Coverage Policy Manual
Policy #: 2000021
Category: Medicine
Initiated: May 2000
Last Review: June 2022
  Photodynamic Therapy for Ophthalmology

Description:
Severe vision loss can occur with ocular neovascularization, the growth of abnormal blood vessels in the retina or choroid. Neovascularization occurs in a number of ocular diseases, including age-related macular degeneration.
 
Age-related macular degeneration is a degenerative disease of the retina that results in loss of central vision. Two distinctive forms, known as dry and wet degeneration, may be observed. The dry form (also known atrophic or areolar) is more common and is often a precursor of the wet form (also known as exudative neovascular or disciform). The wet form is more devastating and characterized by serous or hemorrhagic detachment of the retinal pigment epithelium and development of choroidal neovascularization, which greatly increases the risk of developing severe irreversible loss of vision. Choroidal neovascularization is categorized as classic or occult. Classic choroidal neovascularization appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult choroidal neovascularization lacks the characteristic angiographic pattern. Classic choroidal neovascularization carries a worse prognosis for vision than occult choroidal neovascularization, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of age-related macular degeneration.
 
Pathologic myopia refers to an abnormal elongation of the eye associated with severe near-sightedness. It generally occurs among people older than 30 years of age and can result in a progressive, severe loss of vision, frequently related to the development of choroidal neovascularization. Verteporfin photodynamic therapy has also been investigated in patients with choroidal neovascularization related to pathologic myopia. Antivascular endothelial growth factor therapy is now considered a first-line intervention in patients with myopic choroidal neovascularization.
 
Presumed ocular histoplasmosis may be the second most common cause of blindness in patients younger than 50 years of age in certain endemic areas (Ohio and Mississippi River Valleys in the United States). This condition is characterized by a positive skin test for histoplasmosis, miliary opacities of the lungs, tiny choroidal scars, peripapillary disruption of the choriocapillaris, and exudation or hemorrhage from choroidal lesions in or near the macula. The condition is asymptomatic and benign, unless the choroidal neovascularization lesions, which may develop many years after chorioretinal scarring has taken place, affect the macula.
 
Central serous chorioretinopathy refers to an idiopathic disease in which there is a serous detachment of the macula due to leakage of fluid from the choriocapillaris through the retinal pigment epithelium. This condition is avascular; however, neovascularization can occur as a secondary complication. In most cases, central serous chorioretinopathy resolves spontaneously in 3 to 4 months. However, in a few cases, chronic progression or recurrence can lead to the progressive decline of visual acuity. Central serous chorioretinopathy has been treated with medication and laser photocoagulation, but these treatments have limited efficacy. Multiple definitions have been used in the literature to classify central serous chorioretinopathy as acute or chronic based cutoff time points (eg, persistent fluid for <3, 4 or 6 months) or less frequently based on the timing of treatment. For example, acute central serous chorioretinopathy defined as the first attempted treatment to improve visual acuity, and chronic central serous chorioretinopathy is defined as being refractory to treatment. Further, multiple verteporfin photodynamic therapy strategies that use either reduced-dose or half-fluency have been evaluated for the treatment of central serous chorioretinopathy because full-dose verteporfin photodynamic therapy used in age-related macular degeneration has shown a potentially higher risk of developing choroidal ischemia and retinal atrophic changes.
 
Polypoidal choroidal vasculopathy arises primarily from abnormal choroidal circulation, resulting in characteristic lesions comprising well-defined vascular networks of vessels ending in polyp-like structures. A less common subtype is polypoidal choroidal neovascularization, and it may be considered a subtype of age-related macular degeneration. Eyes that develop a cluster of grape-like polypoidal dilations are at high risk for severe vision loss.
 
Choroidal hemangioma is an uncommon, benign vascular tumor, manifesting as an orange-red mass in the posterior pole of the eye. Visual loss may be progressive and irreversible because of chronic foveal detachment.
 
Angioid streaks result from crack-like breaks in the Bruch membrane (the innermost layer of the choroid) and occur in patients spontaneously or due to blunt trauma or associated with some systemic diseases such as pseudoxanthoma elasticum, Paget disease of bone, or sickle hemoglobinopathy. Vision loss in eyes with angioid streaks occurs most frequently as a result of choroidal neovascularization.
 
Available therapeutic options for choroidal neovascularization include antivascular endothelial growth factor inhibitors, verteporfin photodynamic therapy, antioxidants, thermal laser photocoagulation, and corticosteroids. The safety and efficacy of each treatment depends on the form and location of the neovascularization.
 
Verteporfin photodynamic therapy is a treatment modality designed to selectively occlude ocular choroidal neovascular tissue. The therapy is a 2-step process, consisting of an injection of the photosensitizer verteporfin, followed 15 minutes later by laser treatment to the targeted sites of retinal neovascularization. The laser treatment selectively damages the vascular endothelium and occludes the neovacularized tissue. Patients may be retreated if leakage from choroidal neovascularization persists.
 
Monotherapy with vascular endothelial growth factor inhibitors is now standard treatment of choroidal neovascularization due to age-related macular degeneration and pathologic myopia. Combining verteporfin photodynamic therapy with antivascular endothelial growth factor inhibitors, concurrently or sequentially, has a biologic basis and has been investigated in multiple trials particularly in the treatment of choroidal neovascularization due to age-related macular degeneration and pathologic myopia.
 
The use of verteporfin photodynamic therapy in choroidal neovascularization has decreased substantially with the availability of antivascular endothelial growth factor therapy. Subsequent to U.S. Food and Drug Administration (FDA) approval of verteporfin photodynamic therapy in 2000, the FDA approved pegaptanib in 2004 and ranibizumab in 2006 for treatment of age-related macular degeneration related choroidal neovascularization. The approval of pegaptanib was based on a sham-controlled RCT while ranibizumab was approved based on a head-to-head comparison with verteporfin photodynamic therapy in the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) trial (Gragoudas, 2004; Chakravarthy, 2006; Brown, 2006). Intravitreal injections of antivascular endothelial growth factor drugs such as ranibizumab and bevacizumab have shown superior efficacy compared with verteporfin photodynamic therapy in multiple head-to-head trials. Currently, verteporfin photodynamic therapy is used for patients in whom vascular endothelial growth factor inhibitors are contraindicated or for those who fail to benefit from vascular endothelial growth factor inhibitors.
 
In 2000, verteporfin for injection (Visudyne®; Novartis), an intravenous photodynamic therapy agent, was approved by the U.S. Food and Drug Administration for the treatment of age related macular degeneration for the treatment of age-related macular degeneration in patients with predominantly classic subfoveal choroidal neovascularization. Subsequently, in 2001, the indication was expanded to include presumed ocular histoplasmosis and pathologic myopia.
 

Policy/
Coverage:
Effective January 2013
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy with light activated drugs meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following ophthalmic disorders:
 
    • Classic subfoveal choroidal neovascularization associated with age-related macular degeneration, presumed ocular histoplasmosis or pathologic myopia.
    • Predominantly occult subfoveal choroidal neovascularization
    • Age-related macular degeneration in patients with predominantly occult subfoveal choroidal neovascularization and recent presumed disease progression.
    • Concurrent bilateral treatment is covered provided there has been at least one successful treatment in one eye. (If patients present with eligible lesions in both eyes, the most aggressive lesion should be treated first.  The other eye may be treated a week later if no toxicity has occurred.)
    • Chronic central serous chorioretinopathy
    • Choroidal hemangioma
 
The U.S. Food and Drug Administration (FDA) labeling for verteporfin indicates that the physician should re-evaluate the patient every 3 months and, if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated. The FDA labeling does not address the total number of treatments but states, “The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.”
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Photodynamic therapy does not meet member benefit certificate Primary Coverage Criteria of effectiveness for the treatment of other ophthalmologic disorders including, but not limited to, acute central serous chorioretinopathy.
 
