Mixed Results in Triple Therapy for AMD
Eight studies produce a range of benefits but no firm conclusions.
Andre J. Witkin, MD • Julia A. Haller, MD
In 2000, the FDA approved the use of photodynamic therapy for treatment of predominantly classic choroidal neovascularization secondary to age-related macular degeneration, which slowed the rate of vision loss but did not offer vision gain for the vast majority of patients with exudative AMD.1,2 In 2006, ranibizumab, a recombinant antibody fragment targeted against vascular endothelial growth factor type A (VEGF-A), was approved by the FDA and demonstrated stabilization and even unprecedented visual acuity gains in eyes with all subtypes of exudative AMD.3,4
Since then, treatment with ranibizumab and bevacizumab has become the mainstay of therapy for exudative AMD (Figure 1). However, because anti-VEGF treatment requires frequent clinic visits and injections, alternative methods of therapy to reduce the number of treatments and visits have been investigated, and used as well, for eyes “resistant” to anti-VEGF injections alone. Triple therapy — using PDT, anti-VEGF therapy and corticosteroids — has been advocated to reduce the number of treatments, while potentially offering comparable visual results to anti-VEGF monotherapy and as “rescue therapy” for eyes classified as nonresponders.5-12
FIgure 1. Anti-VEGF medications have become the mainstay for treatment of exudative AMD.
STANDARD TREATMENT PROS AND CONS
The standard PDT protocol involves intravenous infusion of verteporfin, followed by administration of nonthermal lowenergy red laser light over 83 seconds. Photoactivation of verteporfin within the CNV lesion results in free radical formation, which causes damage to the vascular endothelium and, finally, vessel occlusion.1,2 Although much less destructive than standard laser photocoagulation, PDT can induce choroidal hypoperfusion, and the release of free radicals is postulated to cause some irreversible damage to the choroid.13,14 PDT has also been shown to induce up-regulation of intraocular levels of VEGF.15
Attempts have been made to reduce some of the toxicity of PDT by reducing the “fluence” of treatment,16-18 or by combining PDT with intraocular corticosteroid injections.19-21 Reduced-fluence PDT involves either reducing the power of laser light (<50 J/cm2) or reducing the time of exposure (<83 seconds). Studies have shown that reduced-fluence PDT has similar therapeutic effects on CNV membranes, while potentially reducing the amount of choroidal toxicity seen with full-fluence PDT.16-18 Combining intravitreal corticosteroid injection with PDT may improve visual outcomes compared to PDT alone, possibly by diminishing some of the secondary pro-inflammatory effects of PDT. Combining these two therapies also decreased the need for retreatment with PDT in several studies.19-21
Prior to the FDA approval of ranibizumab, intravitreal injections of the full-length humanized monoclonal antibody targeted against VEGF-A, bevacizumab, gained widespread use for treatment of exudative AMD, with results apparently comparable to ranibizumab.22 Since 2006, both ranibizumab and bevacizumab have been used by clinicians to treat exudative AMD. Recently, results from the large, prospective, randomized Comparison of AMD Treat ments Trial (CATT) showed at one year that ranibizumab and bevacizumab have roughly equivalent effects on visual acuity in patients with exudative age-related macular degeneration.23
Ranibizumab and bevacizumab were revolutionary advances in the treatment of exudative AMD; however, the burden of repeated monthly injections was and is significant. Clinicians immediately attempted to decrease the number of injections by using PRN protocols. With the use of optical coherence tomography and strict retreatment criteria, PRN dosing with intravitreal ranibizumab and bevacizumab has approached equivalent visual acuity results to monthly dosing.23,24 Although anti-VEGF therapy is visually and anatomically beneficial in a large number of patients, some CNV membranes do not respond to these medications as well as others. Despite monthly dosing with anti-VEGF medications for one year, roughly 5% of patients continue to have signs of exudation on OCT.25,26
Several studies have suggested a benefit to combining intravitreal anti-VEGF therapy with either PDT or intravitreal corticosteroids.27-31 In addition, combination therapy for exudative AMD has been proposed as a solution for patients who continue to have signs of exudation on OCT despite monthly anti-VEGF injections. This type of multipronged approach is apparently analogous to that used by oncologists to treat multifactorial, malignant, proliferative diseases, and is credited with leading to the eradication of disease, as opposed to disease stabilization.32
By the same rationale, “triple-therapy” with all three medications may reduce the number of injections needed for visual and anatomic improvement. In theory, the PDT arm of the triad causes vaso-occlusion within the CNV membrane, while secondary upregulation of proinflammatory cytokines and VEGF released after PDT is inhibited by corticosteroids and anti-VEGF medications. The results of eight studies using triple therapy for exudative AMD are reviewed below.5-12
Four studies used dexamethasone as an intravitreal corticosteroid,5-8 two studies used intravitreal triamcinolone acetonide9,10 and one study used sub-Tenon's triamcinolone.11 Of note is the fact that none of these published studies was randomized or controlled. One additional prospective, randomized, controlled study, the RADICAL study, is currently examining triple therapy with PDT, dexamethasone and ranibizumab; however, the results remain unpublished.12 All eight studies allowed all types of CNV lesions to be included. Results from these studies are summarized in Table 1.
