Are the submacular surgery trials still relevant in an era of photodynamic therapy?
2001; Elsevier BV; Volume: 108; Issue: 3 Linguagem: Inglês
10.1016/s0161-6420(00)00666-7
ISSN1549-4713
AutoresNeil M. Bressler, Barbara S. Hawkins, Paul Steinberg, H. Richard McDonald,
Tópico(s)Retinal Imaging and Analysis
ResumoThe Submacular Surgery Trials (SST) include three randomized clinical trials to determine whether submacular surgery more often stabilizes or improves vision compared to observation in selected cases of subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), the ocular histoplasmosis syndrome, or idiopathic causes.1Bressler N.M. Submacular surgery. Are randomized trials necessary?.Arch Ophthalmol. 1995; 113 ([editorial]): 1557-1560Crossref PubMed Scopus (50) Google ScholarThe SST investigators, along with investigators in any randomized clinical trial, must be aware of and prepared to respond to relevant external events that may affect the design or conduct of these trials. One such external event relevant to the SST concerns results published by the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group.2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar, 3Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials – TAP Report 2. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol (in press).Google ScholarIn October 1999 this group reported that in a randomized clinical trial, photodynamic therapy (PDT) with verteporfin reduced the risk of moderate and severe visual acuity loss one year after enrollment in a predefined group of over 200 patients with subfoveal CNV due to AMD in which the composition of the lesion was predominantly classic CNV on fluorescein angiography (area of classic CNV at least 50% area of entire lesion).2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar Furthermore, a second randomized clinical trial showed that PDT with verteporfin increased the chance of stable or improved visual acuity in 120 patients enrolled with subfoveal CNV due to pathologic myopia.4Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin: one-year results of a randomized clinical trial – VIP Report 1. Verteporfin with Photodynamic Therapy (VIP) Study Group. Ophthalmology (in press).Google ScholarOphthalmologists who manage patients in the SST, refer patients to the SST, or enroll patients in the SST, and patients already enrolled in the SST or considering enrolling in the SST, may question whether the SST remains relevant in an era in which photodynamic therapy has been proven effective for treating selected cases of CNV. In response to this question, the SST Data and Safety Monitoring Committee (DSMC), after reviewing published information on verteporfin therapy,2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar submacular surgery, and unpublished data available from the completed SST Pilot Study and the on-going SST clinical trials, made their recommendations, summarized below, to the SST Executive Committee responsible for the scientific conduct of the SST. The Executive Committee endorsed these recommendations which have been implemented with the full support of the SST Research Group.SST Group H Protocol. The DSMC recommended that the on-going SST continue, and that there be no change to the protocol for eligible patients with CNV associated with the ocular histoplasmosis syndrome (OHS) or idiopathic causes. Photodynamic therapy with verteporfin has not been shown to be beneficial in eyes with neovascular lesions attributed to OHS or to idiopathic causes. The SST investigators have concluded that published findings from the TAP investigation are not applicable to patients participating in or eligible to be enrolled in the SST Group H Protocol. The natural course of subfoveal CNV associated with OHS or idiopathic causes is not as deleterious to vision as subfoveal lesions which are predominantly classic CNV in AMD and may differ from the natural course of subfoveal neovascular lesions due to pathologic myopia. The SST investigators believe that only if data in patients with subfoveal CNV due to OHS or idiopathic causes become available from randomized clinical trials that demonstrate better outcomes in patients receiving PDT with verteporfin (or any other therapy) compared to observation, should that therapy, and not observation, be the comparison arm in evaluations of submacular surgery or future promising treatments. The SST investigators believe that if PDT with verteporfin (or any other therapy) and submacular surgery (or another management approach) are shown to be better than observation in separate randomized clinical trials, then trials to compare the two therapies directly should be considered, taking account of the cost-effectiveness of each treatment arm and the cost of conducting such trials which necessarily would be large. Presently the SST Research Group is continuing the clinical trial to