Verteporfin (Visudyne) Photodynamic Therapy

Number: 0594

Policy

Choroidal Neovascularization

Aetna considers photodynamic therapy (PDT) with light-activated verteporfin (Visudyne) medically necessary for treatment of predominantly classic subfoveal choroidal neovascularization (CNV) when both of the following criteria are met:
1. Member has predominantly classic subfoveal choroidal neovascularization due to ONE of the following:
  1. Age-related macular degeneration (AMD); or
  2. Chronic central serous chorioretinopathy (also includes retinal pigment epithelial leakage without evident CNV); or
  3. Presumed ocular histoplasmosis; or
  4. Pathologic myopia; and
2. The treatment spot size is less than or equal to 6.4 mm in diameter.
Choroidal Hemangioma: Aetna considers photodynamic therapy (PDT) with light-activated verteporfin (Visudyne) medically necessary for treatment of choroidal hemangioma; or
Continuation of therapy

Aetna considers continued treatment with Visudyne therapy medically necessary for members who have demonstrated a positive clinical response to Visudyne therapy.

Note: Most individuals treated with verteporfin will need to be re-treated every 3 months. All individuals having a re-treatment will need to have a flourescein angiogram or ocular coherence tomography (OCT) performed prior to each treatment. Re-treatment is necessary if fluorescein angiograms or OCT show any signs of recurrence or persistence of leakage.
Experimental Indications

Aetna considers Visudyne PDT experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:
1. Alopecia areata
2. Angioid streaks
3. Angiomatous lesions secondary to systemic diseases
4. Atherosclerotic plaque
5. Telangiectasia
6. Basal cell carcinoma
7. Breast cancer
8. Choroidal metastasis
9. CNV associated with macular dystrophy or secondary to choroiditis and retino-choroiditis
10. Diseases without CNV (e.g., choroidal osteoma, choroidal melanoma, and retinal hamartoma)
11. Endometrial cancer
12. Glioma
13. Idiopathic CNV
14. Iris metastasis
15. Neovascular glaucoma
16. Ovarian cancer
17. Pancreatic cancer
18. Parafoveal CNV (occult CNV lesions with no classic component)
19. Polypoidal choroidal vasculopathy
20. Psoriasis
21. Retinal angiomatous proliferation
22. Retinal capillary hemangioma
23. Retinoblastoma
24. Rubeosis iridis
25. Sentinel lymph node metastasis
Aetna considers the simultaneous use of Visudyne PDT in combination with anti-angiogenic agents for the treatment of CNV due to AMD experimental and investigational because the safety and effectiveness of such combination therapy has not been established.

Dosing Recommendations

Verteporfin is available as Visudyne for injection in a 15 mg lyophilized single use vial.

The desired dose of verteporfin is 6 mg/m² body surface area. See Full Prescribing Information for details.

Source: Bausch + Lomb, a division of Valeant Pharmaceutcials North Americal LLC 2017.

Background

Verteporfin (Visudyne) is a light-activated drug used in photodynamic therapy (PDT). Once verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion.

Because of PDT's potential for selective tissue injury, it offers advantages over conventional laser treatments. Photodynamic therapy's potential to selectively affect choroidal neovascularization (CNV) is attributable to preferential localization of the photosensitizer dye to the CNV complex and irradiation of the complex with light levels far lower than required for thermal injury.

Visudyne (verteporfin for injection) therapy is a two‐stage process requiring administration of both verteporfin for injection and nonthermal red light. Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short‐lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo‐oxygenase (leukotriene) and cyclo‐oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.

Visudyne (verteporfin for injection) has been approved by the U.S. Food and Drug Administration for the treatment of: age‐related macular degeneration, associated with classic subfoveal choroidal neovascularization; presumed ocular histoplasmosis associated with classic subfoveal choroidal neovascularization; pathologic myopia, associated with classic subfoveal choroidal neovascularization.

Age-Related Macular Degeneration

Age‐related macular degeneration (AMD) is a major cause of painless central vision loss and is a leading cause of blindness in people over 60. Dry AMD is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. Approximately 10‐20% of patients with dry AMD eventually progress to wet AMD.

Wet AMD is associated with growth of abnormal blood vessels under the macula. These new blood vessels tend to be very fragile and often leak blood and fluid and cause scar tissue that destroys the central retina. The blood and fluid raise the macula from its normal place at the back of the eye. Damage to the macula occurs rapidly and results in a deterioration of sight over a period of months to years. Between 80% to 90% of AMD is dry, yet more than 80% of the visual loss attributable to AMD is caused by the wet form.

Photodynamic therapy with verteporfin has been shown in 2 randomized controlled studies (RCTs) involving 609 patients to be effective for patients with CNV secondary to age-related macular degeneration (so-called "wet AMD"), the type of late age-related macular degeneration that is the most frequent cause of visual loss to the level of legal blindness or worse. In clinical studies, patients with predominantly classic CNV (CNV with distinct, subretinal neovascular membranes) showed clinically significant results; in comparison, among patients demonstrating less than 50 % classic CNV at the initial visit, there was no improvement in outcome compared to placebo treatment. After 12 months, 67 %of patients treated with verteporfin lost less than 3 lines of visual acuity, compared to 40 % of patients treated with placebo (sham treatment). Patients with predominantly classic (as opposed to occult) CNV lesions exhibited the greatest benefit, with 77 % of verteporfin-treated patients versus 27 % of placebo-treated patients losing less than 3 lines of visual acuity at 12 months.

A multi-center RCT conducted in Europe showed significant benefit of PDT with verteporfin for patients with predominantly occult CNV lesions. In this study, 258 of the 339 patients included in this study had occult CNV. After 2 years, 45 % of verteporfin-treated patients with occult CNV lost less than 15 letters (equivalent to approximately 3 lines), compared with 32 % of placebo-treated patients.

A recent update of a consensus guideline on the use of Visudyne for choroidal neovascularization due to AMD and other causes (Verteporfin Roundtable Participants, 2005) stated that additional courses of treatment should be considered as often as every 3 months (+/- 2 weeks) if fluorescein leakage from CNV is noted at that time. Moreover, additional courses of treatment could be deferred if the biomicroscopic and fluorescein angiographic appearances of the lesion are unchanged and show minimal fluorescein leakage, especially when there is no subretinal fluid or fluorescein leakage from CNV underlying the center of the foveal avascular zone. An analysis by the Centers for Medicare & Medicaid Services (CMS, 2013) found optical coherence tomography (OCT) as an appropriate alternative to fluorescein angiography (FA) to assess treatment response.

Spaide et al (2005) examined the 12-month results of a group of patients treated with combined PDT with verteporfin and intra-vitreal triamcinolone acetonide for CNV secondary to AMD. A total of 26 eyes of 26 patients with CNV secondary to AMD were included in the study -- 13 with CNV, without restriction to type, were not treated with prior PDT (newly treated group); and 13 with prior PDT therapy who experienced visual loss while being treated with PDT alone comprised the remainder (prior PDT group). Patients with CNV were treated with PDT, immediately followed by an intra-vitreal injection of 4 mg of triamcinolone acetonide. Visual acuity was measured by Early Treatment Diabetic Retinopathy Study protocol refraction. Need for re-treatment was based on fluorescein angiographic evidence of leakage at 3-month follow-up intervals. Main outcome measures were visual acuity and re-treatment rate. In the newly treated group, the mean acuity change was an improvement of 2.5 lines (last observation carried forward [LOCF], +2.4 lines; p = 0.011, Wilcoxon signed ranks test, as compared with baseline acuity) for patients completing the 12-month follow-up. In the prior PDT group, the mean change was an improvement of +0.44 lines (LOCF, +0.31 lines; p = 0.53). Re-treatment rates were 1.24 for the newly treated group and 1.2 for the prior PDT group over the first year. Ten patients (38.5 %) developed an intra-ocular pressure of greater than 24 mm Hg during follow-up, a threshold used to institute pressure reduction therapy. No patient developed endophthalmitis. The authors concluded that although the number of patients in this pilot study was limited, the improvement of acuity and the reduced treatment frequency in these patients suggested that combination therapy with PDT and intra-vitreal triamcinolone acetonide, particularly when used as first-line therapy, merits further investigation. Elevated intra-ocular pressure seems to be the most frequent early side effect of the treatment.

Ergun et al (2006) examined the effectiveness of PDT with verteporfin and intra-vitreal triamcinolone acetonide in the treatment of neovascular AMD. A total of 60 eyes of 56 patients with neovascular AMD were treated with PDT with verteporfin followed by an intra-vitreal injection of 4 mg triamcinolone acetonide. The main outcome measures were visual acuity, re-treatment frequency with PDT (and triamcinolone), and frequency of side effects. Mean follow-up was 15.9 months (range of 12 to 30 months, median 15 months). Twenty-three (38.3 %) of 60 eyes had a stable result at 12 months' follow-up (i.e., loss/gain less than 3 lines) and 34 (56.7 %) of 60 had a loss of 3 lines or more. Three patients (5 %) had an improvement of 3 lines or more. Lesion type, patient age, and lesion size had no influence on the outcome, but baseline visual acuity had a statistically significant effect (p = 0.006). The median number of PDT-intra-vitreal triamcinolone acetonide treatments was one. One-third (20 of 60) of all eyes had an increase in intra-ocular pressure that required therapy. There were no cases of endophthalmitis, but 13 patients (21.6 %) developed severe cataract that required surgery. The authors concluded that the combination of PDT and intra-vitreal triamcinolone acetonide requires careful consideration as a treatment option for neovascular AMD. In the present study, this treatment combination did not prevent a considerable decrease in visual acuity.

Augustin and Schmidt-Erfurth (2006) reported that pilot studies as well as large case series suggested that a combination of PDT and intra-vitreal triamcinolone acetonide has the potential to improve visual outcomes and reduce the need for additional PDT treatments. They noted that randomized, prospective clinical trials are underway to confirm the safety and effectiveness of this novel treatment modalty.

Kaiser (2007) discussed the rationale for combining anti-angiogenic treatment with Visudyne PDT in the management of CNV due to AMD and evaluated available evidence for the therapeutic benefits of such approaches. Treatments for CNV due to AMD can be directed at either the vascular component of CNV or the angiogenic component that leads to the development of the condition. Verteporfin targets the vascular component, whereas anti-angiogenic agents (such as pegaptanib and ranibizumab) target key mediators of the angiogenic cascade. The different mechanisms of action of these approaches offer the potential for additive or synergistic effects with combination therapy. In addition, anti-angiogenic agents might counteract up-regulation of angiogenic factors (including vascular endothelial growth factor [VEGF]) that occur after verteporfin PDT. Results from pre-clinical and clinical studies of the combination of ranibizumab or pegaptanib with verteporfin warrant continued investigation. The author concluded that the use of anti-angiogenic agents in combination with verteporfin may have the potential to improve visual outcomes and reduce the number of treatments in eyes with CNV due to AMD, and requires further evaluation in randomized, controlled clinical trials.

In a recent review on verteporfin combination regimens in the treatment of neovascular AMD, Shah and colleagues (2009) concluded that a rationale exists for investigating combination approaches to target different processes in CNV pathogenesis, which may optimize treatment benefits in neovascular AMD.

Central Serous Chorioretinopathy

Visudyne has also been studied for the treatment of central serous chorioretinopathy (CSC). Central serous chorioretinopathy is an idiopathic disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium. Photodynamic therapy is known to have a direct effect on the choroidal circulation but was limited by potential adverse effects, such as macular ischemia. In a pilot study (n = 20 eyes), Yannuzzi et al (2003) reported that indocyanine green angiography-guided PDT with verteporfin seems to aid in the resolution of exudative detachments in patients with chronic CSC. This treatment was associated with a rapid reduction in subretinal fluid and improvement in visual acuity. Although the follow-up time and number of patients in this pilot study were limited, the encouraging results and lack of complications suggest that further study is indicated. In a case reports study (n = 9), Ober et al (2005) stated that the treatment of acute CSC with PDT may result in prompt resolution of neurosensory detachment and fluorescein leakage, which can be associated with rapidly improved vision. Although this case series is limited in follow-up and number of patients, the encouraging results and lack of visually significant complications suggest that further investigation is warranted.

