Combination therapy in exudative age-related macular degeneration: visual outcomes following combined treatment with photodynamic therapy and intravitreal bevacizumab

Combination therapy in exudative age-related macular degeneration: visual outcomes following combined treatment with photodynamic therapy and intravitreal bevacizumab Michael J. Wan, MD; Phil L. Hooper, MD, FRCSC; Tom G. Sheidow, MD, FRCSC ABSTRACT N RE´SUME´ Objective: To measure visual outcomes following combined treatment with photodynamic therapy (PDT) and intravitreal bevacizumab for exudative age-related macular degeneration (AMD). Design: Single-centre, retrospective cohort analysis. Participants: One hundred and seventy-four eyes in 174 patients, representing a consecutive series of all patients with at least 6 months’ follow-up after combined treatment with PDT and bevacizumab for exudative AMD. Methods: Each patient was treated with PDT, followed by intravitreal injection of bevacizumab approximately 30 minutes later. The patients were then followed at 8–12-week intervals. The primary outcome of the study was the mean change in visual acuity (VA) from baseline. Results: One hundred seventy-four eyes in 174 patients completed at least 6 months’ follow-up, with a mean duration of 10 months. The mean number of treatments was 3.0 for bevacizumab and 1.4 for PDT. After stabilization, the mean treatment-free interval was 193 days, and 52% of the patients did not require postinduction retreatment. Mean VA improved from baseline at 2, 4, and 6 months of follow-up (p , 0.05). In the subgroup analysis, treatment-naı¨ve patients had more favorable visual outcomes (p , 0.05). Conclusions: The combination of PDT and intravitreal bevacizumab is an effective therapy for preserving VA in patients with exudative AMD. Objet : Mesure des re´sultats visuels du traitement combine´ par the´rapie photodynamique (TPD) et be´vacizumab intravitre´en pour la de´ge´ne´rescence maculaire lie´e a` l’aˆge (DMLA) exudative. Nature : Analyse re´trospective unicentrique de cohorte. Participants : 174 yeux de 174 patients formant une se´rie de patients conse´cutifs ayant eu 6 mois de suivi apre`s un traitement combine´ de TPD et de be´vacizumab pour DMLA exudative. Me´thodes : Chaque patient a rec¸u un TPD puis une injection intravitre´enne de be´vacizumab environ 30 minutes apre`s. Ils ont ensuite e´te´ suivis a` des intervalles de 8 a` 12 semaines. Le principal re´sultat de l’e´tude a porte´ sur le changement moyen de l’acuite´ visuelle (AV) du de´part. Re´sultats : Cent soixante-quatorze yeux de 174 patients ont comple´te´ le suivi d’au moins 6 mois et d’une dure´e moyenne de 10 mois. Ils ont rec¸u en moyenne 3,0 traitements de be´vacizumab et 1,4 de TPD. Apre`s stabilisation, la moyenne d’intervalle sans traitement a e´te´ de 193 jours, et 52 % des patients n’ont pas eu besoin de re-traitement post-induction. La moyenne de base d’AV s’est ame´liore´e apre`s 2, 4 et 6 mois de suivi (p , 0,05). Dans l’analyse des sous-groupes, les patients naı¨fs de traitement avaient un meilleur re´sultat visuel (p , 0,05). Conclusions : La combinaison de TPD et de be´vacizumab intravitre´en offre une the´rapie efficace pour pre´server l’AV chez les patients atteints de DMLA exudative.

A

ge-related macular degeneration (AMD) is the leading cause of adult visual impairment and irreversible blindness in the Western world.1 The 10% of patients diagnosed with exudative (wet) AMD often experience rapid loss of central vision over a period of months, and early visual stabilization is key in preserving visual acuity (VA). The treatment of exudative AMD has advanced rapidly over the past decade. First, the successful treatment of choroidal neovascularization with photodynamic therapy (PDT) was reported,2,3 and it proved to be an effective

method of avoiding moderate visual loss in patients with exudative AMD.4 More recently, antiangiogenic agents have come to be at the forefront in the treatment of exudative AMD. Antiangiogenic agents, such as pegaptanib (Macugen; OSI Pharmaceuticals, Melville, N.Y.), ranibizumab (Lucentis; Genentech, San Francisco, Calif.), and bevacizumab (Avastin; Genentech) inhibit the process of angiogenesis by targeting vascular endothelial growth factor (VEGF), the main stimulus for the angiogenic cascade. The initial studies with pegaptanib demonstrated

From the Ivey Eye Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ont.

