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ISSN: 2155-9872
Journal of Analytical & Bioanalytical Techniques

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A Review of Photodynamic Therapy for Intraocular Tumors

Tsipursky MS1*, Churgin DS2, Conway MD3 and Peyman GA3

1Carle Physician Group and Carle Foundation Hospital, Urbana, Illinois

2University of Arizona College of Medicine, Phoenix, AZ, USA

3University of Arizona College of Medicine, Tucson, Arizona, USA

*Corresponding Author:
Tsipursky MS
Carle Physician Group and Carle Foundation Hospital
Urbana, Illinois
E-mail: [email protected]

Received date: June 21, 2011; Accepted date: July 19, 2011; Published date: Augutst 02, 2011

Citation: 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

Copyright: © 2011 Tsipursky MS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Photodynamic therapy (PDT) has been used in ophthalmology for various vascular conditions affecting the retina and choroid since the late 1990’s. As of 2000, verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) photosensitizer for ocular conditions was used in treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), pathologic myopia, and presumed ocular histoplasmosis syndrome

Introduction

Photodynamic therapy (PDT) has been used in ophthalmology for various vascular conditions affecting the retina and choroid since the late 1990’s. As of 2000, verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) photosensitizer for ocular conditions was used in treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), pathologic myopia, and presumed ocular histoplasmosis syndrome [1]. PDT has an ability to selectively occlude regions of neovascularization for successful control of these conditions [2-5]. It is thought that PDT stops the leaking vessels in neovascularization by binding to low-density lipoproteins found abundantly in neovascular tissue and then causing a local nonthermal cytotoxic effect and damaging the vascular endothelium [6,7]. Preclinical and clinical verteporfin CNV studies showed that the therapy was minimally disruptive to overlying retinal vessels and underlying choroidal vessels [8,9]. The minimal surrounding disruption caused by verteporfin joined with the accessibility of ocular conditions to laser therapy established the potential for PDT to serve as a treatment option for a multitude of ocular pathologies, including a multitude of ocular tumors. The standard PDT for ocular conditions includes 6mg/m2 intravenous verteporfin infusion over 10 minutes with subsequent application of 689nm diode laser to deliver 50 J/ cm2 with intensity of 600mW/cm2 over 83 seconds. The procedure is performed in the out-patient setting with protocol established by the Treatment of Age-related Macular Degeneration PDT (TAP) Study Group [2]. This review will focus on the current spectrum of PDT use in ocular tumors, including retinal vascular lesions such as diffuse and circumscribed choroidal hemangioma, vasoproliferative lesions, and capillary hemangioma. Also, it will include discussion of astrocytoma as well as malignancies such as retinoblastoma and choroidal metastasis.

Methods

A PubMed search in May 2011 was conducted including the dates from 1995 to 2011, using the following search terms: ‘verteporfin’ or ‘photodynamic therapy’ and ‘ocular tumors’ or ‘hemangioma’ or vasoproliferative’ or ‘astrocytoma’ or ‘retinoblastoma’ or ‘metastasis’ or ‘retina’ or ‘choroid’ or ‘uvea’ or ‘melanoma’, limited to articles in English with an abstract. All abstracts were first screened for application to the topic, and those articles selected were then reviewed. The references of the articles selected were also utilized as a resource.

Results

Retina/Choroid

Vascular tumors: Choroidal hemangiomas: Circumscribed choroidal hemangioma (CCH) is a benign vascular tumor that appears as a circumscribed orange-red choroidal mass, usually in the posterior pole of the retina. It is typically first detected in the second to fourth decade of life and there is no systemic involvement [10]. While often asymptomatic [11,12], vision loss may be caused by partial or total retinal detachment of the neurosensory retina and/or retinal pigment epithelium (RPE) degenerative changes induced by the lesion [10,13]. Circumscribed choroidal hemangiomas have been shown to be composed of endothelium-lined vascular channels that encroach on the full thickness of the choroid [14].

