Photodynamic Therapy (PDT)

From EyeWiki

This page was enrolled in the International Ophthalmologists contest.

Original article contributed by: Sathvik Koneru, Peter A.Karth, MD
All contributors: Peter A.Karth, MD
Assigned editor:
Review: Assigned status Update Pending by Peter A.Karth, MD on August 4, 2017.


Photodynamic Therapy (PDT), introduced to ophthalmology in 2000 [1], is a therapeutic procedure which utilizes the photosensitive intravenous drug, verteporfin (Visudyne, Bausch & Lomb) in combination with a low power, long duration infrared laser. In the eye, it is used to treat vascular issues in the retina and choroid. It was first indicated for neovascular age related macular degeneration (AMD), with large randomized clinical trials showed an improvement in visual acuity versus placebo. Photodynamic therapy’s role in ophthalmology was spurred by the success of the treatment of AMD with PDT (TAP) and Verteporfin in PDT (VIP) studies. The studies proved PDT’s efficacy in treating AMD patients with classical subfoveal choroidal neovascularization. As new therapies have evolved, it is now typically used as a second-line treatment for neovascular AMD. PDT is now most often used to effectively treat cases of Central Serous Retinopathy (CSR) and have been shown to be efficacious by several published studies.

Drug/Laser Mechanism of Action

Verteporfin Drug Information

Verteporfin (marketed as Visudyne), also known as benzoporphyrin derivative, is commonly used as a photosensitizer in Photodynamic Therapy, with a molar mass of 718.794 g and a half-life of 5 to 6 hours. Verteporfin was the second generation photosensitizer developed to treat wet AMD with an intensified long-wavelength absorption maxima at approximately 690 nm, compared to the first generation photosensitizer Photofrin with a weaker wavelength absorption (630 nm), indicating a 50% increase in tissue penetration by light [2]. Moreover, Verteporfin can be rapidly cleared from the body, minimizing patient photosensitivity to 1 to 2 days. Verteporfin has been approved for the treatment of wet AMD since 1999 by the USFDA, having undergone Phase III clinical trials [2].

Verteporfin Mechanism of Action

Photodynamic therapy with verteporfin causes release of free radicals when the verteporfin is activated by the laser energy. The reaction that ensues between the free radicals and blood vessel endothelial cell membranes cause locally increased histamines, thromboxane and TNF-α, all immune modulation factors. The anti-inflammatory response can lead to series of events including vasoconstriction, thrombosis, increased vascular permeability, blood stasis and hypoxia [3]. In the case of neovascularization, this process serves to induce regression of these harmful blood vessels. After injected into the bloodstream, the Visudyne(6 mg/m2 dose) selectively collects in the abnormal blood vessels in the retina and choroid. Fifteen minutes after intravenous infusion, low power laser is applied (standard dose of 50 J/cm2, irradiance of 600 mW/cm2 of 689 nm light over 83 seconds [1]) which activates the phototoxic Visudyne to seal leaking blood vessels by generating these free radicals in areas of necessary treatment.

Indications

Age Related Macular Degeneration (Neovascular)

The wet form of AMD is characterized by the rapid growth of abnormal choroidal neovascular blood vessels under the macula. These new blood vessels often lack integrity and leak blood and fluid that harm the central retina; the damage to the retina causes eventual scarring and drastic vision loss over time.

AMD Trials

Treatment of AMD with Photodynamic Therapy (TAP)

This study, conducted in both Europe and the US, provided evidence showing photodynamic therapy’s promise in achieving reduced loss in visual acuity. The TAP randomized, multi-center, double-masked, placebo-controlled trials enrolled 402 patients with a classic component of choroidal neovascularization (CNV) in the treatment arm ( PDT) and 207 patients in the placebo arm. The primary endpoint was the percentage of eyes that lost less than 15 ETDRS letters from the baseline at the 12 month mark. Patients treated with PDT had a higher percentage of eyes retaining baseline vision than placebo (12 months: 61% treated, 46% placebo; 24 months:53% treated, 37% placebo) [4]. Some of the patients in the 2-year TAP study also continued in the 3-year TAP extension study, to examine PDT’s efficacy and safety in the long term over a 5 year period. The extension study showed no significant systemic safety problems over the 5 year period and demonstrated stable vision over the 60 month period [5].

