It is hard to imagine that a mere decade ago a satisfactory treatment did not exist for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The best retina specialists could do was to perform thermal laser photocoagulation to ablate these lesions.1 The rapid decline in vision following treatment made this approach unpopular among patients and physicians. When verteporfin photodynamic therapy (PDT) was introduced in 2000, it was hailed as a revolutionary therapy that significantly improved visual outcome, reducing the proportion of patients experiencing moderate visual loss by approximately 20%. The treatment benefit was most significant in predominantly classic lesions compared with minimally classic or nonclassic lesions,2-6 which meant that approximately 30% of patients with wet AMD were eligible for PDT.
THE RISE OF ANTI-VEGF MONOTHERAPY
We have come a long way since 2000. In 2004 the US
Food and Drug Administration (FDA) approved pegaptanib
(Macugen; [OSI]EyeTech Pharmaceuticals), the first
vascular endothelial growth factor (VEGF) inhibitor for
ophthalmic clinical use.7
Clinical trials of ranibizumab (Lucentis, Genentech, Inc.) followed soon after. The ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration) and MARINA (Minimally Classic/Occult Trial of the Anti- VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration) trials showed that more than 90% patients treated with intravitreal ranibizumab avoided moderate visual loss (at least 15 letters on the logMAR chart) when they received the therapy for 24 consecutive months, regardless of lesion type and size, patient age, or baseline visual acuity. More than one-third of patients gained at least 3 lines of visual acuity, and one in three patients doubled their visual acuity over the 24-month treatment period. Additionally, about 70% of patients achieved stable vision over this period, gaining up to 2 lines of vision.8-11
These findings resulted in a paradigm shift in the management of neovascular exudative AMD, characterized by vision gained rather than vision lost. Ranibizumab quickly gained acceptance from retinal specialists, governments, and the public. It has become the gold standard against which all other therapies are benchmarked. 11-14
UNMET NEEDS
Despite these remarkable results, unanswered questions
remain with respect to anti-VEGF monotherapy. Can dosing frequency be reduced, and, if so, how? The
economic burden of monthly intravitreal injections, not
to mention the administrative costs and increased risk
of potential ocular and systemic complications of the
procedure and drug, makes monthly treatments on an
indefinite basis untenable for most patients.15-19
Suggestions have been made to reduce the overall number
of treatments without significantly compromising
outcomes through an as-needed approach, with retreatment
triggered by criteria such as vision decline and
quantitative and qualitative changes on optical coherence
tomography (OCT).20 However, the outcomes with
this approach did not match those achieved with
monthly fixed-dosing regimens. Outcomes were even
poorer when the frequency of fixed dosing was reduced
from monthly to quarterly after three initial monthly
treatments.21,22
It has also been shown that a significant number of nonresponders to anti-VEGF monotherapy may have underlying polypoidal choroidal vasculopathy (PCV).23 Several clinical case series have shown that ranibizumab and bevacizumab (Avastin, Genentech, Inc.), the two most widely used anti-VEGF agents, lack efficacy in eliminating polypoidal lesions, despite control of exudation and corresponding improvements in visual acuity and OCT parameters.24,25 Other lesions, such as retinal angiomatous proliferation (RAP), vascularized pigment epithelial detachments (PED), and serous PED, do not respond as favorably to anti-VEGF therapy as CNV.26-34
RATIONALE FOR COMBINATION THERAPY
There is a sound biological rationale for combining
verteporfin PDT with anti-VEGF agents. Their actions
complement each other and may be synergistic. PDT
causes photothrombosis and occlusion of new vessels,
while anti-VEGF agents inhibit vasopermeability and
angiogenesis. One of the reasons why PDT does not
result in significant improvement in vision despite closure
of CNV is the up-regulation of VEGF that occurs
within hours following its administration. This upregulation
occurs because of temporary hypoxia within the
treatment zone. There is a correlation between visual
outcome and treatment zone size, reflecting photoreceptor
and even pigment epithelial damage and toxicity
resulting from this sudden iatrogenic surge of local levels
of VEGF. This is borne out by the clinical observation
of transient increases in exudation soon after PDT, usually
resolving spontaneously within 1 month. This upregulation
of VEGF is therefore an undesirable negative
effect, which may be countered by same-day administration
of an anti-VEGF agent.