Lai et al (2006) assessed the short-term safety of an enhanced PDT protocol with half-dose verteporfin for treating chronic CSC. A total of 20 eyes of 18 patients with symptomatic chronic CSC underwent PDT using 3 mg/m2 verteporfin. Verteporfin was infused over 8 minutes followed by indocyanine green angiography guided laser application 2 minutes later. Serial optical coherence tomography (OCT) and multi-focal electroretinography (mfERG) recordings were performed before PDT, at 4 days, 2 weeks, and 1 month after PDT. The best corrected visual acuity (BCVA), OCT central retinal thickness, and mean mfERG response amplitudes and peak latencies were compared longitudinally. Subgroup analysis was further performed for eyes with or without pigment epithelial detachment (PED). At 1 month after PDT, the median BCVA improved from 20/40 to 20/30 (p = 0.001). The mean central retinal thickness also reduced from 276 micron to 158 micron (p < 0.001) and 17 (85 %) eyes had complete resolution of serous retinal detachment and/or PED. MfERG showed no significant changes in the mean N1 and P1 response amplitude and latency for all eyes. Subgroup analysis showed that eyes without PED had a significant increase in the mean central mfERG P1 response amplitude with reduction in P1 peak latency at 1 month post-PDT. For eyes with PED, transient reduction in the mean central P1 response amplitude was observed at 4 days post-PDT. The authors concluded that the modified safety enhanced PDT protocol with half-dose verteporfin appeared to be a beneficial treatment option for patients with chronic CSC, especially in eyes without serous PED. They stated that further controlled study is needed to demonstrate the long-term safety and effectiveness of this treatment option. Moreover, a practice guideline on PDT for CNV due to AMD and other causes (Verteporfin Roundtable Participants, 2005) did not list CSR as an indication for Visudyne.

In a retrospective case-series study, Butler and colleagues (2012) described the safety and efficacy of very minimal fluence PDT for chronic central serous chorioretinopathy (CCSC). A total of 5 patients with CCSC were included in this study; 2 had previously failed alternative therapies, and 1 was taking concomitant corticosteroids. Patients were treated with very minimal fluence PDT (12 J/cm(2), 150 mW/cm(2), for 80 seconds). Median follow-up time after PDT was 100 days (range of 51 to 154). All patients experienced an improvement in visual acuity and symptoms, as well as complete resolution of sub-retinal fluid. The authors concluded that very minimal fluence PDT appears to be a safe and effective treatment for CCSC. They stated that based on these preliminary findings, a randomized controlled trial is warranted.

Alcubierre et al (2012) evaluated safety and effectiveness of low-fluence PDT (LFPDT) with verteporfin in patients affected with CCSC, in terms of VA and macular morphology measured with OCT. A retrospective, non-randomized and interventionist analysis was performed on 16 eyes in 15 patients with CCSC treated with LFPDT. Best corrected visual acuity with ETDRS optotypes and central foveal thickness (CFT) in OCT were evaluated as outcome measures. The mean follow-up was 10.8 months. The mean BCVA improved from 58.12 to 68.68 ETDRS letters, and CFT decreased from 280.5 to 172.18 microns, with sub-retinal fluid resolution in 14 eyes (87.5 %), 2 of them after a second LFTPD. No complications related to treatment were recorded. The authors concluded that LFPDT with verteporfin can be useful in CCSC to stabilize or improve BCVA, reabsorb sub-retinal fluid and reduce CFT. They stated that randomized studies with a longer follow-up are needed to assure the role of this treatment and to optimize parameters for higher safety and effectiveness in CCSC patients.

Boni and colleagues (2012) stated that in persistent CSC resolution of detachment can be achieved by PDT. These investigators evaluated the effectiveness of half-dose verteporfin compared to full-dose verteporfin. In 2009, the standard PDT regimen for CSC in the authors’ clinic was changed from full-dose to half-dose verteporfin. After a retrospective analysis, 11 cases of half-dose PDT with documented course in 11 patients were presented. A comparison was performed with a control group of 11 consecutive patients with documented course who had received full-dose PDT before 2009. Prior to PDT, there were no statistically significant differences between the groups concerning age, CFT, thickness of detachment, BCVA (EDTRS) and size of spot. Six weeks after PDT, a significant reduction of foveal thickness and detachment was detected in both groups, as well as a significant increase in BCVA. No statistically significant differences in outcome could be found between the 2 groups (Mann-Whitney U-test, p < 0.05). The authors concluded that PDT with half-dose verteporfin seems to be an effective and safe treatment for persistent CSC. These findings showed comparable results after half-dose and after full-dose PDT.

In a retrospective, consecutive case-series study, Jirarattanasopa et al (2012) evaluated the 1-year results of half-dose PDT with verteporfin in chronic or recurrent CSC. A total of 27 eyes of 27 patients with chronic symptomatic CSC or recurrent CSC underwent PDT with half-dose (3 mg/m2) verteporfin. The demographic data such as age, side, gender spot sizes of laser PDT were recorded. The primary outcomes were the BCVA, CFT using the OCT and complication were recorded as secondary outcome at baseline, month 1, 3, 6, and 12 post-PDT. At 12 months after half-dose PDT, the mean logMAR BCVA improved from 0.32 to 0.18 (p = 0.001), the mean CFT decreased from 375.52 microm to 186.52 microm (p < 0.001). The results also showed significant improvement of logMAR BCVA and decreased CFT after 1 month (0.32 to 0.22, p = 0.003 and 375.52 microm to 175.41 microm, p < 0.001) and maintained the results until 1-year follow-up. Twenty-five eyes (92.6 %) showed complete resolution of subretinal fluid at 1 month, 27 patients (100 %) showed complete resolution at 3 month and all sustained the complete resolution until the last visit. No serious complications were recorded during and after the treatment. The authors concluded that the half-dose PDT in area of fluorescein leakage is one of the effective treatment options for chronic or recurrent CSC, especially in patients who cannot undergo focal laser photocoagulation. The treatment sustained the good visual results and has no serious complications up to 1-year.

In a retrospective case-series study, Li et al (2012) evaluated the effect of spectral HRA + OCT-guided PDT with half-dose verteporfin in the treatment of chronic or recurrent CSC. A total of 20 eyes of 18 patients with chronic or recurrent CSC were included. Photodynamic therapy was applied with half-dose verteporfin (3 mg/m(2)) on the site of active area shown on spectral HRA + OCT (defined as focal or diffuse retinal pigment epithelial leakage, choroidal hyperpermeability, or pigment epithelial detachment located within the neurosensory detachment), and patients were observed to determine the anatomic and functional outcomes. Statistical analysis was performed using SAS (version 9.2). A “p” value of 0.05 was considered statistically significant. Comparisons of pre- and post-treatment BCVA and CFT were performed using a paired-t test. The relationship between BCVA and CFT post-treatment was analyzed by linear correlation analysis. Comparisons of the BCVA of eyes with and without the integrity of photoreceptor IS-OS and/or external limiting membrane at the last follow-up visit were performed using 2 sample t-test. The median CSC duration was 4.5 months (ranged 1 month to 2 years). The median follow-up period after PDT was 8 months (ranged 6 to 20 months). The mean BCVA before PDT was 0.35 ± 0.16 (ranged 0.05 to 0.6), at 3 months after PDT was 0.72 ± 0.32 (ranged 0.1 to 1.5) and at the last follow-up visit was 0.78 ± 0.29 (ranged 0.3 to 1.5) (t = 6.444, 6.883, p < 0.05). Fifteen eyes (75.0 %) had improved vision, and 5 eyes (25.0 %) had stable vision. The mean CFT was reduced from (369.0 ± 120.9) µm before PDT to (193.3 ± 30.6) µm 1 month after PDT, (194.9 ± 28.3) µm 3 month after PDT and (190.6 ± 33.7) µm at the last follow-up visit (t = -6.836, -6.826, -7.316; p < 0.05). At the last follow-up visit BCVA was not correlated with CFT (r = 0.166, p > 0.05), but BCVA of the eyes with the integrity of photoreceptor IS-OS and/or external limiting membrane was better than that of without (t = -3.53, p < 0.05). Subretinal fluid disappeared in all eyes 1 month after PDT and there was no recurrence during the follow-up. The authors concluded that spectral HRA + OCT-guided PDT with half-dose of verteporfin seems effective and safe for the treatment of chronic or recurrent CSC.

Lim et al (2013) examined the effectiveness of half-fluence PDT depending on the degree of hyper-fluorescence based on indocyanine green angiography (ICGA) for treatment of chronic CSC (CCSC). These researchers conducted a prospective study of 30 eyes of 30 patients with CCSC. Half-fluence PDT (25 J/cm(2) for 83 s) with ICGA guidance was applied to the area of choroidal hyperpermeability. The baseline middle-phase ICGA findings were classified as intense or weak hyper-fluorescence depending on the degree of hyperpermeability from choriocapillaris. Changes in mean BCVA, resolution of subretinal fluid, recurrence rate, and complications were compared between the 2 groups. The baseline ICGA findings showed intense hyper-fluorescence in 16 eyes (53.3 %) and weak hyper-fluorescence in 14 eyes (46.7 %). Subretinal fluid showed complete resolution in both the groups 1 month after a single application of half-fluence PDT. Recurrence of subretinal fluid was observed in 1 of 14 eyes (7.1 %) with weak hyper-fluorescence and in no eyes (0 %) with intense hyper-fluorescence. No statistically significant difference in the rate of recurrence was observed between the 2 groups. The authors concluded that half-fluence PDT appears to be an effective and safe treatment option for patients with CCSC regardless of the degree of hyper-fluorescence based on ICGA. According to these findings, choroidal hyperpermeability, rather than dysfunction of retinal pigment epithelium, might be more important as primary pathogenesis of CCSC.

Karakus et al (2013) evaluated the safety and effectiveness of PDT with half-dose verteporfin in patients with CCSC and retinal functional changes, by functional acuity contrast test (FACT). In this study, 27 eyes of 24 patients with CCSC were treated with PDT with half-dose verteporfin. Best-corrected visual acuity, CFT and resolution of subretinal fluid on OCT, and leakage on FA and ICGA were assessed. Contrast sensitivity test was performed at baseline and at 12 months for investigating retinal functional changes. The mean follow-up period was 25.33 ± 11.08 months. The mean age was 43.7 ± 8.6 years. Seventeen patients were male (70.8 %) and 7 patients were female (29.2 %). Post-PDT at 1st, 3rd, 6th, 12th month and at last follow-up, BCVA were significantly improved compared with the baseline BCVA (p < 0.001), and CFT post-PDT were significantly thinner than the baseline measurement (p < 0.001). There was significant difference between pre- and post-PDT 12th month contrast sensitivities at all 5 different spatial frequency channels (p < 0.01). The authors concluded that the half-dose PDT is safe and effective in treating CCSC with anatomical and functional success. The measurement of contrast sensitivity by FACT can be useful for evaluating the functional effectiveness of half-dose PDT for CCSC.

Ohkuma et al (2013) evaluated the effectiveness of reduced-fluence PDT (RFPDT) for CSC. This retrospective medical record review of consecutive CSC patients treated with RFPDT (full-dose verteporfin and laser fluence of 25 J/cm(2)) examined 22 eyes of 21 patients (20 males and 1 female). All patients were followed-up for 1 year. Best-corrected visual acuity, complete resolution of subretinal fluid (CR of SRF), central retinal thickness (CRT), the outer nuclear layer (ONL) thickness, and the photoreceptor inner and outer segments (IS/OS) line determined by OCT imaging were evaluated at baseline, 1, 3, 6, 9, and 12 months after initial RFPDT. A single RFPDT session was performed in all cases during a 12-month period. Complete resolution of SRF was identified in all patients; BCVA significantly improved between 3 and 12 months (p < 0.05). The CRT significantly decreased between 1 and 12 months. A significantly thicker ONL was observed at 1 month, and 17 eyes (77.2 %) showed recovery of the continuous foveal IS/OS line. Outer nuclear layer thickness was correlated with BCVA at 12 months (p < 0.01). Stepwise analysis indicated that pre-treatment BCVA (p < 0.01) and ONL thickness (p < 0.01) were significant predictive factors for BCVA at 12 months. Neither ocular nor systemic adverse effects were observed during the follow-up period. The authors concluded that RFPDT appears to be an effective treatment for CSC. Outer nuclear layer thickness is an important visual predictive factor of RFPDT for CSC.