Correspondence to Tom G. Sheidow, MD, Ivey Eye Institute, 750 Commissioners Rd. E, London ON N6A 4G5; [email protected]

Presented at the Association for Research in Vision and Ophthalmology Annual Meeting, Fort Lauderdale, Fla., April 2008

This article has been peer-reviewed. Cet article a e´te´ e´value´ par les pairs.

Originally received Feb. 19, 2009. Final revision Oct. 31, 2009 Accepted Dec. 18, 2009 Published online May 26, 2010

Can J Ophthalmol 2010;45:375–80 doi:10.3129/i10-011

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Combination therapy in exudative AMD—Wan et al. the efficacy of these agents across all lesion subtypes and supported the concept of a common underlying stimulus for lesion development and growth.5 Subsequently, a new level of success was established with the introduction of ranibizumab. With ranibizumab, a mean gain in VA was achieved for the first time.6,7 With greater than 90% success in avoiding moderate visual loss and a 30%–40% chance of a 3-line gain, this agent has become the gold standard in the treatment of wet AMD. Closely related to ranibizumab is bevacizumab, a humanized monoclonal antibody against all forms of VEGF, which was initially developed for systemic administration in the treatment of metastatic colorectal cancer.8,9 Although both PDT and bevacizumab are independently effective in the treatment of exudative AMD, there is a potential drawback to monotherapy. The pathogenesis of exudative AMD involves several different mechanisms and it is therefore possible that targeting a single mechanism will not inhibit, and may even stimulate, other disease pathways. For instance, although PDT causes occlusion of newly formed choroidal neovasculature, the resulting hypoxia actually up-regulates VEGF and other angiogenic factors, potentially accelerating further neovascularization.10 Similarly, although bevacizumab inhibits the formation of new blood vessels and may even trigger the regression of immature vessels, there may be no effect on established neovasculature.11 Therefore, the rationale for using combined therapy is that an additive or synergistic effect may be achieved by simultaneously targeting multiple mechanisms of neovascularization, thereby leading to a reduction in the frequency and overall number of treatments needed.12 A number of clinical studies13–17 and one randomized controlled pilot clinical trial18 have looked at the combination of PDT and bevacizumab in the treatment of exudative AMD. However, the currently available studies have either had a relatively small number of subjects (50 or fewer)13–17 or a limited period of follow-up (3 months or less).13,16,18 Therefore, the purpose of this study was to report the visual outcomes from a large cohort of patients with exudative AMD who were followed for at least 6 months after receiving combined treatment with PDT and intravitreal bevacizumab. METHODS

Ethics committee approval was obtained from the Research Ethics Board of the University of Western Ontario. The design of the study was a single-centre, retrospective cohort analysis. The patient population was composed of a consecutive series of all patients with exudative AMD who were treated with combined PDT and intravitreal bevacizumab by the Vitreoretinal Service at the Ivey Eye Institute in London, Ont., between January 2006 and October 2007. To meet the inclusion criteria, patients had to have at least 6 months of follow-up after