The diffuse choroidal hemangioma variant may be associated with Sturge-Weber syndrome (SWS)—a non-hereditary encephalofacial hemangiomatosis syndrome which typically includes ipsilateral hemangiomas of the face and leptomeninges. The diffuse variant appears on exam as a “tomato-catsup” fundus with choroidal thickening and increased tortuosity of retinal vessels. The findings are subtle, and the lesion lacks defined borders [10]. The lesion often involves more than one half of the fundus area. The diffuse variant can be associated with serous retinal detachment with shifting subretinal fluid, whether spontaneous or iatrogenic in nature. This subtype may also cause visual loss by inducing refractive error and foveal distortion [10,15].

The pathobiology of these tumors is unknown. Typically, both variants are unilateral. A multitude of treatment modalities have been employed to treat each subclass of the choroidal hemangiomas. Both subtypes have had attempted treatments with various radiotherapies, photocoagulation, and transpupillary thermotherapy (TTT), with a recent addition of anti-vascular endothelial growth factors (VEGF) [15]. PDT with verteporfin has become the main treatment modality for choroidal hemangiomas in recent years [11,15].

There have been many reports and several case series of PDT showing efficacy in treatment of circumscribed choroidal hemangiomas. The largest of these studies was conducted by Boixadera et al. in 2009 [16]. 32 patients were included in this trial. If the hemangioma diameter was larger than the laser spot size, then multiple spots were administered to cover the lesion, with care to avoid overlapping spots. All patients who had cystoid macular edema (48%) showed regression, and retinal thickness was significantly reduced. Most patients demonstrated recovery of vision (69%), some remained stable at their pre-treatment vision level (27.5%), and 1 patient had slight visual acuity decrease. Specifically, patients with pretreatment vision of 20/200 showed minimal if any change to visual acuity after PDT. Additionally, choroidal hemangioma thickness decreased from a mean of 3 ± 1mm to a mean of 1.7 ± 0.9mm.

Another study by Schmidt-Erfurth et al. with follow-up by Michels et al. [18]. showed similar results in their case series of 15 patients [17,18]. The standard technique for verteporfin therapy was modified by delivery of verteporfin as a bolus of 6mg/m2, and 689nm laser at energy of 100J/cm2 was applied over 166 seconds (which is sometimes referred to in the literature as the Essen protocol). Between 1 to 4 PDT treatments were required for all patients to display complete tumor regression [18]. Case series by Jurklies et al. involving 19 patients, Porinni et al. involving 10 patients, and Singh et al. involving 10 patients also showed similar results [12,19,20].

There are 6 case reports of successful diffuse choroidal hemangioma treatment utilizing PDT with verteporfin. PDT is a potentially ideal technique for treating these vascular tumors, as PDT allows for selective vaso-occlusion while sparing the fragile surrounding environment. The techniques used in the 6 cases were similar, with variations only in number of spots (1 to 7), spot size (2,500 to 7,700mm), duration of treatment (60 to 83 seconds), and treatment versus avoidance of the fovea. A 6mg/m2 dose of verteporfin was used in all cases, and overlapping spot treatment was avoided in all but 1 case. Every case showed resolution of the exudative retinal detachment and improvement in visual acuity. However, there was a wide range of visual acuity outcomes (20/25 endpoint versus 20/400 endpoint), likely related to the duration and extent of the retinal detachment, and the pre-operative visual acuity. There was a consistent observation of worsening visual acuity and exudative detachment for up to 1 month after treatment, with gradual improvement continuing for up to 6 months after treatment. There have been no reported recurrences of exudative retinal detachment at follow-up (ranging from 5 months to 6 years) [15,21-25].