Smretschnig et al (2013) evaluated the results of ICGA-guided verteporfin (Visudyne) PDT with half-fluence rate in the treatment of CCSC. A retrospective review was conducted of 20 eyes of 19 consecutive patients with subfoveal fluid cause by CCSC with choroidal hyperpermeability on ICGA and symptoms of at least 6 months. Indocyanine green angiography-guided verteporfin (6 mg/m) PDT with half-fluence rate (25 J/cm) was performed; ICGA findings were classified as intense, intermediate, or minimal hyper-fluorescence depending on the degree of choroidal hyperpermeability. The resolution of the subretinal fluid and recurrence rates were assessed in relation to the different degrees of choroidal hyper-fluorescence. Best-corrected visual acuity at baseline was 40 letters (± 13; n = 20) according to the ETDRS chart. At 12 months after PDT, the mean BCVA improved to 44 letters (p < 0.01). Pre-treatment CFT was 325 μm and decreased by a mean of 103 μm at month 12 control (p < 0.05). At month 1 after PDT, subretinal fluid in spectral-domain OCT was completely resolved in 100 % of eyes regardless to their degree of choroidal hyper-fluorescence. Two eyes of the intense hyper-fluorescence group and 1 eye of the intermediate hyper-fluorescence group developed recurrence of symptoms over 12 months and received another PDT with half-fluence rate within the 12-month control period. Treatment effect was not depending on the degree of choroidal hyperpermeability at baseline. No systemic side effects were observed during the 12-month follow-up. The authors concluded that ICGA-guided half-fluence PDT with verteporfin is effective in treating CCSC with choroidal hyperpermeability in ICGA, resulting in both visual improvement and reduction of CFT.

Nicholson et al (2013) stated that recent technological advances -- new pathophysiological insights, new imaging techniques for diagnosis and management, and new treatments -- have led to an improved understanding of CSC. The primary role of the choroid has become more widely accepted with widespread use of ICGA. Optical coherence tomography, and particularly enhanced depth imaging OCT, demonstrated a thickened and engorged choroid. Adaptive optics, fundus autofluorescence, mfERG, micro-perimetry, and contrast sensitivity testing revealed that patients with even a mild course suffer previously undetected anatomic and functional loss. Although focal laser and PDT are the current standard of care for persistent subretinal fluid in CSC, they are not appropriate in all cases, and the optimal timing of intervention remains unclear.

Choroidal Hemangioma

In a prospective, multi-center, non-randomized clinical trial, Boixadera and co-workers (2009) evaluated PDT for symptomatic circumscribed choroidal hemangioma (CCH). A total of 31 eyes of 31 patients with posterior pole CCH and symptoms caused by exudation into the macular area were included in this study. Photodynamic therapy was administered by Zeiss laser. Intravenous verteporfin at 6 mg/m(2) body surface was given before treatment, and light emitted at 689 nm for photosensitization. The treatment spot diameter was calculated on early-phase frames of pre-treatment indocyanine green angiography. Fifteen minutes after starting the verteporfin infusion, the laser beam was applied to the retina at radiant exposure 50 J/cm(2) and exposure time 83 seconds. One to 4 treatments were applied at 12-week intervals over 1 year. Standardized evaluation was performed before and at 4-week intervals after each treatment, and at 3, 6, 9, and 12 months. All patients were followed for greater than or equal to 12 months. The primary outcome measure was the absence of exudative retinal detachment at the 12-month follow-up visit on ophthalmoscopy, fluorescein angiography, and optical coherence tomography. Secondary measures were the visual acuity outcome, with best-corrected visual acuity determined by the Early Treatment for Diabetic Retinopathy Study chart, tumor thickness decrease on B-scan ultrasonography, and adverse events. Among the total, 82.8 % of patients required 1, 13.8 % required 2, and 3.4 % needed 3 PDTs to eliminate exudative retinal detachment. to eliminate exudative retinal detachment. Visual acuity increased from a mean of 20/60 to 20/35 (p < 0.001); 69 % of patients demonstrated visual recovery (p < 0.001). Cystoid macular edema regressed in all cases and exudative macular detachment disappeared in all but 2 cases. The CCH thickness decreased in all cases from a mean of 3.0 to 1.7 mm, with the most intense effect seen after 4 weeks of treatment (p < 0.001). Visual fields showed resolution of central scotomas. There were no severe adverse events. The authors concluded that combining PDT with the standard AMD protocol is an effective treatment for CCH in terms of resolution of exudative subretinal fluid and recovery of visual acuity. Moreover, the authors also stated that "because recurrence has been observed long after treatment, a lengthier follow-up period is required to assess the risk of late recurrence and the long-term visual prognosis in these patients".

In a prospective, consecutive, 2-centered, non-comparative, interventional case series, Blasi et al (2010) evaluated the long-term efficacy of verteporfin PDT as the primary treatment for symptomatic CCH (n = 25). All patients had recent onset of visual symptoms and evidence of exudative macular changes on FA and optical OCT. Verteporfin 6 mg/m(2) body surface area was administered intravenously over a 10-minute interval. Five minutes after infusion, a 689-nm laser was applied with a light dose of 50 J/cm(2) for the first 3 patients and a light dose of 100 J/cm(2) for all the other patients. Re-treatments were performed in case of persistent exudation found on OCT. Evaluation of BCVA using ETDRS criteria, FA, indocyanine green angiography (ICGA), OCT, and ultrasound were performed before PDT and on follow-up examinations. All patients were followed for at least 5 years. Primary outcome measures were changes in BCVA and foveal center thickness (FCT) between baseline and month 60. Secondary measures were tumor thickness decrease, absence of leakage on FA, and adverse events. Twenty-two patients received 1 PDT session at 100 J/cm(2), and no recurrences were detected. Three eyes, treated with 50 J/cm(2), received a second PDT session at 100 J/cm(2) 1 month after the first session. After a follow-up of 60 months, BCVA improved an average of 18.5 ETDRS letters (p < 0.001); BCVA improved by greater than or equal to 2 lines in 19 eyes (76 %). The FCT decreased from a mean of 386.20 microm to 179.2 microm, and OCT showed the complete resolution of macular exudation in all cases. All tumors responded with a reduction in size. No treatment-related adverse events or complications were identified. The authors concluded that 5-year results of PDT in treating symptomatic CCH support treatment with a light dose of 100 J/cm(2) after slow intravenous infusion of verteporfin to stabilize or improve visual acuity and resolution of macular exudation. They also stated that RCTs with lon follow-up periods are needed to determine the precise timing of treatment and to compare the different PDT.

Beardsley et al (2013) reported on the recurrence of serous retinal detachment following verteporfin PDT for CCH. A single-center chart review was performed for patients with CCH treated with Visudyne (verteporfin injection; QLT Ophthalmics, Menlo Park, CA) PDT. Initial and post-treatment VA, ultrasound and OCT were evaluated. A total of 4 patients who were treated with PDT for symptomatic serous retinal detachment secondary to CCH were managed for recurrent leakage and followed for an average of 47.5 months. Two patients required 3 re-treatments and 2 required 4 re-treatments for recurrent detachment. Average time to re-treatment was 23.4 months, with successive re-treatment intervals decreasing to 13 months, then 9.5 months, and finally 3.5 months. The authors concluded that Visudyne PDT is a successful initial treatment modality for CCH with serous retinal detachment; however, those patients who require multiple re-treatments may experience recurrent leakage at more frequent intervals.

Choroidal Metastasis

In a retrospective, interventional case series study, Kaliki et al (2012) examined the effectiveness of PDT in the treatment of choroidal metastasis. A total of 9 tumors in 8 eyes of 8 patients were included in this study. Photodynamic therapy using verteporfin at a dose of 6 mg/m(2) body surface area and 689 nm diode laser at an intensity of 600 mW/cm(2) for 83 seconds (50 J/cm(2)) was employed. Main outcome measure was tumor control and BCVA. Nine choroidal metastases in 8 eyes were treated with 1 (8 tumors) or 2 (1 tumor) sessions of PDT. The mean tumor basal diameter was 7 mm (median of 7 mm [range of 2 to 13 mm]), and mean tumor thickness was 2.9 mm (median of 2.9 mm [range of 1.6 to 4.0 mm]). All 9 tumors were associated with shallow subretinal fluid. After PDT, complete control with resolution of subretinal fluid was achieved in 7 tumors (78 %), with mean tumor thickness reduction of 39 % (median of 43 % [range of 6 % to 61 %]). Two tumors failed to respond to PDT, both requiring plaque radiotherapy. Improvement or stabilization of vision was achieved in 7 eyes. Photodynamic therapy-related complications included intra-retinal hemorrhage in 1 eye. The authors concluded that PDT can be an effective alternative for the treatment of choroidal metastasis. Moreover, they noted that additional studies with long-term results in a large cohort will assist in further defining the role and limitations of PDT for management of choroidal metastasis.

Myopic Choroidal Neovascularization

Pathologic, or degenerative, myopia typically develops by age 12 in those with an extraordinarily elongated eyeball. About two percent of Americans are afflicted. The stretching of the eyeball worsens with age and can result in a progressive and severe loss of vision. Compounding the problem in many cases is an abnormal growth of new blood vessels (neovascularization) beneath the macula.

Visudyne has been approved by the FDA for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to pathologic myopia.

Yoon and colleagues (2010) compared visual outcomes after treatment with intra-vitreal anti-VEGF injection or PDT in patients with myopic CNV. A total of 142 eyes (128 consecutive patients) treated with anti-VEGF (ranibizumab or bevacizumab) and/or PDT for myopic CNV were retrospectively reviewed. Patients were categorized into 3 groups:

PDT (51 eyes),
anti-VEGF (63 eyes), and
a combination group (PDT with anti-VEGF) (28 eyes).

Corrected VA values at baseline and 3, 6, 9, and 12 months after treatment were compared. The anti-VEGF group showed significant post-operative improvement in VA compared with the PDT and combination groups (p = 0.01 and 0.04, respectively). The anti-VEGF group demonstrated visual improvement from baseline at every follow-up visit after treatment (p = 0.04, 0.02, 0.01, and 0.002, respectively). The anti-VEGF group showed visual improvement (Snellen equivalent) from 0.57 logarithm of the minimum angle of resolution (0.27) to 0.33 logarithm of the minimum angle of resolution (0.47) (p = 0.01). Furthermore, 98.4 % of patients in the anti-VEGF group and 92.8 % of those in the combination group lost less than 15 letters from baseline VA compared with 72.6 % in the PDT group (p = 0.001 and 0.02, respectively). In the anti-VEGF group, 39.7 % of patients improved from baseline by 15 or more letters compared with 17.7 % in the PDT group (p = 0.02) and 21.4 % in the combination group (p = 0.07). The authors concluded that intra-vitreal anti-VEGF injection is superior to PDT alone or a combination of PDT with anti-VEGF for treating myopic CNV.

The evidence of effectiveness of verteporfin for pathologic myopia is based on a RCT involving 120 patients. (2001). After 1 year of treatment, 86 % of verteporfin-treated patients lost less than 3 lines of visual acuity, compared to 67 % of patients receiving placebo (sham) treatment. After 2 years, a difference persisted between groups in favor of the verteporfin-treated group (79 % for verteporfin patients compared to 72 % for placebo patients), but the difference was not statistically significant.

