Deeba Husain,
Evangelos S. Gragoudas,
Joan W. Miller
INTRODUCTION
Photodynamic therapy (PDT) involves the use of photoactivatable compounds (photosensitizers) which accumulate in, and are retained by, proliferating tissues. When these molecules are activated by light at the appropriate wavelength, active forms of oxygen and free radicals are generated, which result in photochemical damage to cells in which the photosensitizer is present. Thus PDT can be used to treat diseased areas selectively while sparing the normal tissue. PDT has been extensively studied in the treatment of neoplasia and more recently for neovascularization. At this time in ophthalmology, it is approved by the US FDA and other agencies for the treatment of subfoveal choroidal neovascularization, and has been used for management of other ocular neovascularization.
HISTORICAL BACKGROUND
The earliest report on the action of light-activated chemicals on biological systems was published in 1900 by Raab, who described the lethal effect of light on paramecium treated with acridine dye.[1] von Tappeiner in 1904 demonstrated oxygen dependence of this photosensitization reaction and coined the term 'photodynamic action'.[2] Meyer-Betz demonstrated photosensitizing properties of hematoporphyrin derivative (HPD) in 1913.[3] In 1942, Aueler and Banzer for the first time used HPD for photodynamic destruction of tumors in animals.[4] Lipson and colleagues in 1961 reported on the use of HPD for fluorescence detection of neoplastic tissue, and subsequent treatment in patients with breast cancer.[5]
In 1978, Dougherty et al reported the first large series of patients with cutaneous malignancies that exhibited partial or complete response to photoradiation therapy using HPD and light.[6] The active components of HPD were identified to be dihematoporphyrin ethers and esters (DHE), and the commercial preparation of DHE is known as porfimer sodium or Photofrin (PF).[7] PDT with benzoporphyrin derivative (BPD) has shown beneficial effect in preliminary trials in the treatment of many diseases such as basal cell carcinoma, metastatic skin lesions, and the elimination of leukemia progenitor cells in the marrow of patients with chronic myelogenous leukemia.[8] PDT has been used for nononcological conditions outside the eye including psoriasis, atherosclerotic plaque and restenosis, bone marrow purging for the treatment of leukemias with autologous bone marrow transplant, inactivation of viruses in blood or blood products, and several autoimmune conditions including rheumatoid arthritis.[9] PDT with BPD (Verteporfin) for choroidal neovascularization (CNV) secondary to macular degeneration was approved by US FDA in 2000, and since then it is approved and being used all over the world for this indication.
MECHANISM OF ACTION
PDT requires the administration, usually intravenous, of a photosensitizer dye that accumulates in neoplastic and neovascular tissues. The targeted tissue is then irradiated using light of a wavelength at an absorption peak of the dye. A photochemical reaction[10] is initiated with the absorption of light by the photosensitizer molecule in the ground state (S), which is excited to enter a higher-energy triplet state (3S). The triplet state molecules are short-lived reactive species that transfer their energy via two pathways that can cause cytotoxicity leading to physiological responses such as necrosis and/or apoptosis. Energy can be transferred from the triplet state photosensitizer to molecular oxygen converting it to singlet oxygen (1O2), while returning to their ground state (type II reaction).[11] The triplet state molecules may also directly transfer energy through a free radical mechanism to form cytotoxic intermediates (type I reaction) (Fig. 147.1). The type II mediated pathway accounts for the majority of tissue destruction and is responsible for the oxygen dependence of PDT. The extent of oxygen dependence varies somewhat among photosensitizers; under anoxic conditions PDT effects are abolished for Photofrin.[12]
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FIGURE 147.1 Schematic representation of photodynamic action. Photons are absorbed by photosensitizer molecules in ground state (S). This causes them to enter in a higher-energy excited triplet state (3S). The short-lived reactive triplet state photosensitizer molecule leads to transfer of energy causing the formation of singlet oxygen and free radicals that cause cytotoxicity. |