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receiving combination treatment on the same day for a fluorescein angiography–confirmed diagnosis of exudative AMD. Patients were excluded from the analysis if there was another possible etiology of choroidal neovascularization such as high myopia, presumed ocular histoplasmosis syndrome, angioid streaks, or ocular trauma. The primary outcome of the study was the mean change in VA following combined therapy with bevacizumab and PDT. Secondary analyses were performed to determine the proportion of patients who had either significant visual loss or visual gain and to compare the visual outcomes of subgroups within the overall patient population. At the initial visit, each patient received PDT, followed by intravitreal bevacizumab approximately 30 minutes later. PDT was administered using a consistent protocol with low laser fluence rates (25 J/cm2, 300 mW/cm2 for 83 seconds), and bevacizumab (1.25 mg) was injected through the pars plana using standard and accepted procedures for intravitreal injection. Standard induction protocol within our clinic involved a second injection of bevacizumab 6 weeks after the initial treatment unless the patient had complete stabilization of his or her disease. Patients were considered to be stable if there was no interval decline in their best-corrected VA, along with no new hemorrhage on dilated eye examination and an absence of intraretinal and subretinal fluid on optical coherence tomography (OCT). Patients received repeat fluorescein angiography following the second bevacizumab injection when repeat PDT was being considered and 3 months after each PDT was performed. If no additional PDT was used, patients were followed with OCT alone. Patients were scheduled for follow-up appointments every 8 to 12 weeks, depending on clinical response and need for further treatment. With each follow-up appointment, VA was recorded using a lighted LCD display Early Treatment Diabetic Retinopathy Study (ETDRS)-like Snellen chart, and further treatment with PDT, bevacizumab, or both was initiated if deemed necessary by the supervising ophthalmologist (Tom G. Sheidow or Phil Hooper). Retreatment with PDT was based on the presence of leakage on intravenous fluorescein angiography. Retreatment with bevacizumab was based on intraretinal or subretinal fluid on OCT. At the end of data collection, statistical analysis was performed by biostatisticians at QLT (QLT Inc, Vancouver, B.C.). The follow-up appointments were set at 2-month intervals. No imputation was used if a patient was not seen during a specific interval. Snellen VA scores were converted to logMAR for statistical analyses, using the calculation logMAR value 5 log10 (1/Snellen). LogMAR values were converted to letter scores such that 5 letters were equal to 0.10 unit of logMAR difference. The VA range was Snellen 20/20 to 20/400. VA scores below Snellen 20/400 were assigned as counting fingers (logMAR value of 1.7), hand motion (logMAR value of 2.5), or light perception (logMAR value of 3.0). Paired t tests were used to calculate the p values for mean change in VA from baseline. Two

Combination therapy in exudative AMD—Wan et al. sample t tests were used to calculate the p values for comparisons of mean change in VA between subgroups (i.e., previously treated vs treatment naı¨ve, predominantly classic lesions vs other types, hypertensive vs normotensive, and older than 80 years vs younger than 80 years). RESULTS

The study included 174 eyes in 174 patients who had at least 6 months’ follow-up after combination therapy with PDT and bevacizumab. The results were divided into 2-month intervals for the purpose of analysis; however, because appointments were scheduled 8–12 weeks apart, not every patient was seen at each follow-up interval. There were 134 patients (77%) seen at 6 months of follow-up, 85 patients (49%) seen at 8 months of follow-up, 54 patients (31%) seen at 10 months of follow-up, and 49 patients (28%) seen at 12 months of follow-up. The mean duration of follow-up was 300 days (10 months). The baseline characteristics of the patient population are summarized in Tables 1 and 2. During the study, the mean number of treatments with bevacizumab was 3.0 and the mean number of treatments with PDT was 1.4. All the patients in the study received combination therapy at baseline and 91% of the patients in the study received the second injection of bevacizumab at 6 weeks. With induction therapy, 79% of the patients had stabilization of their disease at their next follow-up appointment and 52% did not require any form of retreatment for the remainder of the study. A further 16% of the

patients were stabilized after receiving additional treatment with PDT or bevacizumab. Therefore, 95% of the patients in the study achieved stabilization of their disease. Once patients were stabilized, the mean treatment-free interval was 193 days (range 35–494 days) and 95% of the patients remained stable for at least 48 days. The mean best-corrected VA showed statistically significant improvement over the first 6 months of follow-up (p , 0.05) (Fig. 1). VA continued to show improvement at 8–12 months of follow-up, but the degree of improvement declined and was not statistically significant. In the subgroup analysis, patients who were treatment naı¨ve had significantly better outcomes compared with patients who had received previous treatment (Fig. 2). In addition, at 6 months of follow-up, patients who were hypertensive improved by +7.1 letters compared with an improvement of +0.3 letters for patients without hypertension (p , 0.05). The visual outcomes and subgroup analysis are summarized in Table 3 with a frequency distribution of significant visual outcomes in Table 4. No safety concerns were identified during the study. None of the patients developed serious ocular complications such endophthalmitis, uveitis, retinal detachment, ocular toxicity, or ocular hypertension. In addition, none