In a Health Technology Assessment on “Verteporfin photodynamic therapy for neovascular age-related macular degeneration”, Reeves and colleagues (2012) stated that “VPDT also has potential as monotherapy in the management of vascular malformations of the retina and choroid and with trials underway in neovascularisation due to myopia and polypoidal choroidopathy”.

Zhou et al (2014) compared the BCVA between verteporfin PDT and intra-vitreal anti-VEGF in patients with myopic CNV. Published literature from Medline, Premedline, Embase and the Cochrane Library from inception until November 2013 were retrieved. All studies evaluating the BCVA between Verteporfin with PDT and intra-vitreal anti-VEGF for myopic CNV were included. The results were pooled using mean difference (MD), a corresponding 95 % confidence interval (CI). A total of 5 studies (49 eyes) were included in the meta-analysis. These researchers inferred that the BCVA of myopic CNV after the treatment of anti-VEGF was significantly better compared with verteporfin PDT (MD = 0.25, 95 % CI: 0.17 to 0.33, Z = 5.97, p < 0.00001). The authors concluded that the findings of this meta-analysis suggested that intra-vitreal anti-VEGF could have a better BCVA after treatment than verteporfin PDT for myopic CNV.

Claxton et al (2014) evaluated the cost effectiveness of ranibizumab compared with verteporfin PDT (vPDT) or no treatment (observation) in patients with visual impairment due to myopic CNV. A Markov model with health states defined by BCVA and a 3-month cycle length was developed. It had a healthcare provider (UK National Health Service and personal social services) perspective, a lifetime time horizon, and was based on 2011 prices; future costs and health outcomes were discounted at 3.5 % per annum. Baseline characteristics were based on the phase III RADIANCE (Ranibizumab and vPDT Evaluation in Myopic CNV) study, and year 1 health-state transitions were based on this and the VIP (verteporfin in photodynamic therapy) study. Extensive sensitivity analyses tested the robustness of the model. The lifetime cost of treating myopic CNV with ranibizumab was £12,866, whereas vPDT and observation were associated with total costs of £14,421 and £8,163, respectively. Ranibizumab treatment produced higher cumulative quality-adjusted life-years (QALYs; 12.99) than vPDT (12.60) or observation (12.45). Ranibizumab treatment was therefore dominant, with greater health gains and lower overall costs than vPDT. Ranibizumab was cost-effective compared with observation, with an incremental cost-effectiveness ratio of £8,778/QALY. In the probabilistic sensitivity analysis, ranibizumab had a 100 % and 88 % probability of being cost-effective compared with vPDT and observation, respectively, at a willingness-to-pay threshold of £20,000/QALY. The authors concluded that this study indicated that ranibizumab therapy is dominant over vPDT for the treatment of visual impairment due to CNV secondary to pathologic myopia in the UK healthcare setting and cost-effective compared with observation.

Ocular Histoplasmosis

Presumed ocular histoplasmosis is characterized by peripheral atrophic chorioretinal scars, peripapillary scarring, and maculopathy. This condition is believed to be secondary to exposure to Histoplasma capsulatum, although this fungus rarely has been isolated or cultured from an eye with the typically associated clinical findings. Visual loss in POHS is secondary to the development of macular choroidal neovascularization (CNV).

The Food and Drug Administration's approval of verteporfin for presumed ocular histoplasmosis is based on a non-randomized open-label study involving 26 patients. Verteporfin-treated patients demonstrated a reduction in the number of episodes of severe visual acuity loss (greater than 6 lines of loss) compared with historical control data.

Warnings and Precautions

Patients who experience severe decrease of vision of ≥4 lines within one week after treatment with Visudyne should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.
Examples of other products used to treat AMD include Avastin (compendia listed indication), Lucentis, and Macugen.
For concurrent bilateral treatment (CBT); if patient already received previous therapy in one eye with acceptable safety profile, both eyes can be treated concurrently following a single verteporfin administration.
The physician should reevaluate the patient every three months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.

Visudyne should not be used in the following:

Hypersensitivity to any component of the preparation.
Patients with porphyria.
May not be used in conjunction with an intraocular VEGF inhibitor such as Avastin, Macugen, or Lucentis.

Pancreatic Cancer

Huggett and colleagues (2014) noted that patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy produces localized tissue necrosis but previous studies using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This phase I/II study assessed a shorter acting photosensitizer, VP. A total of 15 inoperable patients with locally advanced cancers were sensitized with 0.4 mg kg(-1) VP. After 60 to 90 mins, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibers positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each 3 patients) until 12 mm of necrosis was achieved consistently. In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume of 3.5 cm(3) at 40 J). Minor, self-limiting extra-pancreatic effects were seen in multi-fiber patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, 1 patient underwent an R0 Whipple's pancreaticoduodenectomy. The authors concluded that VP PDT-induced tumor necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds. The findings of this safety/feasibility study need to be further evaluated in phase III clinical trials.

Furthermore, the National Comprehensive Cancer Network’s clinical practice guideline on “Pancreatic adenocarcinoma” (Version 1.2014) does not mention the use of verteporfin PDT as a therapeutic option.

Parafoveal CNV (Occult CNV Lesions with No Classic Component)

Cruess and associates (2009) noted that PDT with verteporfin has been used less comprehensively in the treatment of exudative AMD, and specifically of CNV, since the advent of anti-angiogenic therapies. Recently, there has been a renewed interest in PDT as an adjunct to these and other agents in the treatment of neovascular AMD. In light of this new development and the European Medicines Evaluation Agency's (EMEA) recent labeling decision to rescind approval for the use of PDT in occult CNV lesions, these investigators reviewed the evidence supporting its clinical application. Photodynamic therapy provided the first pharmacological treatment for patients suffering from subfoveal CNV, the major cause of severe vision loss in AMD. Key clinical trials evaluating the safety and effectiveness of PDT have examined patients with all lesion subtypes, with the primary labeled indication (i.e., lesions containing a classic component of greater than or equal to 50 %) deriving from the results of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study. The subsequent TAP Study Group post-hoc categorization of lesions as predominantly classic is open to question, however, as it appears that the overall effectiveness in this group only may have reflected the especially strong response in 100 % classic lesions. Based on a subgroup analysis of the verteporfin in Photodynamic Therapy Study, the indication for PDT subsequently was expanded in some jurisdictions, including that of the EMEA, to include occult lesions with no classic component. However, the subsequent Visudyne in Occult Study found no benefit in 100 % occult lesions, resulting in the EMEA rescinding its approval for this indication.

Kaiser (2009) examined if verteporfin PDT can safely reduce the risk of vision loss in patients with subfoveal occult with no classic CNV due to AMD. Eligible patients were greater than or equal to 50 years of age with lesion size less than or equal to 6 disc areas and best-corrected vision 20/40 to 20/200. A total of 364 patients with occult with no classic CNV were randomly assigned 2:1 to verteporfin PDT (n = 244) or placebo (n = 120). The primary outcome measures were loss of greater than or equal to 15 and greater than or equal to 30 letters of visual acuity (VA) from baseline at 12 and 24 months. A total of 37 % and 47 % of verteporfin-treated patients versus 45 % and 53 % of placebo recipients lost greater than or equal to 15 letters of VA at month 12 and month 24, respectively; 16 % and 23 % of verteporfin-treated patients versus 17 % and 25 % of placebo recipients lost greater than or equal to 30 letters at month 12 and month 24, respectively. These differences were not statistically significant. Four (1.6 %) verteporfin-treated patients and 1 placebo patient (who received verteporfin in error) experienced an acute severe VA decrease; all 5 patients recovered some degree of vision. No unexpected ocular or systemic adverse events were identified. The authors concluded that verteporfin PDT in the treatment of occult with no classic CNV was safe and well-tolerated. The differences between the 2 groups in the primary efficacy variables were not significant. Baseline characteristics and patient selection methods may have contributed to the small treatment effect.

Polypoidal Choroidal Vasculopathy

Akaza et al (2007) examined the effectiveness of PDT with verteporfin for polypoidal choroidal vasculopathy (PCV). Photodynamic therapy was performed in 35 patients (35 eyes) with PCV. These researchers evaluated the number of treatments and compared VA, ophthalmological findings, and changes in polypoidal lesions and branching vascular networks by measuring lesion diameters using Heidelberg retina angiography before PDT, and then every 3 months for 1 year after PDT. The mean annual number of treatment sessions was 2.2; VA was improved or maintained in 80 % of the patients. Retinal pigment epithelium detachment, retinal detachment, hemorrhage, and/or exudates disappeared in 69 %, and leakage resolved in 74 % of the patients. Polypoidal lesions disappeared completely on indocyanine green angiography in 83 % of the patients. A ll branching vascular networks persisted. Polypoidal lesions had recurred at the termini of the remaining branching vascular networks at 9 months after the first PDT in 2 eyes and at 12 months in 1 eye. The authors concluded that PDT with verteporfin for PCV appears to improve or maintain VA for the first post-treatment year. Approximately 70 % of PCV cases showed improved ophthalmoscopic findings. However, as polypoidal lesions recur after PDT in some cases, further study is needed to confirm the long-term effectiveness of PDT for PCV.

In a prospective, interventional study, Gomi et al (2008) determined the prevalence of PCV in Japanese patients presumed to have AMD and compared 1-year outcomes after PDT between PCV and CBV secondary to AMD. A total of 93 consecutive patients (93 eyes) met the inclusion criteria: at least 50 years old, BCVA of 34 to 73 on the Early Treatment Diabetic Retinopathy Study (ETDRS) letter chart, a subfoveal lesion 5,400 mum or smaller in greatest linear dimension (GLD) on fluorescein angiography (FA), and eligibility for PDT. Indocyanine green angiography was performed in all subjects, and PCV and AMD were differentiated, treated with PDT, and the patients observed for 1 year. The GLD was determined by FA for AMD and by indocyanine green angiography for PCV, and the diameter of the laser spot size was chosen, with an extra 1,000 microm added to the GLD. Photodynamic therapy was repeated if leakage occurred on FA at 3-month follow-up visits. Main outcome measures were prevalence of PCV at baseline and visual and angiographic changes 1 year after PDT in PCV and AMD. Using indocyanine green angiography, 36 eyes (39 %) were diagnosed with PCV and 54 eyes (58 %) with CNV secondary to AMD. The median change in VA using the ETDRS letter score from baseline to 1 year was -7.0 in AMD eyes and +8.0 in PCV eyes (Mann-Whitney rank sum test; p < 0.001). The VA improved (greater than or equal to 15 letters) in AMD and PCV by 6 % and 25 %, respectively, and decreased (greater than or equal to 15 letters) by 31 % and 8 %, respectively. Fluorescein leakage stopped at 1 year in 86 % of PCV and 61 % of AMD eyes (p = 0.031). Polypoidal choroidal vasculopathy recurred in 2 PCV eyes (5.6 %), and a new PCV lesion developed in 1 PCV eye (2.8 %) and 2 AMD eyes (3.7 %) on indocyanine green angiography at 1 year. The authors concluded that the prevalence of PCV meeting the treatment criteria for PDT for presumed AMD is high in Japanese patients. Photodynamic therapy is more effective for PCV than for AMD, which may explain the good results in Japanese patients. They stated that further study should assess the long-term clinical results because PCV lesions might occur or new lesions might develop.