For contracts without Primary Coverage Criteria, Photodynamic therapy is considered investigational for the treatment of other ophthalmologic disorders including, but not limited to, acute central serous chorioretinopathy.  Investigational services are exclusions in the member benefit certificate of coverage.
 
Effective June 2010 – December 2012
Photodynamic therapy with light activated drugs meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of the following ophthalmic disorders:
 
    • Classic subfoveal choroidal neovascularization associated with age-related macular degeneration, presumed ocular histoplasmosis or pathologic myopia.
    • Predominantly occult subfoveal choroidal neovascularization
    • Age-related macular degeneration in patients with predominantly occult subfoveal choroidal neovascularization and recent presumed disease progression.
    • Concurrent bilateral treatment is covered provided there has been at least one successful treatment in one eye. (If patients present with eligible lesions in both eyes, the most aggressive lesion should be treated first.  The other eye may be treated a week later if no toxicity has occurred.)
 
Photodynamic therapy does not meet member benefit certificate Primary Coverage Criteria of effectiveness for the treatment of other ophthalmologic disorders including, but not limited to, choroidal neovascularization secondary to central serous chorioretinopathy.
 
For contracts without Primary Coverage Criteria, Photodynamic therapy for the treatment of other ophthalmologic disorders including, but not limited to, choroidal neovascularization secondary to central serous chorioretinopathy is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage.
  
The U.S. Food and Drug Administration (FDA) labeling for verteporfin indicates that the physician should re-evaluate the patient every 3 months and, if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated. The FDA labeling does not address the total number of treatments but states, “The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.”
 
Effective, September 2009 – May 2010
Photodynamic therapy with light activated drugs meets member benefit certificate Primary Coverage Criteria of effectiveness in improving health outcomes for the treatment of classic subfoveal choroidal neovascularization associated with age-related macular degeneration, presumed ocular histoplasmosis or pathologic myopia.
 
Photodynamic therapy does not meet member benefit certificate Primary Coverage Criteria of effectiveness for the treatment of other ophthalmologic disorders including predominantly occult subfoveal CNV or CNV secondary to central serous chorioretinopathy.
 
For contracts without Primary Coverage Criteria, Photodynamic therapy for the treatment of other ophthalmologic disorders including predominantly occult subfoveal CNV or CNV secondary to central serous chorioretinopathy is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage.
 
Bilateral treatment is covered if there has been at least one previous treatment in one eye and other coverage criteria are met.
 
The U.S. Food and Drug Administration (FDA) labeling for verteporfin indicates that the physician should re-evaluate the patient every 3 months and, if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated. The FDA labeling does not address the total number of treatments but states, “The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.”
 
Effective, June 2003
Photodynamic therapy with light activated drugs is covered for the treatment of age-related macular degeneration.
 
Effective August 22, 2001 photodynamic therapy with light activated drugs is also covered for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to presumed ocular histoplasmosis or pathologic myopia.
 
The frequency and total number of treatments are not addressed in the FDA-labeled indication.  However, in the clinical pivotal trials presented to the FDA, patients were treated every three months if additional leakage was identified.  Data were not presented on patients treated for more than one year, therefore the safety and effectiveness of chronic therapy beyond one year has not been validated.
 
Bilateral treatment is covered if there has been at least one previous treatment in one eye and other coverage criteria are met.
 
Effective, September 2001
Photodynamic therapy with light activated drugs is covered for the treatment of age-related macular degeneration in patients with (1) Evidence of predominantly classic choroidal neovascularization membrane on fluorescein angiography; (2) Best corrected visual acuity of 20/200 or better on the day of the procedure; (3) Lesion greatest  linear dimension of 5400 microns or less.  This measurement includes all classic and occult choroidal neovascularization, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium.  The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc.  
 
Effective 08/22/2001 photodynamic therapy with light activated drugs is also covered for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to presumed ocular histoplasmosis or pathologic myopia.
 
The frequency and total number of treatments are not addressed in the FDA-labeled indication.  However, in the clinical pivotal trials presented to the FDA, patients were treated every three months if additional leakage was identified.  Data were not presented on patients treated for more than one year, therefore the safety and effectiveness of chronic therapy beyond one year has not been validated.
 
Bilateral treatment is covered if there has been at least one previous treatment in one eye and other coverage criteria are met.
 
 
Effective, May 2000
Photodynamic therapy with light activated drugs is covered for the treatment of age-related macular degeneration in patients with (1) Evidence of predominantly classic choroidal neovascularization membrane on fluorescein angiography; (2) Best corrected visual acuity of 20/200 or better on the day of the procedure; (3) Lesion greatest  linear dimension of 5400 microns or less. This measurement includes all classic and occult choroidal neovacularization, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium.  The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc.  
 
The frequency and total number of treatments are not addressed in the FDA-labeled indication.  However, in the clinical pivotal trials presented to the FDA, patients were treated every three months if additional leakage was identified.  Data were not presented on patients treated for more than one year, therefore the safety and effectiveness of chronic therapy beyond one year has not been validated.
 
Bilateral treatment is covered if there has been at least one previous treatment in one eye and other coverage criteria are met.
 
Research using photodynamic therapy with light activated drugs is ongoing but at the current time this procedure is not covered for other ophthalmologic disorders, including, but not limited to, other types of choroidal neovascularization or choroidal neovascularization not associated with age-related macular degeneration.
 
 
 
 
 
 
 
 

Rationale:
This policy was initially developed as a result of the FDA approval of verteporfin for injection.  A 2000 Blue Cross Blue Shield TEC Assessment offered the following conclusions:
 
    • Two multicenter, double-masked, randomized placebo-controlled trials including 402 patients reported that, at 1 year of follow-up, fewer patients treated with photodynamic therapy experienced a clinically significant loss of visual acuity compared to those treated with placebo: 38.8% compared to 53.6% (p<0.001).
    • Subgroup analysis suggests that the treatment effect is predominantly experienced by patients with AMD characterized by at least 50% classic CNV.
    • There were inadequate data to permit scientific conclusions regarding other etiologies of CNV.
 
The TEC Assessment did not specifically address the issue of frequency of treatment or treatment extending beyond 1 year.
 
Since the completion of the TEC Assessment, the 2-year results of the pivotal randomized trial Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) were published (Bressler, 2001).  Beneficial outcomes regarding visual acuity and contrast sensitivity noted after 12 months were sustained through 24 months. At the end of 2 years, 53% of the treatment group, as compared to 38% of the placebo group, lost fewer than 15 letters. The average number of applications of verteporfin treatment in the second year (2.2) was lower than that required during the first year.   A subgroup analysis was reported, comparing results between those patients with predominantly classic CNV (>50% of lesional area) compared to minimally classic CNV (<50%). For patients with minimally classic disease, no statistically significant differences in visual acuity were noted.
 
