Triple therapy for neovascular age-related macular degeneration (verteporfin photodynamic therapy, intravitreal dexamethasone, and intravitreal bevacizumab) David Ehmann, BSc; Rau´l Garcı´a, MD ABSTRACT N RE´SUME´ Objective: Age-related macular degeneration is a multifactorial disease involving inflammation, neovascularization, and vascular leakage. As a result, a rationale exists for investigating combination treatments that target the different pathological processes involved in this disease. We propose triple therapy consisting of verteporfin photodynamic therapy (PDT), intravitreal bevacizumab, and intravitreal dexamethasone. Design: Retrospective chart review. Participants: Thirty-two eyes of 30 patients were included. None of the patients demonstrated concurrent eye pathology, and none of the patients had received previous treatment for their choroidal neovascularization. Methods: One cycle of triple therapy consisted of reduced-fluence PDT (300 mW/cm2 for 83 seconds to deliver 25 J/cm2) followed immediately by an 800 mg (0.08 mL) intravitreal dexamethasone (IVD) injection. At 1 and 7 weeks after PDT and IVD, patients received a 1.25 mg (0.05 mL) bevacizumab injection. At 13 weeks after PDT and IVD, each patient had a repeat optical coherence tomography and fluorescein angiography to assess choroidal neovascularization activity. Patients were followed for 12 months. Results: The mean number of treatment cycles was 1.4. The mean number of bevacizumab injections was 2.8. Visual acuity improved from 0.74 (SD 0.33) logMAR (20/100) to 0.53 (SD 0.32) logMAR (20/70) (p , 0.005). Foveal thickness decreased from 328 (SD 116) mm to 216 (SD 85) mm (p , 0.001). Ninety-four percent of patients lost fewer than 3 lines, 31% gained more than 3 lines, and 6% lost more than 3 lines. Conclusions: By combining agents with complementary mechanisms of action, triple therapy could maintain visual acuity and macular anatomy while allowing a reduction in the number of anti-vascular endothelial growth factor injections required. Objet : La de´ge´ne´rescence maculaire lie´e a` l’aˆge est une maladie multifactorielle impliquant l’inflammation, la ne´ovascularisation et la fuite vasculaire. Il est donc logique d’investiguer une combinaison de traitements visant les divers processus pathologiques implique´s dans la maladie. Nous proposons une triple the´rapie compose´e de la the´rapie photodynamique (TPD) a` la verteporfine, de bevacizumab intravitre´en et de dexame´thasone intravitre´enne. Nature : Examen re´trospectif de dossiers. Participants : L’examen a porte´ sur 32 yeux de 30 patients. Aucun patient n’a montre´ de pathologie oculaire concomitante et aucun n’avait rec¸u de traitement ante´rieur pour ne´ovascularisation choroı¨dienne. Me´thodes : Un cycle de triple the´rapie comprenait une TPD a` fluence re´duite (300 mW/cm2 pendant 83 secondes pour livrer 25 J/cm2) suivie imme´diatement d’une injection de 800 mg (0,08 mL) de dexame´thasone intravitre´enne (DIV). Une semaine et 7 semaines apre`s le TPD et la DIV, les patients recevaient une injection de 1,25 mg (0,05 mL) de bevacizumab. Treize semaines apre`s le TPD et la DIV, pour chaque patient, on reprenait la tomographie par cohe´rence optique et l’angiographie a` la fluoresce´ine pour e´valuer l’activite´ de ne´ovascularisation choroı¨dienne. Les patients ont ainsi e´te´ suivis pendant douze mois. Re´sultats : L’on compta en moyenne 1,4 cycles de traitements. Le nombre d’injections de bevacizumab e´tait de 2,8 en moyenne. L’acuite´ visuelle s’e´tait ame´liore´e de 0,74 (E´T, 0,33) logMAR (20/100) a` 0,53 (E´T 0,32) logMAR (20/70) (p , 0.005). L’e´paisseur de la fove´a avait diminue´ de 328 (E´T, 116) mm a` 216 (E´T, 85) mm (p , 0.001). Quatre-vingtquatorze pour cent des patients avaient perdu moins de 3 lignes, 31 % avaient gagne´ plus de 3 lignes et 6 % avaient perdu plus de 3 lignes. Conclusions : En combinant les agents avec les me´canismes d’action comple´mentaires, la triple the´rapie pourrait maintenir l’acuite´ visuelle et l’anatomie maculaire tout en permettant de re´duire le nombre des injections requises contre le facteur de croissance endothe´liale vasculaire.