Dexamethasone, Bevacizumab and PDT
Augustin et al. reported a prospective, noncomparative, interventional case series of triple therapy in 104 patients with exudative AMD.5 All patients were treatment-naïve. The authors used mildly reduced-fluence PDT (70 vs 83 seconds) initially, followed by a same-day single-port 25-gauge vitrectomy (removal of 0.5 mL) and an injection of 0.8 mg dexamethasone and 1.5 mg of bevacizumab. Patients were subsequently followed at six-week intervals, with a mean follow-up of 40 weeks (range 22-60 weeks).
Eighteen patients (17%) received a single additional intravitreal injection of bevacizumab for persistent macular edema on OCT without detectable angiographic leakage. In an additional five cases (5%), a second cycle of triple therapy was used to treat recurrent angiographic CNV activity. Mean visual acuity improved significantly, from 20/126 to 20/85 (P<.01), and 39.4% of the patients gained three or more lines of vision, while mean retinal thickness decreased from 464 to 281 μm (P<.01). No patients had a significant increase in intraocular pressure.
Bakri et al. reported a retrospective case series of triple therapy for AMD in 31 patients.6 Eighteen patients (58%) had received anti-VEGF therapy prior to enrollment (mean 3.6 injections). They used reduced-fluence PDT (25 vs 50 J/cm2), followed by intravitreal injections of 0.2 mg dexamethasone and 1.25 mg bevacizumab at the same visit. Patients had at least 12 months of follow-up (mean 13.7 months) and were followed at one- to two-month intervals. Retreatment was given in all patients, and the retreatment criteria were physician-dependent.
A mean of 1.7 anti-VEGF injections and 0.2 repeat triple therapy treatments per patient were given in the first six months, and a mean of 2.3 anti-VEGF injections and 0.3 repeat triple therapy treatments were given throughout follow-up. Mean visual acuity improved only minimally, from 20/81 to 20/76 (P=.7), while there was a modest improvement in mean retinal thickness (293 to 245 μm, P=.05). No patients had a significant increase in IOP.
Forte et al. reported a retrospective comparative case series comparing triple therapy in 61 eyes (56 patients) to monotherapy with anti-VEGF medications in 40 eyes (40 patients).7 All patients were treatment-naïve. For triple therapy, the authors used full-fluence PDT, followed by intravitreal injections of 0.4 mg dexamethasone and either 1.25 mg bevacizumab (26 eyes) or 0.5 mg ranibizumab (35 eyes) on the same day. Patients in both groups had at least 12 months of follow-up (mean 14.1 months in the triple therapy group) and were followed at one- to two-month intervals. Retreatment was given at the discretion of the physician, and a mean of 0.92 retreatments with triple therapy were given over 12 months to the triple therapy group.
Mean visual acuity at 12 months in the triple therapy group improved from 20/174 to 20/120 (P =.02), and mean retinal thickness improved from 323 to 212 μm (P <.01). The triple therapy group showed a significantly lower total number of treatments during follow-up (1.92 vs. 3.12), a significantly lower number of treatments per month (0.13 vs 0.19) and a significantly longer time before the first retreatment (5.4 vs 3.6 months) when compared to the monotherapy group.
