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Photodynamic therapy for age-related macular degeneration: a candid appraisal
PERSPECTIVE Photodynamic Therapy for Age-Related Macular Degeneration: A Candid Appraisal PAUL STERNBERG, Jr., MD, AND HILEL LEWIS, MD
I
N APRIL 2000, THE FOOD AND DRUG ADMINISTRATION
approved photodynamic therapy with verteporfin (Visudyne) for the treatment of predominantly classic choroidal neovascularization associated with age-related macular degeneration (AMD). Soon afterward, Visudyne became the first line of treatment for eligible cases of neovascular AMD. However, with time, the benefits of this treatment have been disappointing, leading to renewed interest in alternative, potentially more efficacious therapies. Photodynamic therapy is a concept that was first discussed in the early 1900s. Although originally conceived as an oncology treatment to occlude tumor vasculature, photodynamic therapy appeared applicable to ophthalmology, owing to the accessibility of the retina to directed light exposure. In this treatment, a photosensitizer with a specific absorbance profile is administered, followed by exposure of the photosensitizer to an appropriate wavelength of light that elevates the photosensitizer to a higher energy state creating a cascade of photochemical events. For choroidal neovascularization, verteporfin (6 mg/m2) is infused intravenously over a 10-minute period, and 5 minutes later, the lesion is exposed to a 689 nm light dose of 50 J/cm2 for 83 seconds. With this protocol, the laser excites the photosensitizer, which then is thought to generate singlet oxygen and reactive oxygen intermediates that damage cellular structures. Specifically, preclinical studies in experimental animals demonstrated that verteporfin selectively occluded experimentally induced choroidal neovascularization with minimal associated effects to surrounding normal tissues.
Accepted for publication Nov 4, 2003. From the Department of Ophthalmology and Visual Sciences (P.S.), Vanderbilt University Medical Center, Nashville, Tennessee, and the Cole Eye Institute and Division of Ophthalmology (H.L.), Cleveland Clinic Foundation, Cleveland, Ohio. Doctor Lewis was an Investigator in the TAP and VIP studies, and travel funds were provided by Novartis to attend the study meetings. Doctor Sternberg was an Investigator in the VIP, VOH, and VER studies. Neither Dr. Sternberg nor Dr. Lewis has any financial interest or any conflict of interest. Inquiries to Hilel Lewis, MD, Cole Eye Institute/i30, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; fax: (216) 445– 7654; e-mail: [email protected] 0002-9394/04/$30.00 doi:10.1016/j.ajo.2003.11.023
©
2004 BY
The clinical benefits of verteporfin were demonstrated in two large multicenter randomized clinical trials: the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study,1 and the Visudyne in Photodynamic Therapy (VIP) trial.2 Although both studies showed statistically significant efficacy for the treatment, several observations are noteworthy. Using a system of classification developed in the Macular Photocoagulation Study (MPS), investigators determined the percentage of each neovascular complex composed of classic or nonclassic (occult) leakage. Of the patients in the TAP investigation, 242 were determined to have more than 50% classic choroidal neovascularization, 306 had 50% or less classic choroidal neovascularization (minimally classic), and 61 patients who were enrolled incorrectly were found to have no classic choroidal neovascularization.1 The TAP investigation demonstrated that verteporfin reduced the risk of 3 lines of vision loss at both 12 and 24 months compared with placebo in the entire study population. However, with subgroup analysis, the benefit was limited principally to eyes with a predominantly classic pattern of leakage on fluorescein angiography. It should be noted that 70% of verteporfin-treated patients and 77% of patients randomly assigned to placebo still lost vision. (The baseline visual acuity was 20/80 for both groups, and the median visual acuity at 24 months was 20/160 for verteporfin-treated patients and 20/200 for controls.)1 The VIP trial was designed to study patients who were not included in the TAP investigation and comprised 339 AMD patients with occult and no classic choroidal neovascularization or with classic-containing lesions and good vision.2 In this group of 339 eyes, there was no statistically significant reduction in patients with moderate vision loss at month 12, but a 13% absolute reduction at month 24, which was statistically significant. It should be noted that in the VIP study for occult only choroidal neovascularization, 87% of patients treated with verteporfin continued to lose vision after 24 months. (The baseline visual acuity was 20/50 and the mean Snellen equivalent visual acuity at 24 months was 20/126 in the verteporfin group and 20/160 in the control group.)