compare submacular surgery with observation for cases eligible to enroll into the SST Group H Protocol. Ophthalmologists who see such patients are encouraged to inform them about the SST and the possibility of participation at one of over 20 centers in the United States.5Submacular Surgery Trials (SST). Bethesda, MD: NIH, National Eye Institute, 1997. [cited Dec. 11, 2000]. Available from URL: http://www.nei.nih.gov/neitrials_script/studydtl.asp?id=52.Google ScholarSST Group B Protocol. The DSMC recommended continued enrollment of eligible patients with subfoveal lesions in the SST Group B Protocol. Eligible patients have AMD and subfoveal lesions that are predominantly blood, (i.e., the area of blood occupies at least 50% of the area of the entire subfoveal lesion). Patients in Group B are assigned randomly to submacular surgery or to observation without treatment. Photodynamic therapy clinical trials have not included lesions that were predominantly blood because it is unlikely that the laser light used to activate the drug to cause a photodynamic effect can penetrate typical amounts of blood present in cases eligible for the Group B Protocol. The SST Research Group is continuing the clinical trial to compare submacular surgery to observation for cases eligible to enroll in the SST Group B Protocol. The SST Protocol always has recommended laser photocoagulation of a neovascular lesion that would benefit from such treatment whenever such a lesion is identified by the ophthalmologist as the blood clears. A modification has been implemented that recommends either PDT or laser photocoagulation, with the choice depending upon the lesion composition and the preferences of the patient and ophthalmologist, whenever a lesion is identified that might benefit from either or both treatments as the blood clears. Ophthalmologists who see patients who are potentially eligible for the SST Group B Protocol are encouraged to inform them about the SST and the possibility of participation and to refer those who are interested to an SST center5Submacular Surgery Trials (SST). Bethesda, MD: NIH, National Eye Institute, 1997. [cited Dec. 11, 2000]. Available from URL: http://www.nei.nih.gov/neitrials_script/studydtl.asp?id=52.Google Scholar.SST Group N Protocol. The DSMC recommended continued enrollment of patients with AMD who have subfoveal lesions that have some classic CNV but are not predominantly classic CNV. Such patients experienced no visual acuity benefit with verteporfin therapy compared to observation. If such patients are eligible for the Group N Protocol, they are assigned randomly to submacular surgery or observation. With respect to patients eligible for the Group N Protocol who have predominantly classic lesions, for which PDT has been shown to reduce the risk of moderate and severe vision loss for at least 2 years, the DSMC recommended, and the SST investigators have adopted, a policy of informing all such patients about PDT with verteporfin. Each patient then decides whether to elect PDT or enroll in the SST. Evaluation of submacular surgery for these lesions in comparison to observation continues in the SST. Reasons as to why a patient with a subfoveal lesion from AMD that is predominantly classic might want to enroll in the SST include, for example, a severe adverse event following verteporfin therapy in the first affected eye such that the patient refuses to consider verteporfin therapy when a predominantly classic lesion develops in the second eye, and the hope that a single surgical procedure will reduce the need for retreatment of recurrent CNV.With respect to patients already enrolled or those yet to be enrolled in the SST Group N Protocol whose eyes have not been treated, photodynamic therapy with verteporfin is recommended whenever the ophthalmologist notes that a subfoveal lesion has become predominantly classic CNV and meets other criteria for which PDT with verteporfin has been shown to be beneficial. However, caution is advised when considering PDT with verteporfin for an otherwise eligible lesion that arises after surgery as this treatment may not be effective after submacular surgery. Thus, patients participating in the SST can expect to receive appropriate treatment for either the study eye or the fellow eye or both whenever a treatment has been demonstrated to be beneficial in well-designed and well-conducted clinical trials, regardless of the random assignment in the SST.Relevance of SST in Era of Photodynamic Therapy. Publication of findings from the TAP investigation that demonstrate the benefits of photodynamic therapy with verteporfin for selected patients with subfoveal CNV from AMD provide an example of how clinical trial investigators and Data and Safety Monitoring Committee members may respond to external events relevant to a particular clinical trial. The SST Research Group believes the SST continues to be relevant