Yamashita et al (2010) reported 1-year results of reduced-fluence PDT for PCV in Japanese patients. In the present study, 28 treatment-naïve eyes of 28 consecutive patients underwent PDT with a reduced laser fluence of 25 J/cm(2). Patients were followed-up at 1 week and 3, 6, 9, and 12 months after PDT. Choroidal perfusion changes were evaluated by indocyanine green angiography and leakage from PCV lesions and exudative changes by fluorescein angiography and OCT. Treatment safety was assessed according to VA and adverse events. The BCVA obtained by Landolt ring tests was converted into the logarithm of the minimal angle of resolution (logMAR). At baseline, the mean logMAR BCVA was 0.45 (geometric mean: 7/20). At 12 months, the mean logMAR BCVA significantly improved to 0.29 (geometric mean: 10/20) (p = 0.0001). The logMAR BCVA was stable or improved by greater than or equal to 0.2 in 26 eyes (93 %) at 1-year follow-up. In 10 eyes with VA better than 20/40 at baseline, the mean logMAR BCVA was significantly improved compared with baseline at 12 months. Although 16 of 28 eyes (57 %) showed mild-to-moderate non-perfusion of choriocapillaris in early indocyanine green angiography at 1 week, 27 eyes (96 %) showed recovery to pre-treatment levels at 3 months. Mean number of treatment sessions during the 12 months was 1.3. No severe side effects related to treatment were encountered. The authors concluded that reduced-fluence PDT is an effective treatment for PCV and could improve vision even in eyes with VA better than 20/40. Moreover, they stated that the limitations of this study included small sample size and the lack of control; further studies with longer follow-up periods are needed to assess treatment safety and effectiveness.

Wong et al (2015) evaluated the 3-year outcome in eyes with PCV treated with verteporfin PDT. These investigators performed a retrospective study of patients with PCV who were treated with PDT between January 2007 and December 2008. Patients were excluded if they had received PDT before the study period, but those who received previous treatment with other modalities (thermal laser or intra-vitreal therapies) were allowed. The main outcome measures were BCVA, repeat PDT, and recurrence of PCV at the end of years 1, 2, and 3. These researchers further conducted a systematic review of the literature using the terms "polypoidal choroidal vasculopathy" and "photodynamic therapy" and compared the visual outcome of studies over 3 years using meta-analytical methods. The retrospective study included 68 eyes. The mean BCVA was 0.73 ± 0.56 logMAR (20/107, Snellen equivalent) at baseline, 0.73 ± 0.70 logMAR (20/107, Snellen equivalent) at 1 year, 0.96 ± 0.76 logMAR (20/182, Snellen equivalent) at 2 years, and 1.07 ± 0.81 logMAR (20/235, Snellen equivalent) at 3 years. The cumulative recurrence rates of PCV were 16.1 % (1 year), 34.9 % (2 years), and 52.7 % (3 years) and eyes with recurrence were more likely to suffer greater than or equal to 3 lines loss compared with eyes without recurrence (63.2 versus 17.6 %, p = 0.006). The systematic review summarized results from 48 published studies and the authors’ retrospective study. The pooled analysis from 29 studies (316 eyes reporting the 3-year visual outcome) reported mean BCVA improvement of 0.115 logMAR at 1 year (n = 1,669), 0.066 logMAR at 2 years (n = 701), and 0.027 logMAR at 3 years (n = 316). Reported recurrence rates were 5.9 % to 50.0 % after 1 year, 9.1 % to 83.3 % after 2 years, and 40.0 % to 78.6 % after 3 years or longer of follow-up. The authors concluded that the visual outcome in eyes with PCV was stable until 2 years, but the outcome at 3 years worsened, particularly in eyes that experienced recurrence.

Wong and colleagues (2017) reported on a case of a Caucasian female who developed active PCV at the edge of a stable choroidal nevus and was successfully treated with verteporfin PDT. No active polyp was detectable on ICGA 2 years after treatment, and good vision was maintained. Indocyanine green angiography is a useful investigation to diagnose PCV and may be under-utilized. The authors concluded that unlike treatment of choroidal neovascularization secondary to choroidal nevus, management of PCV secondary to nevus may not require intra-vitreal anti-VEGF therapy; PDT alone may be an effective treatment of secondary PCV. Moreover, they stated that further studies are needed to understand the mechanisms of pathogenesis and evaluate optimal therapeutic options.

Zhao and co-workers (2017) reported a cohort of patients with PCV treated with PDT followed by intra-vitreal ranibizumab injection 24 to 48 hours later, and compared the results between eyes with PCV treated by PDT followed by intravitreal anti- VEGF injection and intravitreal anti-VEGF injection followed by PDT by meta-analysis. Medical records of patients with PCV who were initially treated using PDT followed by intravitreal ranibizumab injection 24 to 48 hours after PDT and had completed at least 2 years follow-up were reviewed and analyzed. Clinical data, including age, sex, BCVA, fundus photograph, FA, ICGA and OCT were investigated. A systematic literature review was also conducted, and a visual outcome of studies over 1 year was compared using meta-analysis. A total of 52 patients were included in the study. Mean BCVA at baseline and follow-up at 1 year or 2 years were 0.71 ± 0.61, 0.51 ± 0.36 and 0.68 ± 0.51 logMAR, respectively. The cumulative hazard rates for recurrence at 1- and 2-year follow-up was 15.4 % and 30.3 %, respectively. The percentages of eyes with polyps regression at 3, 12 and 24 months follow-up were 88.5 %, 84.6 % and 67.3 %, respectively. A meta-analysis based on 22 independent studies showed the overall vision improvements at 1-, 2- and 3-year follow-up were 0.13 ± 0.04 (p < 0.001), 0.12 ± 0.03 (p < 0.001), 0.16 ± 0.06 (p < 0.001), respectively. The proportion of polyps regression at 1-year follow-up was 64.6 % (95 % CI: 51.5 % to 77.7 %, p < 0.001) in 434 eyes treated by intravitreal anti-VEGF agents before PDT and 76.0 % (95 % CI: 64.8 % to 87.3 %, p = 0.001) in 199 eyes treated by intravitreal anti-VEGF agents after PDT. The authors concluded that intra-vitreal ranibizumab injection 24 to 48 hours following PDT effectively stabilized VA in the eye with PCV. They stated that PDT followed by intravitreal anti-VEGF agents may contribute to a relatively higher proportion of polyps' regression as compared to that of intra-vitreal anti-VEGF before PDT.

The authors stated that this study had several drawbacks. They only reported a cohort of patients with PCV treated by PDT followed by intra-vitreal ranibizumab injection 24 to 48 hours later, without a control group of patients with PCV treated by intra-vitreal ranibizumab before PDT. They could not show the optimal time for intra-vitreal ranibizumab injection in combined therapy in the current retrospective study. The retrospective study design was prone to bias. For example, in the long follow-up period at a tertiary center, a significant number of patients failed to continue their treatment and follow-up. The patients with recurrence and aggressive disease tended to be more compliant during follow-up. There was no strict and specified interval for ICGA or FA, and the judgment of recurrence and decision of repeated combined treatments might be delayed for 1 or 2 months. There might have been an inter-device difference in the OCT results, as some were time-domain OCT and others spectral-domain OCT. Taking into account that CFT measured by time-domain OCT was thinner and a great proportion of patients in this study had CFT measured by time-domain OCT, these researchers omitted the result of CFT changes during follow-up. Because most of the patients underwent time-domain OCT at baseline, the authors considered the CFT at baseline as a potential risk factor for visual outcome in the statistical analysis. Further prospective study with a fixed spectral-domain OCT device may help to demonstrate the nature of changes to CFT after combined treatment. Because these investigators had only 9 eyes with VA loss, other risk factors failed to relate to poor visual outcome in this study, including larger lesion size, proximity to fovea, type of PED, and scar or atrophy of the macula. Further studies should look into the potential risk factors in detail. It is well-known repeat PDT treatments may damage the retinal pigment epithelial, the 2 cases with visual loss who had experienced sub-retinal hemorrhage due to recurrent polyps within the original PDT lesion in this cohort did not show significant retinal pigment epithelial (RPE) damages on their follow-up OCTs. The protocol of PDT treatment using small and multi-spots to cover the recurrent polyps and the macular sparing treatment may help to reduce the damages of PDT to RPE at fovea. The authors stated that further studies with longer follow-up and more recurrent cases may help to address the relationship between RPE damages and VA loss. For the pooled analysis, these researchers failed to include studies without logMAR scores of mean BCVA at baseline or most recent follow-up. They noted that pooling data from such heterogeneous studies may limit the application of the results of this meta-analysis; the variations in study design, follow-up period, anti-VEGF agents and population should be taken into account when interpreting these findings.

Qian and colleagues (2018) noted that combined treatment with intravitreal anti-VEGF and verteporfin PDT is widely used for patients with PCV, although clinical evidence regarding the safety and efficacy of such treatment remains lacking. These investigators performed a meta-analysis of previously reported studies comparing combination treatment, PDT monotherapy, and anti-VEGF monotherapy. Primary outcome measures included changes in BCVA and CRT. The proportion of patients with polyp regression was regarded as the secondary outcome measure. A total of 20 studies (3 RCTs and 19 retrospective studies) involving 1,178 patients with PCV were selected. Significant differences in the proportion of patients with polyps were observed between the PDT and anti-VEGF monotherapy groups at 3 and greater than or equal to 6 months (p < 0.00001; and p = 0.0001, respectively). Significantly greater reductions in CRT were observed in the anti-VEGF than in the PDT group at the 3-month follow-up (p = 0.04). Significantly greater improvements in BCVA were observed in the combined therapy group than in the PDT monotherapy group at 3, 6, 12, and 24 months (p = 0.03; p = 0.005; p = 0.02; and p < 0.00001, respectively). Combined treatment also resulted in significantly greater improvements in BCVA than monotherapy with anti-VEGF at 6 and 24 months (p = 0.001; p < 0.00001, respectively), and significantly greater polyp regression than that observed following anti-VEGF treatment at 3 and greater than or equal to 6 months (p < 0.00001; p < 0.0001, respectively). The authors concluded that combined therapy involving anti-VEGF agents and PDT may be more effective in improving long-term outcomes for patients with PCV than monotherapy.

The authors stated that this study had several drawbacks. First, inadequate random sequence generation and blinding may have resulted in selection bias, and patients with PCV whose condition worsened may have switched treatment. Nonetheless, selection bias was less likely to occur, as the major study characteristics of the eyes in the 3 groups were comparable at baseline. Second, some studies did not report all detailed outcome indicators, which caused some comparison only included 2 or 3 studies. For example, when comparing the mean change in CRT from baseline between combined treatment and PDT monotherapy at 6 months, the pooled results were insufficient for determining a statistically significant difference (p = 0.05). Therefore, more data may have resulted in a statistically significant difference. Third, publication bias could not be fully excluded because these researchers could not gain access to unopen results and unpublished studies. Nevertheless, the findings of the present meta‐analysis suggested that combined treatment with PDT and intravitreal anti‐VEGF injection therapy resulted in better long‐term improvements in VA, reductions in CRT, and more substantial regression of polyps. These findings indicated that combined therapy may be more effective than monotherapy in the treatment of PCV. Despite these encouraging findings, the inherent limitations of the included studies should be considered. Thus, these researchers stated that more detailed data at different follow‐up time-points and further large‐volume RCTs are needed to improve the accuracy and robustness of these findings for clinical application.

Psoriasis

Choi et al (2015) noted that PDT for psoriasis showed promise in the early 1990s with reports of plaque clearance following topical ALA-PDT. In December 2013, these researchers conducted a systematic search of the PubMed Medline database using the keywords "psoriasis" and "photodynamic therapy". Numerous clinical studies have failed to demonstrate a consistent, effective response to topical ALA-PDT. Furthermore, severe pain and burning sensations were repeatedly reported, many cases being intolerable for patients. The authors concluded that the variability in clinical response and the painful side effects have made topical ALA-PDT an unsuitable treatment option for chronic plaque psoriasis. Nonetheless, early clinical studies of other modalities such as topical hypericin and methylene blue, as well as systemic ALA and verteporfin, have shown that these photosensitizers are effective and much better tolerated than topical ALA. The authors stated that with the current landscape of phototherapy dominated by psoralen combined with ultraviolet A (PUVA) and narrow-band ultraviolet B (NB-UVB), an alternative light therapy utilizing the visible spectrum is certainly promising and a worthwhile endeavor to pursue.