The verteporfin in photodynamic therapy (VIP) trial is another randomized study that primarily focused on efficacy of photodynamic therapy in patients with occult but no classic lesions who were presumed to have progressive disease due to visual or anatomic deterioration within the previous 3 months. Of the 339 patients enrolled in the trial, 76% had occult disease; the remainder had early classic CNV with good visual acuity.  Similar to other randomized trials, the primary outcome was the proportion of eyes with fewer than 15 letters of visual acuity loss. While there was no significant difference between the treatment and placebo groups at 12 months, by 24 months, a significantly lower percentage of those with occult CNV had lost vision (55% vs. 68%, p=0.032). These results contrast with those of the TAP trial, although the patient populations are slightly different. The TAP trial required all patients to have some percentage of classic CNV, while the VIP trial recruited patients with occult disease without evidence of classic CNV. In addition, the VIP trial required patients with occult disease to have experienced recent deterioration in vision. Results for the subgroup of patients with classic CNV but good visual acuity were not reported separately.
 
Photodynamic therapy has also been investigated in patients with CNV related to pathologic myopia and presumed ocular histoplasmosis. A second arm of the VIP trial focused on 120 patients with pathologic myopia and CNV, either classic, occult, or mixed (although 90% of patients had classic CNV) who were randomized to receive photodynamic therapy or placebo. At month 12, photodynamic therapy stabilized or improved vision (as defined by a loss of fewer than 8 letters on a standard eye chart) in 72% of patients versus 44% on placebo.  The authors concluded that verteporfin therapy increases the chance of stabilizing or improving vision compared to placebo treatment for at least 1 year. Results were not reported separately for those with predominantly classic CNV versus occult CNV.
 
There are minimal published data regarding the use of photodynamic therapy in patients with CNV related to ocular histoplasmosis. The FDA approval was based on an open-label safety study involving 26 patients with ocular histoplasmosis. Visual acuity improved by an average of more than 1 line on a standard eye chart at 12 months (6.7 letters on a standard eye chart) with 28% of patients experiencing a visual acuity improvement of 3 lines (15 letters) or more. Visual acuity decreased by less than 3 lines of vision in 88% of patients during the same time period.
 
Updates
A 2004 review of the peer-reviewed literature based on MEDLINE identified 3 additional reports from the TAP trial.  These reports demonstrated positive outcomes with the use of photodynamic therapy for subfoveal choroidal neovascularization and further supported the findings of the earlier TAP trial reports (Bressler, 2002) (Rubin, 2002) (Blumenkranz, 2002). A Cochrane review was published during this time period that concluded that photodynamic therapy is effective in preventing visual loss in classic and occult CNV due to AMD (Wormald, 2004).  
Ergun and colleagues reported on a case series of photodynamic therapy for CNV secondary to central serous chorioretinopathy on 26 eyes in 24 patients (Ergun, 2004).  Results demonstrated a mean increase in 2.2 lines of visual improvement at 2 years and no adverse outcomes. While promising, larger and comparative studies are warranted for photodynamic therapy for this indication. Therefore, photodynamic therapy for CNV is no longer considered investigational and photodynamic therapy for CNV secondary to central serous chorioretinopathy is added to the policy statement as investigational.
 
A 2005 literature review identified 2 articles that support the use of photodynamic therapy for CNV due to age-related macular degeneration. The Visudyne in Minimally Classic Choroidal Neovascularization (VIM) Study Group randomized 117 patients to verteporfin or placebo infusion with standard or reduced light fluence rates (Azab, 2004). The authors concluded after 24 months of follow-up that verteporfin therapy was safe and reduced the risks of disease progression to predominantly classic CNV and visual acuity loss of at least 15 letters. In a meta-analysis of the safety of photodynamic therapy, Azab and colleagues analyzed data from the 24-month TAP A and B and VIP trials, totaling 948 patients with AMD (Azab, 2005).  The authors concluded that the safety profile of verteporfin therapy was not statistically different from placebo. An October 2005 TEC Special Report on the treatment of AMD also supports the conclusions given here and notes that the pathway leading to CNV is complex.  
 
Photodynamic Therapy (PDT) in Combination Therapies
The October 2005 TEC Special Report notes that therapies are available for AMD to potentially modify (angiostatic agents) and palliate (PDT) the disease. Combining these modalities concurrently or sequentially has a biological basis. The 2005 TEC Special Report found that a host of trials are in progress combining an angiostatic agent with PDT. The angiostatic agents being studied in trials include pegaptanib, ranibizumab, anecortave acetate, squalamine, vitalinib, and triamcinolone. For example, in the pegaptanib trial, PDT was administered at physician discretion but an analysis was not provided that examined possible synergistic effects (Gradoudas, 2004).
 
2006-2008 Updates
Searches of the MEDLINE database for the periods of October 2005 through February 2007 and March 2007 through April 2008 found no evidence to support a change in the policy statement. A Cochrane review evaluated results from 3 randomized controlled trials (total of 1,022 patients), which included the TAP and VIP trials described here (Wormald, 2007).  Meta-analysis showed a 24-month risk ratio of losing 6 or more lines of visual acuity of 0.62 compared to the control group. The authors concluded that photodynamic therapy is probably effective in treating CNV due to AMD, though there is doubt about the size of the effect. Kaiser reported results of a 3-year open-label extension of the TAP study (Kaiser, 2006).  Of 402 verteporfin-treated patients who completed the 24-month randomized study, 320 (80%) enrolled in the extension protocol. Patients who chose not to participate in the TAP extension were more likely to be older, have a poorer level of visual acuity, and have evidence of fluorescein leakage, or evidence of progression, at the 24-month examination. Of the 320 enrolled, 193 (60%) completed the 60-month examination and 122 (38%) discontinued prematurely, 3 (1%) were noncompliant. Yearly treatment rates declined from 3.5 treatments in the first year to 0.1 in the fifth year; subjects who remained in the study lost an additional 2.3 lines of letters over the 3-year extension.
 
Ranibizumab was compared with photodynamic therapy in a multicenter, double-blind study (423 patients) by the ANCHOR study group (Brown, 2006).  Following 12 monthly treatments, patient groups treated with ranibizumab (0.3 or 0.5 mg) and sham verteporfin had 94% to 96% of subjects lose fewer than 15 letters. The patient group treated with monthly sham injection and active verteporfin therapy (average 2.8 times over the year) had 64% of subjects lose fewer than 15 letters. Visual acuity improved by more than 15 letters in 36% and 40% of the ranibizumab groups (average dose-dependent gain of 8.5 and 11.3 letters), in comparison with 5.6% of subjects in the verteporfin group (average loss of 9.5 letters). Intraocular inflammation occurred in 10.2% and 15% of ranibizumab-treated patients, with presumed endophthalmitis in 1.4% and serious uveitis in 0.7% of patients treated with the highest dose.
 
It appears, based on numerous case reports and case series, that photodynamic therapy is being used in an attempt to decrease CNV of many different etiologies. For example, photodynamic therapy has been reported to slow down, but not prevent or reverse, the progression of disease of CNV associated with angioid streaks and inflammatory chorioretinal disease  (Heimann, 2005) (Lim, 2006). Controlled studies are lacking, and photodynamic therapy is considered investigational for ophthalmologic disorders other than AMD, pathologic myopia, or presumed ocular histoplasmosis.
 