ELSEVIER INC. ALL
RIGHTS RESERVED.
483
While verteporfin treatment reduced the chance of significant visual loss, it rarely resulted in significant improvement in visual acuity. For example, in the TAP study, 16% of verteporfin-treated patients and 10% of control patients had improvement in vision; only 6% of verteporfin-treated patients showed a 3-line improvement at 12 months. In the VIP study, only 13% of verteporfintreated patients and 5% of control patients with occultonly choroidal neovascularization had any visual improvement after 24 months.2 The TAP and VIP protocols required reevaluation of patients with fluorescein angiography at 3-month intervals, and in both trials retreatments were common. In the TAP study, verteporfin-treated patients required an average of 3.4 treatments in the first year and 2.2 treatments in the second year, for a total of 5.6 treatments over a 24-month period. After several years of experience, a number of advantages of photodynamic therapy with verteporfin have emerged. First, for a group of patients with neovascular AMD, this is the only treatment, other than the more destructive thermal laser photocoagulation, that has been proven to be superior to placebo in the treatment of subfoveal choroidal neovascularization. The treatment has minimal side effects and a very low complication rate. In addition, the treatment can be performed in the office, as compared with some investigational surgical treatments of choroidal neovascularization, such as submacular surgery and macular translocation. However, there are considerable disadvantages. Primarily, verteporfin treatment rarely leads to visual improvement. Although our patients are attracted by an intervention that is less likely to destroy foveal retina, their goal for treatment is to regain reading or driving visual function. Unfortunately, this level of acuity is rarely achieved. The high persistence/recurrence rate is also problematic: patients need to return for multiple repeat treatments, despite them not perceiving any obvious benefit. Because Medicare or private insurance often covers only a percentage of the drug and treatment charges, patients often are left with considerable personal costs, particularly in cases requiring multiple treatments and for off-label treatment of occult lesions. Verteporfin photodynamic therapy has also led to a significant change in how we manage our office practice. In addition to purchasing a special laser for the treatment, photodynamic therapy requires the ability to perform infusion therapy, similar to what is done in an oncology practice. Patient height and weight need to be measured, drug dosage must be calculated, and the proper dosage mixed and drawn into a syringe. An intravenous line must be placed, and the medication infused for 10 minutes. The office needs to employ an individual capable of starting and maintaining the infusion. In a hospital-based setting, this requires the employment of a registered nurse to comply with the regulations of the Joint Commission on Accred484
AMERICAN JOURNAL
itation of Healthcare Organizations. When the infusion is complete, the physician must activate the medication with the laser treatment. If the physician is examining or talking with a patient, he or she must be interrupted to complete the photodynamic therapy treatment. Thus, the addition of photodynamic therapy to our practice has required the purchase of a laser, infusion pump, the hiring of additional personnel, and, most importantly, forced us to compromise patient interactions to leave and perform the treatment. It is inevitable that any new treatment for a debilitating disease will be met with hope and anticipation. Understandably, many patients with AMD looked to photodynamic therapy to stop or reverse the inexorable progression of their visual decline. Verteporfin is arguably the most marketed medication in the history of retina, and some believe that the publication of the multicenter studies and the advertisement of the drug have provided physicians and the public with an unwarranted enthusiasm about this therapy. The authors of the study concluded that photodynamic therapy with verteporfin provided a visual acuity “benefit” for subfoveal lesions that were predominantly classic.1 However, “benefit” in the context of the study was less loss of vision rather than improvement in vision. As ophthalmologists, we have the responsibility of providing our patients with accurate information and of explaining to them that, although the treatment is better than no treatment, it rarely results in improvement in vision and that most patients continue to lose vision. We need to ask if simply reducing the magnitude of the vision loss improves the quality of life of patients with AMD. Did photodynamic therapy allow them to drive, read, or recognize faces? For patients with unilateral disease and good vision in the fellow eye, the answer is clearly no; for patients with bilateral disease, it