Ehmann et al. reported a retrospective interventional case series in 32 eyes of 30 patients.8 All patients were treatment-naïve. The authors used half-fluence PDT (25 vs 50 J/cm2), followed by an intravitreal injection of 0.8 mg dexamethasone the same day and intravitreal injections of 1.25 mg bevacizumab at one and seven weeks after PDT. All patients were followed for 12 months. At 13 weeks after PDT and dexamethasone, each patient had a repeat OCT and fluorescein angiography to assess CNV activity.
The mean number of treatment cycles was 1.4; 22 (69%) eyes required only one cycle of treatment, eight (25%) received two cycles, one (3%) received three cycles, and one (3%) received four cycles of treatment. Visual acuity improved from 20/110 to 20/68 (P <.01) at 12 months, and 31% gained more than three lines. Foveal thickness decreased from 328 to 216 μm (P <.01). No patients had a significant increase in IOP.
Triamcinolone, Bevacizumab and PDT
Ahmadieh et al. reported a prospective interventional case series in 17 eyes with we AMD.9 All patients were treatment-naïve. They used full-fluence PDT, followed by intravitreal injections of 2 mg triamcinolone and 1.25 mg bevacizumab 48 hours after PDT. Patients had a mean follow-up of 50.4 weeks (±15.5 weeks) and were followed at six-week intervals. Retreatment with bevacizumab was given for signs of CNV activity on angiography.
Seven eyes (41%) remained stable following the initial therapy, while 10 eyes (59%) needed retreatment (one ([n=1], two [n=7], or three [n=2] additional bevacizumab injections). Mean visual acuity in the triple therapy group improved from 20/110 to 20/51 (P <.01) after 24 weeks, and mean retinal thickness improved from 395 to 221 μm (P =.05) after 24 weeks. In one patient, IOP increased to 34 mm Hg after one week, which was controlled with eyedrops.
Yip et al. reported a prospective interventional case series in 36 eyes.10 Fifteen eyes (42%) had undergone prior treatment with PDT. In this study, the authors used full-fluence PDT, followed by intravitreal injections of 4 mg triamcinolone and 1.25 mg bevacizumab at the same visit. Patients had a mean follow-up of 14.7 (6.9–19.2) months. Patients were followed-up at one week, six weeks and three months, and then every three months after treatment. Intravitreal bevacizumab was injected if fluorescein angiography showed signs of active CNV at three months; eight eyes (22%) required a repeat injection of bevacizumab.
Mean visual acuity improved only minimally after six months, from 20/332 to 20/303 (P =.60), although visual acuity was better at three months after triple therapy (20/276, P =.32). At six months, 28% of patients gained three or more lines of vision; however, 25% of patients lost three or more lines. Retinal thickness on OCT was not calculated. One eye lost more than six lines due to a retinal pigment epithelium rip, three eyes developed a significant cataract requiring surgery, and three had elevations in IOP that were controlled with drops.
Kovacs et al. reported a retrospective case series of triple therapy in 26 patients.11 All patients were treatment-naïve. The authors used half-fluence PDT (25 vs 50 J/cm2), followed by an intravitreal injection of 1.25 mg bevacizumab and a sub-Tenon's injection of 40 mg triamcinolone at the same visit. Patients were followed for 56.7 (+/−28.1) weeks; patients were monitored at variable intervals at the physician's discretion. Retreatment with intravitreal bevacizumab was given at the physician's discretion. Thirteen of 26 eyes (50%) needed retreatment during the study.
At the three-month time point, only four of 24 eyes (16.7%) required retreatment, while nine of 22 eyes (40.9%) required retreatment by six months, and 11 of 18 eyes (61.1%) required retreatment by 12 months. Mean visual acuity improved only mildly at 12 months, from 20/243 to 20/218 (P =.21), although improvement in visual acuity was statistically significant at three and six months after triple therapy. Mean OCT thickness decreased by 102 μm at 12 months (n=10). In one patient, an increase in IOP after treatment was controlled with eyedrops.
Dexamethasone, Ranibizumab and PDT
The RADICAL study is a phase 2 trial comparing the efficacy of ranibizumab or reduced-fluence PDT combination therapy, with or without dexamethasone, in 162 treatmentna�ve patients with exudative AMD; results were presented at the 2010 ASRS meeting but have not yet been published.12 At 12 months, triple therapy with half-fluence PDT, 0.5 mg ranibizumab, and 0.5 mg dexamethasone resulted in a VA improvement of 6.8 letters, compared with 6.5 letters in the ranibizumab monotherapy group. After 24 months, triple therapy resulted in a mean of 4.2 vs 8.9 retreatment visits in the ranibizumab monotherapy group.