Vasoproliferative lesions: Vasoproliferative tumors of the retina (VPTR) are uncommon lesions that were not deemed a distinct entity until 1995 by Shields et al. [26]. These tumors are classified as either primary or secondary, with known secondary causes including intermediate uveitis, retinitis pigmentosa, toxoplasmosis, toxocariasis, retinal detachment surgery, sickle cell disease, retinochoroidal coloboma, Coat’s disease, retinopathy of prematurity, and Waardenburg’s syndrome [27]. Idiopathic primary presentation is much more common (74%) than secondary disease (26%) [26]. VPTR are typically unilateral, although bilateral manifestations may occur in secondary VPTR. They have a distinct predilection for formation at the inferior temporal peripheral retina. The lesions are association with macular edema and epiretinal membrane formation, both of which can lead to visual loss. VPTR appear globular or dome-shaped, have variable color, typically have surface telangectasias, and may have small aneurysms. The lesions may be accompanied by hemorrhage, may have sub- and intraretinal exudation which may lead to exudative retinal detachment, and sometimes have RPE hyperplasia. The pathogenesis of these tumors is unknown, although histopathologically they are known to be comprised of glial and vascular elements. There is some debate in the literature as to whether or not these are truly tumors, or instead, reactive entities on the spectrum of proliferative vitreoretinopathy [28].

Current management options for VPTR include observational management if the lesion does not cause large exudates or macular involvement, triple freeze thaw transconjunctival cryotherapy, plaque brachytherapy, anti-VEGF therapy, and PDT. Blasi et al. utilized verteporfin PDT in 3 patients with VPTR, following the protocol of 6mg/m2 infusion with 689nm laser at energy of 100J/cm2 over 166 seconds. There was reduction in tumor size, resolution of macular exudates, and improvement in visual acuity. No patient required retreatment [29]. 3 other case reports demonstrate successful treatment of VPTR after PDT therapy [30-32]. There are no large case series or clinical trials to further evaluate PDT as a treatment for VPTR.

Capillary hemangiomas: Retinal capillary hemangioma (RCH) is a benign hamartomatous tumor that arises from the vasculature of the retina which can involve the vessels on or around the optic nerve (papillary or juxtapapillary) or be far away from the optic nerve (extrapapillary). This tumor may form as an idiopathic isolated lesion, or may occur in the setting of von Hippul-Lindau syndrome (VHLS). RCH presents unifocally or multifocally, can be unilateral or bilateral, and can progressively increase in size. Typically, isolated RCH tends to be unifocal and unilateral, whereas syndromic RCH tends to be multifocal and bilateral. Age at diagnosis usually occurs between 15 and 35 years. The lesion appears as red and spherical, and is fed by tortuous blood vessels. There may be surrounding subretinal and intraretinal exudation, and complications of chronic exudation and detachment may lead to iris neovascularization and neovascular glaucoma [38].

Treatment options for symptomatic RCH lesions include observation, laser photocoagulation, cryotherapy, trans-scleral penetrating diathermy, vitreoretinal surgery, and PDT. Success with the traditional treatment modalities has greatly varied and limited, leading to PDT as a recent area of study interest. The vascular nature of these tumors and the limited effects on the surrounding retina make PDT a viable treatment opportunity for RCH [39]. Thus far, researchers have produced 11 separate case studies showing efficacy of PDT for treatment of RCH, with 2 studies utilizing co-treatment with intravitreal anti- VEGF therapy, and 1 study utilizing intravitreal triamcinolone acetonide co-treatment [40-50]. These case studies showed promising results, however follow-up was variable, as were treatment protocols. 3 case series have recently been conducted, showing moderately favorable results and some drawbacks. The largest of the studies was authored by Sachdeva et al. and included 5 patients and 6 eyes, with 2 patients having juxtapapillary (adjacent to the optic nerve) lesions. Patients received standard PDT administration for 1 to 3 treatments, and follow-up until 32 months. All eyes showed tumor size regression or stabilization, improvement in subretinal fluid and exudation. Only 3 patients had stabilization or improvement in visual acuity. Additionally, 3 patients required PDT retreatment due to recurrence of subretinal fluid, and 3 patients experienced epiretinal membrane worsening, which necessitated vitreoretinal reparative surgery. These authors concluded that PDT is an effective therapy for RCH; however, worsening epiretinal membrane is a concern and requires larger studies to further characterize this complication [39].