Combination Therapies
The FOCUS study group reported first- and second-year results of a blinded phase I/II multicenter, randomized controlled trial of ranibizumab (0.5 mg) combined with photodynamic therapy (Heier, 2006) (Antoszyk, 2008).  Patients with subfoveal CNV secondary to AMD were randomized in a 2:1 ratio to ranibizumab (n=106) or sham (n=56) injection (initially 7 days) following verteporfin photodynamic therapy. PDT was repeated only if fluorescein angiography revealed persistent or recurrent leakage from CNV at evaluation visits (3-month intervals). A higher than expected rate of serious intraocular inflammation occurred in the first patients, and the 2 treatments were subsequently scheduled no closer than 21 days apart. Intent-to-treat analysis showed an average improvement in acuity of 5 letters at both 12 and 24 months (85% retention) with ranibizumab, compared with a decrease of 8 letters in the PDT-alone group. Twenty-nine percent of patients in the ranibizumab group received additional PDT treatment (average of 0.4 treatment), compared with 93% of patients in the PDT-alone group (average of 3 treatments). Visual acuity improved by 15 or more letters in 25% of patients treated with ranibizumab (plus PDT as needed) compared with 7% of the patients treated with PDT alone. Endophthalmitis or intraocular inflammation was observed in 16 (15%) patients treated with ranizumab. The majority of adverse events (9%) reported for the PDT-alone group were AMD-related (i.e., CNV, macular degeneration, retinal hemorrhage).
 
An open-label assessor-blinded trial (n=165) from Croatia with short-term (3-month) follow-up reported similar results with bevacizumab and PDT (Lazic, 2007).  The frequency of treatment was described only as “standard procedures.” Twenty-two of 52 (42%) patients improved by >0.2 (logarithm of the minimum angle of resolution) following combined treatment, compared with 1 (2%) patient treated with bevacizumab alone and none treated with PDT alone. Adverse events (21%) in the bevacizumab groups (alone or combined) were frequent, and included 3 pigment epithelial tears, 12 posterior vitreous detachments, and 7 cataract progressions.
 
The combined use of corticosteroids and PDT is not supported by recent trial results (Gilson, 2007) Iriyama, 2008).
 
Preferred Practice Patterns (practice guidelines) on photodynamic therapy from the American Academy of Ophthalmology (AAO) are based on the TAP and VIP reports described here.  The AAO recommends PDT with verteporfin for subfoveal CNV where the classic component is greater than 50% of the lesion and the entire lesion is 5400 microns or less in diameter.  While PDT was recommended for recurrent juxtafoveal CNV, evidence was considered insufficient to guide treatment recommendations for the primary use of PDT for juxtafoveal CNV. Combination therapy with VEGF inhibitors and PDT was not discussed.
 
2012 Update
A literature search was conducted using the MEDLINE database through June 2012.  There was no new information identified that would prompt a change in the coverage statement. Several publications were identified involving non-covered indications including central serous chorioretinopathy, polypoidal choroidal vasculopathy, choroidal hemangioma, angioid streaks and inflammatory conditions. This update focuses on these conditions.
 
Central Serous Chorioretinopathy
In 2010, Chan et al. published a systematic review of PDT for non-standard indications, which included 12 case series (119 eyes) on PDT for central serous chorioretinopathy (Chan, 2010). In addition, 2 nonrandomized comparative studies and 2 small randomized controlled trials with reduced dose (verteporfin) and reduced fluence (laser) PDT have been identified.
 
Acute Central Serous Chorioretinopathy. Chan et al reported a randomized double-masked placebo controlled trial of reduced dose PDT for acute central serous chorioretinopathy in 2008 (Chan, 2008).  Reduced dose verteporfin was examined due to adverse effects, including CNV, with full dose PDT. A total of 63 patients were randomized in a 2:1 ratio to half-dose verteporfin or placebo prior to laser treatment. The primary outcome measure, the proportion of eyes with absence of subretinal fluid at the macula at 12 months, was observed in 94.9% of eyes in the verteporfin group compared with 57.9% of eyes in the placebo group. The mean central foveal thickness was lower compared to the placebo group at 12 months (161 vs. 278 microns). At 3 months after treatment, the mean logMAR of the PDT group was 0.00 (Snellen equivalent 20/20), whereas the placebo group improved to 0.08 (Snellen equivalent 20/24). At 12 months, the mean logarithm of the minimum angle of resolution (logMAR) remained statistically better in the PDT group compared with placebo (-0.05 vs. 0.05); however, since this is equivalent to visual acuity of 20/18 versus 20/22, this would not be a clinically meaningful difference. The mean increase of BCVA was 1.8 lines compared to 0.6 lines for the placebo group, whereas a difference of 2 lines is considered to be clinically meaningful. No ocular or systemic adverse event was encountered.
 
Chronic Central Serous Chorioretinopathy. Bae et al compared low-fluence PDT versus 3 monthly injections of ranibizumab in a small randomized trial of 16 eyes with chronic or recurrent central serous chorioretinopathy (Bae, 2011). Rescue with the opposite treatment was allowed after 3 months since a gold standard treatment for chronic central serous chorioretinopathy had not been established. The main outcome measures were excess foveal thickness, resolution of subretinal fluid, choroidal perfusion, and BCVA. For both groups at baseline, the mean logMAR was 0.34 (20/44 Snellen equivalent). The mean excess foveal thickness was significantly higher in the PDT group at baseline (74.1 vs. 26.3 microns), but showed a greater reduction with treatment. Six eyes (75%) in the PDT group achieved complete resolution of subretinal fluid and reduction of choroidal hyperpermeability compared with 2 (25%) eyes in the ranibizumab group. At 3 months, there was a trend toward improvement in BCVA in the PDT group (from 0.30 to 0.18 logMAR, p=0.075), whereas the ranibizumab group had significantly improved BCVA (from 0.38 to 0.18 logMAR). There was a trend for a greater proportion of eyes needing rescue treatment in the ranibizumab group versus the PDT group (75% vs. 25%, p=0.066). During the follow-up period, no systemic or ocular complications associated with treatment were observed. The main limitations of this study are its small size, lack of investigator blinding, and lack of an untreated control group.
 
Reibaldi et al compared the efficacy of half-fluence PDT compared to conventional PDT in a prospective multicenter, investigator-masked comparative study of 42 eyes (42 patients) with chronic central serous chorioretinopathy (Reibaldi, 2010). It is not clear whether the group assignment was based on patient preference or investigator preference, although the groups were comparable at baseline. The primary outcome measures were the changes in BCVA and the proportion of eyes with complete resolution of subretinal fluid. Secondary outcome measures were the changes in mean central foveal thickness and the rate of eyes with post-PDT changes in choroidal perfusion. At 1 month follow-up, BCVA had improved to a similar extent in both the low-fluence group (from 0.46 to 0.28 logMAR) and the conventional fluence group (from 0.43 to 0.27 logMAR). Complete resolution of subretinal fluid was observed in 96% of the low-fluence group and 89% of the conventional PDT group (not significantly different). At 12 months’ follow-up, BCVA continued to improve in the low-fluence group (0.16 logMAR) but remained stable in the conventional fluence group (0.24 logMAR). Complete subretinal fluid reabsorption was seen in 91% of low-fluence-treated eyes and 79% of conventional PDT-treated eyes (not significantly different). Moderate choriocapillaris hypoperfusion (an adverse effect) was seen in 0% of low-fluence-treated eyes and 44% of conventional PDT-treated eyes. One eye in the conventional PDT group developed CNV requiring further treatment. A strength of this study is the prospective 12-month follow-up after a single treatment. Limitations of this study are the nonrandomization and the lack of an untreated control group.
 
