Combination Therapy for NeovascularAge-Related Macular DegenerationRefractory to AntieVascular EndothelialGrowth Factor Agents

Kevin Tozer, MD,1,2 A. Brock Roller, MD,3 Lawrence P. Chong, MD,1,2 Srinivas Sadda, MD,1

James C. Folk, MD,3 Vinit B. Mahajan, MD, PhD,3 Stephen R. Russell, MD,3 H. Culver Boldt, MD,3

Elliott H. Sohn, MD3

Objective: To examine the outcomes of combination antievascular endothelial growth factor (VEGF) andphotodynamic therapy (PDT) for the treatment of neovascular age-related macular degeneration (AMD) refractoryto anti-VEGF monotherapy.

Design: Retrospective, interventional case series.Participants: Twenty-six eyes of 26 patients treated with anti-VEGF monotherapy for neovascular AMD with

persistent subretinal or intraretinal fluid after at least 3 anti-VEGF injections in the 7 months before combinationtreatment.

Intervention: Combination anti-VEGF treatment and PDT.Main Outcome Measures: Visual acuity at 1 or 2, 3, and 6 months and central retinal thickness at 1 or 2, 3,

and 6 months. Secondary outcome measures were change in number of fluid-free visits and interval betweentreatments in the 7 months before and 6 months after combination therapy.

Results: Statistically significant improvements in logarithm of the minimum angle of resolution visual acuitieswere present at 1 month (P ¼ 0.01) and 3 months (P ¼ 0.01). Significant decreases in central subfield retinalthickness on optic coherence tomography (OCT) were seen at 1 month (P ¼ 4�10�5), 3 months (P ¼ 3�10�4),and 6 months (P ¼ 4�10�5) as compared with precombination treatment OCT scans. The percentage of patientvisits with no subretinal fluid increased from 0.5% to 41% after the initiation of combination therapy (P ¼ 1�10�5).The interval between treatments increased from once every 1.6 months in the 7 months before combinationtreatment to once every 2.7 months in the 6 months after combination treatment (P ¼ 0.002). No ocularcomplications attributable to PDT were seen.

Conclusions: Rescue therapy with the combination of anti-VEGF and PDT in eyes that have failed anti-VEGFmonotherapy resulted in a mean improvement in vision, a decreased central subfield retinal thickness, and anincrease in fluid-free intervals.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussedin this article. Ophthalmology 2013;-:1e6 ª 2013 by the American Academy of Ophthalmology.

Age-related macular degeneration (AMD) is the leadingcause of blindness in the Western world. In the United Statesalone, 1.75 million people have AMD, and that number isexpected to increase to 2.95 million by 2020.1 Theneovascular form of AMD accounts for only 10% to 20%of all cases of AMD, but is responsible for 80% to 90% ofcases resulting in severe visual deficits.2 Early in the lastdecade, the advent of first aptamers and then antibodiesdirected against vascular endothelial derived growth factor(VEGF) injected into the vitreous revolutionized thetreatment paradigm for wet AMD, largely supplantingphotodynamic therapy (PDT).3,4

Because of the short half-life of intravitreal anti-VEGF,monthly monitoring, if not monthly injections, are necessary.

� 2013 by the American Academy of OphthalmologyPublished by Elsevier Inc.

Even with monthly injections of ranibizumab (Lucentis;Genentech, Inc, South San Francisco, CA), the MinimallyClassic/Occult Trial of theAnti-VEGFAntibodyRanibizumabin the Treatment of Neovascular AMD study and the Anti-VEGF Antibody for the Treatment of Predominantly ClassicChoroidal Neovascularization in AMD study showed that 9%and 10% of patients, respectively, lost more than 15 letters ofvision.5 The Prospective Optical Coherence TomographyImaging of Patients with Neovascular Age-Related MacularDegeneration Treated with Intra-Ocular Lucentis (Ranibizu-mab) study, which examined an optical coherence tomography(OCT)-guided variable dosing regimen of intravitreal bev-acizumab for wet AMD, had 13.5% of patients lose at least 5letters of vision at the 2-year follow-up.6

1ISSN 0161-6420/13/$ - see front matterhttp://dx.doi.org/10.1016/j.ophtha.2013.03.016

Ophthalmology Volume -, Number -, Month 2013

Several studies have assessed the efficacy of combined PDTand anti-VEGF of treatment-naïve wet AMD or a mixed pop-ulation of primary and recurrent AMD patients.7e9 However,few of these studies have focused on the role of combinationtherapy as a rescue treatment in eyes that did not respond toanti-VEGF agents, which is the topic assessed in our study.

