Archived Policies - Other

Photodynamic Therapy for Subfoveal Choroidal Neovascularization


Effective Date:11-01-2007

End Date:01-14-2010


Photodynamic therapy may be considered medically necessary as a treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration, pathologic myopia, or presumed ocular histoplasmosis. 

Photodynamic therapy is considered experimental, investigational and unproven for other ophthalmologic disorders, including but not limited to central serous chorioretinopathy.


Photodynamic therapy is a treatment modality designed to selectively occlude ocular choroidal neovascular tissue.  The therapy is a two-step process, consisting initially of an injection of the photosensitizer verteporfin, followed 15 minutes later by laser treatment to the targeted sites of neovascularization in the retina.  The laser treatment selectively damages the vascular endothelium.  Patients may be re-treated if leakage from choroidal neovascularization persists.

There is currently one intravenous photodynamic therapy agent that has received approval by the U.S. Food and Drug Administration (FDA) for treatment of choroidal neovascularization, verteporfin (Visudyne™).  While choroidal neovascularization may be associated with a wide variety of ophthalmologic conditions, the labeled indications include predominantly classic subfoveal choroidal neovascularization associated with age-related macular degeneration, pathologic myopia, and presumed ocular histoplasmosis.  The FDA-labeled indications note that there is insufficient evidence for verteporfin use in predominately occult subfoveal choroidal neovascularization, and it is contraindicated in patients with porphyria.

Prior to the availability of photodynamic therapy, choroidal neovascularization was treated with photocoagulation using either argon, green, or infrared lasers.  This conventional photocoagulation was limited to extrafoveal lesions due to the risk of retinal burns.  However, recently, infrared lasers used at a low-power setting have been investigational as a technique to photocoagulate subfoveal lesions.  

Age-related macular degeneration (ARMD) is a painless, insidious process.  In its earliest stages, it is characterized by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination.  As AMD progresses, two distinctively different forms of degeneration may be observed.  The first, called the atrophic or areolar or dry form, evolves slowly.  Atrophic ARMD is the most common form of degeneration and is often a precursor of the second form, the more devastating exudative neovascular form, also referred to as disciform or wet degeneration.  The wet form is distinguished from the atrophic form by serous or hemorrhagic detachment of the retinal pigment epithelium and the development of CNV, sometimes called neovascular membranes. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV. The pattern of CNV, as revealed by fluorescein or indocyanine angiography, is further categorized as classic or occult.  For example, classic CNV appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult CNV lacks the characteristic angiographic pattern, either due to the opacity of coexisting subretinal hemorrhage or, especially in CNV associated with ARMD, by a tendency for epithelial cells to proliferate and partially or completely surround the new vessels.  Interestingly, lesions consisting only of classic CNV carry a worse visual prognosis than those made up of only occult CNV, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of ARMD.

Presumed ocular histoplasmosis may be the second most common cause of blindness in patients younger than 50 years of age in certain endemic areas (the Ohio and Mississippi River valleys in the U.S.).  It is a condition 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 neovascular lesions, which may develop many years after chorioretinal scarring has taken place, affect the macula.

Pathologic myopia refers to an abnormal elongation of the eye associated with severe near-sightedness.  It generally occurs among people over 30 years of age and can result in a progressive, severe loss of vision, frequently related to the development of CNV.

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.  Central serous chorioretinopathy may resolve spontaneously or can be treated with medication and laser photocoagulation.

For additional treatment modalities for AMD or ARMD see related policies section.


This policy is based in part on a 2000 Blue Cross Blue Shield Technology Evaluation Center Assessment (TEC) that offered the following observations and conclusions:

  • Two multicenter, double-masked, randomized placebo-controlled trials including 402 patients reported that at one 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 age-related macular degeneration characterized by at least 50% classic choroidal neovascularization.
  • There were inadequate data to permit scientific conclusions regarding other etiologies of choroidal neovascularization.