Monthly intravitreal injections with ranibizumab remain the gold standard for the treatment of exudative AMD, although one-year results from the CATT trial suggest that monthly injections of bevacizumab, as well as PRN dosing with either medication, are roughly equivalent to monthly ranibizumab.23 However, monthly injections are burdensome; even PRN treatment requires frequent visits. Triple therapy offers the potential for a longer-lasting alternative for patients who are unable to visit the clinic frequently, and it may be an option for treatment of patients who continue to demonstrate signs of exudation despite monthly anti-VEGF monotherapy. The trade-off in terms of visual acuity, however, remains poorly defined.
The results of the studies summarized above suggest the approach may have some promise, particularly the studies by Augustin et al.,5 Ehmann et al.8 and Ahmadieh et al.,9 as well as preliminary results from the RADICAL study.12 The more modest visual im provement in the other studies is difficult to interpret. It may be due, in part, to the inclusion of patients who had undergone prior treatment for AMD, as in the studies by Bakri et al.6 and Yip et al.,10 or a lack of standardized follow-up and retreatment protocols, or it may accurately reflect the therapy's visual drawbacks. In the studies by Yip et al.10 and Kovacs et al.,11 visual improvement was seen at three months after triple therapy, followed by deterioration of visual acuity at the six-month visit, but whether this result is due to a need for closer follow-up or repeated scheduled treatment or reflects lesser efficacy of the treatment remains unknown.
In addition to the lack of clear guidelines for when, and if, triple therapy is indicated in exudative AMD, the exact doses and types of medications that should be used in triple therapy remain unclear. The majority of studies summarized above utilized reduced-fluence PDT, but the doses varied; bevacizumab was the anti-VEGF agent of choice. Dexamethasone is more potent than triamcinolone, while its half-life is significantly shorter. Side effects of intraocular corticosteroids include increased IOP and cataract formation.33 Dexamethasone seemed to have a similar beneficial effect to triamcinolone, while decreasing the risk of IOP elevation; none of the 228 patients who received dexamethasone required treatment for increased IOP, while five of 80 patients who received triamcinolone required IOP-lowering medications.5-11
To date, triple therapy with PDT, anti-VEGF medication and corticosteroids remains an incompletely evaluated, but potentially useful, alternative to anti-VEGF monotherapy in selected patients with exudative AMD. Further results, especially from prospective, randomized, controlled trials such as the RADICAL study, will help elucidate the efficacy of triple therapy in comparison to anti-VEGF monotherapy. Drug selection and dosage, fluence of PDT, and treatment and follow-up schedules are variables that remain to be carefully studied and compared. RP
1. 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: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol. 1999; 117:1329-1345.
2. Azab M, Boyer DS, Bressler NM, et al; Visudyne in Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol. 2005;123: 448-457.
3. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
4. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;35:1432-1444.
5. Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27:133-140.
6. 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;29:573-578.
7. Forte R, Bonavolontà P, Benayoun Y, Adenis JP, Robert PY. Intravitreal ranibizumab and bevacizumab in combination with full-fluence verteporfin therapy and dexamethasone for exudative age-related macular degeneration. Ophthalmic Res. 2011;45:129-134.
8. Ehmann D, Garc�a R. Triple therapy for neovascular age-related macular degeneration (verteporfin photodynamic therapy, intravitreal dexamethasone, and intravitreal bevacizumab). Can J Ophthalmol. 2010;45:36-40.
9. Ahmadieh H, Taei R, Soheilian M, Riazi-Esfahani M, Karkhaneh R, Lashay A, Azarmina M, Dehghan MH, Moradian S. Single-session photodynamic therapy combined with intravitreal bevacizumab and triamcinolone for neovascular age-related macular degeneration. BMC Ophthalmol. 2007;7:10.
10. Yip PP, Woo CF, Tang HH, Ho CK. Triple therapy for neovascular age-related macular degeneration using single-session photodynamic therapy combined with intravitreal bevacizumab and triamcinolone. Br J Ophthalmol. 2009; 93 :754-758.