Schmidt-Erfurth et al. conducted a case series involving 5 patients with decompensated papillary RCH receiving 6mg/ kg verteporfin therapy with 100J/cm2 energy, using 692 nm laser with average of 3 treatments and 12 months follow-up. It was found that tumor regression and resolution of macular exudate and serous retinal detachment occurred in all cases. However, 3 patients experienced a decline in visual acuity, and complications included transient decompensation of vascular permeability, occlusion of retinal vessels, and ischemia of the optic nerve. The authors concluded that while PDT offers effective treatment for regression of RCH and its associated pathologies, the side effects were too great to consider the protocol used in their PDT treatment as recommendable. It was noted, however, that it is unknown whether these adverse outcomes were due to the disease itself or PDT, and whether a different protocol for PDT delivery could change these outcomes [51].

The final study by Aaberg et al. included 3 patients with extrapapillary RCH, who underwent PDT using the standard protocol. The authors reported regression of the lesion in all cases, and improvement in visual acuity in all cases. 1 patient experienced tractional retinal detachment as a result of tumor fibrosis, and required vitrectomy. This patient was then discovered to have choroidal and retinal neovascularization [52].

To summarize, multiple complications of PDT treatment have been reported in the setting of RCH. Sachdeva et al. reported worsening epiretinal membrane in 3 patients and recurrence of subretinal fluid in 3 patients, Schmidt-Erfurth et al. reported 1 patient with retinal vascular occlusion, 1 patient with scotoma and optic neuropathy, 1 patient vitreous hemorrhage and optic neuropathy in their case series, Aaberg et al. reported tractional retinal detachment in 1 patient in their case series, and multiple authors report transient increase in subretinal fluid, Bakri et al. reported increased subretinal fluid in their case report, and Baba et al. reported a massive subretinal hemorrhage after treatment for juxtapapillary RCH in their case report
[39,51,52,47,53].

Other retinal tumors

Astrocytomas: Retinal astrocytic hamartomas are rare tumors that typically occur in patients with tuberous sclerosis complex (TSC), and mostly do not progress or cause visual complications [54]. However, acquired idiopathic retinal astrocytomas that occur in the absence of tuberous sclerosis may have aggressive progression [55,56]. These lesions are known to grow unremittingly even in the face of standard treatments [56,57]. Retinal asytrocytomas can cause lipid exudation, exudative retinal detachment, neovascular glaucoma, phthisis bulbi and eventually may require enucleation secondary to a painful blind eye [57]. On examination, they appear as either multifocal and bilateral when seen in TSC, or unifocal and unilateral when sporadic [58]. These tumors have been found to arise from astrocytes of the sensory retina, and are identical to the subependymal giant cell astrocytomas found in TSC in the brain [57,58]. The tumors are typically detected during childhood or adolescence, and appear as a white, superficial retinal mass [58].

Attempted treatments have included argon laser photocoagulation, vitreoretinal surgery, plaque brachytherapy, cryotherapy, and PDT [57,59]. PDT was attempted due to the poor outcomes associated with the traditional treatment measures. Although there have been limited studies of PDT use in retinal astrocytoma treatment, the results are promising. Eskelin et al. conducted a case series of 2 patients with aggressive retinal astrocytomas. They utilized standard verteporfin therapy and followed the patients for 2 years. It was discovered that the vascularized, enlarging portion of the astrocytomas underwent regression, with little change in the lesion areas with poor vascularization. Exudative retinal detachments resolved entirely, and tumor height decreased. Visual acuity improved in 1 patient, and the other patient’s visual acuity stabilized. 1 patient was found to have intraretinal microvascular abnormalities and scattered hemorrhages 2 months after treatment [59].