PDT offers some degree of selectivity in the destruction of tumor and neovascular tissue, with minimal local and systemic side effects. This is due to two factors: a preferential localization of the photosensitizer in these tissues and precise laser light irradiation of the targeted tissue.[13] The mechanism of accumulation of the photosensitizer in the neovascular and neoplastic tissue is not known, but several theories have been proposed. Photosensitizers are taken up by most tissues of the body, but are retained longer in neoplastic tissue, as well as in normal liver, spleen, kidney, and wound healing tissue. Henderson et al have suggested that pooling and retention of photosensitizers in tumors could occur due to a larger interstitial space and poor lymphatic network.[14] The cells with high mitotic activity such as tumor and neovascular endothelial cells were found to have a high expression of low-density lipoprotein (LDL) receptors (e.g., the apo B/E receptor),[15] which might result in more efficient uptake of LDL-bound molecules by receptor-mediated endocytosis.[16] Therefore various methods to enhance the LDL-mediated mechanism have been investigated, including formulation of photosensitizer in liposomes, lipid-based emulsions, as well as preincorporation with LDL. Other techniques used are delivery with biodegradable nanospheres, attaching photosensitizers covalently to polymers, and using inclusion complexes such as cyclodextrins. Selective localization of photosensitizers in tumors has also been improved by binding the dye to targeting molecules such as peptides or monoclonal antibodies (Mab) that recognize specific antigens on tumor cells.[17] Targeted PDT is a new modality to improve the efficacy of PDT; here photosensitizer is bound to the targeting peptide which in turn binds to VEGF receptors on the neovascularization thus resulting in efficient localization of the photosensitizer.[18]
The mechanisms of PDT-mediated tissue destruction include cellular, vascular, and immunological damage. Direct cellular destruction is due to the damage of cellular membranes through lipid peroxidation and protein damage, by singlet oxygen and free radical intermediates,[7] leading to structural and functional damage to cellular membranes. Apoptosis of the cells has also been reported by a biomolecular cascade induced by PDT-related damage to mitochondrion, lysosomes, and nuclear components.[19] Vascular damage is an important mechanism of tissue destruction in PDT with certain photosensitizers, and probably occurs secondary to endothelial damage and subsequent platelet aggregation, and vessel thrombosis. Eiconasoids are released following PDT including thromboxane, histamine, and tumor necrosis factor-? and may contribute to vascular occlusion.[20] Finally, immunomodulation may play a role in PDT-induced tissue destruction. Treatment of various tumors with PDT has demonstrated increased tissue levels of cytokines,[21] enhanced killing activity of specific cytotoxic T-lymphocytes,[22] increased natural killer cell activity,[23] and tumor-associated macrophage accumulation in tissue[24] with TNF-? release, and macrophage-mediated cytotoxicity. Immunomodulation following PDT is being investigated for application in organ transplantation and the treatment of autoimmune diseases.
CLINICALLY APPROVED PHOTOSENSITIZERS
The effective penetration depth of the PDT treatment is dependent on the wavelength of the light and optical properties such as absorption and scatter of the targeted tissue. Typically, the effective penetration depth is 2-3 mm at 630nm and increases to 5- 6 mm at longer wavelengths (700-800nm).[25] These values can be altered by changing the biological and physical characteristics of the photosensitizer (Table 147.1). In general, photosensitizers with longer wavelengths and higher molar absorption at these wavelengths are more efficient photodynamic agents (Fig. 147.2.[10]
TABLE 147.1 -- Photosensitizers in Ophthalmology
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Xanthene Derivative |
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Rose bengal |
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Tetrapyrrole Derivatives |
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Hematoporphyrin derivative |
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Photofrin (dihematoporphyrin ether) |
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Benzoporphyrin derivative |
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Chlorins and Bacteriochlorins |
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Mono-aspartyl chlorin e6 |
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Bacteriochlorin a |
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Tin etiopurpurin |
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ATX-S10 |
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Phthalocyanines |
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Chloroaluminum sulfonated phthalocyanine |
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Zinc phthalocyanine |
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FIGURE 147.2 Absorption spectra of selected photosensitizers that have been used in PDT. PF, Photofrin; BPD-MA, benzoporphyrin derivative monoacid; Ce6, Chlorin 6; CASPc, chloroaluminum sulfonated phthalocyanine. |
Most clinical experience comes from the porphyrin family of photosensitizers, including hematoporphyrin derivative (HPD) and dihematoporphyrin ether (DHE). DHE is a complex mixture of oligomeric esters and ethers of HPD, with inherent variability (Fig. 147.3).[26] The commercial preparation of DHE, called Photofrin (Fig. 147.3a), has been used in clinical trials for bladder, lung, stomach, and cervix cancer. The main problems with Photofrin were prolonged skin photosensitivity and relatively low absorption in the wavelength region of therapeutic interest (600-1100nm).[10] This has provided an incentive to develop second-generation photosensitizers.
