- Email: [email protected]
Update in retina: photodynamic therapy for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration
ANNUAL REVIEW
Update in retina: photodynamic therapy for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration Sanjay Sharma, MD, FRCSC, MSc(Epid) ge-related macular degeneration (AMD) is the leading cause of blindness in patients over the age of 50 years in the United States. The Beaver Dam Eye Study, 1 the Rotterdam study 2 and the Blue Mountains Eye Study 3 are well-designed population-based studies that provide accurate estimates of the prevalence of AMD in the general population. They indicate that 0.1% to 0.42% of the population aged 55 to 64 years have "wet" AMD, as do 7.4% to 12.2% of those over the age of 85 years. There are no population-based studies of the prevalence of AMD in Canada. If we use weighted prevalence figures from these three studies, stratified by age, we can estimate that currently there are more than 100 000 Canadians with the wet form of AMD. By 2026 there will be over 300 000 people with wet AMD in this country. The quality of life of patients with AMD is dramatically reduced because of the visual loss that is associated with this condition. Using the time trade-off technique to measure patient-based utilities, my colleagues and I recently were able to determine that, on average, patients with AMD were willing to trade 30% of their remaining years of life to obtain 6/6 vision in their better-seeing eye. 4 Those with legal blindness had a reduction in quality of life of 60%.
A
THERMAL LASER PHOTOCOAGULATION
The Macular Photocoagulation Study (MPS), a multicentre randomized clinical trial, showed that thermal laser photocoagulation was of benefit for patients with extrafoveal, juxtafoveal and subfoveal choroidal neo-
Reprint requests to: Dr. Sanjay Sharma, Director, Cost-Effective Ocular Health Policy Unit, Hotel Dieu Hospital, 224B-166 Brock St., Kingston ON K7L 5G2; [email protected]
Can j Ophthalmal 200 I;36:7-1 0
Photodynamic therapy-Sharma
vascularization (CNV). 5 However, given that the MPS included only patients with "classic" CNV, in clinical practice only 1 in 10 patients with wet AMD meets the treatment criteria as defined by the study. In addition, thermal laser photocoagulation is associated with a high rate of recurrence of CNV. Furthermore, although the MPS demonstrated that thermal laser photocoagulation was beneficial for the treatment of subfoveal CNV, this treatment has not gained widespread acceptance among clinicians, as most patients lose significant vision from the laser treatment itself. PHOTODYNAMIC THERAPY WITH VERTEPORFIN
Given the limitations of thermal laser photocoagulation and the emerging public health problem of AMD, new therapies are being sought for the treatment of wet AMD. One of these treatments, photodynamic therapy with Visudyne (verteporfin) (CIBA Vision Corp., Duluth, Ga.), was recently evaluated by the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study group, who conducted two randomized clinical trials. 6 The TAP results showed that: • At 1 year, 61% of eyes that received photodynamic therapy lost fewer than 15 letters of visual acuity, compared with 46% of eyes that received placebo. • In patients with the "predominantly classic" form of CNV, 37% of eyes that received photodynamic therapy lost significant vision, compared with 61% of those that received placebo, at 1 year. • The treatment effect was even more pronounced in patients with classic CNV without any evidence of occult CNV: 23% of eyes in this subgroup that received photodynamic therapy lost significant vision, compared with 73% of those that received placebo, at 1 year. • At 2 years, in patients with predominantly classic CNV, 37% of eyes that received photodynamic
7
Photodynamic therapy-Sharma
therapy lost significant vision, compared with 69% of those that received placebo. • The average number of treatments administered in the photodynamic therapy group was 3.4 by 1 year and 5.5 by 2 years. Steps involved 1. Determining whether subfoveal CNV is predominantly classic (more than 50% of the lesion has the classic form of CNV). If a lesion is predominantly classic, its greatest linear dimension is measured. This dimension includes the areas of classic CNV, any occult CNV and any features that obscure the identification of CNV (heme or hypofluorescence not from blood, or a serous detachment of the retinal pigment epithelium). Therapy is offered for lesions that measure less than 5400 Jl in greatest linear dimension. A border of 500 11 is added so that the treatment area will have a diameter 1000 11 greater than the greatest linear dimension of the lesion. 2. Delivering the drug. Visudyne is supplied in a single-use 15-mg vial that is reconstituted with 7 mL of water for injection to give a final concentration of 2 mg/mL. This is diluted with 5% dextrose to a volume of 30 mL to be infused over 10 minutes at a dosage of 6 mg/m2 of body surface area. The patient's body surface area is calculated with the use of a nomogram that inputs his or her weight and height. 3. Treating with the laser. Fifteen minutes after the start of the infusion, the lesion is treated with a diode laser with a wavelength of 689 nm and a laser spot that is I 000 11 greater than the greatest linear dimension of the lesion. The laser used delivers 50 J/cm2 at an intensity of 600 mW/cm2 over 83 seconds.