Patients and Methods

This study was a retrospective, noncomparative, interventional caseseries. The clinical databases of the VMR Institute, the Doheny EyeInstitute, and the University of Iowa Department of Ophthalmologywere searched for patients who had received treatment with bothPDT and intravitreal injection of bevacizumab or ranibizumabwithin a 7-day period. All aspects of the study were approved by theHuman Subjects Review Boards at the University of SouthernCalifornia and the University of Iowa, and all study proceduresconformed to the tenets of the Health Insurance Portability andAccountability Act and the Declaration of Helsinki for researchinvolving human participants.

Our definition for treatment failure was defined by our inclusioncriteria. Inclusion criteria for the study were subfoveal choroidalneovascularization (CNV) secondary to AMD, persistence of sub-retinal fluid or retinal thickening of more than 250 mm by OCT atevery time point before PDT, and a minimum of 3 intravitrealinjections of anti-VEGF therapy in a period of 7 months. All neo-vascular lesion typesdoccult, classic, or mixeddas determined byfluorescein angiography were included. Exclusion criteria werepresence of subretinal fibrosis, severe retinal pigment epitheliumatrophy, CNV not related to AMD, polypoidal choroidal vasculo-pathy, history of panretinal photocoagulation or macular laserphotocoagulation, cataract surgery within 3 months before receivingcombined anti-VEGF and PDT, or concurrent ocular disease thatcould confound the visual acuity or OCT measurements.

Combination therapy consisted of an intravitreal injection ofeither 1.25 mg or 2.5 mg of bevacizumab (Avastin; Genentech, Inc)or 0.5 mg or 1.0 mg of ranibizumab followed within 7 days by half-fluence PDT (300 mW, 25 J for 83 seconds) with verteporfin(Visudyne; Novartis AG, Basel, Switzerland). Photodynamictherapy was performed using a 690-nm laser system (Visulas 690plus; Carl Zeiss Meditec, Inc, Dublin, CA).

All patients were examined on a near monthly basis fora minimum of 7 months before and 6 months after combinationtreatment. At each visit, visual acuity was measured using Snellen orEarly Treatment Diabetic Retinopathy Study charts. Opticalcoherence tomography measurements and a dilated fundus andmacula examination also were performed. Fluorescein angiogramswere obtained within 7 days before the PDT treatment. All fluo-rescein angiograms were obtained with a digital camera (Topcon50x system; Topcon Corp, Tokyo, Japan.) All OCT evaluationswere completed on spectral-domain instruments (SLO-OCT OPKOHealth, Miami, FL; Cirrus OCT, Humphrey Instruments, SanLeandro, CA; Spectralis OCT, Heidelberg Engineering, Heidelberg,Germany; or 3D OCT1000, Topcon Corp). Each patient was fol-lowed up exclusively by one of these instruments.

Consideration for retreatment with PDT was given at least 90days after the last PDT treatment.8 Although the final decision forretreatment was left to the attending physician, criteria includedpersistent or recurrent intraretinal or subretinal fluid.

Optical coherence tomography images for each visit wereclassified as either dry or wet by 2 masked readers. Presence ofsubretinal fluid or retinal thickening of more than 250 mm consti-tuted a wet status. Absence of subretinal fluid and retinal thick-ening of more than 250 mm constituted a fluid-free status. The

2

central 1000-mm zone was analyzed (central subfield) using theautomated software for each OCT machine to generate centralsubfield thickness values. Accurate segmentation of the internallimiting membrane and retinal pigment epithelium layers by theOCT algorithm was confirmed by the operator and was correctedmanually if needed.