is possible that there is some benefit, but does this “benefit” translate into improvement in their daily life activities? Although there is some evidence of improved contrast sensitivity, the TAP and VIP studies did not measure quality of life. The expectations of patients may be unreasonably high due in part to aggressive and misleading advertisement. Many of these problems of perception are not unique to photodynamic therapy or to ophthalmology. As physicians, we have to be concerned about our responsibility to patients and to the public. The TAP and VIP studies are some of the best-designed and best-conducted studies in ophthalmology. Despite this, additional guidelines are necessary to ensure that the rigorous design, review, and approval process of a multicenter clinical trial demonstrates benefits that are not only statistically significant, but also impact the quality of life of patients. After spending millions of dollars in research and development, pharmaceutical companies have an interest in bringing drugs to market. Some studies are designed to obtain approval for the drug, rather than to optimize patient benefit. OF
OPHTHALMOLOGY
MARCH 2004
There is a need for policy development to avoid the conflict of interest faced by physicians who have a financial interest or a career development interest in new medicines, therapies, or devices. There is also a need for policy development to ensure that accurate, ethical, and balanced information reaches the physicians and the public. Frequently, physicians and pharmaceutical companies highlight product “benefit” by placing less emphasis on cost effectiveness and product risk. We in ophthalmology recognize the importance of the pharmaceutical industry and its growing support of research, journals, and education. However, we must not only adhere to existing guidelines regarding professional interactions with the pharmaceutical industry, but we should establish and enforce guidelines to prevent any corruption, either real or perceived, of our standards of care and our professional reputation. We recommend that the following guidelines be considered: (1) there should be full and honest disclosure of the financial relationships between the physicians and the institutions conducting the clinical trials and the pharmaceutical industry or surgical companies, both present and anticipated (including compensation, travel and other expenses, stock options, and other benefits); (2) a committee of experts who are not employees of the pharmaceutical, surgical companies, or investigators in the study should approve the study design; (3) the FDA should require quality of life at least as a secondary outcome measure of the studies; (4) cost effectiveness should be measured and reported; (5) representatives of the pharmaceutical or surgical companies should not be members of the Writing Committee and should not influence the writing of the manuscripts; (6) ophthalmic journals should construct a “firewall” between the editorial staff who decide what content to publish and the advertising staff who solicits advertisement (implemented at THE JOURNAL); (7) the accuracy of advertisements should be monitored, and (8) participation in educational courses funded by a single company should be discouraged. If pharmaceutical or surgical companies want to sponsor programs in oph-
VOL. 137, NO. 3
thalmic education, this should be done with unrestricted grants with no participation in the design or content of the program or influence on the choice of speakers participating in the program. From our perspective, photodynamic therapy remains the best currently available, approved treatment of neovascular age-related macular degeneration. Unfortunately, it only benefits a modest subgroup of patients with overall disappointing results. There is rare improvement in vision, many patients describe a steady decline in vision, and there is often some degree of patient disappointment and dissatisfaction. In addition, the treatment has led to a significant change in the logistics of managing a busy retinal practice. As a result, there is currently considerable interest in exploring other treatments for choroidal neovascularization. As new therapies for AMD and choroidal neovascularization enter the market, it is essential that we maintain professional and scientific integrity in the conduct of clinical trials and impartiality in the reporting and interpretation of their results. Stricter guidelines regarding the roles of physicians, pharmaceutical companies, and other parties with significant interest in clinical trials may help to optimize patient benefit, minimize waste of health-care resources, and preserve the integrity of our profession.
REFERENCES 1. 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 no. 2. Arch Ophthalmol 2001;119:198 –207. 2. Verteporfin in Photodynamic Therapy (VIP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy report 2. Am J Ophthalmol 2001;131:541– 560.