Ver­­te­porfin in Pho­todynamic The­­­­rapy trial (VIP)

In the VIP trial, 339 (average age of 75), primarily with occult CNV lesions were enrolled. The trial examined patients over a period of two years, allowing for patients to be potentially treated 8 times. In a 24 month period, PDT treatment demonstrated greater efficacy than the placebo at 46.2% versus 33.3% (percentage of eyes losing less than 15 ETDRS letters) [6].

The Ver­te­por­fin in Mi­ni­mal­ly Classic trial (VIM)

This study analyzed PDT treatment in minimally classic CNV lesions, as well as the effects of the standard full fluence (600 mW/cm2 for 83 seconds at 50 J/cm3) versus a reduced half fluence (300 mW/cm2 for 83 seconds at 25 J/cm3) treatment. The results of the standard treatment protocol indicated no apparent vision loss over the 12 and 24 month periods; each treatment had a reduced risk of losing 15 letters of visual acuity compared with the 18 (47%)of 38 eyes assigned to placebo (reduced fluence group P=0.002; standard fluence group P=0.08) [7]. However, data from patients treated with half fluence had better results, with a greater percentage of eyes retaining vision above the baseline (P = 0.15) [7].

Central Serous Retinopathy

Central serous retinopathy (CSR) is an eye disease in which a serous pigment epithelial detachment occurs, causing subretinal fluid and choroidal leakage. To treat this, PDT was first used in a pilot study, where Yannuzzi found in a sample of n = 20 eyes that indocyanine green angiography-guided PDT with verteporfin [aided the resolution of detachments] of chronic CSC [8]. Yannuzzi reported that the use of PDT treatment was effective in reducing excess fluid in the retina and improving overall vision. In another study, Ober found that the use of PDT for CSC also caused rapid vision improvement in a sample of n = 9 individuals [9]. In a meta-analysis of 117 citations and 31 studies describing 787 CSR eyes treated with photodynamic therapy, Erikitola, Crosby-Nwaobi, Lotery, and Sivaprasad concluded that PDT showed promise in treating chronic CSR in the short-term but identified that the studies analyzed lacked large sample sizes and follow ups to determine the long term efficacy of PDT treatment in CSR [10].

Ocular Tumors

PDT has also shown promise in the treatment of various ocular treatments:

Choroidal Hemangiomas

Circumscribed choroidal hemangiomas (CCH) are non-malignant vascular tumors occurring as a circumscribed orange-red choroidal mass in the posterior pole of the retina [11]. The largest study investigating PDT’s efficacy in circumscribed choroidal hemangiomas was conducted by Boixadera et al. in 2009 [11]. This study was a prospective, multicenter, nonrandomized trial that enrolled 31 patients and issued one to four treatments at 12-week intervals over a period of one year [12]. Results indicated that 82.8% of patients required 1 treatment, 13.8% required 2 treatments, and 3.4% required 3 PDT treatments to eliminate associated exudative retinal detachment. In this study, visual acuity increased from a mean of 20/60 to 20/35 (P<0.001).

Capillary hemangiomas

Retinal Capillary Hemangiomas (RCHs) are benign hamartomatous tumors characterized by dilated retinal capillaries. PDT’s ability to treat RCH has been noted by several different case studies; the largest of these, Sachdeva et al, studied six eyes (3 with juxtapapillary and 3 with extrapapillary) of five patients. Patients were administered PDT 1-3 times and were studied until 32 months. All eyes demonstrated tumor regression or stabilization as well improvement in subretinal fluid (SRF) and lipid exudation; however, only 3 eyes experienced an increase in visual acuity, and the other three eyes required retreatment of PDT due to recurrent RCF. The authors concluded that PDT is effective in the treatment of RCH, however noted that visual acuity only increased in half of the eyes and that a larger study would be required to validate these results [13].