because the benefits of verteporfin therapy have not been demonstrated for the majority of patients eligible for the SST, namely, those eligible for the Group H and Group B protocols and those eligible for the Group N protocol who have less than 50% of the subfoveal lesion composed of classic CNV. In addition, some patients may elect to participate in the SST despite the expected benefit from PDT when eligible for both.As a word of caution, the benefits of photodynamic therapy with verteporfin in selected cases of subfoveal CNV should not lead to an instant acceptance of some or all new therapies under investigation for CNV. Recently, there has been a plethora of new ideas for treating CNV, including, for example, macular translocation, antiangiogenesis therapies, transpupillary thermotherapy, rheotherapy, and other drugs for photodynamic therapy. However, given the variable natural course of CNV on vision, positive outcomes from well-designed randomized clinical trials are needed to give ophthalmologists critical information to decide which, if any, of these therapies should be incorporated into the standard management of these cases. If physicians make treatment decisions based only on “public opinion” or capricious claims without strong scientific backing, improvements in clinical care may not progress as rapidly as they will if interventions are made following proof that those interventions are beneficial, usually from well-designed randomized clinical trials.Ophthalmologists are fortunate that the National Eye Institute, part of the National Institutes of Health, sponsors the SST and many other randomized clinical trials.6Fine S.L. Clinical trials and the practice of ophthalmology.Arch Ophthalmol. 1984; 102: 1282-1285Crossref PubMed Scopus (11) Google Scholar, 7Fine S.L. Maguire M.G. We are very spoiled.Arch Ophthalmol. 1997; 115 ([editorial]): 915-916Crossref PubMed Scopus (2) Google Scholar Such sponsorship affords ophthalmologists the opportunity to offer to their patients, who are eligible and willing to participate, a way to receive state-of-the-art ophthalmic care as well as to contribute directly to advancing knowledge on how to best treat their disease. The SST will provide scientific evidence on which to base a decision about adding submacular surgery to the current treatment armamentarium for selected subfoveal neovascular lesions. Continued referral of patients to the SST will provide the answer in the most expeditious and scientifically sound manner. The Submacular Surgery Trials (SST) include three randomized clinical trials to determine whether submacular surgery more often stabilizes or improves vision compared to observation in selected cases of subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD), the ocular histoplasmosis syndrome, or idiopathic causes.1Bressler N.M. Submacular surgery. Are randomized trials necessary?.Arch Ophthalmol. 1995; 113 ([editorial]): 1557-1560Crossref PubMed Scopus (50) Google ScholarThe SST investigators, along with investigators in any randomized clinical trial, must be aware of and prepared to respond to relevant external events that may affect the design or conduct of these trials. One such external event relevant to the SST concerns results published by the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group.2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar, 3Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials – TAP Report 2. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol (in press).Google ScholarIn October 1999 this group reported that in a randomized clinical trial, photodynamic therapy (PDT) with verteporfin reduced the risk of moderate and severe visual acuity loss one year after enrollment in a predefined group of over 200 patients with subfoveal CNV due to AMD in which the composition of the lesion was predominantly classic CNV on fluorescein angiography (area of classic CNV at least 50% area of entire lesion).2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar Furthermore, a second randomized clinical trial showed that PDT with verteporfin increased the chance of stable or improved visual acuity in 120 patients enrolled with subfoveal CNV due to pathologic myopia.4Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin: one-year results of a randomized clinical trial – VIP Report 1. Verteporfin with Photodynamic Therapy (VIP) Study Group. Ophthalmology (in press).Google Scholar Ophthalmologists who manage patients in the SST, refer patients to the SST, or enroll patients in the SST, and patients already enrolled in the SST or considering enrolling in the SST, may question whether the SST remains relevant in an era in which photodynamic therapy has been proven effective for treating selected cases of CNV. In response to this question, the SST Data and Safety Monitoring Committee (DSMC), after reviewing published information on verteporfin therapy,2Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials – TAP Report 1. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329–45.Google Scholar submacular surgery, and unpublished data available from the completed SST Pilot Study and the on-going SST clinical trials, made their recommendations, summarized below, to the SST Executive Committee responsible for the scientific conduct of the SST. The Executive Committee endorsed these recommendations which have been implemented with the full support of the SST Research Group. SST Group H Protocol. The DSMC recommended that the on-going SST continue, and that there be no change to the protocol for eligible patients with CNV associated with the ocular histoplasmosis syndrome (OHS) or idiopathic causes. Photodynamic therapy with verteporfin has not been shown to be beneficial in eyes with neovascular lesions attributed to OHS or to idiopathic causes. The SST investigators have concluded that published findings from the TAP investigation are not applicable to patients participating in or eligible to be enrolled in the SST Group H Protocol. The natural course of subfoveal CNV associated with OHS or idiopathic causes is not as deleterious to vision as subfoveal lesions which are predominantly classic CNV in AMD and may differ from the natural course of subfoveal neovascular lesions due to pathologic myopia. The SST investigators believe that only if data in patients with subfoveal CNV due to OHS or idiopathic causes become available from randomized clinical trials that demonstrate better outcomes in patients receiving PDT with verteporfin (or any other therapy) compared to observation, should that therapy, and not observation, be the comparison arm in evaluations of submacular surgery or future promising treatments. The SST investigators believe that if PDT with verteporfin (or any other therapy) and submacular surgery (or another management approach) are shown to be better than observation in separate randomized clinical trials, then trials to compare the two therapies directly should be considered, taking account of the cost-effectiveness of each treatment arm and the cost of conducting such trials which necessarily would be large. Presently the SST Research Group is continuing the clinical trial to compare submacular surgery with observation for cases eligible to enroll into the SST Group H Protocol. Ophthalmologists who see such patients are encouraged to inform them about the SST and the possibility of participation at one of over 20 centers in the United States.5Submacular Surgery Trials (SST). Bethesda, MD: NIH, National Eye Institute, 1997. [cited Dec. 11, 2000]. Available from URL: http://www.nei.nih.gov/neitrials_script/studydtl.asp?id=52.Google Scholar SST Group B Protocol. The DSMC recommended continued enrollment of eligible patients with subfoveal lesions in the SST Group B Protocol. Eligible patients have AMD and subfoveal lesions that are predominantly blood, (i.e., the area of blood occupies at least 50% of the area of the entire subfoveal lesion). Patients in Group B are assigned randomly to submacular surgery or to observation without treatment. Photodynamic therapy clinical trials have not included lesions that were predominantly blood because it is unlikely that the laser light used to activate the drug to cause a photodynamic effect can penetrate typical amounts of blood present in cases eligible for the Group B Protocol. The SST Research Group is continuing the clinical trial to compare submacular surgery to observation for cases eligible to enroll in the SST Group B Protocol. The SST Protocol always has recommended laser photocoagulation of a neovascular lesion that would benefit from such treatment whenever such a lesion is identified by the ophthalmologist as the blood clears. A modification has been implemented that recommends either PDT or laser photocoagulation, with the choice depending upon the lesion composition and the preferences of the patient and ophthalmologist, whenever a lesion is identified that might benefit from either or both treatments as the blood clears. Ophthalmologists who see patients who are potentially eligible for the SST Group B Protocol are encouraged to inform them about the SST and the possibility of participation and to refer those who are interested to an SST center5Submacular Surgery Trials (SST). Bethesda, MD: NIH, National Eye Institute, 1997. [cited Dec. 11, 2000]. Available from URL: http://www.nei.nih.gov/neitrials_script/studydtl.asp?id=52.Google Scholar. SST Group N Protocol. The DSMC recommended continued enrollment of patients with AMD who have subfoveal lesions that have some classic CNV but are not predominantly classic CNV. Such patients experienced no visual acuity benefit with verteporfin therapy compared to observation. If such patients are eligible for the Group N Protocol, they are assigned randomly to