The TEC Assessment did not specifically address the issue of frequency of treatment or treatment extending beyond one year.  Since the completion of the TEC Assessment, the two-year results of the pivotal Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) randomized trial of patients with AMD were published.  Beneficial outcomes regarding visual acuity and contrast sensitivity noted after 12 months were sustained through 24 months.  At the end of two 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 that were presumed to have progressive disease due to visual or anatomic deterioration within the previous three 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 Treatment of AMD with Photodynamic Therapy (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 any 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 eight 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 one 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 one 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 three lines (15 letters) or more. Visual acuity decreased by less than three lines of vision in 88% of patients during the same time period.

TAP trial 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.  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 age-related macular degeneration. 

Ergun and colleagues reported on a case series of photodynamic therapy for CNV secondary to central serous chorioretinopathy on 26 eyes in 24 patients.  Results demonstrated a mean increase in 2.2 lines of visual improvement at two years and no adverse outcomes.  While promising, larger and comparative studies are warranted for photodynamic therapy for this indication.

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.  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 age-related macular degeneration.  The authors concluded the safety profile of verteporfin therapy was not statistically different from placebo.  An October 2005 TEC Special Report on the treatment of age-related macular degeneration also supports the conclusions given here and notes that the pathway leading to choroidal neovascularization is complex. 

An October 2005 BCBSA TEC Special Report noted that therapies are available for AMD to potentially modify (angiostatic agents) and palliate photodynamic therapy (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.

Efficacy for pegaptanib was demonstrated at one year.  However, superiority over PDT has not been shown (i.e., head-to-head comparison).  There is an absence of evidence to guide the use of combination therapy.  Until trials in progress combining angiostatic agents with PDT are completed, it is impossible to assess potential benefit or harm.  Furthermore, it may ultimately be difficult to compare effects of combination therapies unless such studies allow comparison, albeit indirectly, to existing trials.  Of concern is that as therapies become approved, combination therapy without supportive evidence could become commonplace—particularly for those not responding to initial monotherapy.

Kaiser reported results of a three-year, open-label extension of the TAP study.  Out 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, three (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 three-year extension.

The FOCUS study group reported first year results of a blinded phase I/II multicenter, randomized controlled trial of ranibuzumab (0.5 mg) combined with photodynamic therapy.  Patients with choroidal neovascularization secondary to age-related macular degeneration were randomized in a 2:1 ratio to ranibizumab (n=106) or sham (n=56) injection (initially seven days) following verteporfin photodynamic therapy.  A higher than expected rate of serious intraocular inflammation occurred in the first patients, and the two treatments were subsequently scheduled no closer than 21 days apart.  Intent-to-treat analysis (93% retention) showed an average improvement in acuity of 4.9 letters, compared with a decrease of 8.2 letters in the verteporfin group alone.  The percentage of subjects who gained more than 15 letters was 24% for the combined treatment in comparison with 5% for photodynamic therapy alone.  Interpretation of this study is limited, since there was no control group treated with ranibizumab without photodynamic therapy.  Thus, one can not determine whether combined treatment is more effective than intravitreal injection of ranibizumab alone.

Ranibizumab was compared with photodynamic therapy in a multicenter, double-blind study (423 patients) by the ANCHOR study group.  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).  The improvement in visual acuity observed in this study, combined with the results of the FOCUS study described above, suggests that combined treatment of ranibizumab and photodynamic therapy may be no more effective than ranibizumab alone.  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.

Based on numerous case reports and case series, that photodynamic therapy is being used in an attempt to decrease choroidal neovascularization of many different etiologies.  For example, photodynamic therapy has been reported to slow down, but not prevent or reverse, the progression of disease of choroidal neovascularization associated with angioid streaks (n=15) and inflammatory chorioretinal disease (n=5).  Controlled studies are lacking, and photodynamic therapy is considered investigational for ophthalmologic disorders other than age-related macular degeneration, pathologic myopia, or presumed ocular histoplasmosis.