PERSPECTIVE
485
I
N APRIL 2000, THE FOOD AND DRUG ADMINISTRATION
approved photodynamic therapy with verteporfin (Visudyne) for the treatment of predominantly classic choroidal neovascularization associated with age-related macular degeneration (AMD). Soon afterward, Visudyne became the first line of treatment for eligible cases of neovascular AMD. However, with time, the benefits of this treatment have been disappointing, leading to renewed interest in alternative, potentially more efficacious therapies. Photodynamic therapy is a concept that was first discussed in the early 1900s. Although originally conceived as an oncology treatment to occlude tumor vasculature, photodynamic therapy appeared applicable to ophthalmology, owing to the accessibility of the retina to directed light exposure. In this treatment, a photosensitizer with a specific absorbance profile is administered, followed by exposure of the photosensitizer to an appropriate wavelength of light that elevates the photosensitizer to a higher energy state creating a cascade of photochemical events. For choroidal neovascularization, verteporfin (6 mg/m2) is infused intravenously over a 10-minute period, and 5 minutes later, the lesion is exposed to a 689 nm light dose of 50 J/cm2 for 83 seconds. With this protocol, the laser excites the photosensitizer, which then is thought to generate singlet oxygen and reactive oxygen intermediates that damage cellular structures. Specifically, preclinical studies in experimental animals demonstrated that verteporfin selectively occluded experimentally induced choroidal neovascularization with minimal associated effects to surrounding normal tissues.
Accepted for publication Nov 4, 2003. From the Department of Ophthalmology and Visual Sciences (P.S.), Vanderbilt University Medical Center, Nashville, Tennessee, and the Cole Eye Institute and Division of Ophthalmology (H.L.), Cleveland Clinic Foundation, Cleveland, Ohio. Doctor Lewis was an Investigator in the TAP and VIP studies, and travel funds were provided by Novartis to attend the study meetings. Doctor Sternberg was an Investigator in the VIP, VOH, and VER studies. Neither Dr. Sternberg nor Dr. Lewis has any financial interest or any conflict of interest. Inquiries to Hilel Lewis, MD, Cole Eye Institute/i30, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; fax: (216) 445– 7654; e-mail: [email protected] 0002-9394/04/$30.00 doi:10.1016/j.ajo.2003.11.023
©
2004 BY
The clinical benefits of verteporfin were demonstrated in two large multicenter randomized clinical trials: the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study,1 and the Visudyne in Photodynamic Therapy (VIP) trial.2 Although both studies showed statistically significant efficacy for the treatment, several observations are noteworthy. Using a system of classification developed in the Macular Photocoagulation Study (MPS), investigators determined the percentage of each neovascular complex composed of classic or nonclassic (occult) leakage. Of the patients in the TAP investigation, 242 were determined to have more than 50% classic choroidal neovascularization, 306 had 50% or less classic choroidal neovascularization (minimally classic), and 61 patients who were enrolled incorrectly were found to have no classic choroidal neovascularization.1 The TAP investigation demonstrated that verteporfin reduced the risk of 3 lines of vision loss at both 12 and 24 months compared with placebo in the entire study population. However, with subgroup analysis, the benefit was limited principally to eyes with a predominantly classic pattern of leakage on fluorescein angiography. It should be noted that 70% of verteporfin-treated patients and 77% of patients randomly assigned to placebo still lost vision. (The baseline visual acuity was 20/80 for both groups, and the median visual acuity at 24 months was 20/160 for verteporfin-treated patients and 20/200 for controls.)1 The VIP trial was designed to study patients who were not included in the TAP investigation and comprised 339 AMD patients with occult and no classic choroidal neovascularization or with classic-containing lesions and good vision.2 In this group of 339 eyes, there was no statistically significant reduction in patients with moderate vision loss at month 12, but a 13% absolute reduction at month 24, which was statistically significant. It should be noted that in the VIP study for occult only choroidal neovascularization, 87% of patients treated with verteporfin continued to lose vision after 24 months. (The baseline visual acuity was 20/50 and the mean Snellen equivalent visual acuity at 24 months was 20/126 in the verteporfin group and 20/160 in the control group.)
