Over the past decade, new treatment options have become available for the management of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). These treatments help delay the progress of CNV, offering a temporary slowing and even some reversal of new blood vessel growth. Some provide improvements in visual acuity.
The difficulty in finding a more robust and lasting treatment for this condition is multifactorial; it may be due, in part, to the fact that no single action or chain of events is responsible for all of the damage to the retina. Multiple pathways or factors are involved, and treatments must address each of these pathways in order to be efficacious. Therefore, combination therapies that target two or more of these factors may be the most ideal way to treat CNV.
NEOVASCULARIZATION AND THE ANGIOGENIC CASCADE
In normal, healthy humans, angiogenesis plays a crucial physiologic role in tissue and organ growth, wound healing, and many other processes. However, irregular and uncontrolled proliferation of new blood vessels can promote metastasis or tumor growth. In the context of eye disease, this proliferation presents as CNV (Figure 1A).
Although vascular endothelial growth factor (VEGF) is the most important growth factor in neovascularization, it is not the initiating factor. After normal aging, smoking1 is one of the most significant contributing factors in the development of AMD because it induces oxidative stress in the retinal vasculature. Other risk factors known to induce trauma or stress in the blood vessels include high body mass index and waist circumference, lack of physical exercise,2 elevated systolic blood pressure, and subclinical atherosclerosis.3
It must also be noted that VEGF expression occurs as an epiphenomenon secondary to other processes that have different triggers. It has been shown, for example, that the expression of VEGF is upregulated in the endothelial layer of the choriocapillaris as well as in larger choroidal vessels in eyes that have undergone photodynamic therapy (PDT). Also, CNV itself triggers inflammation in the adjoining tissue, and this again upregulates the expression of VEGF.
TREATMENT OPTIONS AND THEIR LIMITATIONS
Anti-VEGF drugs
In the therapeutic setting, treating CNV is not as simple as targeting the angiogenic cascade or any one of its stages. Three antiangiogenic therapies are now widely available: the VEGF aptamer pegaptanib sodium (Macugen; OSI/Eyetech Pharmaceuticals, New York, New York), and the monoclonal antibodies ranibizumab (Lucentis; Genentech, South San Francisco, California), and bevacizumab (Avastin; Genentech). Each of these acts by inhibiting the formation of new blood vessels, and has shown some efficacy in reducing CNV.
But although anti-VEGF monotherapy appears useful for blocking new blood vessel formation, recent research has suggested that it also stimulates the release of compensatory proangiogenic factors that counteract its anti-VEGF activity and induce new blood vessel formation (Figure 1B). This compensatory reaction was not seen in laboratory animals that received a combination therapy involving three elements: an anti-VEGF agent, an integrin-antagonist, and an antagonist of VE cadherin-mediated adhesion. It was observed in animals treated with anti-VEGF monotherapy.4
Anti-VEGF treatment will antagonize CNV, reduce or stop vessel leakage, and alleviate edema, but this effect lasts only as long as the anti-VEGF agent itself. Once the anti-VEGF effect has worn off, leakage and edema recur. This happens because the compensatory action of releasing new VEGF continues to stimulate neovascular growth, even as the anti-VEGF treatment blocks the formation of abnormal vasculature. Patients could conceivably be required to undergo anti-VEGF treatments for an unlimited and unknown length of time.
Furthermore, in view of the upregulation of proangiogenic factors in response to anti-VEGF treatment, this could suggest a rebound effect should the patient ever discontinue anti-VEGF therapy.5 Therefore, controlling or antagonizing the upregulation of VEGF in any of its isoforms is now thought to be only one of the processes involved in treating CNV.
PDT
A second aspect of treating CNV is eradicating the existing neovascularization. No matter how effective an antiangiogenic drug may be in preventing the sprouting of new blood vessels in the retina, it does nothing to address the issue of already established CNV. Verteporfin PDT (Visudyne, Novartis, Basel, Switzerland), approved as a treatment for CNV in 1999, offers a complementary action to that of anti-VEGF agents. Whereas anti-VEGF drugs arrest or slow the development of new blood vessels, PDT eradicates CNV that has already formed.
Numerous studies have demonstrated the benefit of PDT in patients with classic subfoveal, predominantly classic, and occult CNV. Most trials with PDT as monotherapy demonstrate a reduction or slowing in vision loss rather than an improvement in visual acuity.
In recent years, certain drawbacks to PDT monotherapy have been identified. First, the therapy requires additional treatments as new CNV arises. Second, PDT leads to overexpression of VEGF in the endothelial layer of the choriocapillaris as well as within larger vessels. Thus, like anti-VEGF when used as monotherapy, PDT also stimulates VEGF expression, which could in turn lead to more neovascular proliferation. Third, PDT is known to cause inflammation, which exacerbates the cycle of VEGF upregulation and can trigger neovascularization.