The main outcomes measured were mean visual acuity at 1 or 2,3, and 6 months after combined PDT and anti-VEGF treatment andcentral subfield retinal thickness at 1 or 2, 3, and 6 months aftercombined PDT and anti-VEGF treatment. The secondary outcomemeasures were number of subretinal fluid-free visits, number oftreatment interventions, number of fluid-free visits, and length oftreatment-free intervals in the 7-month period before combinedPDT and anti-VEGF compared with the 6-month period aftercombined PDT and anti-VEGF.

All visual acuity measurements were converted to logarithm ofthe minimum angle of resolution (logMAR) units for comparisonand analysis using a Wilcoxon 2-tailed test. A 2-tailed paired t testwas used to determine significance of the macular thickness beforeand after combination therapy and changes in the interinjectioninterval. Data analysis was restricted to the 7 months beforecombination therapy and the 6 months after. Any patients whosedata were missing for a given follow-up point were not included inthe statistical calculations for that follow-up.

Results

One hundred forty-nine eyes were identified in the combinedclinical databases of the University of Iowa, the University ofSouthern California, and the VMR Institute as receiving PDT. Ofthese 149 eyes, 26 eyes in 26 patients received both PDT and anintravitreal injection of bevacizumab or ranibizumab within a 7-dayperiod and met the inclusion criteria for this study. These eyes werethe subjects of this study. Patient age, eye, and treatment historiesare shown in Table 1 (available at http://aaojournal.org). In the 7months immediately before combination therapy, the 26 eyes hadreceived a total of 127 injections. Despite this, no patient hada dry macula by OCT examination in the 6 months beforedeclaration of treatment failure. All patients had near monthlyvisits (average, 9.4 of a potential 13 monthly visits) for at least 7months before and 6 months after combined anti-VEGF andPDT treatment.

At baseline (defined as the time of initial combination therapy),the mean logMAR visual acuity was 0.74 (Fig 1). Compared withbaseline, the mean logMAR visual acuity improved significantlyat 1 month (0.64; P ¼ 0.01) and at 3 months (0.63; P ¼ 0.01),with a trend toward improvement at 6 months (0.63; P ¼ 0.06).At 1 month, 9 (34%) of 26 eyes improved by at least 1 line and 3(12%) of 26 eyes decreased by at least 1 line. At 3 months, 13(50%) of 26 eyes improved by at least 1 line and 5 (19%) of 26eyes had lost at least 1 line. At 6 months, 12 (46%) of 26 eyesimproved by at least 1 line and 5 (19%) of 26 eyes had lost atleast 1 line. At 6 months, 6 (23%) of 26 eyes had improved by atleast 3 lines and 1 (4%) of 26 eyes had lost at least 3 lines of vision.

At baseline, mean central subfield retinal thickness was 385 mm(Fig 2). Compared with baseline, central subfield significantlydecreased at 1 month (272 mm; P ¼ 4�10�5), at 3 months (290mm; P ¼ 3�10�4), and at 6 months (273 mm; P ¼ 4�10�5).

In the 7 months before combination therapy, 1 (4%) of the 26eyes had a dry macula (Table 2, available at http://aaojournal.org).However, in the 6 months after combination treatment, 13 (50%) ofthe 26 eyes had a dry macula on any monthly visit. Aggregatingall monthly visits, 1 (0.5%) of the 171 eye-visits had a drymacula before combination treatment compared with 41 (41%)of the 101 eye-visits in the 6 months after combination treatment(P¼ 1�10�5). At 1 month, 8 eyes (31%) were completely dry; at 3

Figure 1. Bar graph showing mean logarithm of the minimum angle ofresolution (logMAR) visual acuities. PDT ¼ photodynamic therapy.

Tozer et al � PDT and Anti-VEGF for Refractory AMD

months, 10 eyes (39%) were dry; and at 6 months, 11 eyes (42%)were dry.