Outcomes from low-fluence PDT were also compared to conventional PDT in a retrospective multicenter study of 60 patients with chronic central serous chorioretinopathy (34 eyes treated with low-fluence PDT and 33 eyes treated with conventional PDT) (Shin, 2011).  All eyes treated at one center received conventional PDT and all consecutive eyes treated at another center between 2006 and 2009 received low-fluence PDT. Follow-up examinations were done at 1 and 3 months after PDT and as needed thereafter, with a mean follow-up period of 12.6 months (range, 6-33 months) for the low-fluence PDT group and 13.4 months (range, 5-25 months) for the conventional PDT group. Treatment success without recurrence was achieved in 94.1% of eyes treated with low-fluence PDT and 100% of eyes treated with conventional PDT (not significantly different). BCVA improved with treatment in both groups with no significant difference in final BCVA between the 2 groups (0.17 vs 0.21 logMAR) at the final follow-up. Choriocapillaris nonperfusion was significantly more severe in the conventional PDT group.
 
Chan et al have also reported reduced dose of verteporfin for the treatment of chronic central serous chorioretinopathy in a prospective series of 48 patients (Chan, 2008). The mean duration of central serous chorioretinopathy was 8.2 months (range, 3-40 months). At 12 months after PDT, the mean BCVA improved from 0.31 to 0.15 logMAR, an improvement of 1.6 lines.
 
Conclusions: Evidence on use of PDT for central serous chorioretinopathy is limited. The available evidence indicates substantial numbers of adverse events with standard PDT. Reduced dose PDT may result in improved anatomical outcomes for acute central serous chorioretinopathy, but clinically significant improvements in visual acuity have not been shown for this self-limiting disease. Recent studies of reduced fluence and reduced dose PDT for chronic central serous chorioretinopathy suggest a possible beneficial effect of this treatment. Sham controlled trials are needed to evaluate the efficacy of this treatment with greater certainty.
 
Polypoidal Choroidal Vasculopathy
The systematic review by Chan et al. included 30 studies on PDT in patients with polypoidal choroidal vasculopathy (Chan, 2010). Chan et al. found numerous case series reporting favorable anatomical and visual acuity outcomes for patients treated with PDT. Also reported in the review was an ongoing manufacturer-sponsored RCT of PDT as monotherapy or combined with ranibizumab for treatment of polypoidal choroidal vasculopathy.
 
Lim et al. This study randomized 31 patients with AMD and 10 patients with polypoidal choroidal vasculopathy to bevacizumab monotherapy or bevacizumab in combination with PDT (Lim, 2012).  Bevacizumab was administered at 6-week intervals for the first 18 weeks, and then at 3-month intervals as needed. At 12 months, the monotherapy and combined treatment groups showed similar improvements in best corrected visual acuity (BCVA) and central foveal thickness. Patients with polypoidal choroidal vasculopathy did not show significant improvement in BCVA (p=0.05037) or central foveal thickness (p=0.0875) when analyzed alone; however, the study is likely to be underpowered for this subset analysis.
 
Several non-randomized studies from Asia were reported in 2011. The largest was a prospective consecutive series of 220 eyes of 210 Japanese patients with polypoidal choroidal vasculopathy who were followed for 1 year after the primary PDT treatment (Hikichi, 2011). A single physician diagnosed, treated, and followed all patients (not masked). Retreatment was considered every 3 months based on the findings of examinations, and there was an average of 1.37 treatments. Fluid, exudates, and hemorrhages had resolved in 205 eyes (93%) at 1-year follow-up. Average visual acuity improved by more than 0.3 logMAR in 25% of eyes, remained stable in 65% of eyes, and decreased more than 0.3 logMAR in 10% of eyes. Stepwise logistic regression analysis showed that younger age, smaller greatest linear dimension, better baseline visual acuity, less baseline hemorrhage, and the presence of a serous macular detachment at baseline were independent predictors of improvement in visual acuity.
 
Akaza et al. reported 3-year follow-up of 43 eyes treated with PDT for polypoidal choroidal vasculopathy (Akaza, 2011). Before the initial PDT, 40 eyes (93%) exhibited polypoidal choroidal vasculopathy in the narrow sense, and 3 (7%) exhibited polypoidal CNV. The number of treatment sessions during follow-up ranged from 1 to 8. At 3-year follow-up, mean visual acuity decreased to below baseline. Polypoidal lesions recurred in 33 of the 43 eyes (77%) at 3 years, although the 3 eyes with polypoidal CNV showed essentially no changes except for enlargement and recurrence. The authors concluded that long-term visual outcomes following PDT were not good due to the high frequency of recurrent polypoidal lesions, as well as enlargement and neovascular changes involving abnormal vascular networks.
 
Kim and Yu conducted a retrospective review of 39 consecutive patients with polypoidal choroidal vasculopathy who received PDT monotherapy (before April 2007) or a combination of PDT and intravitreal bevacizumab (after April 2007) (Kim, 2011). During 12 months of follow-up, the patients in the monotherapy group (n=19) received a mean of 1.89 PDTs, and patients in the combined therapy group (n=20) received a mean of 1.30 PDTs and 2.90 bevacizumab injections. BCVA improved by 3.0 lines in the combined therapy group compared with 1.6 lines in the PDT monotherapy group. Improvement in BCVA of 3 lines or more was achieved in 55.0% of patients in the combined therapy group versus 36.8% of patients in the monotherapy group.
 
Conclusions: The available evidence from case series is insufficient to permit conclusions regarding the efficacy of PDT for polypoidal choroidal vasculopathy. Randomized controlled trials with longer follow-up are needed to evaluate the efficacy of PDT (monotherapy or combined) compared to anti-VEGF therapy.
 
Choroidal Hemangioma
The 2010 systematic review by Chan et al. included 11 case series on PDT in patients with choroidal hemangioma (Chan, 2010). PDT has been reported to induce complete and irreversible occlusion of the microvasculature, although this may require more than one treatment. Several case series demonstrated encouraging visual and anatomical outcomes in 150 patients with circumscribed choroidal hemangioma who were treated with various PDT regimens.
 
In 2010, Blasi et al reported 5-year outcomes from a prospective series 25 consecutive patients with symptomatic choroidal hemangioma (Blasi, 2010). Twenty-two of the patients (88%) received a single PDT session and 3 eyes received a second PDT session. Follow-up examinations were performed 2 weeks, 1 month, 3 months, and every 6 months after treatment. All tumors responded with a reduction in size, and there were no recurrences through the 5 years of follow-up. At 1 year, BCVA improved by an average of 18.2 letters. Visual acuity improved by 2 or more lines in 20 eyes (80%) and by 3 or more lines in 12 eyes (48%). No treated eyes lost visual acuity between the 1- and 5-year follow-up. Foveal center thickness decreased from a mean of 386.20 to 179.2 microns at 5 years, and there was resolution of macular exudation in all cases. No treatment-related adverse events or complications were identified.
 
Conclusions: While promising, larger and comparative studies are needed to evaluate the effect of PDT on health outcomes for this indication.
 
Angioid Streaks
The 2010 systematic review by Chan et al. included 8 case series on PDT in 148 patients with angioid streaks (Chan, 2010). The authors concluded the PDT might limit or slow vision loss compared with the expected natural course of CNV due to angioid streaks, but one study showed a decrease in visual acuity following PDT, and others showed that substantial proportions of patients continued to lose visual acuity. Thus, further studies to assess its long-term safety and efficacy are warranted.
 