A
ge-related macular degeneration (AMD), the leading cause of irreversible blindness in people over 50 years of age in the developed world,1–4 is a multifactorial disease
involving inflammation, neovascularization, and vascular leakage.5–7 Neovascular AMD is characterized by the presence of choroidal neovascularization (CNV),1,2,4,6–10
From Pasqua Hospital Eye Centre, University of Saskatchewan, Regina, Sask.
Correspondence to Rau´l Garcı´a, MD, 1-4101 Dewdney Ave., Regina, SK S4T 1A5;
[email protected]
Presented in part at the meeting of Retina Canada in Montreal, Que., in May 2009. Originally received Aug. 13, 2009. Revised Oct. 8, 2009 Accepted for publication Oct. 26, 2009 Published online Jan. 14, 2010
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This article has been peer-reviewed. Cet article a e´te´ e´value´ par les pairs. Can J Ophthalmol 2010;45:36–40 doi:10.3129/i09-243
Triple therapy for neovascular AMD—Ehmann & Garcı´a which has detrimental effects on macular anatomy and function. Photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis AG, Basel, Switzerland) was first approved in 20009,11 and was widely used until a few years ago.7 Since the introduction of anti-vascular endothelial growth factor (VEGF) agents in 2003, the visual prognosis in patients with neovascular AMD has improved considerably and has led to the rapid adoption of anti-VEGF agents as a first-line treatment modality for the disease.7 Several reports investigating the efficacy of monotherapy for neovascular AMD have been published. The TAP9,12 and VIP13 reports recognized PDT monotherapy as an effective treatment option for neovascular AMD.9 On average, PDT monotherapy resulted in a reduced risk of vision loss, rather than an improvement in visual acuity.5–7 The MARINA1 and ANCHOR9 studies demonstrated both prevention of visual loss and visual improvement in eyes treated with monthly ranibizumab. Anti-VEGF agents, although effective in inhibiting continuous neovascularization, do not appear to eradicate the underlying CNV.6,7 As a result, multiple repeat injections are required to maintain the visual benefits of such therapies.5–7,11 This not only incurs great costs to the health care system, but also creates a significant burden on patients and their families.6,7,11 Despite successes in current treatments, it is clear that no single treatment modality is able to address the multifactorial nature of this disease.6 As a result, the current aim has shifted towards finding a treatment regimen that provides the same results as anti-VEGF monotherapy, if not better, with fewer retreatments required.5–7,11,14–16 Several articles investigating combination therapy for neovascular AMD with promising results have been published.5–7,11,14–16 We propose triple therapy, consisting of verteporfin PDT, intravitreal bevacizumab, and intravitreal dexamethasone (IVD), for treatment of CNV secondary to AMD. METHODS
Thirty-two eyes of 30 patients with CNV secondary to AMD and treated with triple therapy were included in this retrospective chart review. All patients were recruited from a database search of one vitreoretinal practice in Regina, Sask. None of the patients demonstrated concurrent eye pathology, and none of the patients had received previous treatment for their CNV. Prior to treatment, all
patients underwent a complete ophthalmic examination, including best-corrected Snellen visual acuity with conversion to logMAR, Goldman applanation tonometry, optical coherence tomography (OCT), and fluorescein angiography (FA). One cycle of triple therapy consisted of reducedfluence PDT (300 mW/cm2 for 83 seconds to deliver 25 J/cm2) followed immediately by an 800 mg (0.08 mL) IVD injection. At 1 and 7 weeks after PDT and IVD, patients received a 1.25 mg (0.05 mL) bevacizumab injection. All study eyes were prepped using a lid speculum, 0.5% tetracaine, and subconjunctival lidocaine, followed by Betadine irrigation. At 13 weeks after PDT and IVD, each patient had a repeat OCT and FA to assess CNV activity. Patients with either visible leakage on FA or increased foveal thickness on OCT with vision loss underwent an additional round of triple therapy. If no CNV activity was noted, patients were reviewed with a complete ophthalmic examination, FA, and OCT 3 months later. All patients were treated between December 2006 and September 2007. Follow-up was 12 months. Study approval was granted by the Regina Qu’Appelle Health Region’s Research Ethics Board. RESULTS
A total of 32 eyes were included in the study. The mean age was 81 (SD 6) years. There were 20 females and 12 males. Twenty-nine eyes (90%) had subfoveal CNV, and 3 eyes (10%) had juxtafoveal CNV. In 18 (56%) of the study eyes, the CNV was occult; in 11 (34%), it was predominantly classic; and in 3 (10%), it was minimally classic. The mean number of treatment cycles was 1.4 in 12 months: 22 (69%) of the study eyes required 1 cycle of treatment, 8 (25%) received 2 cycles of treatment, 1 (3%) received 3 cycles of treatment, and 1 (3%) received 4 cycles of treatment. The mean number of bevacizumab injections was 2.8 per patient with a range of 2–8 (Tables 1 and 2). The mean baseline greater linear diameter was 3093 (SD 1436) mm. Mean baseline visual acuity was 0.74 (SD 0.33) logMAR (20/100) and mean vision on final follow-up at 12 months was 0.53 (SD 0.32) logMAR (20/70) (p , 0.005). The baseline foveal thickness by OCT was Table 2—Results summary Baseline
12 months
p value
logMAR
0.74 ¡ 0.33
0.53 ¡ 0.32
,0.005
Foveal thickness (mm)
328 ¡ 116
216 ¡ 85
,0.001
Note: Values are means ¡ SD. Patients received an average of 1.4 treatment cycles and 2.8 injections in 12 months.