In the 7 months before combination therapy, an injection wasadministered every 1.6 monthly visits. In the 6 months aftercombination treatment, the mean intertreatment interval increasedto 2.7 monthly visits per treatment (P¼ 0.002; Table 2, available athttp://aaojournal.org).

By 6 months after combination treatment, 76 retreatments wereadministered: 19 eyes had only repeat anti-VEGF injections, 4 eyesreceived repeat anti-VEGF and PDT combination therapy(1 combination and 1 anti-VEGF treatment, 1 combination and 2anti-VEGF treatments, 1 combination and 3 anti-VEGF treatments,and 1 combination treatment only, respectively), and 3 eyes did notrequire retreatment (Table 3, available at http://aaojournal.org).

No serious adverse events were recorded during this study toeither anti-VEGF injections or PDT. One patient did reporta 24-hour episode of moderate arm swelling after verteporfininjection the day after the first combination treatment that was notrelated to extravasation. No other events were reported.

Case Report

A 77-year-old white woman had classic CNV in her right eye.After 14 consecutive bevacizumab injections at 4- to 6-weekintervals over an 18-month period, she continued to have fluid

Figure 2. Graph showing macular thickness of the central 1000-mm region.Values were normalized to equal a percent of normal thickness for eachmachine used: Opko SLO/OCT ¼ 254 mm,24 Topcon ¼ 231 mm, Cirrus ¼262 mm,25 Spectralis ¼ 288 mm.26 OCT ¼ optical coherence tomography.

on OCT refractory to therapy at all visits (Fig 3AeE). Threemonths after combined bevacizumab and PDT, her visual acuityhad improved from 20/125 to 20/70 and subretinal fluid andedema had resolved completely (Fig 3F). Her OCT remainedclassified as showing a dry macula at all subsequent visits, andno further anti-VEGF therapy was administered. One year aftercombination therapy, her vision was 20/50 without recurrence offluid on OCT (Fig 3G).

Discussion

Most published studies report on PDT in patients who have notbeen treated previously. The 12-month results of the DENALItrial (the North America arm of the SUMMIT study) failed toshow noninferiority between monthly ranibizumab mono-therapy and pro re nata combined half-fluence or full-fluencePDT and ranibizumab injections with regard to visual acuityin treatment-naïve patients. However, it did show thatcombination therapy led to fewer retreatments.9 The MONTBLANC study showed a noninferior visual acuity responseat 12 months with pro re nata combined standard fluencePDT and ranibizumab injections as compared with ran-ibizumab monotherapy monthly injections, but the study didnot show benefits with respect to reducing the number ofranibizumab retreaments over 12 months in previouslyuntreated patients.10 The secondary end point of meanchange in central retinal thickness mirrored the mainoutcome of changes in visual acuity in these studies in thatranibizumab monotherapy was superior to combinationtherapy in the DENALI study and was not significantlydifferent between the 2 groups in the MONT BLANC study.Any added effect of PDT was probably masked by theoverwhelming effectiveness of anti-VEGF monotherapy forthe treatment of newly diagnosed CNV membranes. Otherlarge, prospective clinical trials also focused only on treat-ment-naïve eyes.11e14

A careful search using PubMed and Medline found 3studies in which combination therapy was used in patientswho previously had been treated with anti-VEGF mono-therapy. Shima et al15 retrospectively revieweda consecutive series of combined PDT and intravitrealbevacizumab in 22 eyes with serous pigment epithelialdetachment (pigment epithelial detachment with variouschoroidal vascular abnormalities). It is unclear, however,how many of these eyes had CNV resulting from AMD.

Bakri et al16 examined retrospectively the records of31 patients who were treated with triple therapy(bevacizumab, dexamethasone, and PDT). Eighteen ofthese patients had been treated previously with intravitrealbevacizumab, ranibizumab, or pegaptanib. Four of these18 patients had retinal angiomatous proliferation. In thispreviously treated subset, mean baseline visual acuity was0.67 logMAR initially and 0.76 logMAR at last follow-up(P ¼ 0.31) Mean central macular thickness was 325 mm atbaseline and 265 mm at last follow-up (P ¼ 0.10). Thesepatients received a mean of 2.4 anti-VEGF injections and0.2 repeat triple therapy treatments 6 months after tripletherapy.