Risks and side effects
In the TAP Study photodynamic therapy was generally well tolerated. 6 However, 13.4% of patients had injection-site-related events, 3% had photosensitivity reactions, and 2% had low back pain related to the infusion. A total of 17% of patients had visual disturbance (abnormal vision, decreased vision or visual field defect), compared with 11.6% of those who received placebo. It is generally recommended that patients limit their exposure to sunlight (and other bright lights, including tanning beds and halogen lights) for up to 48 hours after the treatment. Effect on quality of life
My colleagues and I recently performed a decision analysis to determine the effect of photodynamic therapy on a hypothetical cohort of Canadian patients presenting with predominantly classic subfoveal CNV. We estimated that the treatment would be associated with an improvement in quality of life of 10.1% compared with placebo (unpublished data, 2000). HOW GOOD A TREATMENT IS PHOTODYNAMIC THERAPY WITH VERTEPORFIN?
Efficacy is traditionally measured in terms of significant differences between treatment and placebo groups. In clinical trials significance is usually defined at a level of 0.01 (i.e., the probability of falsely accepting the alternative hypothesis is only 1 in 100). The TAP Study6 was a study with a statistically significant result. After 1 year of follow-up, photodynamic therapy with verteporfin in patients with the predominantly
Table 1-Efficacy of photodynamic therapy with verteporfin at I year6 in terms of reduction in relative and absolute ·risk and numbers needed to treat to obtain one therapeutic success*
Patient group All eligible patients Patients with predominantly classic choroidal neovascularization Patients with exclusively classic choroidal neovascularization
Relative risk reduction
Absolute risk reduction
Numbers needed to treat
0.24
0.15
6.7
0.39
0.24
4
0.68
0.50
2
*Level of significance for difference between treatment and placebo groups p < 0.00 I.
8
CAN j OPHTHALMOL-VOL 36, NO. I, 2001
Photodynamic therapy-Sharma
Table 2-Reduction in relative and absolute risk and numbers needed to treat in other ophthalmic and non-ophthalmic clinical trials
Patient group Early Treatment Diabetic Retinopathy Stud/ (with involvement of the centre) Diabetic Retinopathy Study8 Sickle cell retinopathy9 Diabetes and Complications Trial 10 Treatment of diastolic blood pressure of 90 to 109 mm Hg 11 Breast examinations plus mammography 12
classic form of subfoveal CNV was associated with a reduction in relative risk of 39%, a reduction in absolute risk of 24%, and a numbers needed to treat of 4 (meaning that four patients with subfoveal CNV secondary to AMD needed to be treated for one patient to have a therapeutic success) (Table 1). The 2-year results are even more promising: the reduction in absolute risk was 28%, and the numbers needed to treat was 3. For patients with the exclusively classic form of CNV the reduction in relative risk was 68%, the reduction in absolute risk was 50%, and the numbers needed to treat was 2. The reduction in relative and absolute risk and numbers needed to treat associated with laser treatment of other retinal conditions are shown in Table 2. The Early Treatment Diabetic Retinopathy Study? and the Diabetic Retinopathy Study, 8 both of which are regarded as extremely well designed clinical trials that demonstrated significant therapeutic efficacy, are associated with lower reductions in absolute risk and higher numbers needed to treat than the TAP Study. 6 Also included in Table 2 are the treatment of mild hypertension and breast cancer screening with mammography. In terms of numbers needed to treat, a metric that compares treatment success to the natural history, photodynamic therapy for the treatment of subfoveal CNV is one of the most effective treatments in medicine.
