A Very Effective Treatment for Neovascular Macular Degeneration
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《新英格兰医药杂志》
Age-related macular degeneration, a potentially blinding disease, is now epidemic in the developed world. Roughly one in three people will be affected to some degree by the age of 75 years.1 Medicine's tremendous successes in the battles against cancer, diabetes, hypertension, heart disease, and other common killers have raised the average life expectancy in many countries to more than 75 years and in so doing have inadvertently delivered a new scourge to mankind.
In this issue of the Journal, de Jong2 discusses age-related macular degeneration as a complex disorder that begins decades before a patient becomes symptomatic, a molecular derangement in or near Bruch's membrane — the multilaminar sandwich of extracellular matrix that lies between the retinal pigment epithelium and the anastomotic blood supply of the outer retina, known as the choriocapillaris. In perhaps 10% of patients with the condition, this derangement eventually leads to the growth of new blood vessels from the choriocapillaris through Bruch's membrane and into the subretinal pigment epithelial or subretinal space. This neovascular complication can be so damaging to the structure and function of the retina that even though it occurs in only a small subgroup of patients with age-related macular degeneration, it is responsible for the vast majority of cases of legal blindness attributable to this disease (Figure 1).3
Figure 1. Photograph of the Left Eye of a 93-Year-Old Man with Age-Related Macular Degeneration.
A subfoveal choroidal neovascular membrane has bled into the subretinal pigment epithelial and subretinal spaces. The visual acuity is 20/300.
An effective treatment for choroidal neovascularization has been sought for more than two decades. In the 1980s, the Macular Photocoagulation Study showed that photocoagulation with a thermal laser was often better than no treatment, especially when the neovascular complex was well-defined and spared the center of the retina.4 Unfortunately, choroidal neovascularization is usually ill-defined and subfoveal when first discovered, which limits the number of people who can be successfully treated with this approach. More recently, a photosensitizing drug was coupled with a low-power laser treatment in an effort to spare the overlying retina and to permit the treatment of subfoveal lesions without an immediate iatrogenic loss of vision.5 Although this photodynamic therapy was clearly an advance, few patients have an improvement in vision with this treatment alone, and many patients continue to have a progressive loss of vision, albeit at a somewhat reduced rate.
In the early 1970s, Folkman put forth the notion that the growth of cancer cells depended on blood-vessel growth and that control of vascular growth might prove to be an effective cancer therapy.6 Later, vascular endothelial growth factor (VEGF) emerged as an important molecule in the angiogenic process7 and, hence, as a major therapeutic target. Several drugs have now been designed that inhibit the action of VEGF. Two of these agents, ranibizumab and bevacizumab, are recombinant monoclonal antibodies directed against the VEGF protein. The primary molecular difference between these two drugs is their molecular weight: ranibizumab is a 48-kD Fab fragment, whereas bevacizumab is a complete 149-kD antibody. The difference in molecular weight could result in differing abilities of the drugs to reach their site of action (smaller may be better) and to stay in the eye after injection (larger may be better).8
Bevacizumab was approved by the Food and Drug Administration (FDA) as a treatment for metastatic colon cancer in 2004, and ranibizumab was FDA-approved for treatment of choroidal neovascularization this past June. Before the approval and release of ranibizumab, some physicians used bevacizumab in an off-label manner as a treatment for choroidal neovascularization. Three uncontrolled, retrospective studies with limited follow-up9,10,11 and one small, prospective study12 of such off-label use suggested that bevacizumab was reasonably safe and fairly effective for the treatment of choroidal neovascularization. Some physicians still use this drug because its cost is dramatically lower than that of ranibizumab.13
This issue of the Journal also contains the results of two large, randomized, prospective clinical trials investigating the efficacy of ranibizumab in patients with choroidal neovascularization secondary to age-related macular degeneration. Rosenfeld et al.14 studied 716 patients affected with minimally classic or occult choroidal neovascularization and evaluated two different doses of the drug, given at monthly intervals over a period of 2 years, as compared with sham injection. Brown et al.15 studied 423 patients with predominantly classic choroidal neovascularization and evaluated two different doses of ranibizumab, as compared with photodynamic therapy. Rosenfeld et al. showed that over the 2-year course of the study, the average patient receiving ranibizumab gained more than one line of visual acuity on a standardized eye chart, whereas the average patient receiving sham injections lost more than two lines. In a similar result, Brown et al. found that the average patient receiving ranibizumab gained about two lines of acuity at 1 year, whereas the average patient receiving photodynamic therapy lost about two lines. In both studies, the most feared complication of the treatment, bacterial infection inside the eye, occurred in 1 of every 2000 injections.