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FIGURE 147.3 Chemical structures of (a) dihematoporphyrin ether, DHE; (b) benzoporphyrin derivative monoacid, BPD-MA; (c) mono-aspartyl chlorin e6, NP e6; (d) meta-tetra (hydroxyphenyl) chlorin, mTHPC; (e) tin etiopurpurin, SnET2; (f) 5-amino-levulinic acid, ALA. |
The clinically tested second-generation photosensitizers include Verteporfin (BPD-MA) (Fig. 147.3b), mono-l-aspartyl chlorin e6 (NPe6) (Fig. 147.3c), Hypericin, protoporphyrin IX, Foscan (mTHPC) (Fig. 147.3d), Purlytin (SnET2) (Fig. 147.3e), 5-amino-levulinic acid, ALA (Fig. 147.3f), and Lu-Tex. BPD, a second-generation photosensitizer, is formally a chlorin, since it has a reduced pyrrole ring as well as a fused six-membered isocyclic ring (Fig. 147.3b).[27] BPD has absorption maxima at 354, 418, 574, 626, and 688nm; this allows deeper tissue penetration and effective treatment. BPD has a rapid rate of clearance, with no significant photosensitivity after 24 h, and is metabolized to inactive forms prior to excretion through the feces.[28]
PDT OF CHOROIDAL NEOVASCULARIZATION
PDT is a potentially selective treatment modality for neovascularization. It offers a treatment for CNV, where the neovascularization can be occluded and the overlying neurosensory retina is spared avoiding the sudden decrease of vision seen as a complication of thermal photocoagulation of subfoveal CNV. Several investigators have studied the efficacy of various photosensitizers for PDT of experimental CNV.
Experimental CNV was created in a monkey model by inducing argon laser injury to the macula, which leads to development of CNV in 2-4 weeks (Fig. 147.4a-c).[29] Thomas and Langhofer[30] in 1987 demonstrated successful thrombosis of experimental CNV without occlusion of the choriocapillaris, in the monkey model using DHE. Kliman et al[31] studied PDT of experimental CNV using chloroaluminum sulfonated phthalocyanine (CASPc). These preliminary studies suggest that closure of experimental CNV can be accomplished over a wide range of treatment parameters, but the selectivity of effect, and the damage to retinal structures and human safety was not investigated. Miller and Miller[32] studied the efficacy of rose bengal, a xanthene derivative to treat experimental CNV. It was found that PDT with rose bengal led to disruption of CNV but did not destroy the new vessels completely, and the required dye dose was 27 times higher than the dose which has been demonstrated to be safe clinically.
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FIGURE 147.4 (a). Fundus photograph showing elevated yellow-gray areas (arrows) of choroidal neovascularization in the experimental model of choroidal neovascularization in the monkey eye. (b) Early phase fluorescein angiogram of the eye in (a) showing the typical lacy pattern of hyperfluorescence in areas of experimental CNV (arrow). (c) Late phase angiogram of the eye in (b) showing increasing hyperfluorescence and fluorescein leakage by the CNV (arrows). |
Preliminary work has been carried out with tin etiopurpurins (SnET2).[33] The treatment parameters include a dye dose of 1 mg/kg with a light of 665nm, an irradiance of 600 mW/cm2 and fluence of 35-70J/cm2. A spot size of 1200 ?m was used and light exposure lasted 60-120 s. It has been shown to be effective in closure of experimental CNV. Clinical trials were conducted to study the role of SnET2 (Purlytin) in the treatment of wet age related macular degeneration (AMD). The pooled data at 2 years showed that 58% of SnET2-treated patients lost 15 letters or less compared to 42% of placebo patients. This effect was only seen in lesions smaller than 3 mm and with better visual acuity (46-67 letters).[34] The systemic photosensitivity lasted 4 weeks. The drug failed to reach its efficacy end point in Phase III studies and at this time is not used in the treatment of AMD.