There is debate over the optimal timing or sequence of anti-VEGF injection in relation to PDT application. Results of the QUEST study35 suggest that same-day application of PDT followed by anti-VEGF injection produced superior results. Furthermore, the addition of a corticosteroid such as dexamethasone or triamcinolone has been advocated to dampen the inflammatory stimulus of PDT, assist in stabilizing the blood-retinal barrier, and further reduce the vasopermeability of capillaries. This triple therapy yielded better results than dual therapy without steroid in the QUEST study.35
Another strategy to reduce the deleterious effects of PDT is to use reduced laser energy (fluence) or reduced dose of verteporfin.36-39 Potter et al40 demonstrated that reducing fluence by half or one-quarter led to better visual outcomes compared with full-fluence treatment. We await results of the DENALI trial41 (part of the SUMMIT clinical trials), which is evaluating the use of combination therapy for neovascular AMD, to validate this observation.
CASE SERIES
Cases series have demonstrated the efficacy of combination
therapy in visual outcome and in reduced
overall number of anti-VEGF injections required. Most
cases required a single PDT treatment, and the average
total number of anti-VEGF injections was 2.3 over 12
months.36-38,42-44 The MONT BLANC study in Europe
showed that combination therapy was not inferior to
monotherapy in terms of visual outcome, although the
overall number of ranibizumab injections required over
the course of 12 months was not significantly reduced.
Advocates for combination therapy propose that possible reasons that study did not demonstrate a greater benefit in outcomes could include the use of full-fluence rather than reduced-fluence PDT and the omission of corticosteroids from the treatment.
THE PCV CONUNDRUM
In Asia, especially among patients of East Asian
descent, PCV has been reported to account for at least
30% of all cases of serosanguineous maculopathy.45,46 In
contrast, the prevalence of PCV is only about 10% in
non-Asian populations. Thus, the diagnosis of PCV
might not be made in a significant proportion of Asian patients of Western retina practices if indocyanine
green angiography (ICGA) is not performed due to lack
of availability, accessibility, or awareness on the part of
the physician. The response of PCV to anti-VEGF
monotherapy is unsatisfactory; one-third of patients do
not respond, and polypoidal lesions persist in nine of 10
cases.24,25 Verteporfin PDT has been shown to be effective
in achieving polyp closure when used alone or in
combination with ranibizumab.24,47-50 Hopefully, the
recently concluded EVEREST trial, a part of the SUMMIT
clinical trial series that specifically evaluated the
efficacy of PDT in angiographic closure of PCV, will provide
guidance in using PDT to treat this condition.51
WHERE DO WE GO FROM HERE?
In summary, there remains a definite role for PDT in
the management of exudative maculopathy, especially
for polypoidal choroidal vasculopathy. Undoubtedly,
anti-VEGF therapy has yielded excellent results, but it
has significant drawbacks as well. We await stronger evidence
that the combination of PDT and anti-VEGF therapy
results in equally good visual outcomes with fewer
overall treatments than anti-VEGF monotherapy. Retinal
specialists eagerly await results of the DENALI trial,
which are expected to be available in the second quarter
of 2010. In the near future, as more powerful and effective
agents become available to treat CNV, combination
therapy with these new agents might also be beneficial.
My current use of PDT in neovascular AMD is for predominantly
classic CNV, (regardless of lesion size), small
minimally classic, and nonclassic lesions (preferably less
than four Macular Photocoagulation Study disc areas),
and for all PCV cases. All other lesions are treated with
anti-VEGF monotherapy. My preferred settings for PDT
are reduced fluence (25 mJ/m2) with rapid bolus infusion
and laser application after 15 minutes of injection.
I administer intravitreal anti-VEGF in combination with
200 μg dexamethasone on the same day, usually within
30 minutes after PDT. Additional anti-VEGF injections
are on an as-needed basis, with monthly follow-up for
at least 3 months. Subsequently, review intervals may be
gradually increased in increments of 2 weeks.
To successfully deal with difficult chronic conditions such as AMD, I believe retina specialists need all the tools at their disposal to achieve the best outcomes for patients, while minimizing the number of treatments, reducing potential ocular and systemic complications, and lightening the financial burden on patients and society.
Adrian H. C. Koh, MBBS, MMed (Ophth), FRCS(Ed), FAMS, is Director and Senior Consultant Ophthalmic Surgeon at Eye & Retina Surgeons in Singapore. Dr. Koh has no financial interests regarding any products mentioned in this article. He can be reached at+ 65 6738 2000; fax: + 65 6738 2111; or via e-mail at dradriankoh@eyeretinasurgeons.com.
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