For any physician who has ever intentionally destroyed the fovea of a patient with a krypton laser in an attempt to limit the eventual size of a macular scar, the efficacy of ranibizumab in these two studies14,15 and of bevacizumab in several previous ones9,10,11,12 is miraculous. However, as with most exciting results, there remain questions that merit further investigation. A large and growing body of anecdotal experience and at least four clinical studies (which were admittedly uncontrolled and short-term)9,10,11,12 suggest that bevacizumab is an effective treatment for choroidal neovascularization. These reports, coupled with the fact that the cost of this drug is less than 1/10 that of ranibizumab, suggest that a head-to-head comparison of the two drugs is warranted.
The same anecdotal and retrospective data also suggest that many patients with choroidal neovascularization could be effectively treated with fewer than the 24 monthly injections evaluated by Rosenfeld et al.14 For example, a physician might administer three or more injections to gain control of the choroidal neovascularization and then follow the patient with frequent clinical examinations and optical coherence tomography to determine whether and, if so, when additional injections are needed. A prospective clinical trial of such a strategy — using ranibizumab, bevacizumab, or both — would be of great benefit to the medical community.
Finally, the notion of combining anti-VEGF medications with photodynamic therapy, intravitreal triamcinolone, and other treatments is already being explored by a number of investigators. However, if one includes variations in timing, sequence, and dose, the myriad possible combinations of these interventions could easily become more confusing than helpful to physicians who are trying to do what is best for their patients. A head-to-head study of ranibizumab and bevacizumab and a careful evaluation of an "induction and follow-up" strategy with either drug are probably the next most useful steps in this field.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Carver Family Center for Macular Degeneration, Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City.
References
Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933-943.
de Jong PTVM. Age-related macular degeneration. N Engl J Med 2006;355:1474-1485.
Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182-191.
Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three-year results from randomized clinical trials. Arch Ophthalmol 1986;104:694-701.
Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials -- TAP Report 2. Arch Ophthalmol 2001;119:198-207.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306-1309.
Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;27:536-544.
Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383-390.
Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.
Avery R, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363-372.
Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1-9.
Rosenfeld PJ. Intravitreal Avastin: the low cost alternative to lucentis? Am J Ophthalmol 2006;142:141-143.
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444.(Edwin M. Stone, M.D., Ph.)
In this issue of the Journal, de Jong2 discusses age-related macular degeneration as a complex disorder that begins decades before a patient becomes symptomatic, a molecular derangement in or near Bruch's membrane — the multilaminar sandwich of extracellular matrix that lies between the retinal pigment epithelium and the anastomotic blood supply of the outer retina, known as the choriocapillaris. In perhaps 10% of patients with the condition, this derangement eventually leads to the growth of new blood vessels from the choriocapillaris through Bruch's membrane and into the subretinal pigment epithelial or subretinal space. This neovascular complication can be so damaging to the structure and function of the retina that even though it occurs in only a small subgroup of patients with age-related macular degeneration, it is responsible for the vast majority of cases of legal blindness attributable to this disease (Figure 1).3
Figure 1. Photograph of the Left Eye of a 93-Year-Old Man with Age-Related Macular Degeneration.
A subfoveal choroidal neovascular membrane has bled into the subretinal pigment epithelial and subretinal spaces. The visual acuity is 20/300.
An effective treatment for choroidal neovascularization has been sought for more than two decades. In the 1980s, the Macular Photocoagulation Study showed that photocoagulation with a thermal laser was often better than no treatment, especially when the neovascular complex was well-defined and spared the center of the retina.4 Unfortunately, choroidal neovascularization is usually ill-defined and subfoveal when first discovered, which limits the number of people who can be successfully treated with this approach. More recently, a photosensitizing drug was coupled with a low-power laser treatment in an effort to spare the overlying retina and to permit the treatment of subfoveal lesions without an immediate iatrogenic loss of vision.5 Although this photodynamic therapy was clearly an advance, few patients have an improvement in vision with this treatment alone, and many patients continue to have a progressive loss of vision, albeit at a somewhat reduced rate.