Relative risk reduction
Absolute risk reduction
Numbers needed to treat
0.61 0.55 0.64
0.2 0.2 0.053
5 5 19
0.71
0.068
IS
0.14
0.0078
128
0.27
0.0009
1075
Foundation, Toronto, the Jeanne Mance Foundation, Hotel Dieu Hospital, Kingston, Ont., and the Canadian Foundation for Innovation, Ottawa. REFERENCES
1. Klein R, Klein BEK, Linton KLP. Prevalence of agerelated maculopathy- the Beaver Dam Eye Study. Ophthalmology 1992;99:933-43. 2. Vingerling JR, Dielemans I, Hofman A, Grobbee D, Hijmering M, Kramer CFL, et al. The prevalence of agerelated maculopathy in the Rotterdam study. Ophthalmology 1995;102:205-10. 3. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995;102:1450-60. 4. Brown GC, Sharma S, Brown MM, Kistler J. Utilities and age related macular degeneration. Arch Ophthalmol 2000; 118:47-51. 5. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch Ophthalmol 1991; 109:1220--31. 6. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized trials - TAP report. Arch Ophthalmo/1999;117:1329-45.
7. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report no. 4. Int Ophthalmol Clin 1987;27(4):265-72. 8. Diabetic Retinopathy Study Research Group. Photocoagu-
CAN J OPHTHALMOL-VOL. 36, NO. I, 200 I
9
Photodynamic therapy-Sharrna
lation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981;88:583-600. 9. Farber MD, Jampol LE, Fox P, Moriarty BJ, Acheson RW, Rabb MF, et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle retinopathy. Arch Ophthalmol199l;109:363-7. l 0. Diabetes and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995;122: 561-8.
I0
CAN J OPHTHALMOL-VOL. 36, NO. I, 2001
11. Medical Research Council Working Party (MRC). MRC trial of treatment of mild hypertension: principal results. BMJ 1985;291:97-104. 12. Nystrom L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Ryden S, et al. Breast cancer screening with mammography: overview of Swedish randomized trials. Lancet 1993;341:973-8.
Key words: photodynamic therapy, verteporfin, efficacy, macular degeneration
Update in retina: photodynamic therapy for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration Sanjay Sharma, MD, FRCSC, MSc(Epid) ge-related macular degeneration (AMD) is the leading cause of blindness in patients over the age of 50 years in the United States. The Beaver Dam Eye Study, 1 the Rotterdam study 2 and the Blue Mountains Eye Study 3 are well-designed population-based studies that provide accurate estimates of the prevalence of AMD in the general population. They indicate that 0.1% to 0.42% of the population aged 55 to 64 years have "wet" AMD, as do 7.4% to 12.2% of those over the age of 85 years. There are no population-based studies of the prevalence of AMD in Canada. If we use weighted prevalence figures from these three studies, stratified by age, we can estimate that currently there are more than 100 000 Canadians with the wet form of AMD. By 2026 there will be over 300 000 people with wet AMD in this country. The quality of life of patients with AMD is dramatically reduced because of the visual loss that is associated with this condition. Using the time trade-off technique to measure patient-based utilities, my colleagues and I recently were able to determine that, on average, patients with AMD were willing to trade 30% of their remaining years of life to obtain 6/6 vision in their better-seeing eye. 4 Those with legal blindness had a reduction in quality of life of 60%.