submacular surgery or observation. With respect to patients eligible for the Group N Protocol who have predominantly classic lesions, for which PDT has been shown to reduce the risk of moderate and severe vision loss for at least 2 years, the DSMC recommended, and the SST investigators have adopted, a policy of informing all such patients about PDT with verteporfin. Each patient then decides whether to elect PDT or enroll in the SST. Evaluation of submacular surgery for these lesions in comparison to observation continues in the SST. Reasons as to why a patient with a subfoveal lesion from AMD that is predominantly classic might want to enroll in the SST include, for example, a severe adverse event following verteporfin therapy in the first affected eye such that the patient refuses to consider verteporfin therapy when a predominantly classic lesion develops in the second eye, and the hope that a single surgical procedure will reduce the need for retreatment of recurrent CNV. With respect to patients already enrolled or those yet to be enrolled in the SST Group N Protocol whose eyes have not been treated, photodynamic therapy with verteporfin is recommended whenever the ophthalmologist notes that a subfoveal lesion has become predominantly classic CNV and meets other criteria for which PDT with verteporfin has been shown to be beneficial. However, caution is advised when considering PDT with verteporfin for an otherwise eligible lesion that arises after surgery as this treatment may not be effective after submacular surgery. Thus, patients participating in the SST can expect to receive appropriate treatment for either the study eye or the fellow eye or both whenever a treatment has been demonstrated to be beneficial in well-designed and well-conducted clinical trials, regardless of the random assignment in the SST. Relevance of SST in Era of Photodynamic Therapy. Publication of findings from the TAP investigation that demonstrate the benefits of photodynamic therapy with verteporfin for selected patients with subfoveal CNV from AMD provide an example of how clinical trial investigators and Data and Safety Monitoring Committee members may respond to external events relevant to a particular clinical trial. The SST Research Group believes the SST continues to be relevant because the benefits of verteporfin therapy have not been demonstrated for the majority of patients eligible for the SST, namely, those eligible for the Group H and Group B protocols and those eligible for the Group N protocol who have less than 50% of the subfoveal lesion composed of classic CNV. In addition, some patients may elect to participate in the SST despite the expected benefit from PDT when eligible for both. As a word of caution, the benefits of photodynamic therapy with verteporfin in selected cases of subfoveal CNV should not lead to an instant acceptance of some or all new therapies under investigation for CNV. Recently, there has been a plethora of new ideas for treating CNV, including, for example, macular translocation, antiangiogenesis therapies, transpupillary thermotherapy, rheotherapy, and other drugs for photodynamic therapy. However, given the variable natural course of CNV on vision, positive outcomes from well-designed randomized clinical trials are needed to give ophthalmologists critical information to decide which, if any, of these therapies should be incorporated into the standard management of these cases. If physicians make treatment decisions based only on “public opinion” or capricious claims without strong scientific backing, improvements in clinical care may not progress as rapidly as they will if interventions are made following proof that those interventions are beneficial, usually from well-designed randomized clinical trials. Ophthalmologists are fortunate that the National Eye Institute, part of the National Institutes of Health, sponsors the SST and many other randomized clinical trials.6Fine S.L. Clinical trials and the practice of ophthalmology.Arch Ophthalmol. 1984; 102: 1282-1285Crossref PubMed Scopus (11) Google Scholar, 7Fine S.L. Maguire M.G. We are very spoiled.Arch Ophthalmol. 1997; 115 ([editorial]): 915-916Crossref PubMed Scopus (2) Google Scholar Such sponsorship affords ophthalmologists the opportunity to offer to their patients, who are eligible and willing to participate, a way to receive state-of-the-art ophthalmic care as well as to contribute directly to advancing knowledge on how to best treat their disease. The SST will provide scientific evidence on which to base a decision about adding submacular surgery to the current treatment armamentarium for selected subfoveal neovascular lesions. Continued referral of patients to the SST will provide the answer in the most expeditious and scientifically sound manner. ErrataOphthalmologyVol. 108Issue 6Preview Full-Text PDF
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