Table 1—Demographic data of patients with at least 6 months’ follow-up after combined therapy Age, mean y

80.4

Baseline visual acuity, % §20/50

7

20/60 to ,20/100

20

20/100 to ,20/200

15

20/200 to ,20/400

29

20/400

13

Counting fingers Female/male, n/n (%/%) Treatment naı¨ve, n (%)

Fig. 1—Mean change in visual acuity after combined treatment with photodynamic therapy and intravitreal bevacizumab (with 95% CIs).

16 104/70 (60/40) 111 (64)

Smoking, n (%)

23 (13)

Diabetes mellitus, n (%)

28 (17)

Hypertension, n (%)

94 (54)

Glaucoma, n (%)

18 (10)

Note: y, years.

Table 2—Baseline CNV lesion characteristics (n 5 174) Mean lesion size, mm (range)

2666 (661–5435)

CNV location, n (%) Subfoveal Juxtafoveal

157 (90) 17 (10)

Lesion type, n (%) Predominantly classic

136 (78)*

Minimally classic

22 (13)

Occult

16 (9)

*In Ontario, only patients with PC lesions are covered for photodynamic therapy and hence, the large proportion of patients in this study with PC lesions reflects access to therapy. Note: CNV, choroidal neovascularization.

Fig. 2—Mean change in visual acuity after combined treatment with photodynamic therapy and intravitreal bevacizumab in treatmentnaı¨ve patients compared with patients with previous treatment for exudative age-related macular degeneration. CAN J OPHTHALMOL—VOL. 45, NO. 4, 2010

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Combination therapy in exudative AMD—Wan et al. of the patients reported major systemic adverse effects such as hypertensive encephalopathy or thromboembolic events, which have been reported with the systemic administration of bevacizumab.19,20 CONCLUSIONS

Our results suggest that the combination of PDT and bevacizumab is effective in the treatment of exudative AMD, especially in treatment-naı¨ve patients. During the study, the mean VA of all subjects improved significantly over the first 6 months and remained above baseline throughout the follow-up period. In the subgroup analysis, treatment-naı¨ve patients had significantly better visual outcomes than patients who had had previous treatment. Patients in the non–treatment-naı¨ve group saw a gradual net decline in VA with time, similar in nature to the general trend with PDT treatment alone. Although there were fewer patients in the longer follow-up periods, and hence the data were limited in prognostic ability, further longterm follow-up is required to ensure that patients who are not treatment naı¨ve are not harmed visually by the use of combination therapy over bevacizumab alone. Interestingly, patients with hypertension had better visual outcomes after 6 months of follow-up. This is surprising because the Macular Photocoagulation Studies in the 1990s, which evaluated thermal laser for choroidal neovascularization, showed worse outcomes in patients with hypertension.21 We currently do not have a satisfactory explanation for this finding and it would be worthwhile to look at hypertension in future studies to determine if there is a similar pattern. Several previous cohort studies have reported promising visual outcomes from patients treated with combination therapy. Ladewig et al.16 followed 30 patients over 3 months and reported a mean improvement of 4.3 letters. Costa et al.14 followed 11 patients over 6 months and reported an improvement of 1.49 lines at 3 months and 0.98 lines at 6 months. Lazic´ et al.15 followed 46 patients over 6 months and found a mean improvement of 1.45 lines at last follow-up. Finally, Dhalla et al.17 reported results from 24 patients over 7 months, all treatment naı¨ve, finding that there was a mean improvement of 2.04 Snellen