Table 1—Study demographics Gender n 32
CNVM location (%)
CNVM type (%)
Treatments needed (%)
Mean age (y)
Mean GLD (mm)
M
F
SF
JF
Occ
PC
MC
1
2
3
4
81
3093
12
20
90
10
56
34
10
69
25
3
3
Note: GLD, greater linear diameter; CNVM, choroidal neovascular membrane; M, male; F, female; SF, subfoveal; JF, juxtafoveal; Occ, occult; PC, predominantly classic; MC, minimally classic.
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Triple therapy for neovascular AMD—Ehmann & Garcı´a 328 (SD 116) mm and the final foveal thickness was 216 (SD 85) mm (p , 0.001) (Table 2). In this group of patients, 94% of the eyes lost fewer than 3 lines, 62% gained vision, 31% gained more than 3 lines, and 6% lost more than 3 lines. No rise in intraocular pressure was noted in any of the patients and none of the patients involved in the study experienced any adverse events such as endophthalmitis or stroke during the study period. CONCLUSIONS
AMD is a multifactorial disease involving neovascularization, inflammation, and vascular leakage.5–7 As a result, a strong rationale exists for the use of combination therapy.5–7 By combining agents with complementary mechanisms of action, triple therapy can maintain visual acuity and macular anatomy while allowing a reduction in the number of anti-VEGF injections required.5–7 Although the visual outcomes of anti-VEGF monotherapy are promising, the need for repeat injections exposes the patient to an increased risk of infection and places a burden on the patient and his or her caregivers.5–7,11 In addition, antiVEGF monotherapy incurs a significant cost to the health care system.6,7,11 In our study, we treated 32 eyes with triple therapy consisting of verteporfin PDT, IVD, and intravitreal bevacizumab, with the goal of achieving a visual outcome similar to anti-VEGF monotherapy with the need for fewer anti-VEGF injections. Our triple therapy regimen resulted in a statistically significant improvement in visual acuity and foveal thickness, with fewer intravitreal bevacizumab injections over a 12-month follow-up period. PDT with verteporfin has a powerful angio-occlusive effect on CNV, with evidence of a significant decrease in CNV perfusion as early as 1 week after treatment.15 PDT is thought to be most effective against classic CNV; however, positive results have been demonstrated with occult CNV as well.10,13,15 Problems with PDT include a high cost, CNV recurrences, and the possibility of retinal pigment epithelium atrophy with repeated use.5,15 In addition, PDT treatment is known to induce an inflammatory response, which leads to increased levels of VEGF that may act to perpetuate neovasularization.5,6,11,15 In our study, we used reduced-fluence PDT (300 mW/cm2 for 83 seconds to deliver 25 J/cm2) in an attempt to focus the treatment on the desired lesion and thus minimize the inflammatory reaction.11
In our study, 800 mg (0.08 mL) of dexamethasone was injected intravitreally immediately after PDT treatment to blunt the PDT-induced inflammatory response. Beyond its anti-inflammatory actions, dexamethasone has been shown to have antifibrotic, antiproliferative, and antimigratory properties that may further inhibit CNV pathogenesis.6,11 The antiproliferative effects are reduced in the presence of VEGF; thus, combination therapy with direct VEGF inhibitors may enhance the effects of dexamethasone.6,11 Previous studies have used triamcinolone.5,15 Triamcinolone has a half-life of 18.6 days, compared with 3.45 days for dexamethasone, and dexamethasone is 5 times more potent.11 As a result, patients treated with triamcinolone have a higher incidence of intraocular pressure spikes and cataract formation.5,6,11 These adverse effects were not found in our study. VEGF has been implicated as the major angiogenic stimulus responsible for neovascularization in AMD and thus the use of anti-VEGF agents is critical for the successful treatment of neovascular AMD.1,6,16,17 Pegaptanib was the first anti-VEGF agent used to treat neovascular AMD17 and it showed a modest but statistically significant benefit compared with placebo.3,4,10 Bevacizumab, used off-label since 2005,11 is a full-length antibody with 2 binding sites that binds all isoforms of VEGF.5,6,10,17 It has been proposed that impediment of larger molecules such as bevacizumab may occur at the inner limiting membrane, inner plexiform layer, and outer plexiform layer.10 As a result, ranibizumab was developed and approved in 200611,14 with the idea that it would penetrate the retina better than bevacizumab.10,17 Ranibizumab is an antibody fragment with a single