ELSEVIER INC. ALL
RIGHTS RESERVED.
483
While verteporfin treatment reduced the chance of significant visual loss, it rarely resulted in significant improvement in visual acuity. For example, in the TAP study, 16% of verteporfin-treated patients and 10% of control patients had improvement in vision; only 6% of verteporfin-treated patients showed a 3-line improvement at 12 months. In the VIP study, only 13% of verteporfintreated patients and 5% of control patients with occultonly choroidal neovascularization had any visual improvement after 24 months.2 The TAP and VIP protocols required reevaluation of patients with fluorescein angiography at 3-month intervals, and in both trials retreatments were common. In the TAP study, verteporfin-treated patients required an average of 3.4 treatments in the first year and 2.2 treatments in the second year, for a total of 5.6 treatments over a 24-month period. After several years of experience, a number of advantages of photodynamic therapy with verteporfin have emerged. First, for a group of patients with neovascular AMD, this is the only treatment, other than the more destructive thermal laser photocoagulation, that has been proven to be superior to placebo in the treatment of subfoveal choroidal neovascularization. The treatment has minimal side effects and a very low complication rate. In addition, the treatment can be performed in the office, as compared with some investigational surgical treatments of choroidal neovascularization, such as submacular surgery and macular translocation. However, there are considerable disadvantages. Primarily, verteporfin treatment rarely leads to visual improvement. Although our patients are attracted by an intervention that is less likely to destroy foveal retina, their goal for treatment is to regain reading or driving visual function. Unfortunately, this level of acuity is rarely achieved. The high persistence/recurrence rate is also problematic: patients need to return for multiple repeat treatments, despite them not perceiving any obvious benefit. Because Medicare or private insurance often covers only a percentage of the drug and treatment charges, patients often are left with considerable personal costs, particularly in cases requiring multiple treatments and for off-label treatment of occult lesions. Verteporfin photodynamic therapy has also led to a significant change in how we manage our office practice. In addition to purchasing a special laser for the treatment, photodynamic therapy requires the ability to perform infusion therapy, similar to what is done in an oncology practice. Patient height and weight need to be measured, drug dosage must be calculated, and the proper dosage mixed and drawn into a syringe. An intravenous line must be placed, and the medication infused for 10 minutes. The office needs to employ an individual capable of starting and maintaining the infusion. In a hospital-based setting, this requires the employment of a registered nurse to comply with the regulations of the Joint Commission on Accred484
AMERICAN JOURNAL
itation of Healthcare Organizations. When the infusion is complete, the physician must activate the medication with the laser treatment. If the physician is examining or talking with a patient, he or she must be interrupted to complete the photodynamic therapy treatment. Thus, the addition of photodynamic therapy to our practice has required the purchase of a laser, infusion pump, the hiring of additional personnel, and, most importantly, forced us to compromise patient interactions to leave and perform the treatment. It is inevitable that any new treatment for a debilitating disease will be met with hope and anticipation. Understandably, many patients with AMD looked to photodynamic therapy to stop or reverse the inexorable progression of their visual decline. Verteporfin is arguably the most marketed medication in the history of retina, and some believe that the publication of the multicenter studies and the advertisement of the drug have provided physicians and the public with an unwarranted enthusiasm about this therapy. The authors of the study concluded that photodynamic therapy with verteporfin provided a visual acuity “benefit” for subfoveal lesions that were predominantly classic.1 However, “benefit” in the context of the study was less loss of vision rather than improvement in vision. As ophthalmologists, we have the responsibility of providing our patients with accurate information and of explaining to them that, although the treatment is better than no treatment, it rarely results in improvement in vision and that most patients continue to lose vision. We need to ask if simply reducing the magnitude of the vision loss improves the quality of life of patients with AMD. Did photodynamic therapy allow them to drive, read, or recognize faces? For patients with unilateral disease and good vision in the fellow eye, the answer is clearly no; for patients with bilateral disease, it is