Goff et al17 retrospectively identified 54 eyes thatpreviously had received bevacizumab monotherapy. Twenty

3

Figure 3. Images obtained 18 months before combination therapy: (A) color fundus photograph, (B) early fluorescein angiography (FA) image, (C) late FAimage, and (D) axial scan through the fovea; (E) axial scan through the fovea at the time of combination therapy and (F) axial scan through the fovea 3months after combination therapy and (G) axial scan through the fovea obtained 1 year after combination therapy.

Ophthalmology Volume -, Number -, Month 2013

percent of these eyes had intravitreal bevacizumab combinedwith PDT. Of the 38 eyes that received previous treatment, 8had been treated with the anti-VEGF drug pegaptanib, but itis not indicated in the article if any of these eyes receivedcombination anti-VEGF and PDT. These are the 3 publishedreports of previously treated patients who were given combi-nation therapy of PDT along with an anti-VEGF agent.Clinicians have recognized this group of patients who initiallyor after previous success no longer respond to anti-VEGFdrugs. The Super-Dose Anti-VEGF trial is evaluating2.0-mg ranibizumab injections to treat individuals withrecurrent fluid after conventional dose injections. Preliminary12-month results are encouraging and showed significantanatomic and visual acuity improvement.18

The study that most closely mirrors our was done byKloos et al19 in Germany. Their study examined 18 AMDpatients who had received on average 7.1 injections andthen were treated with PDT. They defined treatment failureas only 2 consecutive injections with no improvement insubretinal fluid. They showed that adding PDT to thetreatment regimen stabilized visual acuity and resulted infewer anti-VEGF retreatments, findings very similar to ourown.

Our study adds to the limited literature supportingcombined anti-VEGF and PDT as an effective treatment foreyes partially responsive or nonresponsive to anti-VEGFmonotherapy. Statistically significant improvements inlogMAR visual acuities were seen at 1 and 3 months, andsignificant decreases in central subfield retinal thickness wereseen at 1, 3, and 6 months. Although the visual acuityimprovements were statistically significant, they were smalland may not be clinically significant. However, anyimprovement in this population is important because of theprogressive visual loss the patients had been experiencing inthe 6 months before combination therapy (Fig 1). Thenumber of visits with no subretinal fluid increased from0.5% to 45% after the initiation of combination therapy.

4

The interval between treatments increased from once every1.6 months in the year before combination therapycompared with once every 2.7 months (P�0.05) aftercombination therapy. The reason similar results were notfound in some previous studies involving combinationtherapy may be the result of differences in the study patientpopulation. Because anti-VEGF is so overwhelminglyeffective in most patients, by studying treatment-naïve indi-viduals, the additive effects of PDT are not apparent.However, by solely studying patients who already have beenshown to respond poorly to anti-VEGF, we believe our studyis able to show more clearly the potential of combinationtherapy over anti-VEGF monotherapy.

The rationale behind using the combination of PDT andanti-VEGF for refractory AMD relates to the mechanism ofaction of the 2 treatment methods and their effect on angio-genesis. The pathogenesis of choroidal new vessel formationis complex and therapies that target different pathways of thisprocess have the potential to be synergistic. The effects ofVEGF are mediated through complex pathways that affectcell proliferation and vasopermeability, cell migration, geneexpression,20 nitrous oxide production,21 focal adhesionturnover,22 and actin reorganization.23 Newly formedvessels, however, quickly become enveloped by pericytes,which have been shown to protect vessels from the effectsof anti-VEGF agents.24 Photodynamic therapy occludesthese abnormal new vessels using light-stimulated verte-porfin. The increased concentration of low-density lipopro-tein present in neovascular tissue allows the verteporfin toaccumulate selectively in that tissue while sparing mostnormal retinal vasculature. On stimulation with the properwavelength light, the porphyrin molecule causes oxidativedamage that destroys and occludes any adjacent vessels.25,26

By combining PDT with an anti-VEGF agent, both sup-pression of a VEGF-driven angiogenesis process and thedestruction of abnormal mature vasculature are achieved andthus are additive.