Combined Therapies

Combined therapy approaches in PDT have also been studied to maximize efficacy of treatments. The SUMMIT study group, which consisted of three randomized clinical trials, DENALI, EVEREST, and MONT BLANC, tested the combined therapy of PDT and ranibizumab (branded Lucentis) [14].

DENALI

The DENALI study was a randomized, double-blind two-year study, conducted in the US and Canada, that enrolled patients with subfoveal CNV and tested the efficacy of the combined ranibizumab and standard fluence (SF) PDT and the combined ranibizumab and reduced fluence (RF) PDT therapies (ranibizumab - 0.5 mg administered intravitreally 3 times and additional injections administered on a monthly as-needed basis) [15]. The combined verteporfin PDT with ranibizumab increased visual acuity in standard fluence PDT by 5.3 letters and by 4.4 letters in reduced fluence PDT, compared to 8.1 letters with ranibizumab monotherapy. While there was no clinical benefit and the endpoint of noninferiority (by a 7 letter margin) was not met, the combination therapy reduced the number of injections: 5.1 with SF PDT and 5.7 with RF PDT combination therapy, compared to 10.d5 for ranibizumab monotherapy [15].

EVEREST

The EVEREST trial was a multicenter, double-masked, indocyanine green angiography-guided trial conducted in Asia that studied the combined efficacy of verteporfin PDT and ranibizumab compared to ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy (PCV). The EVEREST trial found the verteporfin PDT (71.4%) and combined verteporfin PDT and ranibizumab (77.8%) treatments exhibited a greater polypoidal regression than the individual ranibizumab monotherapy (28.6%). The authors concluded verteporfin PDT with 0.5 mg ranibizumab or lone PDT treatment were superior to ranibizumab monotherapy in achieving complete regression of polyps in patients with PCV [16].

MONT BLANC

The MONT BLANC study, conducted across 50 centers in Europe, was a prospective, multicenter, double-masked, randomized trial that enrolled 255 patients exhibiting active subfoveal choroidal neovascularization (CNV) who were randomly selected to receive either ranibizumab monotherapy or a combined standard fluence (SF) PDT and ranibizumab treatment. Results at the end of the 12 month period indicated the noninferiority (by a 7 letter margin) of the combined verteporfin PDT and ranibizumab treatment in comparison to the ranibizumab monotherapy; the authors found the combination therapy to be well tolerated and concluded the combined therapy to be more effective in achieving BCVA gain compared to ranibizumab monotherapy, but also found that there was no change in the frequency of ranibizumab treatments administered [17].

Risks/Side Effects

The primary effect of photodynamic therapy treatment is an increase in photosensitivity of the skin, attributed to the administration of verteporfin. For this reason, it is recommended that patients wear a wide-brimmed hat, clothes with full skin coverage, as well as sunglasses for 3-5 days after the treatment. It has been reported that a few patients could potentially suffer from an minimal allergic reaction to verteporfin, causing skin inflammation at the injection site. Other PDT side effects may also include:

  • Dry eyes
  • Irritation of eyelids
  • Headache
  • Nausea
  • Back/joint pain


1-4% have severe vision decrease, which is typically transient and is reduced with the reduced fluence treatment protocol

Procedure

Laser Settings

Full Fluence: 50 J/cm2, irradiance of 600 mW/cm2 of 689 nm light over 83 seconds

Half Fluence: 25 J/cm2, irradiance of 600 mW/cm2 of 689 nm light over 83 seconds

Steps

  1. Expect for the treatment to take at least 20 minutes of patient time and possibly 5 minutes of physician time, but may be much longer.
  2. Verteporfin is first injected intravenously and left for 10 minutes to collect in the target blood vessels
  3. Topical anesthetic eye drops will be applied and a laser contact lens will be placed on the cornea of the treatment eye
  4. Laser is applied over a period of 83 seconds to the lesion area to activate the verteporfin. This is painless and invisible, due to infrared wavelength

Post-treatment

Patients are typically followed every 4-12 weeks, depending on the physician's preference. After an initial treatment period, patients may often be tested with fluorescence angiography to investigate the efficacy of the treatment. Further treatment with injections or additional PDT may be administered if deemed necessary.