Inflammatory Conditions
The 2010 systematic review by Chan et al. included 15 case reports on PDT in 115 patients with inflammatory eye conditions (Chan, 2010). Encouraging visual and anatomical outcomes have been reported with PDT for punctuate inner choroidopathy, choroiditis and toxoplasmic retinochoroiditis, and subfoveal CNV secondary to posterior uveitis. While promising, larger and comparative studies are needed to evaluate the effect of PDT on health outcomes for this indication.
 
2013 Update
PDT in Combination with VEGF Antagonists
Results from the DENALI and MONT BLANC trials were reported in 2012 (Kaiser, 2012; Larsen, 2012).
 
DENALI trial
DENALI was a multicenter, double-blind, randomized Phase IIIb trial that tested whether ranibizumab in combination with either standard fluence PDT (n=104), or reduced fluence PDT (n=105) was noninferior to ranibizumab given monthly (n=112) (Kaiser, 2012). The 2 combination-therapy groups received ranibizumab monthly for the first 3 months, followed by retreatment with PDT or ranibizumab as needed (pro re nata; PRN) based on specified retreatment criteria at monthly monitoring. The ranibizumab monotherapy group received sham PDT, and patients in the combination groups who did not require ranibizumab at the monthly follow-up visit received sham intravitreal injections. The 2 main outcome measures were the change in best corrected visual acuity (BCVA) from baseline and the proportion of patients in the combination therapy groups with a treatment-free interval of 3 months or longer. A ranibizumab-free interval of 3 months or longer was achieved in most of the patients in the standard (92.6%) and reduced (83.5%) fluence combination groups. Patients in the monotherapy arm received an average of 10.5 injections, while patients in the standard and reduced fluence combination groups received an average of 5.1 and 5.7 injections. About 20% of patients in the combination groups did not receive any ranibizumab retreatments after the loading phase up until month 11. However, the mean BCVA change at 12 months was +5.3 and +4.4 letters for standard and reduced fluence PDT, respectively, compared with +8.1 letters for the ranibizumab monotherapy group, and non-inferiority of visual outcomes was not demonstrated. Mean central retinal thickness, measured at a central reading center, was reduced more in the ranibizumab monotherapy group (172.2 microns) compared to the reduced fluence (140.9 microns) group. Florescein leakage was higher in the combination therapy groups (standard fluence: 58.2%, p=0.008; reduced fluence: 54.5%, p=0.075) compared with the ranibizumab monotherapy group (41.8%).
 
 
MONT BLANC trial
MONT BLANC was a multicenter, double-blind, randomized noninferiority trial that compared combination PDT/ranibizumab versus PRN ranibizumab monotherapy (with sham PDT) in 255 patients with CNV related to AMD (Larsen, 2012). Both groups received 3 consecutive monthly injections followed by PRN retreatments (active or sham) based on specified retreatment criteria. As with the DENALI trial, the 2 main outcome measures were the change in BCVA from baseline and the proportion of patients in the combination therapy group with a treatment-free interval of 3 months or longer. At 12 months, the proportion of patients with a treatment-free interval of 3 months or more was similar in the 2 groups (96% combination therapy and 92% monotherapy), and the change in BCVA with combination therapy (+2.5 letters) was found to be noninferior to ranibizumab monotherapy (+4.4 letters). On average, patients received 4.8 ranibizumab injections in the combination group compared with 5.1 injections in the monotherapy group over 12 months. Decreases in mean central retinal thickness were similar in the combination (115.3 microns) and monotherapy (107.7 microns) groups. This well-conducted study found that PDT did not reduce the number of ranibizumab injections when ranibizumab was administered PRN.
 
Chronic Central Serous Chorioretinopathy
Use of reduced dose verteporfin PDT has also been reported. Uetani et al. compared half-dose versus one-third dose PDT for chronic central serous chorioretinopathy in a small (n=16) prospective open-label trial (Uetani, 2012). Patients were assessed at baseline and at 4 days, 1 month, and 3 months after PDT. At 3 months, all 10 eyes (100%) in the half-dose PDT group and 2 eyes (33%) in the one-third dose PDT group had complete resolution of subretinal fluid. Patients in the half-dose PDT group gained an average of 5.4 letters while patients in the one-third-dose group gained 1.7 letters (not significantly different).
 
Summary
For combination therapy, the literature to date, has not demonstrated which includes 2 high-quality randomized trials, shows no improvement in outcomes or reduction in the number of intravitreal injections with combined PDT and anti-VEGF therapy, nor with a combination of PDT and corticosteroids. Based on results of case series and expert opinion chronic central serous chorioretinopathy and choroidal hemangioma meet primary coverage criteria..
 
2014 Update
A search of the MEDLINE database was conducted through December 2013. There was no new literature identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A multi-center, unblinded trial randomized 60 patients to ranibizumab with half-fluence PDT or ranibizumab alone (Williams, 2012). Patients in the ranibizumab group received 3 monthly injections followed by treatment as needed, resulting in a total of 6.8 injections over the year. For the combined treatment group, ranibizumab was given if it was less than 90 days since the prior treatment. Patients in this group received a total of 3 injections over 12 months. The difference between groups in the number of injections was not significantly different using a chi-square test. BCVA improved by a mean of 9.9 letters in the ranibizumab group compared to a gain of 2.6 letters in the combined treatment group. This difference was not significantly different by t-test. A similar number of patients gained 15 or more letters (33% monotherapy and 31% combination therapy).
 
A small, unblinded randomized trial compared low-fluence PDT versus intravitreal bevacizumab in 22 patients with chronic central serous chorioretinopathy (Semeraro, 2012). Follow-up visits were scheduled at 1, 3, 6, and 9 months. At 9 months' follow-up, BCVA improved from 30 letters to 40 letters in the PDT group and from 20 letters to 43 letters in the bevacizumab group. Central retinal thickness improved to 114 microns with PDT and 127 microns with bevacizumab. There was no significant difference in visual acuity or central retinal thickness between the 2 groups. This study is limited by its small size, unequal baseline measures, and lack of blinding.
 
EVEREST was a small, exploratory, multi-center double-blind randomized trial of PDT, ranibizumab, or combination treatment in 61 treatment-naïve Asian patients with polypoidal choroidal vasculopathy (Koh, 2012). Patients in the PDT monotherapy group (angio-occlusive) received sham ranibizumab, and patients in the ranibizumab monotherapy group (antiangiogenic and antipermeability) received sham PDT. The primary endpoint, the proportion of patients with complete regression of polyps at 6 months, showed PDT alone (71.4%) or in combination with ranibizumab (77.8%) to be superior to ranibizumab monotherapy (28.6%) in achieving complete polyp regression. The mean improvement in BCVA was generally similar for the 3 groups (7.5 letters for PDT, 10.9 for combined treatment, and 9.2 for ranibizumab alone). The proportion of patients gaining at least 15 letters was 19% in the PDT group, 21% in the combination group, and 33.3% in the ranibizumab monotherapy group. Interpretation of the visual acuity results is limited, as the study was not powered to assess differences in BCVA. There were no new safety findings.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Acute Central Serous Chorioretinopathy
In 2015, Zhao and colleagues reported a double-masked, randomized, non-inferiority trial with 131 patients that compared a 50% versus 30% dose of verteporfin PDT for acute (<6 mos) central serous chorioretinopathy (Zhao, 2015). The 2 primary outcome measures were the proportion of eyes with complete absorption of subretinal fluid and the proportion of eyes with complete disappearance of fluorescein leakage at 6 and 12 months. The 30% dose did not achieve non-inferiority. At 12 months the proportion of eyes with complete absorption of retinal fluid was 75.4% in the 30% dose compared with 94.6% in the half-dose group (p=0.004). Complete disappearance of fluorescein leakage at 12 months was observed in 68.9% of the 30% dose vs 92.9% of the half-dose group (p=0.001). Visual acuity, a secondary outcome measure, improved from 20/32 to 20/20 in both groups, with a mean difference between the groups of 1.7 letters. In the 30% dose group 4 eyes (6.6%) lost 5 or more letters compared with 0 eyes in the half-dose group. This study, although of high methodologic quality, does not provide sufficient evidence of a functional benefit that would outweigh the potential risk of treatment with PDT for acute central serous chorioretinopathy.
 