Tozer et al � PDT and Anti-VEGF for Refractory AMD

This study is limited by the small number of patients and itsretrospective design, the absence of protocol visual acuitymeasurements and refraction, and the use of 3 different OCTmachines. The inherently limited nature of our retrospectivedesign led to the inclusion of patients who had less than perfectfollow-up. Despite our routine of monthly examinations andOCTs, follow-up was not perfect. For this reason, we incor-porated into the study design a comparison of parametersreflecting treatment outcome between an extended periodbefore combination therapy and an extended period aftercombination therapy. The choice of 7 months before combi-nation therapy and 6 months after combination therapy wasentirely arbitrary. However, comparing the 6 patients who hadperfect follow-up in the 7 months before combination therapywith the remaining 20 patients actually showed no differencein final outcome. The 6 patients with perfect monthly follow-up on average received more injections in the prior 7 monthsthan the rest of the study patients (6.7 vs. 4.4 injections), buthad no difference in baseline visual acuity (P¼ 0.21) or centralretinal thickness (P ¼ 0.77). There was also no statisticaldifference in visual acuity or central retinal thickness betweenthe 2 groups at 6 months after combination therapy (P ¼ 0.26and P ¼ 0.53, respectively). The pro re nata treatmentapproach we used in our study has been validated by theComparisons of Age-Related Macular Degeneration Treat-ments Trials (CATT).27 Although OCT measurements wereperformed on 3 different spectral-domain machines, eachpatient was followed up exclusively by 1 machine, althoughpatients were followed up by different doctors with similar, ifnot identical, treatment preferences. We used a clinicallyrelevant interpretation of the OCT in our assessment of a dryversus a wet macula, one that the average practicing retinaspecialist would use to treat or defer treatment. This is differentfrom the CATT reading center interpretation, which concludedthat more than 50% of maculae in the CATT study had fluideven after 24 months of monthly intravitreal anti-VEGFinjections.28 Additionally, we could not find the data thatexplicitly indicate what percent of CATT patients wouldhave met our inclusion criteria. The chairman of the studyhas suggested that this microscopic fluid identified by thereading center was not clinically relevant and did notcorrelate to decreased vision (Martin DF. Pyon lecture.Presented at: American Society of Retina Specialist AnnualMeeting, August 26, 2012; Las Vegas).

In this study, both main outcome measures (visual acuityand central retinal thickness) and secondary outcomemeasures(number of fluid-free visits and interval between treatments)improved in the 6 months after PDT was initiated comparedwith the 7 months before PDT. We cannot say whetherachieving the non-visual acuity end points would result inbetter visual acuity results, but fluid-free intervals, centralretinal thickness, and treatment intervals are important markersof disease control for clinicians.

The failure of anti-VEGF monotherapy to provide a long-lasting resolution of intraretinal or subretinal fluid is a majorproblem for retina specialists and will not be solved untillonger-lasting agents are developed.29 Even with longer-lasting drugs, however, there will probably be some eyesthat eventually become resistant to treatment. The additiveeffect of PDT with verteporfin dye is available to all

practitioners as a Food andDrugAdministration-approved andeffective therapeutic strategy for these eyes. This combinationtherapy seems to be safe in that it does not cause vision loss,but also reduces fluid and improves visual acuity. To the bestof our knowledge, this is the first study to show the additiveeffect of combining PDT and anti-VEGF treatment in a pop-ulation of patients with wet AMD who are either partially orcompletely nonresponsive to anti-VEGF monotherapy.

References

1. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Oph-thalmol 2004;122:564–72.

2. Ferris FL III, Fine SL, Hyman L. Age-related maculardegeneration and blindness due to neovascular maculopathy.Arch Ophthalmology 1984;102:1640–2.