Lu-Tex or lutetium texaphyrin is a water-soluble photosensitizer that has an absorption peak of 732nm. It has been shown to localize in choroidal neovascularization in the monkey eye. PDT using 1-2 mg/kg body weight of Lu-Tex, and a light dose of 50-100J/cm2 has been shown to cause closure of CNV in the monkey eye.[35] Phase I and II clinical trials with Lu-Tex showed that the drug was effective in causing CNV occlusion, but the drug caused peripheral parasthesias in a significant number of patients and therefore the clinical trials were halted.
Normal choroidal vasculature has been occluded using newer photosensitizers and it has been extrapolated that these dyes can potentially be used to treat CNV. Mori et al[36] have demonstrated effective and selective occlusion of choroidal vessels in Japanese monkey eyes using 2-10 mg/kg of mono-l-aspartyl chlorin e6 (NP e6) and 664nm light (0.4-7.5J/cm2). Obana et al[37] performed PDT on the retina and choroid of monkeys using ATX-S10, a new chlorin derivative (dose of 8-12 mg/kg) using a light of 670nm (3.5J/cm2), 30-74 min after the dye injection. Histopathology of these eyes demonstrated photothrombosis of choriocapillaris and choroidal vessels with no obvious damage to the neurosensory retina.
VERTEPORFIN PDT FOR CHOROIDAL NEOVASCULARIZATION
Preclinical Studies
Work in our laboratory has used a tetrapyrrol derivative benzoporphyrin derivative monoacid (BPD, Verteporfin, Visudyne). This photosensitizer has a long absorption wavelength at 690nm,[38] therefore allowing deeper tissue penetration for effective treatment, through blood, fluid, and fibrosis that is important in the treatment of CNV. When injected intravenously, BPD has a serum half-life of 30 min. The high-est tissue levels are reached in 3 h, declining rapidly and cleared in the first 24 h, therefore reducing the risk of the systemic photosensitivity.[39] It has been found to be safe for human use, and was first studied in clinical trials in dermatology for malignant skin tumors.[40]
Initial studies in experimental CNV were done using a lipoprotein-associated preparation of BPD at doses of 1-2 mg/kg and light of 692nm generated from an argon/dye laser that was delivered via a slit-lamp delivery system with a spot size of 1250 ?m. Effective vascular occlusion was seen when irradiation was performed 1-80 min after the dye injection, with a fluence of 50-150J/cm2 and irradiance of 150-600 mW/cm2.[41] No thermal damage was seen at irradiances as high as 1800 mW/cm2.[42]
Further refinement of dosimetry was carried out using the liposomal preparation of BPD.[43] The mechanism of photosensitizer uptake by the neovascular tissue is not known, but it has been observed that neovascular and neoplastic tissue have high density of lipoprotein receptors which may enhance preferential uptake of the photosensitizer.[44] BPD fundus angiography has also demonstrated that liposomal BPD accumulates in CNV.[45] Dye doses of 0.25-1 mg/kg of liposomal BPD were studied and a minimal dose of 0.375 mg/kg caused effective closure of CNV. The optimal time for irradiation appeared to be 20-50 min after a bolus intravenous injection of dye with a spot size of 1250 ?m at an irradiance of 600 mW/cm2 and a fluence of 150J/cm2.[43]
Since damage to normal retina and choroidal structures was difficult to assess in the experimental CNV model, selectivity of PDT was assessed in normal retina and choroid using the same parameters as for CNV.[43] Fluorescein angiography demonstrated early hypofluorescence in the treated areas followed by hyperfluorescence starting at the periphery of the lesion in the later frames of the angiogram. A grading system for assessing damage to retina and choroid was devised. Damage to RPE and choriocapillaris was seen in all irradiated eyes, and the grading scheme was based on the damage to the neurosensory retina and medium to large choroidal vessels. Some damage to the photoreceptors was noted throughout all grades, typically mild vacuolization and disorientation of the inner and outer segments of the photoreceptors. When PDT was performed with liposomal BPD doses of 0.25, 0.375, or 0.5 mg/kg, at 20-50 min after dye injection, the retinal structure was well preserved and PDT was sufficiently selective.