Chronic Central Serous Chorioretinopathy
Ma and colleagues conducted a systematic review of PDT for central serous chorioretinopathy (Ma, 2014).  Included were 9 studies with a total of 319 patients (range: 16-67). Six studies were prospective comparisons and 3 were randomized. Only 2 studies had masking of treatments. Meta-analysis found that PDT was more effective than laser photocoagulation and anti-VEGF drugs in resolving subretinal fluid (p<0.01) and more rapid than anti-VEGF drugs in decreasing central macular thickness (p<0.01). There was no significant difference between treatments for improving BCVA. Both half-dose and half-fluence PDT were effective for improving BCVA, decreasing central macular thickness, and resolving subretinal thickness compared with placebo.
 
American Academy of Ophthalmology
2015 Preferred Practice Patterns (practice guidelines) on AMD from the American Academy of Ophthalmology (AAO) describe PDT as a U.S. Food and Drug Administration- approved option for the treatment of subfoveal lesions and predominantly classic CNV related to AMD (AAO, 2015).
 
The 2015 update states that anti-VEGF therapies have become first line therapy for treatment and stabilizing most cases of AMD. PDT is a less commonly used treatment for neovascular AMD; recommendations state that the following diagnoses are eligible for PDT treatment with verteporfin:
  • Macular CNV, new or recurrent where the classic component is >50% of the lesion and 5400μm in greatest linear diameter
  • Occult CNV may be considered for PDT with vision <20/50 or if the CNV is <4 MPS [macular photocoagulation study] disc areas in size when the vision is >20/50
  • Juxtafoveal CNV is an off-label indication for PDT but may be considered in select cases
 
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Semeraro and colleagues published an RCT of 75 patients with treatment-naive exudative CNV due to AMD (Semeraro, 2015). Patients were randomized into 3 groups: ranibizumab monotherapy, ranibizumab combined with reduced-fluence verteporfin PDT, and ranibizumab combined with ketorolac eye drops. At the 12-month follow-up, BCVA (SD) was superior in the ranibizumab plus ketorolac group (-0.25 [0.60] logMAR), compared with ranibizumab monotherapy (-0.14 [0.52] logMAR) or ranibizumab combined with PDT (-0.10 [0.30] logMAR). Change in mean (SD) central retinal thickness was also superior in the ranibizumab plus ketorolac group (-141 [21] μm) compared with the ranibizumab monotherapy group (-125 [15] μm) and the ranibizumab plus PDT group (-130 [15] μm).
 
A Cochrane systematic review on the treatment of CSC, both acute and chronic, was published in 2015 (Salehi, 2015). For PDT monotherapy, there was 1 low-quality trial of patients with acute CSC comparing PDT to no treatment using a sham control. There was a small improvement in visual acuity for the PDT group (mean difference, -0.10 logMAR; 95% CI, -0.18 to -0.02). There was also a decrease in recurrence of CSC (risk ratio, 0.10; 95% CI, 0.01 to 0.81) and a trend toward a lower risk of persistent CSC (risk ratio, 0.12; 95% CI, 0.01 to 1.02). Two low-quality trials compared anti-VEGF agents with PDT and reported no difference in BCVA at 1 year. There was a trend toward less recurrence and less persistent CSC in the PDT group, but these results were inconsistent across trials.
 
Tang and colleagues published a systematic review in 2015 evaluating treatment for polypoidal choroidal vasculopathy (Tang, 2015).  PDT alone was compared to ranibizumab alone and to combination ranibizumab plus PDT. This review included 3 RCTs and 6 retrospective comparative studies. For PDT alone versus ranibizumab alone, 2 RCTs reported the weighted mean difference in visual acuity was 0.06 logMAR (95% CI, -0.01 to 0.12) in favor of ranibizumab alone, but this difference was not statistically significant. For combination therapy versus PDT alone, a single RCT reported that there was a nonsignificant weighted mean difference of-0.08 (95% CI, -0.20 to 0.04) in favor of combination therapy.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The use of verteporfin photodynamic therapy (VPDT) in CNV has decreased substantially with the availability of anti-vascular endothelial growth factor (anti-VEGF) therapy. Subsequent to Food and Drug Administration (FDA) approval of VPDT in 2000, FDA approved pegaptanib in 2004 and ranibizumab in 2006 for treatment of AMD-related CNV. The approval of pegaptanib was based on a sham-controlled RCT (Gradoudas, 2004; Chakravarthy, 2006). While ranibizumab was approved based on a head-to-head comparison with VPDT in the ANCHOR trial\l " (Brown, 2006). Intravitreal injections of anti-VEGF drugs such as ranibizumab and bevacizumab have shown superior efficacy compared to VPDT in multiple head-to-head trials. Currently, VPDT is used for patients in whom VEGF inhibitors are contraindicated or for those who fail to benefit from VEGF inhibitors.
 
A systematic review of anti-VEGF injections for treating wet AMD was published in 2015, including a comparison of anti-VEGF monotherapy to anti-VEGF combination therapy plus VPDT (Ba, 2015). Results showed a significant difference in BCVA of 2.74 letters (95% CI, 0.26 to 5.21 letters; p=0.03) in favor of the monotherapy group (note that the conclusions of the systematic review indicated that the difference favored the combination group, which is incorrect). There were no differences between groups on central retinal thickness or lesion size. Reviewers did not report combined analysis of the number of anti-VEGF injections performed in each group. Similar results were reported in a meta-analysis published in 2016 (Tong, 2016).
 
VPDT Plus Anti-VEGF Therapy
Data from a retrospective study for adjunctive VPDT in patients refractory to anti-VEGF monotherapy has suggested favorable effect on visual acuity and anatomic outcomes. Lee and Lee (2016) reported data from a retrospective analysis of 28 eyes of 28 patients who showed persistent subretinal and/or intraretinal fluid after at least 4 anti-VEGF injections in the 6 months before adjunctive VPDT and subsequently received additional VPDT and anti-VEGF therapies (Lee, 2016). Patient charts were reviewed until 12 months after the initial VPDT. During a 1-year follow-up, 17 (60.7%) eyes did not demonstrate recurrent fluid accumulation. Among the 11 eyes requiring retreatment, 7 eyes initially showed complete fluid absorption after the initial PDT. At 12 months, BCVA had improved by 0.3 logMAR or more or was maintained compared with baseline in 27 (96.4%) eyes
 
VPDT Plus Corticosteroids and/or VEGF Inhibitors  
Three RCTs have evaluated combination of VPDT with corticosteroids¾1 trial from Italy (Piermarocchi, 2008), RETINA (Marberley, 2009) and 1 trial from Iran (Piri, 2014). The Italian RCT (2008) assigned 84 treatment-naive patients with exudative AMD to VPDT alone (n=41) or combination intravitreal triamcinolone acetonide plus VPDT (n=43) (Piermarocchi, 2008). Mean visual acuity increased at 1 month of follow-up but decreased progressively by the 24-month point in both groups. In the RETINA trial (2009), 100 patients with CNV due to AMD were randomized to VPDT alone or VPDT plus intravitreal triamcinolone. Combination treatment did not result in a significant difference in the primary outcome of visual acuity at 1 year compared with VPDT alone. The Iranian trial randomized 84 treatment-naive patients with CNV due to AMD to VPDT plus bevacizumab with and without intravitreal triamcinolone (Piri, 2014). There were no significant differences in the BCVA at week 12 and other time points.
 