Almutawa et al (2015) stated that localized phototherapy including topical PUVA and targeted UVB, and PDT had been increasingly used in the treatment of localized psoriasis. Yet, there are no systematic reviews or meta-analyses that scientifically evaluated the pooled efficacy of these treatments in psoriasis. These investigators searched Medline, Embase, and Cochrane databases during the period of January 1980 to June 2012. This systematic search resulted in 765 studies, 23 of them were included in the review. The primary outcome was 75 % reduction in severity score from baseline. A meta-analysis using random effect model found topical PUVA to be more effective than non-laser targeted UVB (odds ratio [OR]: 3.48 (95 % CI: 0.56 to 21.84), p = 0.183). The pooled effect estimate of the efficacy (75 % reduction in severity score) of topical PUVA, targeted UVB, and PDT were as follows: 77 % (topical PUVA), 61 % (targeted UVB), and 22 % (PDT). The authors concluded that topical PUVA and targeted UVB phototherapy are very effective in the treatment of localized psoriasis; topical PUVA seems more effective than non-laser targeted UVB phototherapy. On the other hand, PDT has low efficacy and high percentage of side effects in treating localized psoriasis.

Retinal Capillary Hemangioma

Mitropoulos and colleagues (2014) presented a case of juxtapapillary retinal capillary hemangioma treated with PDT. A 69-year old woman with no previous ocular history presented with blurred vision and photopsias in the right eye 3 months ago. At presentation, her BCVA was 6/9 in the right eye and 6/6 in the left eye. The anterior segment was totally normal and intra-ocular pressure (IOP) was normal in both eyes as well. Dilated fundoscopy revealed a yellowish, well-circumscribed, elevated area with blood vessels, on the inferior margin of the right optic disc, as optic disc edema. Fluorescein angiography and ICGA confirmed the diagnosis of juxtapapillary retinal capillary hemangioma. The patient was treated with PDT with verteporfin (VP) and 3 months later her VA was 6/7.5 in the right eye, while the lesion was slightly smaller. These findings remained stable at the 1-year follow-up. The authors concluded that PDT offers promising anatomical and functional results for juxtapapillary retinal capillary hemangioma, providing VA improvement or even stabilization and restriction of enlargement of the lesion. These preliminary findings from a single case study need to be validated by well-designed studies.

Retinoblastoma

Brodowska et al (2014) stated that VP is clinically used in PDT for neovascular macular degeneration. Recent studies indicated that VP may inhibit growth of hepatoma cells without photo-activation through inhibition of YAP-TEAD complex. These researchers examined the effects of VP without light activation on human retinoblastoma cell lines. Verteporfin but not vehicle control inhibited the growth, proliferation and viability of human retinoblastoma cell lines (Y79 and WERI) in a dose-dependent manner and was associated with down-regulation of YAP-TEAD associated downstream proto-oncogenes such as c-myc, axl, and surviving. In addition VP affected signals involved in cell migration and angiogenesis such as CTGF, cyr61, and VEGF-A but was not associated with significant effect on the mTOR/autophagy pathway. Of interest the pluripotency marker Oct4 were down-regulated by VP treatment. These findings indicated that the clinically used VP is a potent inhibitor of cell growth in retinoblastoma cells, disrupting YAP-TEAD signaling and pluripotential marker OCT4. The authors concluded that this study highlighted for the first time the role of the YAP-TEAD pathway in retinoblastoma and suggested that VP may be a useful adjuvant therapeutic tool in treating patients with retinoblastoma.

Various Indications

Mennel and colleagues (2007) noted that PDT has been performed in several other ocular pathologies with some remarkable results, however, with most reports being case reports and small case series without statistical significance. These extended applications include CNV secondary to choroiditis and retino-choroiditis, angioid streaks, central serous chorioretinopathy, retinal angiomatous proliferation, parafoveal telangiectasia or CNV associated with macular dystrophy and idiopathic CNV, as well as diseases without CNV, such as choroidal hemangioma, retinal hamartoma, choroidal melanoma, chronic central serous chorioretinopathy, angiomatous lesions secondary to systemic diseases, rubeosis iridis or neovascular glaucoma.

Chan and colleagues (2010) stated that verteporfin PDT is approved for the treatment of predominantly classic subfoveal CNV due to AMD, as well as for subfoveal CNV due to pathologic myopia and ocular histoplasmosis syndrome. Verteporfin PDT addresses the underlying pathology of ocular vascular disorders through its angio-occlusive mechanism of action, which reduces both VA loss as well as the underlying leakage associated with lesions. Verteporfin PDT has also been associated with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders (e.g., angioid streaks, central serous chorioretinopathy, choroidal hemangioma, inflammatory CNV, and PCV, i.e., conditions currently considered as non-standard indications of verteporfin PDT). In many studies, outcomes were better than expected based on the natural courses of each of these conditions. Although the anti-VEGF therapies, ranibizumab and pegaptanib, have been approved for CNV due to AMD, their role in these other choroidal vascular disorders remains to be established. The authors concluded that the complex pathogenesis of CNV provides a rationale for investigating combination approaches comprising verteporfin PDT and anti-VEGF therapies. They stated that randomized controlled studies are needed to confirm the preliminary results of verteporfin PDT as a monotherapy or in combination with anti-VEGF therapies in the treatment of a variety of choroidal vascular conditions.

Choroidal Melanoma

Fabian and colleagues (2017) examined the outcomes of primary PDT for small pigmented posterior pole choroidal melanoma. This study was a prospective interventional consecutive case series of 15 patients with small pigmented posterior pole choroidal melanoma, who were treated with 3 sessions of PDT and followed-up thereafter. Risk factors for failure were assessed and outcome measures at presentation were compared to those at last follow-up visit. Tumor control was achieved in 12 (80 %) patients in a median follow-up time of 15 months (mean of 14, range of 8 to 18); 3 patients failed treatment, diagnosed in a median time of 5 months (mean of 4, range of 3 to 6), after first PDT. In all failed cases, lesions were 100 % pigmented; de-novo melanoma rather than transformed nevi and showed a radial growth pattern rather than increased thickness. All failed cases were subsequently successfully treated with radiotherapy. In this cohort, sub-retinal fluid (SRF) was significantly reduced (p < 0.001), vision did not deteriorate (p = 0.11) and even improved in patients with sub-foveal SRF at presentation (p = 0.018), tumor height significantly decreased (p = 0.037) and no complications were recorded. The authors concluded that primary PDT was found to be a safe and efficient treatment modality for small pigmented posterior pole choroidal melanoma, achieving short-term tumor control in 80 % of patients. They stated that PDT offered patients the opportunity to preserve vision by avoiding the retinopathy associated with conventional radiation treatments for choroidal melanoma; however, the long-term local control of these tumors remains uncertain. Moreover, the authors stated that the drawbacks of this study included its small cohort size(n = 15) and relatively short follow-up time (mean of 14 months).

In a retrospective cohort study, Jmor and colleagues (2017) evaluates verteporfin PDT as primary treatment for small, posterior choroidal melanoma. Retrospective case note review of 20 patients with small juxta-papillary and juxta-foveal choroidal melanomas treated with PDT at the Liverpool Ocular Oncology Clinic were included in this review. Patient and tumor characteristics, PDT session details, VA and B-scan ultrasonography (US) measurements as well as color fundus photographs at each examination were collated and analyzed. Main outcome measures were local tumor control and BCVA. The 20 patients (14 men, 6 women) had a mean age of 61.2 years (range of 40 to 85) and were treated between 2001 and 2012; 7 tumors were amelanotic, while 13 were pigmented. Of 20 melanomas, 11 (55 %) showed complete regression on B-scan US and color photography; 5 (25 %) showed partial regression; 4 (20 %) remained unchanged and 2 (10 %) showed further growth, for which alternative standard treatment was required. Baseline BCVA was 0.1 logMAR (mean; range of 0.0 to 0.6) compared to a post-PDT BCVA of 0.4 logMAR (mean; range of -0.2 to 1.7) over a follow-up of 60.0 months (mean; range of 25 to 156 months). The authors concluded that verteporfin PDT can induce tumor regression in a significant proportion of small, posterior, choroidal melanomas but is less reliable than other forms of therapy. They stated that it may have a role in patients with special visual requirements if they accept the increased risk of treatment failure requiring radiotherapy.

Atherosclerotic Plaque

Jain and colleagues (2016) stated that PDT, which is based on the activation of photosensitizers with light, can be used to reduce plaque burden. These researchers hypothesized that intra-arterial photosensitizer administration and photo-activation will lead to high and rapid accumulation within the plaque with reduced systemic adverse effects. Thus, this "intra-arterial" PDT would be expected to have less side effects and due to the short time involved would be compatible with percutaneous coronary interventions (PCIs). These investigators characterized the dose-dependent uptake and effectiveness of intra-arterial PDT using liposomal verteporfin (Visudyne), efficient for cancer-PDT but not tested before for PDT of atherosclerosis. Visudyne (100, 200, and 500 ng/ml) was perfused for 5 to 30 minutes in atherosclerotic aorta isolated from ApoE(-/-) mice. The fluorescence Intensity (FI) after 15 min of Visudyne perfusion increased with doses of 100 (FI-5.5 ± 1.8), 200 (FI-31.9 ± 1.9) or 500 ng/ml (FI-42.9 ± 1.2). Visudyne (500 ng/ml) uptake also increased with the administration time from 5 minutes (FI-9.8 ± 2.5) to 10 minutes (FI-23.3 ± 3.0) and 15 minutes (FI-42.9 ± 3.4) before reaching saturation at 30 minutes (FI-39.3 ± 2.4) contact. Intra-arterial PDT (Fluence: 100 and 200 J/cm(2), irradiance-334 mW/cm(2)) was applied immediately after Visudyne perfusion (500 ng/ml for 15 minutes) using a cylindrical light diffuser coupled to a diode laser (690 nm); PDT led to an increase of reactive oxygen species (ROS) (Dihydroethidium; FI-6.9 ± 1.8, 25.3 ± 5.5, 43.4 ± 13.9) and apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL); 2.5 ± 1.6, 41.3 ± 15.3, 58.9 ± 6 %), mainly plaque macrophages (immuno-staining; 0.3 ± 0.2, 37.6 ± 6.4, 45.3 ± 5.4 %), respectively without laser irradiation, or at 100 and 200 J/cm(2). Limited apoptosis was observed in the medial wall (0.5 ± 0.2, 8.5 ± 4.7, 15.3 ± 12.7 %). Finally, Visudyne-PDT was found to be associated with reduced vessel functionality (Myogram). The authors demonstrated that sufficient accumulation of Visudyne within plaque could be achieved in short-time and therefore validated the feasibility of local intra-vascular administration of photosensitizer. They stated that intra-arterial Visudyne-PDT preferentially affected plaque macrophages and may therefore alter the dynamic progression of plaque development.

Breast Cancer

Sneider and colleagues (2017) noted that triple negative breast cancer (TNBC) continues to present a challenge in the clinic, as there is still no approved targeted therapy. Triple negative breast cancer is the worst sub-type of breast cancer in terms of prognosis and exhibits a deficiency in estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. One possible option for the treatment of TNBC is chemotherapy. The issue with many chemotherapeutic drugs is that their effectiveness is diminished due to poor water solubility, and the method of administration directly or with a co-solvent intravenously can lead to an increase in toxicity. The issues of drug solubility can be avoided by using liposomes as a drug delivery carrier. Liposomes are engineered, biological nano-constructs that possess the ability to encapsulate both hydrophobic as well as hydrophilic drugs and have been clinically approved to treat cancer. Specific targeting of cancer cell receptors through the use of ligands conjugated to the surface of drug-loaded liposomes could lessen damage to normal, healthy tissue. This study focused on polyethylene glycol (PEG)-coated, folate conjugated, benzo-porphyrin derivative (BPD)-loaded liposomes for treatment via PDT. The folate receptor is over-expressed on TNBC cells so these liposomes are targeted for greater uptake into cancer cells. Photodynamic therapy involves remotely irradiating light at 690 nm to trigger BPD, a hydrophobic photosensitive drug, to form reactive oxygen species that cause tumor cell death; BPD also displays a fluorescence signal when excited by light making it possible to image the fluorescence prior to PDT and for theranostics. In this study, free BPD, non-targeted and folate-targeted PEGylated BPD-loaded liposomes were introduced to a metastatic breast cancer cell line (MDA-MB-231) in-vitro. The liposomes were reproducibly synthesized and characterized for size, poly-dispersity index (PDI), zeta potential, stability, and BPD release kinetics. Folate competition tests, fluorescence confocal imaging, and colorimetric MTT assay were used to observe and quantify targeting effectiveness. The toxicity of BPD before and after PDT in monolayer and 3D in-vitro cultures with TNBC cells was observed. The authors concluded that this study may contribute to a novel nanoparticle-mediated approach to target TNBC using PDT.