Dosimetry experiments were done using a bolus intravenous injection of liposomal BPD-MA, but liposomal drugs are typically used clinically as an intravenous infusion, and clinical trials in dermatology using liposomal BPD administered the dye by infusion with success. Further studies were undertaken and designed to evaluate the efficacy and parameters for PDT of experimental CNV using an intravenous infusion of liposomal BPD.[46] Infusion (10 min) was tested and effective closure was achieved when irradiation was performed 20-30 min from the start of infusion using a light of spot size of 1250-3000 ?m of 689 nm light at 600 mW/cm2 and 150J/cm2. Closure of experimental CNV could be seen by fluorescein angiography (Fig. 147.5a-c) and was confirmed by histopathology. Light microscopy showed occluded vessels in the area of CNV, closure of the underlying choriocapillaris, and the overlying retina was essentially normal. Electron microscopy of the vessels in the CNV showed occlusion of the lumen with red blood cells, white blood cells, and platelets, with damaged endothelial cells showing swelling and vacuolation of the cytoplasm, with breaks in the nuclear membrane (Table 147.2).[46]
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FIGURE 147.5 (a) Fundus photograph 24 hours after PDT with irradiation performed at the end of slow dye infusion to the foveal choroidal neovascularization (arrow) and at the end of flush infusion to the choroidal neovascularization temporal to the fovea (arrowhead), showing mild graying of the two treated areas. (b) Early phase fluorescein angiogram 24 h after PDT using liposomal BPD at the end of slow dye infusion (arrow) and at the end of flush (arrowhead), illustrates hypofluorescence (occlusion of CNV) in both areas with perfusion of the overlying normal retinal capillaries confirming occlusion of CNV. (c) Late phase angiogram of the eye in Figure 147.4, showing staining at the edge of the irradiated area. This most likely represents leakage from perfused choriocapillaris through damaged RPE. |
TABLE 147.2 -- Standard Clinical Treatment Parameters for Visudyne PDT
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Selectivity of PDT using liposomal BPD was studied by performing light irradiation of normal monkey retina and choroid with the same parameters. Fundus photography was taken 24 h after PDT and it demonstrated mild graying of the retina at the treated areas (Fig. 147.6a). Fluorescein angiography of these areas showed early hypofluorescence (Fig. 147.6b) with late staining starting from the edges of the lesion (Fig. 147.6c). Light and electron microscopy of the lesions showed occlusion of the choriocapillaris and damage to the retinal pigment epithelium in all cases. Most eyes showed preservation of the medium and larger choroidal vessels, some disarray and vacuolation of the outer segments with mild pyknosis in the outer nuclear layer and normal inner retina.
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FIGURE 147.6 (a) Fundus photograph 24 hours after PDT of normal retina and choroid, showing mild graying of the areas irradiated at the end of dye infusion (small arrow), at the end of flush (long arrow), 10 minutes after end of flush infusion (hollow arrow), and 20 minutes after the end of flush (arrowhead). (b) Early phase fluorescein angiogram of an eye in (a), taken 24 hours after PDT of the normal retina and choroid, showing hypofluorescence of the irradiated areas. (c) Late phase angiogram of eye in (b) showing staining of the irradiated area starting from the periphery of the lesion. This staining is most likely occurring as described in Figure 147.4. |
Studies were carried out to study the long-term effect (4 weeks follow-up) of BPD on the treated CNV.[47] Persistent closure of CNV was seen in most eyes that had been treated with optimal parameters, with histopathology showing a fibrous scar enclosed by proliferating RPE cells with few open capillaries. In normal eyes treated with CNV, the choriocapillaris was re-perfused at 4 weeks. The RPE showed presence of irregular pigmentation with liposomes, phagosomes, and melanosomes indicating some recovery of function. A layer of pigmented macrophages was seen over the RPE. There was some mild disorganization of the photoreceptors. The rest of the neurosensory retina appeared to be normal. Therefore the damage to normal retina and retinal pigment epithelium caused by PDT at 24 h showed histological recovery at 4 weeks.
Long-term recurrence or persistence of CNV after PDT may necessitate repeat treatments, so further studies were carried out to evaluate the effect of repeat treatments on normal monkey retina and choroid.[48] Three consecutive treatments were placed in the monkey eye, using different doses of liposomal BPD doses (6, 12, 18 mg/m2) but constant light dose (689nm; 600 mW/cm2; 100J/cm2). Treatments were separated by an interval of 2 weeks, with histopathologic examination at 2 and 6 weeks after the third treatment. Minimal damage to the retina, choroid, and optic nerve was present in animals treated at 6 mg/m2. Higher dye doses lead to significant cumulative damage to the normal retina, choroid, and optic nerve.