Pathologic Myopia
Pathologic myopia refers to an abnormal elongation of the eye associated with severe near-sightedness. It generally occurs among people older than 30 years of age and can result in a progressive, severe loss of vision, frequently related to the development of CNV. VPDT has also been investigated in patients with CNV related to pathologic myopia. Anti-VEGF therapy is now considered a first-line intervention in patients with myopic CNV. The initial evidence was based primarily on retrospective studies and clinician experience. RADIANCE, a 2014 multicenter RCT compared intravitreal ranibizumab to VPDT in the treatment of myopic CNV and reported improved visual acuity at 12 months in the ranibizumab treatment arm (Wolf, 2014). Zhu and colleagues published a Cochrane review that found treatment with anti-VEGF therapies was more likely to restore visual acuity than VPDT (Zhu, 2016).
 
VPDT vs Placebo
A second arm of the VIP trial focused on 120 patients with pathologic myopia and CNV, either classic, occult, or mixed (although 90% of patients had classic CNV) who were randomized in a 2:1 ratio to receive VPDT or placebo (VIP, 2001). Patients received an average of 3.4 VPDT treatments over 12 months. The primary outcome was the proportion of eyes with fewer than 8 letters of visual acuity lost at 12 months by ITT analysis. At month 12, VPDT-treated eyes lost fewer than 8 letters on a standard eye chart in 58 (72%) of patients versus 17 (44%) receiving placebo. Improvement of at least 5 letters was observed in 26 (32%) VPDT-treated eyes compared with 6 (15%) placebo-treated eyes. Fluorescein angiography showed progression of classic CNV in 36% of VPDT-treated eyes compared with 54% of the placebo group. The authors concluded that VPDT increased the chance of stabilizing or improving vision compared with placebo for at least 1 year. However, the results at 2 years of follow-up were not statistically significantly in favor of VPDT (Blinder, 2003).
 
VPDT Plus With Anti-VEGF Therapy
Rinaldi and colleagues randomized 60 patients to VPDT (standard- and reduced-fluence, n=20 each) plus ranibizumab or to ranibizumab monotherapy (n=20) (Rinaldi, 2017). The primary outcomes were mean change in BCVA and mean change in retinal thickening from baseline to week 48. The trial was likely underpowered to detect a clinical meaningful difference in BVCA for between-group comparisons. Mean BCVA change at 48 weeks was +0.2 and +15 letters with standard- and reduced-fluence VPDT plus ranibizumab, respectively, compared with +16.8 letters with ranibizumab monotherapy. At 48 weeks, mean central foveal thickness decreased from baseline was 58 μm, 91.4 μm, and 85 μm for the 3 groups, respectively.
 
Acute Central Serous Chorioretinopathy
Chan and colleagues conducted a randomized, double-masked, placebo-controlled trial of 63 patients who were randomized in a 2:1 ratio to half-dose VPDT or placebo (Chan, 2008). Thirty-nine patients in the VPDT and 19 in the placebo arm completed the trial. The primary outcome measure (the proportion of eyes with absence of subretinal fluid at the macula at 12 months) was observed in 37 (95%) eyes in the VPDT arm and 11 (58%) eyes in the placebo arm. Mean increase of BCVA was 1.8 and 0.6 lines in the VPDT and placebo arm, respectively. The treatment difference was 1.2 lines, which fell below the threshold of 3 lines considered clinically meaningful. A responder analysis was not reported.
 
Chronic Central Serous Chorioretinopathy
Reductions in subretinal fluid and improvement in retinal anatomy, visual acuity (Chan, 2008; Nicolo, 3023; Lai, 2006; Valmaggia, 2012; Rouvas, 2012; Jirarattanasopa, 2012) and retinal sensitivity (Senturk, 2011; Fujita, 2012; Fujita, 2011; Boni, 2012; Wu, 2011) have been observed in 70% to 100% of cases in multiple retrospective studies. Use of reduced-dose VPDT for chronic CSC also has been reported. Uetani and colleagues compared half-dose versus one-third dose VPDT in a small (N=16 eyes) prospective open-label trial (Uetani, 2012). At 3 months, all 10 (100%) eyes in the half-dose VPDT group and 2 (33%) eyes in the one-third-dose VPDT group had complete resolution of subretinal fluid. Patients in the half-dose VPDT group gained an average of 5.4 letters while patients in the one-third-dose group gained 1.7 letters (p=NS). Chan and colleagues also reported on reduced-dose verteporfin for the treatment of chronic CSC in a prospective series of 48 patients (Chan, 2008). Mean duration of CSC was 8.2 months (range, 3-40 months). At 12 months after VPDT, mean BCVA improved from 0.31 to 0.15 logMAR, an improvement of 1.6 lines.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing:
(NCT01797861) Prospective Randomized Controlled Treatment Trial for Chronic Central Serous Chorioretinoopathy (PLACE); planned enrollment 140; projected completion date February 2017.
 
(NCT02495181) Randomized, Double-masked, Sham-controlled Phase 4 Study, Efficacy, Safety, and Tolerability of Intravitreal Aflibercept Monotherapy Compared to Aflibercept With Adjunctive Photodynamic Therapy in Patients With Polypoidal Choroidal Vasculopathy (ATLANTIC); planned enrollment 50; projected completion date November 2017.
 
NCT02821520) Initial Versus Delayed PDT Combination with Conbercept in PCV; planned enrollment 80; projected completion date December 2019.  
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
National Institute for Health and Care Excellence
In 2018, the National Institute for Health and Care Excellence updated its 2003 guidance on the use of PDT for AMD (NICE, 2003; NICE, 2018). The Institute made the following recommendations: it recommended against use of PDT as monotherapy for late (wet) AMD and against use of PDT as first-line adjunctive therapy to anti-VEGF therapies for late (wet) AMD; it recommended for PDT as second-line adjunctive therapy to anti-VEGF therapies for late (wet) AMD in a trial setting.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Silva et al published a randomized controlled trial that compared the efficacy and safety of intravitreal aflibercept plus either verteporfin or sham photodynamic therapy in 50 individuals with polypoidal choroidal vasculopathy (Silva, 2021). Consistent with the previous RCTs, no statistically significant difference in visual acuity was found between verteporfin photodynamic therapy with antivascular endothelial growth therapies compared to antivascular endothelial growth therapies alone at week 52 (best corrected visual acuity change: 6.5 vs 5; p=.98).

CPT/HCPCS:
67221Destruction of localized lesion of choroid (eg, choroidal neovascularization); photodynamic therapy (includes intravenous infusion)
67225Destruction of localized lesion of choroid (eg, choroidal neovascularization); photodynamic therapy, second eye, at single session (List separately in addition to code for primary eye treatment)
J3396Injection, verteporfin, 0.1 mg
J3490Unclassified drugs

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