Steroids
The use of intravitreal corticosteroids has also been proposed as a treatment for CNV. There are several reasons for this. The steroid triamcinolone acetonide has antiinflammatory properties and so could be beneficial for combating inflammation that results from both oxidative stress and PDT. All inflammatory cells are known to make and release VEGF6; therefore, triamcinolone and other steroids that have antiangiogenic properties could conceivably be used to block this VEGF expression. Steroids also have antifibrotic and antipermeability characteristics that help maintain the blood-retina barrier.
Several studies that have used triamcinolone as monotherapy have produced mixed results, and their results were far from conclusive. When used in combination with PDT, however, triamcinolone seems to offer a synergistic action.7
A drawback to the use of intravitreal triamcinolone is that it may lead to intraocular pressure (IOP) increase.8 Another steroid, dexamethasone, has also been proposed as a useful treatment. It is short-acting, and it exerts little action on the trabecular meshwork. It is, therefore, not associated with the spikes in IOP that are seen with triamcinolone use.
RATIONALE FOR TRIPLE THERAPY
Each of these treatments, when used as monotherapy, has its own benefits in attacking certain aspects of the angiogenic cascade. Each one has drawbacks as well: PDT leads to inflammation, which also stimulates VEGF expression; anti-VEGF drugs stimulate compensatory VEGF expression; and steroids increase IOP and the risk of cataracts. With this in mind, it is reasonable to propose that a combination therapy involving each of these treatments, used concomitantly, might offer some level of synergistic action (Figure 1C).
Augustin and colleagues9,10 treated a total of 225 patients with all forms of CNV lesions with dual therapy of verteporfin PDT and triamcinolone. After one treatment, the majority of patients had significant (P<.0001) and sustained improvement in visual acuity, and for many patients these improvements lasted through 40 weeks to 2 years follow-up.
These results demonstrate that combination therapy with verteporfin PDT and intravitreal triamcinolone is more effective than either agent used as monotherapy. The fact that retreatments were needed, however, suggests that PDT-steroid combination therapy still is not adequate. To address this issue, Augustin et al proposed that, owing to the entirely different but complementary mechanisms of actions among verteporfin PDT, steroids, and antiangiogenic drugs, a combination therapy involving all of these options could potentially improve visual acuity. This improvement could be sustained for longer periods of time, entail fewer treatments, and/or produce fewer adverse side effects.
PATIENTS AND METHODS: UPDATED RESULTS
In an interventional case series, 104 patients with all types of CNV were treated with verteporfin PDT, intravitreal dexamethasone, and bevacizumab and followed for 62 weeks. The antiangiogenic agent bevacizumab was chosen over ranibizumab because bevacizumab, in a previous study, was found to improve visual acuity by as much as 38%, and this improvement lasted approximately 90 days following a single injection.11 Ranibizumab requires an unlimited number of monthly treatments, which is a costly and inconvenient regimen for the patient. One of the endpoints of this investigation was to determine whether comparable sustained improvements in visual acuity could be achieved with a single treatment.
PDT was administered with a reduced light dose (42 J/cm², with light delivery time of 70 seconds). Approximately 16 hours after PDT, dexamethasone (800 µg) and bevacizumab (1.5 mg) were applied intravitreally.
Patients attended follow-up visits every 6 weeks, undergoing visual acuity and IOP measurement, slit-lamp and ophthalmoscopic examinations, and optical coherence tomography (OCT). Fluorescein angiography was performed every 3 months or earlier if OCT showed significant edema.
All 104 patients received one triple therapy cycle. Five patients received a second triple treatment due to remaining CNV activity. The triple therapy was complemented in 23 patients (22.1%) by an additional intravitreal injection of bevacizumab. The mean follow-up period was 62 weeks. Mean improvement in visual acuity was 1.78 lines (P<.01). Mean decrease in retinal thickness was 171 µm (P<.01). No serious adverse events such as IOP increase or cataract progression have been observed. The results are presented in Figures 2 and 3.
CNV is initiated and propagated by a chain of events involving numerous pathways. One drug or treatment will not address every link in this chain of events. Different drugs and different procedures used concomitantly will be needed to counteract each process in the cascade.
Evidence at this time suggests that combination therapies for CNV in AMD are superior to monotherapy in every way. These therapies seem to have functional as well as anatomic benefits, and they may achieve end results comparable to those of monotherapies, such as improved visual acuity, thinning of the retina and regression of angiogenesis, with fewer treatments that have more lasting benefits.
Albert J. Augustin, MD, and Indre Offermann, MD, are in the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany. Dr. Augustin is a member of the Retina Today Editorial Board, and may be reached at 106020.560@compuserve.com. Dr. Offermann may be reached at indre.offermann@gmx.de; phone +49 721 9742001; fax: +49 721 9742009.
Stanislao Rizzo, MD, is in practice at the Eye Surgery Clinic, Santa Chiara Hospital in Pisa, Italy. Dr. Rizzo states that he has no financial interest in the companies or products mentioned. He is a member of the Retina Today Editorial Board and may be reached at stanos@tin.it.
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