Clinical Trials
Phase I/II clinical trials were designed to evaluate safety and maximum tolerated doses of verteporfin therapy for the treatment of patients with classic CNV. Sixty-one patients were reported in a dose escalation protocol.[49,50] Dye doses were 6 or 12 mg/m2 of liposomal BPD with light of 689nm at a fluence of 50-150J/cm2 and an irradiance of 600 mW/cm2. Eligibility criterion included classic CNV of less than or equal to nine macular photocoagulation study (MPS) disc area and refracted vision of 20/40 or worse. In a report on single treatments, the results showed that light-activated verteporfin could cause short-term (1-4 weeks) cessation of fluorescein leakage from CNV without angiographic damage to retinal blood vessels or loss of vision.[51] At 12 weeks follow-up, leakage occurred in most cases, defined as extension of the CNV beyond the original borders. Systemic safety of verteporfin was very good in this Phase I/II investigation (Table 147.3). Specifically, the most frequent adverse event of this open label study was headache (4.7%). Adverse ocular side effects were noted only at the highest light doses with a significant loss of vision in three patients. Side effects attributed to PDT included retinal arteriolar, venular, and capillary occlusion. Side effects which could be attributed to the disease process itself or to PDT included vitreous hemorrhage. The results from the Phase I/II studies suggested that a potentially effective dose of verteporfin to be considered for Phase III trials would be 6 mg/m2 body surface area, which would be infused intravenously over 10 min. Irradiation with a diode laser at 689nm was applied 15 min after the start of the infusion; the light dose delivered was between 50 and 100J/cm2 at an intensity of 600 mW/cm2 over a period of 83 s.
TABLE 147.3 -- The Landmark Clinical Trials of PDT with Verteporfin for CNV
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A Phase III clinical trial was initiated in December 1996, termed as the treatment of age-related macular degeneration with photodynamic therapy (TAP). This was a randomized, placebo-controlled, double-masked, multicentric study (19 centers in North America and Europe) designed to determine the effect of PDT on vision in patients with subfoveal CNV secondary to AMD. Eligibility criteria included subfoveal new or recurrent CNV secondary to AMD with a classic component, best corrected visual acuity of 20/40 to 20/200, and lesion size of 5400 ?m or less. Patients underwent re-treatment every 3 months if angiographic leakage was apparent on follow-up.
The proportion of eyes with at least moderate vision loss (a decrease in the letter score of 15 letters or ?3 lines) was greater in placebo-treated eyes than in verteporfin-treated eyes throughout the period from examination at month 3 to the examination at month 12. In subgroup analysis, the visual acuity benefit of verteporfin therapy was clearly demonstrated in eyes with classic CNV occupying at least 50% of the area of the entire lesion (termed 'predominantly classic' lesions). With respect to predominantly classic lesions, 33% of the verteporfin-treated eyes had at least moderate vision loss at 12 months compared to 60% of the placebo-treated eyes. Furthermore, at this time, 12% of verteporfin-treated eyes and 33% of placebo-treated eyes had severe vision loss. The results were even greater for predominantly classic lesions and no occult CNV; 23% of verteporfin-treated eyes had at least moderate vision loss at 12 months compared to 73% of placebo-treated eyes. Ten percent of the verteporfin-treated eyes had severe vision loss compared to 41% of the placebo-treated eyes. These results prompted the TAP Study Group to recommend verteporfin therapy for all predominantly classic lesions that met the eligibility criteria for the studies. Progression of classic CNV beyond the area of the lesion identified at baseline occurred in only 166 (46%) of 361 verteporfin-treated eyes compared to 133 (71%) of 187 placebo-treated eyes by the month 12 examination.
Few ocular systemic adverse events judged to be of any clinical relevance were noted in Phase III of the study. Compared to placebo patients, verteporfin-treated patients had more transient vision disturbances (18% vs 12%), injection site adverse events (13% vs 3%), transient photosensitivity reactions (3% vs 0%), and infusion-related low back pain (2% vs 0%). However, most of these events were mild to moderate and resolved by themselves. In summary, the TAP[52] investigation showed that verteporfin therapy reduced the risk of at least moderate vision loss compared to placebo for at least 12 months in patients with predominantly classic CNV who presented with subfoveal lesions. In the TAP investigation, the visual acuity results were complemented by similar outcomes for contrast sensitivity evaluations.