Mennel et al. report a case of a symptomatic retinal astrocytic hamartoma that was treated with standard protocol PDT with doubled laser exposure time of 166 seconds. The patient was followed for 4 years. The authors observed that there was no recurrence of tumor vascularization, resolution of metamorphsia, resolution of serous detachment, diminishing lipid exudates, tumor size reduction, and large increase in visual acuity [60].

Shields et al. report a case of successful standard PDT in a patient with symptomatic retinal astrocytoma. They demonstrate regression of subretinal fluid and intraretinal edema, along with improved visual acuity at 12 month follow-up. Similar to the other reports, the tumor showed decreased vascularity, and in this case, only minimal reduction in size [61].

Retinoblastoma: Retinoblastoma (Rb) is the most common ocular malignancy of childhood, seen in approximately 1 in 15-20,000 live births. The affected child most commonly presents with leukocoria, and may also present with strabismus, intraocular inflammation, buphthalmos, or decreased vision [62,63]. The tumor is typically a globular, white-yellow mass with calcifications, and arises from retinoblasts in the developing retina. The median age at diagnosis is between 12 and 24 months. There may be multiple tumors and the lesions may seed the vitreous, cause retinal detachment, or infiltrate diffusely. The majority of tumors are unilateral, and most Rb diagnoses are made before 6 years of age due to increasingly low incidence as age advances [63]. The prognosis is excellent, with long-term survival rates approach 95% [64]. However, poor prognostic indicators include large tumors, older age at detection, extraocular extension, and optic nerve invasion. Rb may be sporadic or inherited, and it is more common for the inherited subtype to develop a late secondary non-ocular malignancy, possibly caused by the current treatment regimens. These secondary malignancies are the leading cause of death in persons with hereditary Rb, and include osteosarcoma, melanoma, brain tumors, and soft tissue sarcomas [63,65].

Current treatment options include enucleation for large tumors, external beam radiation therapy, brachytherapy, cryotherapy, laser photocoagulation, systemic chemotherapy, and most recently targeted delivery of chemotherapy to the ophthalmic artery. Systemic chemotherapy is primarily used in the setting of hematogenous spread, desire to shrink tumor in order to allow further treatment with other modalities, or when there is CNS involvement [63,66]. Unfortunately, most current treatment options lead to loss of retinal function in some areas, assuming the eye is not enucleated [66].

Because of the high morbidity of current treatment regimens and the risk of secondary malignancy after chemotherapy and irradiation in hereditary Rb, PDT has been proposed as a potential conservative treatment for hereditary Rb. PDT could offer a vision-sparing treatment and could diminish the risk of secondary cancers because it is nonmutagenic. At this point, there have been no human trials of PDT in treatment of Rb, but animal studies have shown promise for PDT as a viable treatment option. In 1999, Jin et al. demonstrated that verteporfin causes apoptosis in the established Rb cell line, hence warranting further investigation [67]. Initial trials of PDT using a first generation photosensitizer, Photofrin, were disappointing due to significant side effects [68]. However, the PDT options available today are more specific and require less intratumoral concentration and lower doses of light exposure [69].

Stephan et al. used established Rb cell lines, an Rb subline resistant to chemotherapy, and dissociated cells from a primary Rb, for a total of 5 cell lines to test with verteporfin therapy at varying doses. They found that verteporfin concentration of 50ng/mL and energy of 100J/ cm2 allowed for irreversible killing of all cell lines. The authors felt that the effectiveness of killing warranted further preclinical studies [66].

Aerts et al. created xenograft mouse models using Rb tissue directly from enucleated samples and studied the effects on Rb caused by 2 photosensitizer agents— meta-tetrahydroxyphenylchlorin (mTHPC) 0.1mg/mL administered at 0.6mg/kg and verteporfin 0.3mg/mL and administered at 1mg/kg. All samples used from children with unilateral, non-hereditary disease. Light exposure was performed 24 hours after administration of mTHPC with 514nm Argon laser at 100mW and fluence of 75 J/cm2, and 1 hour after administration of verteporfin with 689nm diode laser at 600mW and fluence of 50 J/cm2. The authors found that PDT with mTHPC or verteporfin may be effective in treated Rb, although in 1 xenograft model the tumor regression was transient. They found that in comparing the 2 photosensitizers, different tumors may be sensitive to some photosensitizers and less sensitive to others. The authors felt there should be further preclinical investigation [69].