possible that there is some benefit, but does this “benefit” translate into improvement in their daily life activities? Although there is some evidence of improved contrast sensitivity, the TAP and VIP studies did not measure quality of life. The expectations of patients may be unreasonably high due in part to aggressive and misleading advertisement. Many of these problems of perception are not unique to photodynamic therapy or to ophthalmology. As physicians, we have to be concerned about our responsibility to patients and to the public. The TAP and VIP studies are some of the best-designed and best-conducted studies in ophthalmology. Despite this, additional guidelines are necessary to ensure that the rigorous design, review, and approval process of a multicenter clinical trial demonstrates benefits that are not only statistically significant, but also impact the quality of life of patients. After spending millions of dollars in research and development, pharmaceutical companies have an interest in bringing drugs to market. Some studies are designed to obtain approval for the drug, rather than to optimize patient benefit. OF
OPHTHALMOLOGY
MARCH 2004
There is a need for policy development to avoid the conflict of interest faced by physicians who have a financial interest or a career development interest in new medicines, therapies, or devices. There is also a need for policy development to ensure that accurate, ethical, and balanced information reaches the physicians and the public. Frequently, physicians and pharmaceutical companies highlight product “benefit” by placing less emphasis on cost effectiveness and product risk. We in ophthalmology recognize the importance of the pharmaceutical industry and its growing support of research, journals, and education. However, we must not only adhere to existing guidelines regarding professional interactions with the pharmaceutical industry, but we should establish and enforce guidelines to prevent any corruption, either real or perceived, of our standards of care and our professional reputation. We recommend that the following guidelines be considered: (1) there should be full and honest disclosure of the financial relationships between the physicians and the institutions conducting the clinical trials and the pharmaceutical industry or surgical companies, both present and anticipated (including compensation, travel and other expenses, stock options, and other benefits); (2) a committee of experts who are not employees of the pharmaceutical, surgical companies, or investigators in the study should approve the study design; (3) the FDA should require quality of life at least as a secondary outcome measure of the studies; (4) cost effectiveness should be measured and reported; (5) representatives of the pharmaceutical or surgical companies should not be members of the Writing Committee and should not influence the writing of the manuscripts; (6) ophthalmic journals should construct a “firewall” between the editorial staff who decide what content to publish and the advertising staff who solicits advertisement (implemented at THE JOURNAL); (7) the accuracy of advertisements should be monitored, and (8) participation in educational courses funded by a single company should be discouraged. If pharmaceutical or surgical companies want to sponsor programs in oph-
VOL. 137, NO. 3
thalmic education, this should be done with unrestricted grants with no participation in the design or content of the program or influence on the choice of speakers participating in the program. From our perspective, photodynamic therapy remains the best currently available, approved treatment of neovascular age-related macular degeneration. Unfortunately, it only benefits a modest subgroup of patients with overall disappointing results. There is rare improvement in vision, many patients describe a steady decline in vision, and there is often some degree of patient disappointment and dissatisfaction. In addition, the treatment has led to a significant change in the logistics of managing a busy retinal practice. As a result, there is currently considerable interest in exploring other treatments for choroidal neovascularization. As new therapies for AMD and choroidal neovascularization enter the market, it is essential that we maintain professional and scientific integrity in the conduct of clinical trials and impartiality in the reporting and interpretation of their results. Stricter guidelines regarding the roles of physicians, pharmaceutical companies, and other parties with significant interest in clinical trials may help to optimize patient benefit, minimize waste of health-care resources, and preserve the integrity of our profession.
REFERENCES 1. 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 no. 2. Arch Ophthalmol 2001;119:198 –207. 2. Verteporfin in Photodynamic Therapy (VIP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy report 2. Am J Ophthalmol 2001;131:541– 560.
PERSPECTIVE
485