The 2-year follow-up report of the TAP investigation showed[53] that the beneficial outcomes with respect to visual acuity and contrast sensitivity noted at the month 12 examination in verteporfin-treated patients were sustained through the month 24 examination. At the month 24 examination for the primary outcome, 213 (53%) of 402 verteporfin-treated patients compared to 78 (38%) of 207 placebo-treated patients lost fewer than 15 letters. In subgroup analyses for predominantly classic lesions at baseline, 94 (59%) of 159 verteporfin-treated patients compared to 26 (31%) of 83 placebo-treated patients lost fewer than 15 letters at the month 24 examination. For minimally classic lesions at baseline, no statistically significant differences in visual acuity were noted. Few additional photosensitivity adverse reactions and injection site adverse events were associated with verteporfin therapy in the second year of follow-up. Therefore, this study concluded that the visual acuity benefits of Verteporfin therapy for AMD patients with predominantly classic CNV subfoveal lesions are safely sustained for 2 years, providing more compelling evidence to use Verteporfin therapy for these cases. In TAP Report No. 5, the 36-month vision and safety results of an open-label extension of the TAP investigation showed that the visual outcomes for patients treated with Verteporfin with predominantly classic lesions at baseline remained stable from month 24 through month 36, and no additional safety concerns.[54]
The role of PDT in the treatment of occult with no classic subfoveal choroidal neovascularization was studied in 339 patients in a multicentric, placebo-controlled, double-masked study (Verteporfin in photodynamic therapy or VIP study) carried over 2 years.[55] It showed that there was a significant reduction in the risk of moderate to severe visual loss. The study also suggested that greater benefit was seen in patients with smaller lesion (4 disc area or smaller) and lower levels of visual acuity (20/50 or less). The evidence for efficacy of PDT in treating the occult-only subtype has weakened with the recently completed Visudyne in occult (VIO) trial, in which the study's primary visual outcome was not reached at either 1 or 2 years.
A recent clinical trial was designed to compare the treatment effect and safety of PDT with verteporfin using a standard (SF) or reduced (RF) light fluence rate with that of placebo therapy in patients with subfoveal minimally classic choroidal neovascularization (CNV) with AMD (Visudyne in minimally classic or VIM trial). This was a multicentric, double-masked, placebo-controlled, randomized clinical trial. Inclusion criteria included initial best-corrected visual acuity of at least 20/250 and a lesion size of no greater than six MPS disc areas. One hundred and seventeen patients were randomly assigned patients (1:1:1) to verteporfin infusion (6 mg/m2) and light application with an RF rate (300 mW/cm2) for 83 s (light dose of 25 J/cm2) or an SF rate (600 mW/cm2) for 83 s (light dose of 50 J/cm2) or to placebo infusion with RF or SF. Treatment was repeated every 3 months if the treating physician noted fluorescein leakage from CNV on angiography. At month 12, a loss of at least 3 lines of visual acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10 (28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38 eyes assigned to placebo. At month 24, this loss occurred in 9 (26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to SF, compared with 23 (62%) of 37 eyes assigned to placebo. Progression to predominantly classic CNV by 24 months was more common in the placebo group 11 (28%) of 39 patients compared with 2 (5%) of 38 in the RF group and 1 (3%) of 37 in the SF group. No unexpected ocular or systemic adverse events were identified. The study concluded that Verteporfin therapy safely reduced the risks of losing at least 15 letters (?3 lines) of visual acuity, and, progression to predominantly classic CNV for at least 2 years in individuals with subfoveal minimally classic lesions due to AMD measuring six MPS disc areas or less. Based on the overall evidence available on Verteporfin therapy for these lesions, the VIM Study Group recommended verteporfin therapy for relatively small minimally classic lesions.[56]
Preliminary study[57] of the treatment of CNV not related to AMD such as myopia, histoplasmosis, angioid streaks, and idiopathic causes, with Verteporfin therapy, achieved short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Verteporfin therapy for subfoveal CNV caused by pathologic myopia was studied in a multicentric, double-masked, placebo-controlled, randomized clinical trial in 110 patients through 2 years of follow-up.[58] It showed that PDT maintained a visual benefit compared with a placebo therapy. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommended verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1 and 2 year results of this randomized clinical trial.
