA. Pegaptanib is safe with more than 50,000 treatments to date, and the main risk is the rare case of endophthalmitis.
To date, no “head-to-head” clinical trial has compared pegaptanib with verteporfin for the treatment of subfoveal CNV. It is unlikely that such a trial will take place because monotherapy with either agent is becoming passé in the retina community with the availability of ranibizumab. Comparison of the results of the TAP, VIP and VIM trials with the VISION trials demonstrates no advantage of one treatment over another; however, in cases of large occult or minimally classic lesions (for which PDT is not recommended), pegaptanib may have an advantage.
New antiangiogenic treatment options
Ranibizumab and bevacizumab have created excitement in the ophthalmologic community and will likely set a new standard for treatment of neovascular AMD.
Recently, two large randomized multicenter clinical trials have reported favorable 12-month results of ranibizumab in the treatment of occult and minimally classic CNV vs. observation (MARINA trial) and ranibizumab vs. PDT (verteporfin) in the treatment of predominantly classic subfoveal CNV in AMD (ANCHOR trial). In the MARINA trial, 716 patients were included; 240 patients received 0.5 mg ranibizumab, 238 patients received 0.3 mg ranibizumab and 238 patients received sham treatment. This study met its primary endpoint with more than 95% of patients in the treatment arm vs. 62% in the sham arm losing less than three lines of vision during the first year of treatment. At all time points, patients who received 0.3 mg of ranibizumab or 0.5 mg on average gained VA, whereas patients who received sham treatment lost vision in a similar fashion to the natural history group of other clinical trials.
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Because bevacizumab and ranibizumab are produced from a common derivative, they may have similar biologic effects. Initial attempts to use bevacizumab focused on intravenous administration because animal studies suggested that the full-length antibody might not penetrate the retina, limiting its ability to treat pathology present in the outer retina. An initial report of intravenous bevacizumab demonstrated a clear-cut biologic effect on reducing retinal edema and subretinal fluid on optical coherence tomography and fluorescein angiographic leakage with associated improved vision. Systemic side effects of intravenous bevacizumab include hypertension, increased risk of thromboembolic events and wound dehiscence.
Initial reports suggested that intravitreal drugs, like intravenous bevacizumab, can rapidly reduce retinal, subretinal and sub-RPE fluid with concomitant visual improvement. These reports are preliminary, and ophthalmologists must await larger controlled trials to determine the benefit of this agent vs. other standard accepted treatments. Bevacizumab appears to be safe and our own experience treating more than 250 patients with subfoveal CNV with up to 6 months of follow-up failed to demonstrate significant ocular or systemic adverse events. Bevacizumab is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer; its intravitreal application in the treatment of AMD is an off-label use.
Combination therapy trials
Given the shortcomings of current therapies and the potential of multiple treatments in future therapies, combination therapy may offer advantages. Combination therapy incorporates multiple mechanisms of action that are potentially additive and may also reduce the total number of treatments. Reducing the frequency of treatment will be desirable as current anti-VEGF protocols require ophthalmologists to inject patients every 4 or 6 weeks.
The first combination therapy to be used was PDT and triamcinolone. The anti-permeability, anti-inflammatory and anti-VEGF effects of triamcinolone indicate it will perform well with PDT. Triamcinolone is inexpensive and readily available, but its use is off-label.
The first series of combination PDT and triamcinolone included 26 patients; half had prior PDT treatments, and half were naive to treatment. In this series, the group without prior PDT demonstrated average improvement, and the others demonstrated stabilization of vision, results that may be better than PDT alone.
Despite the limited controlled clinical data supporting the use of PDT and triamcinolone, its use has gained widespread acceptance in the retina community. Safety issues include endophthalmitis, elevated IOP, cataract and the additional risks associated with PDT. Randomized clinical trials are underway to define the role of combination therapy in AMD management.
Given the benefit of monotherapy with anti-VEGF agents, additional benefit or reduction in retreatment may be possible by adding PDT. One recent clinical trial, the RhuFab V2 Ocular Treatment Combining the Use of Verteporfin to Evaluate Safety (FOCUS) trial, explored combination therapy. In this trial, patients with predominantly classic subfoveal CNV were randomized to PDT alone or in combination with 0.5 mg of ranibizumab. A total of 162 patients were included; 106 patients received ranibizumab and 56 received combination therapy. Not all patients were naive to PDT; nearly 50% of the patients had between one and eight prior PDT treatments before enrollment in this study.
The FOCUS study required initial PDT combined with ranibizumab treatment. The patients received additional ranibizumab therapy every month and consideration for additional PDT every 3 months if the investigator felt it was necessary. Because there was a suggestion that combined therapy might result in significant intraocular inflammation earlier on, the protocol was amended. If additional PDT was performed, the scheduled dose of ranibizumab was not administered for 4 weeks.
At 12 months, 90.5% of patients treated with PDT and ranibizumab lost less than three lines of vision from baseline compared to 67.9% of patients who received PDT with sham injection. Vision improved three or more lines in 23.8% of patients treated with PDT and ranibizumab compared to 5.4% of patients who received PDT alone. The most striking difference, however, was that at 1 year following enrollment the PDT group lost just over 8 letters on the Early Treatment of Diabetic Retinopathy (ETDRS) chart, whereas the combination group experienced an average 5 letters of vision (Figure). The mean number of PDT treatments received by patients in the ranibizumab and PDT arm was 1.3, and 3.4 treatments were received by the patients in the PDT arm. Ranibizumab appeared to be safe in this study, although there was one patient with culture positive endophthalmitis and four patients with significant noninfectious uveitis or culture negative endophthalmitis who received intravitreal antibiotics. Significant systemic side-effects were not evident in this series, and the rates of thromboembolic events were balanced between the groups.
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Figure. At 1 year following enrollment the PDT group lost just over 8 letters on the ETDRS chart, whereas the combination group experienced an average of 5 letters of vision.2 Source: Pieramici D.J. |
Conclusion
With the advent of ranibizumab and bevacizumab, visual outcomes will reach unprecedented levels for patients with subfoveal CNV. For years, PDT has provided better visual outcomes than the natural history. With modern expectations, monotherapy with PDT may no longer be appropriate for most patients. Because the mechanism of action of PDT is different from that of the anti-VEGF agents, combination therapy with the pharmacologic agent may provide better outcomes and/or greater durability than either treatment modality alone. Whether this is true will require good clinical trials of the many potential treatment options. In the end, these newer treatment strategies will produce relief for millions of patients worldwide.
References
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- Avery RL, Pieramici DJ, Rabina M, et al. Bevacizumab in the treatment of neovascular AMD and other retinal vascular diseases. Paper presented at the American Academy of Ophthalmology Annual Meeting Preacademy Retina Meeting; October 2005; Chicago, Ill.
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