binding site and a molecular weight one third that of bevacizumab.1,10,14,17 Studies comparing the safety and efficacy of bevacizumab and ranibizumab are ongoing11 and, as a result, it remains unknown whether one is superior to the other. In our study, we injected 1.25 mg (0.05 mL) bevacizumab at 1 and 7 weeks after initial PDT and IVD. Potential advantages of bevacizumab over ranibizumab include a longer half-life within the vitreous cavity, the presence of 2 binding sites, and a lower cost.11,17 Potential disadvantages include a larger molecular size, the presence of a proinflammatory Fc portion,10 and a possibly longer serum half-life, leading to an increased risk of systemic complications.17 Rich et al.17 and Spaide et al.10 investigated the short-term safety and efficacy of intravitreal bevacizumab for neovascular AMD and reported
Table 3—Triple therapy: photodynamic therapy (PDT), intravitreal dexamethasone (IVD), intravitreal bevacizumab (IVB) study comparison Investigator
No. eyes
Ehmann and Garcı´a (current study) 7
Augustin et al. Bakri et al.12
32
CNVM types All
Regimen PDT + IVD R IVB 1 and 7 wk later
104
All
PDT R vitrectomy 16 h later with IVD + IVB
31
All
Consecutive PDT + IVD + IVB
Note: CNVM, choroidal neovascular membrane; F/U, follow-up; AE, adverse events.
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PDT
IVD, mg (mL)
IVB, mg (mL)
F/U
AE
2
800 (0.08)
1.25 (0.05)
12 mo
None
2
Standard-fluence (600 mW/cm for 70 s to deliver 42 J/cm2)
800 (0.2)
1.5 (0.06)
40 wks
None
Reduced-fluence (300 mW/cm2 for 83 s to deliver 25 J/cm2)
200 (0.05)
1.25 (0.05)
12 mo
None
Reduced-fluence (300 mW/cm for 83 s to deliver 25 J/cm2)
Triple therapy for neovascular AMD—Ehmann & Garcı´a significant short-term improvements in visual acuity and foveal thickness. These findings indicate that despite a larger molecular weight, bevacizumab appears to have a significant inhibitory effect on VEGF, with a corresponding improvement in macular function and anatomy.10 Some ligand-bound Fc receptors act to inhibit inflammation.10 Furthermore, data suggest that the Fc portion of bevacizumab is well tolerated when injected into the eye over the short term.17 Of interest, the maximum tolerated dose of ranibizumab in the eye was reported to be 0.05 mg.17 In our study, we administered 1.25 mg of bevacizumab, a dose well over the maximum tolerated dose of ranibizumab. Despite this, we did not observe any intraocular inflammation in our study patients. This might suggest that ranibizumab has increased immunogenicity compared with bevacizumab.17 In reviewing the literature, several studies investigating the efficacy of combination treatment for neovascular AMD with promising results were found. Bakri et al.11 investigated the effectiveness of same-day triple therapy, consisting of PDT, IVD, and intravitreal bevacizumab, in 31 eyes with neovascular AMD. Mean baseline visual acuity improved from 0.61 logMAR (20/80) to 0.58 logMAR (20/60) and mean foveal thickness improved from 293 mm to 245 mm at 12 months (Tables 3 and 4). Neither of their findings was statistically significant. Of interest, they noted that treatment-naı¨ve patients responded better to the therapy than those who had undergone previous treatment. One explanation for this finding may be that patients previously treated might have reached their visual acuity peak and plateaued after several treatments.11 All patients in our study were treatment naı¨ve. Augustin et al.6 investigated PDT, bevacizumab, and dexamethasone triple therapy in 104 eyes. A major difference in their study was the use of a monoport vitrectomy following PDT to accommodate the intravitreal bevacizumab and dexamethasone. They found that 18 patients required an additional bevacizumab injection over the 40-week follow-up period and 5 patients required another cycle of treatment. Baseline visual acuity improved from 0.802 logMAR (20/126) to 0.625 logMAR (20/85) (p , 0.01) and foveal thickness decreased from 463.5 mm to 281 mm (p , 0.01) (Tables 3 and 4). The RADICAL study is currently comparing the efficacy of reduced-fluence PDT and ranibizumab combination therapy with or without dexamethasone, with Table 4—Triple therapy: photodynamic therapy (PDT), intravitreal dexamethasone (IVD), intravitreal bevacizumab (IVB) results comparison FT (mm)
VA (logMAR) Baseline
F/U
p value
F/U
p value
Ehmann and Garcı´a (current study)
0.74
0.53
,0.005
328
216
,0.001
Augustin et al.7
0.802
0.625
,0.01
463.5
281
,0.01
Bakri et al.12
0.61
0.58
293
245
Investigator
0.69
Note: VA, visual acuity; FT, foveal thickness; F/U, follow up.