Endometrial Cancer

Dasari and colleagues (2017) stated that endometrial carcinoma (EMCA) is the most common gynecologic malignancy and the 4th most common malignancy in women in the U.S. Yes-associated protein (YAP) is a potent transcription co-activator acting via binding to the TEA Domain (TEAD) transcription factor, and plays a critical role in organ size regulation. Verteporfin, a benzoporphyrin derivative, was identified as an inhibitor of YAP-TEAD interaction. These researchers examined the therapeutic efficacy and mechanism of VP in EMCA. The efficacy of VP on cell viability, cytotoxicity and invasion was assayed in EMCA cell lines. An organoid model system was also developed to test the effect of VP on apoptotic markers in an in-vitro model system. Treatment with VP resulted in a decrease in cell viability, invasion and an increase in cytotoxicity of EMCA cells. These effects occurred as early as 15 minutes following treatment. Similarly, VP treatment versus vehicle control increased apoptosis in human organoid model systems. Quantitative reverse transcription polymerase chain reaction (RT-PCR), cDNA-based RT-PCR array analysis and Western blotting were performed to investigate the mechanism of VP action. The cytotoxic and anti-proliferative effects appeared to be independent of its effect on YAP. The authors concluded that these findings suggested that VP is a promising chemotherapeutic agent for the treatment of endometrial cancer.

Ovarian Cancer

Feng and associates (2016) noted that YAP is a key transcriptional co-activator of Hippo pathway and has been shown to be an onco-protein in ovarian cancer (OC). Verteporfin, clinically used in PDT for neovascular macular degeneration, has been recently proven to be a suppressor of YAP-TEAD complex and has shown potential in anti-cancer treatment. In this study, these researchers examined the potential effect of VP in the treatment of OC. The results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time PCR demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In-vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment up-regulated cytoplasmic YAP and phosphorylation YAP and down-regulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. The authors concluded that these findings suggested that VP may be a promising agent for OC, acting by suppressing YAP-TEAD complex. They stated that further investigation about the real efficacy of VP, its pharmacokinetics, or the appropriate administration route should be done.

Glioma

Al-Moujahed and associates (2017) stated that verteporfin (VP) has been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepato-carcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, these researchers examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through Western blot analysis, these investigators identified that human glioma cells that were exposed to VP without light activation demonstrated a down-regulation of YAP-TEAD-associated down-stream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and up-regulation of the tumor growth inhibitor molecule p38 MAPK. In addition, these researchers observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. The authors concluded that the findings of this study suggested that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma. They stated that further studies are needed to elucidate the exact mechanism of VP action and supports further exploration in animal research.

Iris Metastasis

Chen and Hu (2017) noted that uveal metastasis is the most common intra-ocular malignancy. Lung cancer is one of the most common malignancies that metastasize to uvea. Iris involvement is rarely reported. These investigators reported a case of iris metastasis from pulmonary adenocarcinoma that was treated with PDT. A 65-year old man was referred to the authors’ hospital for iris white neoplasm and blurred vision for 2 weeks in his right eye. He underwent pulmonary lobectomy, radiotherapy and chemotherapy for pulmonary adenocarcinoma 1 year ago and liver metastases were found 2 months earlier. At presentation, anterior segment examination of the right eye showed a hypo-pigmented, vascularized papillary 3.8 x 3.19 mm neoplasm located on the temporal iris expanding to 9-clock anterior chamber angle. The patient refused to accept MRI, biopsy and treatment. One week later the tumor grew up to 5.5 x 7.4 mm with diffuse mixed conjunctiva congestion and elevated IOP. A modified PDT was applied. Intravenous verteporfin (3 mg/m2) was infused with a 1-min bolus; PDT with 3 partly overlapped 5-mm laser spots, 689 nm (50 J/cm2) and 166s were performed 4 mins later without contact lens. The neo-genesis vessels were occluded with small patch bleeding on the edema tumor that was separated from the anterior chamber angle in the 3 days follow-up. The authors concluded that PDT may be a safe, non-invasive and psychologically well-accepted treatment for iris metastasis. These preliminary findings need be validated by well-designed studies.

Sentinel Lymph Node Metastasis

Shimada and colleagues (2017) examined the usefulness of PDT for treating sentinel lymph node (SLN) metastasis. Verteporfin, a hydrophobic photo-sensitizer, forms a soluble aggregate with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) (PMB). The concentrations of verteporfin were determined by measuring the fluorescence emitted at 700 nm. Seven days after the inoculation of A431 cells at the forearm of BALB/c nude mice, PMB-verteporfin was injected at dorsum manus and 75 J of light energy was delivered for 1 minute. A total of 53 mice were randomly assigned to the combination of PMB-verteporfin injection and light exposure, light exposure alone, PMB-verteporfin injection alone, and no treatment groups. Ten days after PDT, brachial lymph nodes, which were considered as SLNs, were harvested and evaluated. The concentration of verteporfin in SLN was significantly higher than other organs. The combination of PMB-verteporfin injection and light exposure group significantly reduced the SLN metastasis (13 %) comparing with no treatment group (52 %), light exposure alone group (57 %), and PMB-verteporfin injection alone group (46 %). The authors concluded that these findings suggested that PDT using PMB as a nano-transporter of verteporfin could be a minimally invasive treatment of SLN metastasis in breast cancer and represent a potential alternative procedure to SLN biopsy.

Macular Choroidal Hemangioma

In a prospective, non-comparative, interventional case-series study, Schmidt-Erfurth et al (2002) documented the anatomic and functional outcome of photodynamic therapy (PDT) in symptomatic choroidal hemangioma. A total of 15 patients with circumscribed choroidal hemangioma (CCH) of the posterior pole presenting with progressive vision loss caused by exudation into the macular area were included in this study. PDT using 6 mg/m(2) body surface area (BSA) verteporfin and a light dose of 100 J/cm(2) at 692-nm was performed; 1 to 4 treatments with a single laser spot were applied in 6-week intervals. A standardized evaluation was provided before and at 6-week intervals after each treatment, at 3, 6, and 12 months, and a mean follow-up 19 months after the last application. Main outcome measures included functional tests included best-refracted visual acuity (Early Treatment of Diabetic Retinopathy Study criteria) and scanning laser scotometry. Anatomic results were documented by ophthalmoscopy, fluorescein/indocyanine green angiography (FA/ICGA), and ultrasonography (US). A complete regression of the vascular mass was achieved in all eyes after the last course of 1 to 4 consecutive treatments. Tumors (mean height of 3.8 mm) responded with a reproducible decrease in size to each treatment, with the most intensive effect seen after the 1st application. Progressive occlusion of the angiomatous net without re-canalization was documented angiographically; 2 patients had stable vision with resolution of metamorphopsia; 13 patients demonstrated visual recovery. An overall visual acuity (VA) improvement of an average of 3 lines was documented, with a mean VA level of 20/125 before treatment and 20/80 after therapy. Visual fields showed withdrawal of central scotomas from the macula. No recurrence was seen during a follow-up for up to 50 months. The authors concluded that PDT using verteporfin offered a safe and effective option to treat choroidal hemangiomas. Complete anatomic regression with persistent absence of leakage was associated with substantial improvements in vision.

In a prospective, consecutive, non-comparative, case-series study, Porrini et al (2003) evaluated the safety and effectiveness of PDT in the treatment of symptomatic CCH of the posterior pole. A total of 10 eyes of 10 patients (6 men and 4 women; age range of 38 to 64 years) reporting visual impairment caused by intra-ocular CCH were included in this trial; follow-up was 7 to 16 months; PDT was applied by Zeiss laser emitting a light at 689-nm for photo-sensitization and by using verteporfin at a dose of 6 mg/m(2) BSA administered intravenously before treatment. The diameter of the treatment spot was calculated on early frames of pre-treatment ICGA; the maximum treatment spot diameter was 6,000 micron using a Mainster wide-field lens. In the case of peri-papillary CCH, the laser spot was applied at a distance of 200 micron from the optic disc edge. A laser beam was applied to the retina 15 mins after the start of the infusion. Two different treatment procedures were used according to the height of the lesion. A radiant exposure of 100 J/cm(2) with an exposure time of 186 seconds was applied to lesions larger than 2 mm. For lesions smaller than 2 mm, a radiant exposure of 75 J/cm(2) with an exposure time of 125 seconds was used. Main outcome measures were visual outcomes, pre-treatment findings, and final findings were evaluated using biomicroscopy, FA, ICGA, and US. After a follow-up of 7 to 16 months, FA and ICGA verified the non-perfusion of the vascular channels of the tumor in the treated areas. No retinal pigment epithelium (RPE) changes were observed in the patients who had undergone 2 PDT treatments, whereas minimal alterations were detected in 2 of 4 patients who had undergone 3 treatment sessions. Angiographic cystoid macular edema and exudative macular detachment had completely regressed in all cases. Minimal intra-retinal edema was observed on the FA frames in 2 cases; US found no measurable tumor height in 6 (60 %) cases and a marked reduction in the remaining 4 cases, even after 1 treatment (post-treatment tumor height range of 0.86 to 1.82 mm). An improvement in VA (1 to 6 lines on the Early Treatment for Diabetic Retinopathy Study chart) was observed in all the cases. In 4 cases, the VA returned to 20/20, of which 3 were extra-foveal and 1 was sub-foveal with visual impairment caused by secondary exudative macular detachment without significant RPE alterations. Also in long-standing sub-foveal cases, a marked VA improvement was detected resulting from the disappearance of sub-retinal or intra-retinal fluid, even if functional results were limited by pre-existing RPE alterations. In all cases no damage to retinal vessels was observed. The authors concluded that PDT was a minimally invasive but effective method of treatment for CCH and may be considered as a treatment of choice, especially in patients with foveal location of the tumor. Because of its safety and repeatability, this technique can be used to treat frequent recurrences of the tumor.

In a prospective, multi-center, non-randomized clinical trial, Boixadera et al (2009) evaluate PDT for symptomatic CCH. A total of 31 eyes of 31 patients with posterior pole CCH and symptoms caused by exudation into the macular area were included in this trial; PDT was applied by Zeiss laser. Intravenous verteporfin at 6 mg/m(2) BSA was administered before treatment, and light emitted at 689-nm for photo-sensitization. The treatment spot diameter was calculated on early-phase frames of pre-treatment ICGA; 15 mins after starting the verteporfin infusion, the laser beam was applied to the retina at radiant exposure 50 J/cm(2) and exposure time 83 seconds; 1 to 4 treatments were applied at 12-week intervals over 1 year. Standardized evaluation was performed before and at 4-week intervals after each treatment, and at 3, 6, 9, and 12 months. All patients were followed for greater than or equal to 12 months. The primary outcome measure was the absence of exudative retinal detachment at the 12-month follow-up visit on ophthalmoscopy, FA, and OCT. Secondary measures were the VA outcome, with BCVA determined by the Early Treatment for Diabetic Retinopathy Study chart, tumor thickness decrease on B-scan US, and AEs. Among the total, 82.8 % of patients required 1, 13.8 % 2, and 3.4 % 3 PDTs to eliminate exudative retinal detachment; VA increased from a mean of 20/60 to 20/35 (p < 0.001); 69 % of patients demonstrated visual recovery (p < 0.001). Cystoid macular edema regressed in all cases and exudative macular detachment disappeared in all but 2 cases. The CCH thickness decreased in all cases from a mean of 3.0 to 1.7 mm, with the most intense effect seen after 4 weeks of treatment (p < 0.001). Visual fields showed resolution of central scotomas. There were no severe AEs. The authors concluded that combining PDT with the standard age-related macular degeneration protocol is an effective treatment for CCH in terms of resolution of exudative sub-retinal fluid and recovery of VA.