A
THERMAL LASER PHOTOCOAGULATION
The Macular Photocoagulation Study (MPS), a multicentre randomized clinical trial, showed that thermal laser photocoagulation was of benefit for patients with extrafoveal, juxtafoveal and subfoveal choroidal neo-
Reprint requests to: Dr. Sanjay Sharma, Director, Cost-Effective Ocular Health Policy Unit, Hotel Dieu Hospital, 224B-166 Brock St., Kingston ON K7L 5G2; [email protected]
Can j Ophthalmal 200 I;36:7-1 0
Photodynamic therapy-Sharma
vascularization (CNV). 5 However, given that the MPS included only patients with "classic" CNV, in clinical practice only 1 in 10 patients with wet AMD meets the treatment criteria as defined by the study. In addition, thermal laser photocoagulation is associated with a high rate of recurrence of CNV. Furthermore, although the MPS demonstrated that thermal laser photocoagulation was beneficial for the treatment of subfoveal CNV, this treatment has not gained widespread acceptance among clinicians, as most patients lose significant vision from the laser treatment itself. PHOTODYNAMIC THERAPY WITH VERTEPORFIN
Given the limitations of thermal laser photocoagulation and the emerging public health problem of AMD, new therapies are being sought for the treatment of wet AMD. One of these treatments, photodynamic therapy with Visudyne (verteporfin) (CIBA Vision Corp., Duluth, Ga.), was recently evaluated by the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study group, who conducted two randomized clinical trials. 6 The TAP results showed that: • At 1 year, 61% of eyes that received photodynamic therapy lost fewer than 15 letters of visual acuity, compared with 46% of eyes that received placebo. • In patients with the "predominantly classic" form of CNV, 37% of eyes that received photodynamic therapy lost significant vision, compared with 61% of those that received placebo, at 1 year. • The treatment effect was even more pronounced in patients with classic CNV without any evidence of occult CNV: 23% of eyes in this subgroup that received photodynamic therapy lost significant vision, compared with 73% of those that received placebo, at 1 year. • At 2 years, in patients with predominantly classic CNV, 37% of eyes that received photodynamic
7
Photodynamic therapy-Sharma
therapy lost significant vision, compared with 69% of those that received placebo. • The average number of treatments administered in the photodynamic therapy group was 3.4 by 1 year and 5.5 by 2 years. Steps involved 1. Determining whether subfoveal CNV is predominantly classic (more than 50% of the lesion has the classic form of CNV). If a lesion is predominantly classic, its greatest linear dimension is measured. This dimension includes the areas of classic CNV, any occult CNV and any features that obscure the identification of CNV (heme or hypofluorescence not from blood, or a serous detachment of the retinal pigment epithelium). Therapy is offered for lesions that measure less than 5400 Jl in greatest linear dimension. A border of 500 11 is added so that the treatment area will have a diameter 1000 11 greater than the greatest linear dimension of the lesion. 2. Delivering the drug. Visudyne is supplied in a single-use 15-mg vial that is reconstituted with 7 mL of water for injection to give a final concentration of 2 mg/mL. This is diluted with 5% dextrose to a volume of 30 mL to be infused over 10 minutes at a dosage of 6 mg/m2 of body surface area. The patient's body surface area is calculated with the use of a nomogram that inputs his or her weight and height. 3. Treating with the laser. Fifteen minutes after the start of the infusion, the lesion is treated with a diode laser with a wavelength of 689 nm and a laser spot that is I 000 11 greater than the greatest linear dimension of the lesion. The laser used delivers 50 J/cm2 at an intensity of 600 mW/cm2 over 83 seconds.
Risks and side effects
In the TAP Study photodynamic therapy was generally well tolerated. 6 However, 13.4% of patients had injection-site-related events, 3% had photosensitivity reactions, and 2% had low back pain related to the infusion. A total of 17% of patients had visual disturbance (abnormal vision, decreased vision or visual field defect), compared with 11.6% of those who received placebo. It is generally recommended that patients limit their exposure to sunlight (and other bright lights, including tanning beds and halogen lights) for up to 48 hours after the treatment. Effect on quality of life
My colleagues and I recently performed a decision analysis to determine the effect of photodynamic therapy on a hypothetical cohort of Canadian patients presenting with predominantly classic subfoveal CNV. We estimated that the treatment would be associated with an improvement in quality of life of 10.1% compared with placebo (unpublished data, 2000). HOW GOOD A TREATMENT IS PHOTODYNAMIC THERAPY WITH VERTEPORFIN?
Efficacy is traditionally measured in terms of significant differences between treatment and placebo groups. In clinical trials significance is usually defined at a level of 0.01 (i.e., the probability of falsely accepting the alternative hypothesis is only 1 in 100). The TAP Study6 was a study with a statistically significant result. After 1 year of follow-up, photodynamic therapy with verteporfin in patients with the predominantly
Table 1-Efficacy of photodynamic therapy with verteporfin at I year6 in terms of reduction in relative and absolute ·risk and numbers needed to treat to obtain one therapeutic success*
Patient group All eligible patients Patients with predominantly classic choroidal neovascularization Patients with exclusively classic choroidal neovascularization
Relative risk reduction
Absolute risk reduction
Numbers needed to treat
0.24
0.15
6.7
0.39
0.24
4
0.68
0.50
2
*Level of significance for difference between treatment and placebo groups p < 0.00 I.