3. Rosenfeld PJ, Brown DM, Heier JS, et al, MARINA StudyGroup. Ranibuzmab for neovascular age-related maculardegeneration. N Engl J Med 2006;355:1419–31.

4. Brown DM, Michels M, Kaiser PK, et al; ANCHOR StudyGroup. Ranibizumab versus verteporfin photodynamic therapyfor neovascular age-related macular degeneration: two-yearresults of the ANCHOR Study. Ophthalmology 2009;116:57–65.

5. Rosenfeld PJ, Shapiro H, Tuomi L, et al; MARINA andANCHOR Study Groups. Characteristics of patients losingvision after 2 years of monthly dosing in the phase III rani-bizumab clinical trials. Ophthalmology 2011;118:523–30.

6. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosingregimen for intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study.Am J Ophthalmol 2009;148:43–58.

7. Antoszyk AN, Tuomi L, Chung CY, Singh A; FOCUS StudyGroup. Ranibizumab combined with verteporfin photodynamictherapy in neovascular age-related macular degeneration(FOCUS): year 2 results. Am J Ophthalmol 2008;145:862–74.

8. Treatment of Age-Related Macular Degeneration with Photo-dynamic Therapy (TAP) Study Group. Photodynamic therapyof subfoveal choroidal neovascularization in age-relatedmacular degeneration with verteporfin: one-year results of2 randomized clinical trialsdTAP report 1. Arch Ophthalmol1999;117:1329–45.

9. QTL Inc. 12-month results from DENALI study evaluatingverteporfin PDT (Visudyne) combination therapy [press release].Vancouver, Canada: QTL Inc.; June 15, 2010. Available at:http://www.qltinc.com/newsCenter/2010/100615.htm. AccessedDecember 3, 2010.

10. QTL Inc. QLT announces 12-month results from Novartissponsored Mont Blanc study evaluating standard-fluence Visu-dyne combination therapy [press release]. Vancouver, Canada:QTL Inc.; June 15, 2009. Available at: http://www.qltinc.com/newsCenter/2009/090615.htm. Accessed December 3, 2010.

11. Sacu S, Michels S, Prager F, et al. Randomised clinical trial ofintravitreal Avastin vs photodynamic therapy and intravitrealtriamcinolone: long-term results. Eye (Lond) 2009;23:2223–7.

12. Spielberg L, Leys A. Treatment of neovascular age-relatedmacular degeneration with a variable ranibizumab dosingregimen and one-time reduced-fluence photodynamic therapy:the TORPEDO trial at 2 years. Graefes Arch Clin Exp Oph-thalmol 2010;248:943–56.

13. Potter MJ, Claudio CC, Szabo SM. A randomised trial ofbevacizumab and reduced light dose photodynamic therapy in

5

Ophthalmology Volume -, Number -, Month 2013

age-related macular degeneration: the VIA study. Br J Oph-thalmol 2010;94:174–9.

14. Lim JY, Lee SY, Kim JG, et al. Intravitreal bevacizumab aloneversus in combination with photodynamic therapy for thetreatment of neovascular maculopathy in patients aged 50years or older: 1-year results of a prospective clinical study.Acta Ophthalmol 2012;90:61–7.

15. Shima C, Gomi F, Sawa M, et al. One-year results ofcombined photodynamic therapy and intravitreal bevacizumabinjection for retinal pigment epithelial detachment secondaryto age-related macular degeneration. Graefe’s Arch Clin andExp Ophthalmol 2009;247:899–906.

16. Bakri SJ,CouchSM,McCannelCA,EdwardsAO.Same-day tripletherapy with photodynamic therapy, intravitreal dexamethasone,and bevacizumab in wet age-related macular degeneration. Retina2009;29:573–8.

17. Goff MJ, Johnson RN, McDonald HR, et al. Intravitrealbevacizumab for previously treated choroidal neo-vascularization from age-related macular degeneration. Retina2007;27:432–8.