Choroidal metastasis: Carcinoma leading to uveal metastasis is the most common form of ocular cancer in adults. The high vascularity of the uveal tract is thought to cause its frequent association with metastatic disease, and the choroid—specifically the posterior pole—is by far the most common site within the uveal tract for metastasis [70,71]. Breast and lung carincoma account for the majority of cases, with 2% to 9% of lung and breast cancers causing clinically significant uveal metastases [71]. These tumors usually present later in the course of cancer, with an subsequent life expectancy of a median 6 to 9 months [72,73]. Patients are mostly asymptomatic, and often present with a sudden change in vision, most commonly complaining of blurred vision and sometimes scotoma or pain. The lesions may progress rapidly, cause serous retinal detachment, and may threaten the patient’s central vision. Choroidal metastases appear as flat cream-colored or pale yellow-colored lesions [71].

Treatment options include external beam radiotherapy, cytotoxic chemotherapy, hormonal therapy, biological therapy, brachytherapy, laser photocoagulation, TTT, PDT, and enucleation [71]. Management of choroidal metastatic lesions is performed primarily as a part of palliative care, that is, with the purpose of preserving vision in high stage cancer. Although there have been no large investigations into the efficacy of PDT in choroidal metastases, there have been multiple case reports supporting the use of PDT.

2 cases report successful treatment of metastatic choroidal lesions, the first case in carcinoid tumor, and the second case in lung adenocarcinoma. Harbour published the first case report in the literature to describe successful choroidal metastatic disease treatment with PDT. The patient was found to be unresponsive to the standard chemotherapy and radiation therapy for atypical carcinoid tumor metastasis, and was therefore treated with PDT due to its successes in treating other vascular tumors of the choroid. The standard PDT protocol was used. The author found that there was resolution of the exudative detachment, visual acuity improvement, and the tumor regressed substantially. Follow-up was unfortunately limited by the death of the patient. The author concluded that PDT may be a viable palliative treatment for choroidal metastatic disease [74]. Mauget-Faysse et al. utilized PDT in a patient with metastatic lung adenocarcinoma. The patient was considered for PDT due to ineligibility for additional chemotherapy, and radiotherapy was excluded because the patient had experienced post-chemotherapy retinal nerve fiber layer hemorrhage. Intravenous verteporfin at 6mg/m2 was infused for 4 minutes, then 689nm diode laser was applied at a power of 600 mW/cm2 for 166 seconds. The authors demonstrated improvement in visual acuity, regression of the tumor with decrease in neovascularization, resolution of exudates, and resolution of exudative retinal detachment. Follow-up of 6 months was achieved [75].

2 cases have been reported of successful treatment of choroidal metastatic disease due to breast carcinoma. The first such case by Soucek et al. showed stabilization of visual acuity and regression of the metastatic lesion. This patient was considered for PDT because she was not eligible for an additional course of chemotherapy, and she refused additional radiation treatment. The investigators used the standard verteporfin protocol, and administered PDT during 2 sessions due to a local recurrence of the lesion after the first session. These authors concluded that PDT was an effective palliative treatment for choroidal metastatic disease, especially taking into accounts the minimal side effects and lack of systemic toxicity of PDT in comparison to other treatments [76]. The second case by Isola et al. showed resolution of exudative macular detachment, regression of subretinal fluid, decrease in tumor vascular permeability, and improvement in visual acuity. The standard protocol for PDT was used. The authors conclude that PDT may be a strong candidate for adjunctive therapy to chemotherapy or hormonal therapy in choroidal metastatic disease [77]. Long-term follow-up was limited in both cases by the death of the patient.