Baseline
0.053
ranibizumab monotherapy in 162 treatment-naı¨ve subjects with neovascular AMD. The unpublished one-year results indicate that triple therapy consisting of halffluence PDT with ranibizumab and dexamethasone resulted in a visual improvement of 6.8 letters compared with 6.5 letters in the ranibizumab monotherapy group. In addition, triple therapy resulted in a mean of 3 retreatment visits compared with 5.4 retreatment visits in the ranibizumab monotherapy group. In our study, 94% of the eyes lost fewer than 3 lines and 31% gained more than 3 lines after an average of 2.8 bevacizumab injections over 12 months. These results are very similar to those found in the MARINA study,1 where 94.6% of patients lost fewer than 3 lines and 33.8% gained 3 lines or more after 12 monthly injections of ranibizumab. It is important to note that the treatment regimen used in our series may not be optimal with respect to dosages and time intervals.5,6 As a result, further larger prospective studies are required. Furthermore, we cannot assess the individual contribution of each treatment modality of the regimen. Augustin et al.6 administered dexamethasone 16 hours after PDT in the belief that PDT’s efficacy depends on immunologically mediated processes established within a 16-hour period. By delaying dexamethasone administration by 16 hours, Augustin et al.6 believed they were ensuring PDT’s therapeutic effects while preventing overactivation of the inflammatory cascade. Because of the small sample size (n 5 32), a subgroup analysis comparing visual outcomes among the various types of CNV was not done. FA was used to classify each CNV as occult, predominantly classic, or minimally classic indocyanine green angiography (ICG) has been shown to be superior to FA at diagnosing and classifying CNV, particularly those of the occult nature.2,8 In our study, treatment was the same regardless of CNV type, so it is unlikely that the further knowledge provided by ICG would have led to improved visual outcomes. However, as the search for better treatment options continues for patients with neovascular AMD, so too must our diagnostic and classification abilities. By knowing the exact type of CNV in AMD patients, retina specialists will be better able to design future studies specific to each form of the disease and to assess the relative effectiveness of a chosen therapy for the specific CNV type.2,8 Other weaknesses of our study include its retrospective design and lack of a control arm. In summary, triple therapy consisting of verteporfin PDT, IVD, and intravitreal bevacizumab resulted in a statistically significant improvement in visual acuity and foveal thickness, as well as a decrease in the number of intravitreal bevacizumab injections required. As a result, we feel that triple therapy may be an acceptable alternative to anti-VEGF monotherapy. The authors thank Research Performance Support (Regina Qu’Appelle Health Region) for their assistance with the statistical analysis. The authors have no proprietary or commercial interest in any materials discussed in this article. CAN J OPHTHALMOL—VOL. 45, NO. 1, 2010
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10. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to agerelated macular degeneration. Retina 2006;26:383–90. 11. Bakri SJ, Couch SM, McCannel CA, Edwards AO. Same-day triple therapy with photodynamic therapy, intravitreal dexamethasone, and bevacizumab in wet age-related macular degeneration. Retina 2009;29:573–8. 12. Bressler NM; 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 2. Arch Ophthalmol 2001;119:198–207. 13. Verteporfin in Photodynamic Therapy 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;131:541–60. 14. Antoszyk AN, Tuomi L, Chung CY, Singh A; FOCUS Study Group. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008;145: 862–74. 15. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003; 110:1517–25. 16. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol 2007;143:566–83. 17. 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. Keywords: choroidal neovascularization, bevacizumab, dexamethasone, verteporfin photodynamic therapy