PDT of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome was studied in an uncontrolled, prospective case series of 26 patients. A 24 month examination was completed in 22 of the 26 enrolled participants (85%). At the 24 month examination, median improvement from baseline in visual acuity of the 22 patients evaluated was six letters; median contrast sensitivity improved by 3.5 letters. At the 24 month examination, 10 patients (45%) gained seven or more letters of visual acuity from baseline, whereas four patients (18%) lost eight or more letters, including two patients (9%) who lost at least 15 letters. There was absence of fluorescein angiographic leakage from classic CNV in 17 of the 20 evaluable lesions (85%), and leakage from occult CNV was absent in all eyes. No serious ocular adverse events were reported, and no serious systemic event was considered to be associated with treatment. The study[59] concluded that the median visual acuity improved and fluorescein angiographic leakage decreased after verteporfin therapy in this small, uncontrolled clinical study of patients with subfoveal CNV resulting from OHS. Verteporfin therapy seemed to be relatively safe in these patients.
COMBINATION THERAPY
Preliminary study of PDT in combination with intravitreal kenalog injection has been reported in CNV secondary to AMD and was found to be relatively safe and had reasonable results for lesions with some classic component.[60] Subsequently, a case series[61] was reported on 26 patients with CNV secondary to AMD treated with PDT immediately followed by intravitreal kenalog. Elevated IOP seemed to be the most frequent early side effect of the treatment. 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 intravitreal triamcinolone acetonide, particularly when used as first-line therapy, merits further investigation. The role of the combination of PDT and intravitreal kenalog for nonsubfoveal choroidal neovascularization was studied in another case series of 15 patients followed over 12 months.[62] This pilot study showed that the visual acuity response and the low incidence of subfoveal extension suggest that PDT combined with intravitreal triamcinolone for the treatment of nonsubfoveal choroidal neovascularization merits further investigation as a first-line treatment. Now a clinical trial is underway to study the combined Visudyne therapy with kenalog in CNV secondary to AMD.
Clinical trials are also ongoing to evaluate the safety and efficacy of combination treatment of PDT and pegaptanib sodium (Macugen) for predominantly classic choroidal neovascularization secondary to AMD. Preliminary preclinical data indicate that an intravitreal ranibizumab (Lucentis) injection in combination with verteporfin PDT causes a greater reduction in angiographic leakage than PDT and intravitreal vehicle injection (PDT only) in experimental choroidal neovascularization in the monkey eye.[63] Clinical trials (FOCUS) are ongoing to compare Lucentis in combination with PDT to PDT alone.[64]
Targeted PDT is a new modality to improve the efficacy of PDT. Preclinical work has been done with Verteporfin bound to the targeting peptide, ATWLPPR, which helps it bind to VEGF-receptor 2. The targeted verteporfin resulted in more selective treatment than the control conjugate or standard verteporfin. This study provides the basis for further studies of targeted PDT strategies and subsequent clinical trials.[18]
CONCLUSION
PDT causes selective damage to the proliferating tissues with relative sparing of the surrounding tissues. This led to its vital role in the treatment of ocular neovascularization specially CNV. PDT of choroidal neovascularization using verteporfin (Visudyne) is a proven treatment modality for certain eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration and other causes such as myopia, histoplasmosis, angioid streaks, and idiopathic causes. Clinical trials have shown that it is a safe treatment with minimal chance of transient systemic side effects. In the experimental models, PDT has also been efficacious in the treatment of iris, corneal neovascularization, ocular tumors, and glaucoma and it offers an adjunctive therapy to the existing modalities for these conditions. Further research is ongoing to determine the suitable photosensitizer and the optimal treatment parameters for the ocular applications of PDT. New photosensitizers that may have improved characteristics for PDT of ocular structures continue to be developed. Future strategies will address improved selectivity by complexing photosensitizers to agents that target tumors and neovasculature. Finally, PDT has a major role in a multifaceted approach such as in combination with antiangiogenic and immunogenic modalities.
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