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Combining Therapies

By Dr. Shantan Reddy

The pathophysiology of CNV is complex and a combination of various therapies that have synergistic modes of action may be able to target the multiple components of CNV.  Theoretically, this can reduce the frequency of re-treatments and allow stabilization of the visual improvement above that offered by mono-therapy alone. Verteporfin with PDT produces reactive oxygen species that induce closure of the CNV. Unfortunately, there is also a release of several potent mediators of the immune system (complements, clotting cascades, proteinases, cytokines, and growth factors), which can contribute to the re-growth of the CNV. Corticosteroids are known to exert an inhibitory effect on VEGF expression, vascular permeability, and inflammatory pathway. The complementary action of the immunosuppressive drugs given in combination with vPDT may improve its efficacy. Intravitreal triamcinolone is the drug most tested. This combination (triamcinolone with vPDT) showed an improvement in vision in most subjects that was maintained during two years of follow-up, and re-treatment numbers were lower than that expected from monotherapy. Furthermore, despite the well known side effects of intravitreal corticosteroids (cataract, elevations in intraocular pressure, and endophthalmitis) the preliminary findings suggest that the combination is safe and may be considered as a useful alternative, particularly in pseudophakic patients. A new type of steroid, anecortave acetate, which is an angiostatic steroid that lacks glucocorticoid activity (no cataract or elevations in intraocular pressure), is under evaluation in combination with vPDT. Preliminary data reveal a trend towards more beneficial outcomes than with single treatment alone.

Treatments for CNV can be directed at either the vascular component of the CNV (the new vessels that proliferate and leak blood and fluid) or the angiogenic components that lead to the development of the condition. The combination of vPDT which targets the vascular components and the anti-VEGF therapy which targets key mediators of the angiogenic cascade, may have an additive and synergistic effect to reduce the frequency of treatment. Moreover, the expression of VEGF is increased after vPDT therapy and contributes to the re-growth of the CNV. Different studies have evaluated this combination.

The FOCUS study as well as the PROTECT trial evaluated the safety and efficacy of ranibizumab in combination with vPDT versus vPDT alone. At one year, 91% of treated subjects had stable vision compared with 68% under vPDT alone. The number of vPDT sessions was 2.3 in the combination-treated subjects versus 3.4 in monotherapy. In the same way, 31% of the combination-treated eyes gained at least 3 lines versus 15% in the vPDT monotherapy group. Although ranibizumab treatment increased the risk of serious intraocular inflammation, affected subjects, on average, still experienced visual acuity benefit. Two non-randomized case series evaluated the combination of bevacizumab with vPDT. The results suggested that this combination may be useful by reducing re-treatment rate and improving visual acuity. The combination therapy may be a cost effective alternative for monotherapy by reducing the need for re-treatment. We can inhibit VEGF in various ways. The induction therapy with a pan-VEGF inhibitor (ranibizumab or bevacizumab) will provide an optimal regression of the CNV and an improvement in vision and then the anti-VEGF165 specific inhibitor (pegaptanib) may maintain vessel regression with a better safety profile.

Topics and Subtopics: Eye Care

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