18. Brown DM, Chen E, Mariani A, Major JC Jr; SAVE StudyGroup. Super-dose Anti-VEGF (SAVE) trial: 2.0 mg intravitrealranibizumab for recalcitrant neovascular macular degener-ationdprimary end point. Ophthalmology 2013;120:349–54.

19. Kloos P, Niederberger H, Valmaggia C. Photodynamic therapyin “secondary sick RPE syndrome” after repeated intravitrealinjections of VEGF inhibitors in patients with wet age-relatedmacular degeneration [in German]. Klin Monbl Augenheilkd2011;228:340–4.

20. Ellis L, Hicklin D. VEGF-targeted therapy: mechanism of anti-tumour activity. Nat Rev Cancer 2008;8:579–91.

21. van der Zee R, Murohara T, Luo Z, et al. Vascular endothelialgrowth factor/vascular permeability factor augments nitric

6

oxide release from quiescent rabbit and human vascularendothelium. Circulation 1997;95:1030–7.

22. Abedi H, Zachary I. Vascular endothelial growth factor stim-ulates tyrosine phosphorylation and recruitment to new focaladhesion of focal adhesion kinase and paxillin in endothelialcells. J Biol Chem 1997;272:15442–51.

23. Rousseau S, Houle F, Landry J, Huot J. p38 MAP kinaseactivation by vascular endothelial growth factor mediates actinreorganization and cell migration in human endothelial cells.Oncogene 1997;15:2169–77.

24. Benjamin LE, Hemo I, Keshet E. A plasticity window forblood vessel remodeling is defined by pericyte coverage of thepreformed endothelial network and is regulated by PDGF-Band VEGF. Development 1998;125:1591–8.

25. Dougherty TJ, Henderson BW, Gomer CJ, et al. Photody-namic therapy. J Natl Cancer Inst 1998;90:889–905.

26. Palanker D, Blumenkranz MS, Weiter JJ. Retinal laser therapy:biophysical basis and applications. In: Ryan SJ, ed-in-chief.Retina. 4th ed. vol. 1. Philadelphia, PA: Elsevier Mosby; 2006:539–55.

27. CATT Research Group. Ranibizumab and bevacizumab forneovascular age-related macular degeneration. N Engl J Med2011;364:1897–908.

28. Comparison of Age-Related Macular Degeneration Treat-ments Trials (CATT) Research Group; Martin DF,Maguire MG, Fine SL, et al. Ranibizumab and bev-acizumab for treatment of neovascular age-related maculardegeneration: two-year results. Ophthalmology 2012;119:1388–98.

29. Nguyen QD, Shah SM, Browning DJ, et al. A phase I study ofintravitreal vascular endothelial growth factor Trap-Eye inpatients with neovascular age-related macular degeneration.Ophthalmology 2009;116:2141–8.

Footnotes and Financial Disclosures

Originally received: August 16, 2012.Final revision: March 1, 2013.Accepted: March 8, 2013.Available online: ---. Manuscript no. 2012-1267.1 Doheny Eye Institute and the Department ofOphthalmology, Keck School ofMedicine, University of Southern California, Los Angeles, California.2 VMR Institute, Huntington Beach, California.3 Department of Ophthalmology & Visual Sciences, Carver College ofMedicine, The University of Iowa, Iowa City, Iowa.

Financial Disclosure(s):The author(s) have no proprietary or commercial interest in any materialsdiscussed in this article.

Supported by a Medical Student Fellowship from Research to PreventBlindness, Inc, New York, New York; the National Institutes of Health,Bethesda, Maryland (grant no.: EY03040). James C. Folk is the Judith(Gardner) and Donald H. Beisner, M.D., Professor of VitreoretinalDiseases and Surgery at The University of Iowa. Vinit B. Mahajan issupported by the National Institutes of Health (grant no.: K08EY020530)and by Research to Prevent Blindness, Inc. The funding organizations hadno role in the design or conduct of this research.

Correspondence:Lawrence P. Chong, MD, VMR Institute, 7677 Center Avenue, Suite 400,Huntington Beach, CA 92647. E-mail: lchong@usc.edu.