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Medicare Coverage:

The information contained in this section is for informational purposes only.  HCSC makes no representation as to the accuracy of this information.  It is not to be used for claims adjudication for HCSC Plans.

Medicare (CMS) does have a national coverage position.

A national coverage position for Medicare may have been developed or changed since this medical policy document was written.  See Medicare's National Coverage at <>.


Photodynamic Therapy for Subfoveal Choroidal Neovascularization.  Chicago, Illinois:  Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2000 December) 15(18).

Bressler, N.M.  Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials. TAP Study Group. Archives of Ophthalmology (2001)119(2):198-207.

Verteporfin in Photodynamic Therapy (VIP) Study Group.  Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2.  American Journal of Ophthalmology (2001) 131(5):541-60.

Verteporfin in Photodynamic Therapy (VIP) Study Group.  Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial—VIP report no. 1.  Ophthalmology (2001) 108(5):841-52.

Bressler, N.M., Arnold, J., et al.  Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: additional information regarding baseline lesion composition’s impact on vision outcomes – TAP report No. 3.  Archives of Ophthalmology (2002) 120(11):1443-54.

Rubin, G.S., and N.M. Bressler.  Effects of verteporfin therapy on contrast sensitivity: Results from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) investigation – TAP report No. 4.  Retina (2002) 22(5):536-44.

Blumenkranz, M.S., Bressler, N.M., et al.  Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials – TAP report No. 5. Archives of Ophthalmology (2002) 120(10):1307-14.

Wormald, R., Evans, J., et al.  Photodynamic therapy for neovascular age-related macular degeneration (Cochrane Review).  In: The Cochrane Library, (2004) 1.  Chichester, U.K: John Wiley & Sons, Ltd.

Azab, M., Benchaboune, M., et al.  Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: meta-analysis of 2-year safety results in three randomized clinical trials: Treatment of Age-Related Macular Degeneration with Photodynamic Therapy and Verteporfin in Photodynamic Therapy Study Report no. 4.  Retina (2004) 24(1):1-12.

Gragoudas, E.S., Adamis, A.P., et al.  Pegaptanib for neovascular age-related macular degeneration.  New England Journal of Medicine (2004) 351(27):2805-16.

Ergun, E., Tittl, M., et al.  Photodynamic therapy with verteporfin in subfoveal choroidal neovascularization secondary to central serous chorioretinopathy.  Archives of Ophthalmology (2004)122(1):37-41.

Azab, M., Boyer, D.S., et al.  Verteporfin therapy of subfoveal minimally classic choroidal Neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Archives of Ophthalmology (2005) 123(4):448-57.

Heimann, H., Gelisken, F., et al.  Photodynamic therapy with verteporfin for choroidal neovascularization associated with angioid streaks.  Graefes Archives of Clinical Experimental Ophthalmology (2005) 243(11):1115-23.

TEC Special Report: Current and evolving strategies in the treatment of age-related macular degeneration.  Chicago, Illinois:  Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program Special Report (2005 December) 20(11).

Kaiser, P.K.  Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with anopen-label extension: TAP report no. 8. Graefes Archives of Clinical Experiments in Ophthalmology (2006) 244(9):1132-42.

Heier, J.S., Boyer, D.S., et al.  FOCUS Study Group.  Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study. Archives of Ophthalmology (2006) 124(11):1532-42.

Brown, D.M., Kaiser, P.K., et al.  ANCHOR Study Group.  Ranibizumab versus verteporfin for neovascular age-related macular degeneration.  New England Journal of Medicine (2006) 355(14):1432-44.

Lim, J.I., Flaxel, C.J., et al.  Photodynamic therapy for choroidal neovascularization secondary to inflammatory chorioretinal disease.  Annals of the Academy of Medicine in Singapore (2006) 35(3):198-202.

Photodynamic Therapy for Subfoveal Choroidal Neovascularization.  Chicago, Illinois:  Blue Cross Blue Shield Association Medical Policy Reference Manual (2007 April) Other 9.03.08.

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