8
CAN j OPHTHALMOL-VOL 36, NO. I, 2001
Photodynamic therapy-Sharma
Table 2-Reduction in relative and absolute risk and numbers needed to treat in other ophthalmic and non-ophthalmic clinical trials
Patient group Early Treatment Diabetic Retinopathy Stud/ (with involvement of the centre) Diabetic Retinopathy Study8 Sickle cell retinopathy9 Diabetes and Complications Trial 10 Treatment of diastolic blood pressure of 90 to 109 mm Hg 11 Breast examinations plus mammography 12
classic form of subfoveal CNV was associated with a reduction in relative risk of 39%, a reduction in absolute risk of 24%, and a numbers needed to treat of 4 (meaning that four patients with subfoveal CNV secondary to AMD needed to be treated for one patient to have a therapeutic success) (Table 1). The 2-year results are even more promising: the reduction in absolute risk was 28%, and the numbers needed to treat was 3. For patients with the exclusively classic form of CNV the reduction in relative risk was 68%, the reduction in absolute risk was 50%, and the numbers needed to treat was 2. The reduction in relative and absolute risk and numbers needed to treat associated with laser treatment of other retinal conditions are shown in Table 2. The Early Treatment Diabetic Retinopathy Study? and the Diabetic Retinopathy Study, 8 both of which are regarded as extremely well designed clinical trials that demonstrated significant therapeutic efficacy, are associated with lower reductions in absolute risk and higher numbers needed to treat than the TAP Study. 6 Also included in Table 2 are the treatment of mild hypertension and breast cancer screening with mammography. In terms of numbers needed to treat, a metric that compares treatment success to the natural history, photodynamic therapy for the treatment of subfoveal CNV is one of the most effective treatments in medicine.
Relative risk reduction
Absolute risk reduction
Numbers needed to treat
0.61 0.55 0.64
0.2 0.2 0.053
5 5 19
0.71
0.068
IS
0.14
0.0078
128
0.27
0.0009
1075
Foundation, Toronto, the Jeanne Mance Foundation, Hotel Dieu Hospital, Kingston, Ont., and the Canadian Foundation for Innovation, Ottawa. REFERENCES
1. Klein R, Klein BEK, Linton KLP. Prevalence of agerelated maculopathy- the Beaver Dam Eye Study. Ophthalmology 1992;99:933-43. 2. Vingerling JR, Dielemans I, Hofman A, Grobbee D, Hijmering M, Kramer CFL, et al. The prevalence of agerelated maculopathy in the Rotterdam study. Ophthalmology 1995;102:205-10. 3. Mitchell P, Smith W, Attebo K, Wang JJ. Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995;102:1450-60. 4. Brown GC, Sharma S, Brown MM, Kistler J. Utilities and age related macular degeneration. Arch Ophthalmol 2000; 118:47-51. 5. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: five-year results from randomized clinical trials. Arch Ophthalmol 1991; 109:1220--31. 6. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized trials - TAP report. Arch Ophthalmo/1999;117:1329-45.
7. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report no. 4. Int Ophthalmol Clin 1987;27(4):265-72. 8. Diabetic Retinopathy Study Research Group. Photocoagu-
CAN J OPHTHALMOL-VOL. 36, NO. I, 200 I
9
Photodynamic therapy-Sharrna
lation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981;88:583-600. 9. Farber MD, Jampol LE, Fox P, Moriarty BJ, Acheson RW, Rabb MF, et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle retinopathy. Arch Ophthalmol199l;109:363-7. l 0. Diabetes and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 1995;122: 561-8.
I0
CAN J OPHTHALMOL-VOL. 36, NO. I, 2001
11. Medical Research Council Working Party (MRC). MRC trial of treatment of mild hypertension: principal results. BMJ 1985;291:97-104. 12. Nystrom L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Ryden S, et al. Breast cancer screening with mammography: overview of Swedish randomized trials. Lancet 1993;341:973-8.
Key words: photodynamic therapy, verteporfin, efficacy, macular degeneration