In a prospective, consecutive, 2-centered, non-comparative, interventional case-series study, Blasi et al (2010) evaluated the long-term efficacy of verteporfin PDT as the primary treatment for symptomatic CCH. A total of 25 subjects with symptomatic CCH. All patients had recent onset of visual symptoms and evidence of exudative macular changes on fluorescein angiography (FA) and optical coherence tomography (OCT). Verteporfin 6 mg/m(2) BSA was administered intravenously over a 10-minute interval. Five minutes after infusion, a 689-nm laser was applied with a light dose of 50 J/cm(2) for the first 3 patients and a light dose of 100 J/cm(2) for all the other patients. Re-treatments were performed in case of persistent exudation found on OCT. Evaluation of best-corrected VA (BCVA) using Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria, FA, ICG angiography (ICGA), OCT, and US were performed before PDT and on follow-up examinations. All patients were followed for at least 5 years. Primary outcome measures were changes in BCVA and foveal center thickness (FCT) between baseline and month 60. Secondary measures were tumor thickness decrease, absence of leakage on FA, and adverse events (AEs). A total of 22 patients received 1 PDT session at 100 J/cm(2), and no recurrences were detected; 3 eyes, treated with 50 J/cm(2), received a 2nd PDT session at 100 J/cm(2) 1 month after the 1st session. After a follow-up of 60 months, BCVA improved an average of 18.5 ETDRS letters (p < 0.001); BCVA improved by greater than or equal to 2 lines in 19 eyes (76 %). The FCT decreased from a mean of 386.20 microm to 179.2 microm, and OCT showed the complete resolution of macular exudation in all cases. All tumors responded with a reduction in size. No treatment-related AEs or complications were identified. The authors concluded that the 5-year results of PDT in treating symptomatic CCH supported treatment with a light dose of 100 J/cm(2) after slow intravenous infusion of verteporfin to stabilize or improve VA and resolution of macular exudation.

In a retrospective, consecutive, non-comparative case-series study, Zhang et al (2010) evaluated the safety and efficacy of PDT for macular CCH in Chinese patients. A total of 25 eyes (25 patients) with macular CCH, 18 sub-foveal and 7 peri-foveal, with vision impairment attributable to sub-foveal fluid and retinal detachment underwent VA testing, fundus FA, US, and OCT examinations to evaluate the safety and efficacy of PDT treatment. PDT was performed with a standard concentration of verteporfin and intravenous injection time. Laser was used at 50 J/cm² for 83 seconds on sub-foveal and 75 J/cm² for 125 seconds on peri-foveal lesions. More than 1 spot was used for large lesions and spots overlapped only outside the fovea. The mean follow-up time was 35.5 ± 15 months. All patients were treated with 1 session except in 2 sub-foveal cases. The mean BCVA increased from 0.09 ± 0.11 to 0.31 ± 0.37 (p < 0.01) and 11 patients (44 %) had their vision improve over 4 lines. The remaining 14 patients (56 %) had stabilized vision with the retina re-attached. The mean thickness of the hemangioma before the treatment was 3.2 ± 0.9 mm and decreased to 1.3 ± 1.0 mm post treatment (p < 0.01), with complete regression of tumor in 7 cases (28 %). The authors concluded that PDT with individualized laser parameters for macular CCH was safe and effective, leading to improved or stabilized BCVA as a result of tumor shrinkage and the resolution of the sub-retinal fluid.

Tsipursky et al (2011) reported 3 new cases of patients with Sturge-Weber Syndrome and symptomatic retinal detachments from diffuse choroidal hemangiomas successfully treated with PDT and reviewed medical literature on the available therapeutic options for choroidal hemangiomas. All patients were treated with a single session of PDT with verteporfin infused at a concentration of 6 mg/m(2) and treated for 83 seconds with 689-nm Zeiss laser that was delivered with total energy level of 50 J/cm(2) with an intensity of 600 mW/cm(2). The exudative retinal detachment (RD) and macular edema completely resolved in all cases by 1 to 4 months after PDT treatment; VA improved in all 3 cases with diminished tumor size in the areas of treatment. One case was followed for 5 months, another for 2 years, and the 3rd case for 6 years, with no recurrence of exudative RD. The authors concluded that PDT was an effective therapeutic option for visual deterioration from exudative retinal detachment in patients with diffuse choroidal hemangiomas.

In a retrospective, case-series study, Ho et al (2018) examined the treatment outcomes and predictors of response to PDT in patients with symptomatic CCH. This retrospective case series examined 20 patients with symptomatic CCH (10 sub-macular CCHs and10 juxta-papillary CCHs) who underwent standard PDT (wavelength: 662-nm; light dose: 50J/cm2; exposure time: 83 sec) with verteporfin (6 mg/m2), either as monotherapy (n = 9) or in association with other treatments (n = 11), of which 7 received intra-vitreal injections (IVI) of anti-vascular endothelial growth factor (anti-VEGF). A post-PDT improvement of at least 2 lines in BCVA was the primary outcome measure. Predictors of response were investigated with binary logistic regression analysis; 17 (85 %) patients received 1 PDT session, and 3 patients (15 %) underwent PDT at least twice; 10 patients (50 %) achieved the primary outcome of a post-PDT BCVA improvement of at least 2 lines. Macular atrophy and recalcitrant cystoid macular edema in 2 patients. Binary logistic regression analysis revealed that younger age (less than 50 years) (p = 0.033), pre-PDT BCVA of greater than or equal to 20/200 (p = 0.013), exudative retinal detachment resolved within 1 month after PDT (p = 0.007), and a thinner post-PDT tumor thickness (p = 0.015) were associated with the achievement of a post-PDT BCVA improvement. Additional treatments to PDT including IVI anti-VEGF did not appear to improve visual and anatomical outcomes. The authors concluded that symptomatic CCHs responded generally well to PDT. Patients with younger age (less than 50 years), pre-treatment BCVA of greater than or equal to 20/200, and thinner foveal edema were most likely to benefit from this approach.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
*Photodynamic Therapy (PDT) with Light-Activated Verteporfin (Visudyne)*:
CPT codes covered if selection criteria are met:
67221	Destruction of localized lesion of choroid (e.g., choroidal neovascularization); photodynamic therapy (includes intravenous infusion)
+ 67225	photodynamic therapy, second eye, at single session (List separately in addition to code for primary eye treatment)
CPT codes not covered for indications listed in the CPB:
96567	Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitive drug(s), per day
+96570	Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); first 30 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract)
+96571	Photodynamic therapy by endoscopic application of light to ablate abnormal tissue via activation of photosensitive drug(s); each additional 15 minutes (List separately in addition to code for endoscopy or bronchoscopy procedures of lung and gastrointestinal tract)
96573	Photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day
96574	Debridement of premalignant hyperkeratotic lesion(s) (ie, targeted curettage, abrasion) followed with photodynamic therapy by external application of light to destroy premalignant lesions of the skin and adjacent mucosa with application and illumination/activation of photosensitizing drug(s) provided by a physician or other qualified health care professional, per day
Other CPT codes related to the CPB:
92235	Fluorescein angiography (includes multiframe imaging) with interpretation and report
HCPCS codes covered if selection criteria are met:
J3396	Injection, verteporfin, 0.1 mg [not covered in combination with intravitreal anti-angiogenic agents]
ICD-10 codes covered if selection criteria are met:
B39.4	Histoplasmosis capsulati, unspecified
B39.5	Histoplasmosis duboisii
B39.9	Histoplasmosis, unspecified
D18.09	Hemangioma of other sites [choroidal]
H32	Chorioretinal disorders in diseases classified elsewhere [Histoplasmosis]
H35.051 - H35.059	Retinal neovascularization
H35.30 - H35.3293	Macular degeneration, age related, unspecified, non-exudative and exudative
H35.711 - H35.719	Central serous retinopathy [serous chorioretinopathy]
H44.20 - H44.23	Degenerative myopia [pathologic myopia]
H44.2A1 - H44.2E9	Degenerative myopia with choroidal neovascularization
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C25.0 - C25.9	Malignant neoplasm of pancreas
C44.01, C44.111 - C44.119, C44.211 - C44.219, C44.310 - C44.319, C44.510 - C44.519, C44.611 - C44.619, C44.711 - C44.719, C44.81, C44.91	Basal cell carcinoma
C50.011 - C50.929	Malignant neoplasm of breast
C54.1	Malignant neoplasm of endometrium
C56.1 - C56.9	Malignant neoplasm of ovary
C69.20 - C69.22	Malignant neoplasm of retina [retinoblastoma]
C69.30 - C69.32	Malignant neoplasm of choroid [choroidal melanoma]
C71.9	Malignant neoplasm of brain, unspecified [glioma]
C77.9	Secondary and unspecified malignant neoplasm of lymph node, unspecified [sentinel lymph node metastasis]
D31.30 - D31.32	Benign neoplasm of choroid [choroidal]
E80.0 - E80.29	Disorders of porphyrin metabolism
H21.1x1 - H21.1x9	Other vascular disorders of iris and ciliary body
H30.891 - H30.899 H30.90 - H30.93	Other and unspecified chorioretinal inflammation
H31.8	Other specified disorders of choroid [polypooidal choroidal vasculopathy]
H35.071 - H35.079	Retinal telangiectasia [parafoveal]
H35.20 - H35.23	Other nondiabetic proliferative retinopathy [retinal angiomatous proliferation]
H35.33	Angioid streaks of macula
I70.0 - I70.92	Atherosclerosis
K76.89	Other specified diseases of liver [hepatic impairment or biliary obstruction]
K83.1	Obstruction of bile duct
L40.0 - L40.9	Psoriasis
L63.2	Ophiasis
L63.8 - L63.9	Other and unspecified alopecia areata
*Ocular Coherence Tomography*:
CPT codes covered if selection criteria are met:
92133	Scanning computerized ophthalmic diagnostic imaging, posterior segment, with interpretation and report, unilateral or bilateral; optic nerve
92134	retina
ICD-9 codes covered if selection criteria are met:
B39.4 - B39.9	Histoplasmosis capsulati, duboisii, and unspecified [must be billed with H32]
H32	Chorioretinal disorders in diseases classified elsewhere [must be billed with B39.4 - B39.9]
H35.051 - H35.059	Retinal neovascularization
H35.30 - H35.32	Macular degeneration, unspecified, non-exudative and exudative
H44.20- H44.23	Degenerative myopia

The above policy is based on the following references:

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Last Review 08/11/2020

Effective: 03/08/2002

Next Review: 03/11/2021
Review History
Definitions

Verteporfin (Visudyne) Photodynamic Therapy

Policy

Choroidal Neovascularization

Continuation of therapy

Experimental Indications

Dosing Recommendations

Background

Age-Related Macular Degeneration

Central Serous Chorioretinopathy

Choroidal Hemangioma

Choroidal Metastasis

Myopic Choroidal Neovascularization

Ocular Histoplasmosis

Warnings and Precautions

Pancreatic Cancer

Parafoveal CNV (Occult CNV Lesions with No Classic Component)

Polypoidal Choroidal Vasculopathy

Psoriasis

Retinal Capillary Hemangioma

Retinoblastoma

Various Indications

Choroidal Melanoma

Atherosclerotic Plaque

Breast Cancer

Endometrial Cancer

Ovarian Cancer

Glioma

Iris Metastasis

Sentinel Lymph Node Metastasis

Macular Choroidal Hemangioma

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Photodynamic Therapy (PDT) with Light-Activated Verteporfin (Visudyne):

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

Ocular Coherence Tomography:

CPT codes covered if selection criteria are met:

ICD-9 codes covered if selection criteria are met:

The above policy is based on the following references:

Policy History

Additional Information