Choroidal Melanoma: The choroid is by far the most common site for primary intraocular melanoma, although this disease can arise in the either the ciliary body or iris, as well. Uveal tract melanoma is much more common in white adults, with an increasing incidence with age. The average age at diagnosis is 55-60 years [78,79]. Patients may develop visual symptoms such as blurred vision, visual field defect, flashes, or floaters, typically without pain. Choroidal melanomas appear as a solid brown-to-golden dome shaped mass and may have clumps of orange lipofuscin pigment on the surface. Choroidal melanoma can present with a secondary serous retinal detachment and rarely has associated hemorrhage [79].

Current treatment options for choroidal melanoma include observation, enucleation, radiation therapy, laser therapy, TTT, cryotherapy, microsurgical resection, exenteration, chemotherapy, and multi-modal therapy [79,80]. Choroidal melanoma initially responded to PDT in animal studies [81]. Currently, PDT has been utilized in a small number of case reports and case series when other treatment modalities failed, or when current treatment regimens were not deemed effective. Barbazetto et al. studied the effect of PDT verteporfin therapy in 4 patients who had previously been treated unsuccessfully with brachytherapy and TTT. Patients were treated with standard PDT protocol except the light dose was 100 J/cm2, and the patients were followed for up to 20 months after receiving 1 treatment. 1 patient experienced cessation of tumor growth, another patient experienced tumor size reduction that remained stable at 18 months, and the final 2 patients required enucleation due to continued tumor growth. 1 subject experienced a vitreous hemorrhage and transient increase in intraocular pressure. The authors conclude that PDT saved 2 eyes from enucleation [80].

Two additional cases describe PDT use in amelanotic choroidal melanoma. While the standard of care for choroidal melanoma is plaque brachytherapy, a common side effect is radiation retinopathy and optic neuropathy. While TTT evades these adverse events, it has been shown that TTT may have poor efficacy in treating amelanotic melanoma due to poor absorption of treatment-generated heat [82]. The patient described in Donaldson et al. was found to have a small amelanotic choroidal melanoma and underwent 4 PDT treatments. Initially, standard PDT protocol was used, but limited response was observed. Therefore, in subsequent treatments a bolus dose of verteporfin was given over 1 minute, and then 166 seconds of light exposure at a dose of 100 J/cm2 was then administered. The authors noted complete regression of the lesion, resolution of subretinal fluid, and great increase in visual acuity. Follow-up at 13 months has demonstrated stable results. The authors conclude that while the results for small amelanotic melanoma are promising, there is a concern for potential external recurrence even with a normal internal retina appearance. This is a concern that is also well-known in TTT [83]. Soucek et al. also describe the successful treatment of subfoveal amelanotic choroidal melanoma with standard PDT protocol. PDT was chosen for this patient because of the subfoveal location of the lesion. With current mainstream treatment options, subfoveal locations of this lesion would have caused immediate or subsequent vision loss. The authors found full regression of the tumor, improvement in visual acuity, and no recurrence during 24 months [84].

Discussion

Although PDT is FDA approved only for CNV, it has recently enjoyed versatile application in ophthalmology. PDT has been used successfully for treatment of choroidal hemangioma, vasoproliferative tumor, capillary hemangioma, and astrocytoma. It has been applied as a palliative measure for choroidal metastasis and choroidal melanoma. Preclinical trials have shown potential success for adjunctive treatment of retinoblastoma. In fact, due to the ease of administration, a highly favorable safety profile, and a strong record for treatment effectiveness, PDT treatment with verteporfin has become the mainstay for treatment of both circumscribed and diffuse choroidal hemangiomas [15].

For most ocular tumors reviewed, however, there is still not enough data in the form of standardized protocol and controlled trials to form ultimate conclusions about the utility of PDT.