lines. The most convincing evidence comes from a randomized controlled pilot clinical trial that randomized 165 patients into 3 groups.18 Patients in the study received either PDT alone, bevacizumab alone, or combined treatment. Although the study followed patients for only 3 months, the patients treated with combined therapy improved significantly more than patients treated with bevacizumab or PDT alone. Therefore, our results are consistent with the existing studies and support the efficacy of combined therapy over a period of at least 6 months. Although combined treatment with PDT and bevacizumab has shown promise for the treatment of exudative AMD, there are several clinical issues that require further study, such as the need for retreatment and the optimal timing of follow-up. In our study, 79% of the patients were stabilized using standard induction therapy and more than 50% did not require any postinduction retreatment. Once patients were stabilized, we observed a long mean treatment-free interval of more than 6 months. However, to ensure that recurrent disease was not missed in at least 95% of the patients, the follow-up period after stabilization had to be less than 50 days. Therefore, although combined therapy does appear to decrease the need for retreatment, it may still be desirable to follow patients every 4 to 6 weeks, or as carefully as done in the MARINA,6 ANCHOR,7 and PRONTO22 studies, to administer retreatment early for recurrent disease to help preserve improvements in VA. Another issue with combined treatment has been the lack of safety data. Experimental animal studies have demonstrated that the combination of PDT and bevacizumab is very safe in a primate model,23 but there have not been any large randomized controlled clinical trials to establish safety data in humans. These studies are currently underway and will certainly address many of these Table 4—Frequency distribution of significant visual outcomes 6 months Number of patients, n

12 months

159

60

53 (33)

19 (32)

Stable or improved, n (%)

126 (79)

40 (67)

Avoided moderate visual loss, n (%)

128 (81)

43 (72)

Avoided severe visual loss, n (%)

151 (95)

57 (95)

§15 letters increase, n (%)

Table 3—Mean change in visual acuity (reported in number of letters on a Snellen chart) for the total study population with comparison to subgroups Treatment naı¨ve Total

Yes

n

DVA

p value (change from baseline)

2

171

+5.3

,0.001

4

137

+6.9

,0.001

6

134

+3.8

8

85

+2.1

Follow-up, mo

n

No DVA

p value (treatment naı¨ve vs previous treatment)

60

+3.1

0.08

49

+3.2

0.04

+6.7

47

21.6

0.01

+4.4

37

20.9

0.24

DVA

n

111

+6.5

88

+9.0

0.01

87

0.35

48

10

54

+4.1

0.14

35

+8.3

19

23.7

0.03

12

49

+3.6

0.27

33

+8.2

16

25.9

0.04

Note: mo, months; VA, visual acuity.

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Combination therapy in exudative AMD—Wan et al. concerns. We followed 174 patients for an average of 10 months and none of the patients developed any serious ocular or systemic complications. Although there has been one case report of a retinal detachment and macular hole following combined treatment with bevacizumab and PDT,24 none of the cohort studies on combined therapy have reported any serious adverse effects. The randomized controlled pilot clinical trial by Lazic and Gabric18 reported 4 cases of posterior vitreous detachment and 3 cases of cataract progression out of a total of 55 patients who received combined therapy. However, none of these patients withdrew from the study. Our study had several limitations. One limitation was the use of a Snellen chart to measure VA. The lighted LCD chart provides for more consistent and accurate VA measurement, but does not represent true ETDRS rigor. Another limitation was that follow-up visits varied based on clinical response and need for retreatment, so not all patients were maintained on a uniform follow-up schedule. Finally, the patients were not randomized into experimental and control groups, because all the patients received combined therapy at baseline. In the future, a large randomized controlled clinical trial comparing the combination of PDT and bevacizumab with bevacizumab alone would be helpful to provide more definitive conclusions about the safety and efficacy of combined therapy. Financial support in the form of an investigator grant-in-aid was provided to Dr. Sheidow by QLT Inc. Dr. Sheidow has no financial interest in either QLT Inc or Novartis Ophthalmics but is a member of advisory panels for both companies and receives unrestricted grants-in-aid from QLT for other research projects. Biostatisticians from QLT Inc provided the statistical analyses. QLT was not involved in the study design or interpretation of results. Drs. Wan and Hooper have no conflicts of interest to declare.

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Keywords: age-related maculopathy, bevacizumab, photodynamic therapy, verteporfin