Acknowledgements

Images: Ophthalmic Atlas Images by EyeRounds.org, The University of Iowa are licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.


References

[1]:Rishi P, Agarwal V. Current Role of Photodynamic Therapy in Ophthalmic Practice, Sci J Med & Vis Res Foun 2015;XXXIII:97–99.

[2]: Josefsen LB, Boyle RW. Photodynamic Therapy and the Development of Metal-Based Photosensitisers. Metal-Based Drugs. 2008;2008:276109. doi:10.1155/2008/276109.

[3]: Flores R, and Silva R. Photodynamic Therapy. Amdbook. N.p., n.d. Web. http://www.amdbook.org/content/photodynamic-therapy

[4]: Bressler NM; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol 2001; 119 (2): 198-207.

[5]: Blumenkranz MS, Bressler NM, Bressler SB, Donati G, Fish GE, Haynes LA, Lewis H, Miller JW, Monés JM, Potter MJ, Pournaras C, Reaves A, Rosenfeld PJ, Schachat AP, Schmidt-Erfurth U, Sickenburg M, Singerman LJ, Slakter JS, Strong A, Vannier S; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials--TAP Report no. 5. Arch Ophthalmol 2002; 120 (10): 1307-14.

[6]: Blinder KJ, Bradley S, Bressler NM, Bressler SB, Donati G, Hao Y, Ma C, Menchini U, Miller J, Potter MJ, Pournaras C, Reaves A, Rosenfeld PJ, Strong HA, Stur M, Su XY, Virgili G; Treatment of Age-related Macular Degeneration with Photodynamic Therapy study group; Verteporfin in Photodynamic Therapy study group. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003; 136 (3): 407-18.

[7]: P.J. Rosenfeld, VIM Study Group; Verteporfin In Minimally Classic CNV due to AMD (VIM) – Two–Year Results from a Phase II Controlled Clinical Trial . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2273.

[8]: Yannuzzi LA, Slakter JS, Gross NE, et al. Indocyanine green angiography-guided photodynamic therapy for treatment of chronic central serous chorioretinopathy: A pilot study. Retina. 2003;23(3):288-298.

[9]: Ober MD, Yannuzzi LA, Do DV, et al. Photodynamic therapy for focal retinal pigment epithelial leaks secondary to central serous chorioretinopathy. Ophthalmology. 2005;112(12):2088-2094.

[10]: Erikitola OC, Crosby-Nwaobi R, Lotery AJ, Sivaprasad S. Photodynamic therapy for central serous chorioretinopathy. Eye. 2014;28(8):944-957. doi:10.1038/eye.2014.134.

[11]: Tsipursky MS, Churgin DS, Conway MD, Peyman GA (2011) A Review of Photodynamic Therapy for Intraocular Tumors. J Anal Bioanal Tech S1:001. doi: 10.4172/2155-9872.S1-001

[12]: Boixadera A, Garcia-Arumi J, Martinez-Castillo V, Encinas JL, Elizalde J, et al. (2009) Prospective clinical trial evaluating the efficacy of photodynamic therapy for symptomatic circumscribed choroidal hemangioma. Ophthalmology 116: 100-105.

[13]: Sachdeva R, Dadgostar H, Kaiser PK, Sears JE, Singh AD (2010) Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma. Acta Ophthalmol 88: e334-e340.

[14] J. S. Slakter, DENALI Study Group; SUMMIT: Combination Therapy With Verteporfin PDT and Ranibizumab for Subfoveal Choroidal Neovascularization Due to AMD. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1817.

15]: Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A; DENALI Study Group. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology. 2012 May;119(5):1001-10.

[16]: Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, Weisberger A, Lim TH. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012 Sep;32(8):1453-64.

[17]: Larsen M1, Schmidt-Erfurth U, Lanzetta P, Wolf S, Simader C, Tokaji E, Pilz S, Weisberger A; MONT BLANC Study Group. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results. Ophthalmology. 2012 May;119(5):992-1000. doi: 10.1016/j.ophtha.2012.02.002. Epub 2012 Mar 17. https://www.ncbi.nlm.nih.gov/pubmed/22424834