In the early 1970s, Folkman put forth the notion that the growth of cancer cells depended on blood-vessel growth and that control of vascular growth might prove to be an effective cancer therapy.6 Later, vascular endothelial growth factor (VEGF) emerged as an important molecule in the angiogenic process7 and, hence, as a major therapeutic target. Several drugs have now been designed that inhibit the action of VEGF. Two of these agents, ranibizumab and bevacizumab, are recombinant monoclonal antibodies directed against the VEGF protein. The primary molecular difference between these two drugs is their molecular weight: ranibizumab is a 48-kD Fab fragment, whereas bevacizumab is a complete 149-kD antibody. The difference in molecular weight could result in differing abilities of the drugs to reach their site of action (smaller may be better) and to stay in the eye after injection (larger may be better).8
Bevacizumab was approved by the Food and Drug Administration (FDA) as a treatment for metastatic colon cancer in 2004, and ranibizumab was FDA-approved for treatment of choroidal neovascularization this past June. Before the approval and release of ranibizumab, some physicians used bevacizumab in an off-label manner as a treatment for choroidal neovascularization. Three uncontrolled, retrospective studies with limited follow-up9,10,11 and one small, prospective study12 of such off-label use suggested that bevacizumab was reasonably safe and fairly effective for the treatment of choroidal neovascularization. Some physicians still use this drug because its cost is dramatically lower than that of ranibizumab.13
This issue of the Journal also contains the results of two large, randomized, prospective clinical trials investigating the efficacy of ranibizumab in patients with choroidal neovascularization secondary to age-related macular degeneration. Rosenfeld et al.14 studied 716 patients affected with minimally classic or occult choroidal neovascularization and evaluated two different doses of the drug, given at monthly intervals over a period of 2 years, as compared with sham injection. Brown et al.15 studied 423 patients with predominantly classic choroidal neovascularization and evaluated two different doses of ranibizumab, as compared with photodynamic therapy. Rosenfeld et al. showed that over the 2-year course of the study, the average patient receiving ranibizumab gained more than one line of visual acuity on a standardized eye chart, whereas the average patient receiving sham injections lost more than two lines. In a similar result, Brown et al. found that the average patient receiving ranibizumab gained about two lines of acuity at 1 year, whereas the average patient receiving photodynamic therapy lost about two lines. In both studies, the most feared complication of the treatment, bacterial infection inside the eye, occurred in 1 of every 2000 injections.
For any physician who has ever intentionally destroyed the fovea of a patient with a krypton laser in an attempt to limit the eventual size of a macular scar, the efficacy of ranibizumab in these two studies14,15 and of bevacizumab in several previous ones9,10,11,12 is miraculous. However, as with most exciting results, there remain questions that merit further investigation. A large and growing body of anecdotal experience and at least four clinical studies (which were admittedly uncontrolled and short-term)9,10,11,12 suggest that bevacizumab is an effective treatment for choroidal neovascularization. These reports, coupled with the fact that the cost of this drug is less than 1/10 that of ranibizumab, suggest that a head-to-head comparison of the two drugs is warranted.
The same anecdotal and retrospective data also suggest that many patients with choroidal neovascularization could be effectively treated with fewer than the 24 monthly injections evaluated by Rosenfeld et al.14 For example, a physician might administer three or more injections to gain control of the choroidal neovascularization and then follow the patient with frequent clinical examinations and optical coherence tomography to determine whether and, if so, when additional injections are needed. A prospective clinical trial of such a strategy — using ranibizumab, bevacizumab, or both — would be of great benefit to the medical community.
Finally, the notion of combining anti-VEGF medications with photodynamic therapy, intravitreal triamcinolone, and other treatments is already being explored by a number of investigators. However, if one includes variations in timing, sequence, and dose, the myriad possible combinations of these interventions could easily become more confusing than helpful to physicians who are trying to do what is best for their patients. A head-to-head study of ranibizumab and bevacizumab and a careful evaluation of an "induction and follow-up" strategy with either drug are probably the next most useful steps in this field.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Carver Family Center for Macular Degeneration, Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City.
References
Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933-943.
de Jong PTVM. Age-related macular degeneration. N Engl J Med 2006;355:1474-1485.
Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182-191.
Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: three-year results from randomized clinical trials. Arch Ophthalmol 1986;104:694-701.
Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials -- TAP Report 2. Arch Ophthalmol 2001;119:198-207.
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306-1309.
Mordenti J, Cuthbertson RA, Ferrara N, et al. Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;27:536-544.
Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383-390.
Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495-511.
Avery R, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363-372.
Bashshur ZF, Bazarbachi A, Schakal A, Haddad ZA, El Haibi CP, Noureddin BN. Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1-9.
Rosenfeld PJ. Intravitreal Avastin: the low cost alternative to lucentis? Am J Ophthalmol 2006;142:141-143.
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-1431.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432-1444.(Edwin M. Stone, M.D., Ph.)