11. Kovacs KD, Quirk MT, Kinoshita T, Gautam S, Ceron OM, Murtha TJ, Arroyo JG. A retrospective analysis of triple combination therapy with intravitreal bevacizumab, posterior sub-tenon's triamcinolone acetonide, and low-fluence verteporfin photodynamic therapy in patients with neovascular age-related macular degeneration. Retina. 2011;31:446-452.
12. Hudson H. RADICAL: 24-month results of a phase II exploratory randomized clinical trial of reduced fluence vPDT-anti-VEGF-dexamethasone in AMD. Paper presented at: Annual meeting of the American Society of Retinal Specialists; Vancouver, Canada; August 28-September 1, 2010.
13. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H. Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci. 2002;43:830-841.
14. Michels S, Schmidt-Erfurth U. Sequence of early vascular events after photodynamic therapy. Invest Ophthalmol Vis Sci. 2003;44:2147-2154.
15. Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2003;44:4473-4480.
16. Azab M, Boyer DS, Bressler NM, et al; Visudyne in Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol. 2005;123: 448-457.
17. Michels S, Hansmann F, Geitzenauer W, et al. Influence of treatment parameters on selectivity of verteporfin therapy. Invest Ophthalmol Vis Sci. 2006;47:371-376.
18. Sacu S, Varga A, Michels S, et al. Reduced fluence versus standard photodynamic therapy in combination with intravitreal triamcinolone: short-term results of a randomised study. Br J Ophthalmol. 2008;92:1347-1351.
19. Spaide RF, Sorenson J, Maranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2005;112:301-304.
20. Augustin AJ, Schmidt-Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone in all types of choroidal neovascularization due to age-related macular degeneration. Ophthalmology. 2006;113:14-22.
21. Chan WM, Lai TYY, Wong AL, Tong JP, Liu DTL, Lam DSC. Combined photodynamic therapy and intravitreal triamcinolone injection for the treatment of subfoveal choroidal neovascularization in age related macular degeneration: a comparative study. Br J Ophthalmol. 2006;90:337-341.
22. Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:363-372.
23. CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
24. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomographyguided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.
25. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148:43-58.
26. Gupta OP, Shienbaum G, Patel AH, Fecarotta C, Kaiser RS, Regillo CD. A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact. Ophthalmology. 2010;117:2134-2140.
27. Dhalla MS, Shah GK, Blinder KJ, Ryan Jr EH, Mittra RA and Tewari A. Combined photodynamic therapy with verteporfin and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration. Retina. 2006;26:988-993.
28. Kaiser PK, Boyer DS, Garcia R, et al. Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2009;116(4):747-755.
29. Smith BT, Dhalla MS, Shah GK, Blinder KJ, Ryan Jr EH, and Mittra RA. Intravitreal injection of bevacizumab combined with verteporfin photodynamic therapy for choroidal neovascularization in age-related macular degeneration. Retina. 2008;28:675-681.
30. Heier JS, Boyer DS, Ciulla TA, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: Year 1 results of FOCUS study. Arch Ophthalmol. 2006;124:1532-1543.
31. Ahmadieh H, Taei R, Riazi-Esfahani M, et al. Intravitreal bevacizumab versus combined intravitreal bevacizumab and triamcinolone for neovascular agerelated macular degeneration: six-month results of a randomized clinical trial. Retina. 2011 May 6. [Epub ahead of print]
32. Spaide RF. Perspectives: Rationale for combination therapies for choroidal neovascularization. Am J Ophthalmol. 2006;141:149-156.
33. Rhee DJ, Peck RE, Belmont J, Martidis A, Liu M, Chang J, Fontanarosa J, Moster MR. Intraocular pressure alterations following intravitreal triamcinolone acetonide. Br J Ophthalmol. 2006;90:999-1003.
|Andre J. Witkin, MD, is a vitreoretinal surgery fellow at the Wills Eye Institute in Philadelphia. Julia A. Haller, MD, is ophthalmologist-in-chief at Wills and professor and chair of the department of ophthalmology at Thomas Jefferson University, also in Philadelphia. Neither author reports any financial interest in any products mentioned in this article. Dr. Witkin can be reached via e-mail at firstname.lastname@example.org.|