There remains some controversy in the literature about the appropriate protocol for delivery of PDT. One such discussion surrounds constant infusion versus bolus administration of verteporfin (constant administration for 10 min vs. bolus dose for 1-2 min). Michels et al. found that bolus administration of verteporfin with a light dose of 50 J/cm2 gave increased selectivity of the photodynamic effects for patients undergoing CNV treatment [37]. It was proposed that the collateral effect of PDT caused damage to the physiologic choroid, and bolus administration could help prevent this. However, Pilotto et al. recently performed a randomized trial comparing bolus versus constant infusion of verteporfin for treatment of CCH in 20 patients. They observed that while both routes of administration caused regression of the CCH, the bolus administration was associated with more RPE and retinal changes causing reduced retinal sensitivity. The constant infusion was not associated with these changes [85].

The question of what light dose per area-or fluence-is appropriate for each ocular condition is also under debate. Full fluence may be a good treatment modality for extrafoveal lesions and in patients with healthy retinal pigment epithelium (RPE). It may be safer to use lower fluence PDT for macular lesions or in case of multiple treatments, in order to prevent RPE damage.

The concept of oscillatory PDT (OPDT) was presented by Peyman et al. at the American Society of Retina Specialists in 2010 in Vancouver. They studied oscillatory PDT (OPDT) in 7 eyes with choroidal neovascularization [86]. Oscillatory PDT may be superior to the standard protocol, which can induce changes in the RPE that lead to defects in survival and function of retinal photoreceptors [87]. These RPE changes have been documented both experimentally and clinically [9,88,89,90,91,92,93,94]. In this study, verteporfin was infused using the standard protocol. A 689nm light was applied for 83 seconds (except in 1 case which was 166 second) with oscillation of the beam at 2-3 Hertz/second. Spot size of approximately one half the size of the lesion was used. The adjustment of the spot size with oscillation can make the application of the PDT in such a way as to spare more of the unaffected retina. More aggressive or elevated parts of the lesion may thus receive higher fluence and other less elevated or aggressive parts of the lesion can receive lower fluence in the same application with oscillatory therapy. This makes it a more versatile modality.

One notion especially important to consider in the treatment of variously pigmented melanomas and choroidal metastasis is the effect of pigment on PDT. In the treatment of the lesions of varied pigmentation, clinicians should be aware that highly pigmented lesions make for a more attenuated response to the PDT, while the less pigmented lesions show a more robust response. It is likely that high concentration of pigment does not allow enough light through, or alternatively, the very lightly pigmented fundi may reflect lightly from the sclera into the eye, thereby increasing the PDT response [95].

Further consideration can also be given to the type of photosensitizing agent. Since the TAP trials established verteporfin as the FDA-approved mainstay in ocular conditions, the vast majority of clinical trials and case studies have utilized verteporfin. However, there are a multitude of other photosensitizing agents available, many of which have not been studied extensively for ocular treatment. One potential weakly photosensitizing agent that has been used with 810 nm diode laser in transpupillary therotherapy is indocyanine green (ICG) dye. The utilization of ICG in TTT has allowed for an enhanced laser photocoagulation effect, and has permitted lower fluence use in TTT, thereby inducing less damage to surrounding tissues [96]. ICG’s use in this manner has been termed ICG-mediated photodynamic therapy. Costa et al. successfully used the weak photodynamic effects of ICG in TTT to treat CNV in 2 patients [97]. Peyman et al. recently demonstrated successful treatment of recalcitrant CNV by using 810 nm laser in oscillatory thermotherapy mode, augmented with ICG infusion at 1mg/kg and intravitreal bevacizumab with dexamethasone. They observed regression of CNV, and proposed that ICG augmented TTT utilizes both photodynamic therapy and thermal therapy for an amplified effect in treatment of choroidal neovascular lesions [96].

PDT has proven a successful, and sometimes superior, treatment modality for choroidal hemangioma, vasoproliferative tumor, capillary hemangioma, astrocytoma, choroidal metastasis, and choroidal melanoma, with potential application in retinoblastoma. Further research is needed to further define the role of PDT in these conditions.

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