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`PUBLISHED 20 MARCH 2008
`
`Ron P. Gallemore, MD, PhD, and David Nguyen
`When Anti-VEGF Treatment Fails
`Retina specialists are charting new territory and learning how to spot and react to failed
`anti-VEGF therapy.
`
`Anti-VEGF therapy has become the mainstay for managing patients with wet macular degeneration. While the response rate in
`published studies ranges from 70 to 95 percent depending on the agent used and the treatment paradigm employed, it is clearly
`not 100 percent, and some patients do fail treatment. It is these treatment failures that usually represent the most challenging
`cases. Here, I review the limited data available that relates to the management of such treatment failures and present our
`evolving approach for these uncommon and complicated cases.
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`Recognizing Treatment Failures
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`There is no universally agreed upon definition of treatment failure. Some clinicians identify a treatment failure when multiple anti-
`VEGF treatments have been applied and fluid or leakage persists on optical coherence tomography or fluorescein angiography,
`respectively. Others deem treatment a failure when vision loss continues despite a course of treatment. There is also the
`concept of "treatment disappointments," for example, when continuous monthly injections are required to keep the macula dry or
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`where treatment produces a decrease in edema but no improvement in vision.
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`For practical purposes, I define treatment failures as those patients who no longer respond with an improvement in macular
`edema on OCT or a reduction of leakage on fluorescein angiography following treatment with an anti-VEGF agent. Figure 1
`illustrates a treatment failure of Lucentis in an advanced case of wet age-related macular degeneration with subsequent
`response to combination therapy utilizing Lucentis, Visudyne and intravitreal injection of unpreserved triamcinolone acetate.
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`Macugen Treatment Failures
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`The approach to treatment failures clearly relates to the agent associated with the treatment failure. In the case of pegaptanib
`(Macugen), for example, the approach has been straightforward: switch to an alternative anti-VEGF agent with a response rate
`clearly greater than that of pegaptanib. Pegaptanib was the first approved anti-VEGF treatment for the management of wet
`macular degeneration. This specific and selective agent is an oligonucleic aptamer that binds specifically to the subtype of VEGF
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`most frequently associated with neovascularization—the VEGF 165 isoform. While data supports a treatment effect for Macugen
`with a maximal response rate of about 70 percent, there were significant treatment failures with this agent, as well as "treatment
`disappointments" in a substantial proportion of "responders" who continued to lose vision over time.
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`In contrast, the second approved anti-VEGF agent, Lucentis, exhibited a response rate of 95 percent. Thus, most retina
`specialists have utilized the more potent anti-VEGF agent Lucentis, and its off-label cousin, Avastin, for the management of
`Macugen treatment failures. As a result, Macugen is now rarely used as a sole treatment for wet AMD. In a limited study that
`was prematurely halted, the addition of PDT with intravitreal Macugen did not appear to improve response rates and PDT alone
`is not routinely used for rescue therapy.
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`Lucentis, Avastin Treatment Failures
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`Lucentis and Avastin are anti-VEGF agents derived from monoclonal antibodies that can bind all subtypes of the VEGF
`molecule. Lack of selectivity for VEGF has not been associated with feared complications such as detectable loss of normal
`retinal capillaries, and the much higher response compared to Macugen suggests that more VEGF isoforms may be involved in
`pathologic choroidal neovascularization. With a response rate of 95 percent for Lucentis and an empirically comparable rate for
`Avastin, failures are uncommon. Failures are difficult to predict but one study found that the efficacy of anti-VEGF therapy
`appears to depend on the initial lesion size and initial reading ability. With a bigger choroidal neovascular size and a lower
`reading ability, the chance of responding appears to be reduced.
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`Treatment protocol may also affect response rates and efficacy. The initial Lucentis studies—Marina and ANCHOR—utilized a
`"fixed-interval treatment protocol" whereby patients received monthly injections for one year. Physicians began to deviate from
`this protocol for a variety of reasons including empirical data for VEGF upregulation, higher theoretical risk of endophthalmitis
`and intolerance of scheduled monthly injections by patients. Many adopted the "treat-and-observe" approach, in which a few
`scheduled injections are given and then the patient is observed, with retreatment performed if "significant" edema or vision loss
`develops at subsequent visits. While a reduced frequency of injections could be achieved, some treatment failures may be
`related to this treat-and-observe protocol.
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`In the PrONTO study, a treat-and-observe protocol was utilized in which patients received three initial monthly injections of
`Lucentis and were retreated only when: a) they lost more than five letters of vision and had any fluid on OCT; b) they developed
`new retinal hemorrhage or classic choroidal neovascularization; or c) there was an increase of >100 µm of edema documented
`on the OCT.
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`While the visual acuity results achieved at one year in the PrONTO study were comparable to the results achieved with monthly
`dosing in the Phase III MARINA and ANCHOR trials, the percentage of patients with an overall decrease in vision was higher,
`raising concerns about the treat-and-observe approach utilized in the study.
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`Today, many clinicians utilize a "treat-and-extend" protocol where a series of two or three injections is followed by extending the
`follow-up and retreatment visits to the period of time where fluid recurs. In some patients the retreatments can be extended from
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`every four weeks to every six weeks and so on until reinjections are scheduled three months apart. If edema recurs between
`visits the protocol is reinitiated. This protocol may reduce the rate of treatment failures for both Avastin and Lucentis.
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`When the SAILOR study allowed treatment of patients with wet AMD after they had failed other therapies, we gained experience
`with the use of Lucentis as rescue therapy. In my practice, the majority of patients were receiving Avastin off-label, since
`published data suggested this was the most effective therapy for treatment of non-study patients with wet AMD. Of the 13
`Avastin treatment failures I treated with Lucentis, 10 responded with a reduction in edema and/or improvement in best corrected
`visual acuity.
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`Examples of six best responses on OCT (greatest reductions in edema) are shown in Figure 2. All 13 patients had occult
`choroidal neovascularization with a fibrovascular pigment epithelial detachment. One patient developed a retinal pigment
`epithelial tear outside of the fovea but still recovered 20/25 vision for nearly one year until he recurred and was stabilized with a
`triple-therapy regimen (Avastin/Visudyne/Dexamethasone, see below).
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`Combination Therapies
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`Combination therapy is most commonly used as rescue therapy for patients failing anti-VEGF treatment. The treatment protocols
`are based on the idea that a multi-pronged approach may be more effective than any single approach since multiple factors
`contribute to wet AMD including: 1) abnormal VEGF production; 2) inflammatory mediators; and 3) increased vascular
`permeability of choroidal neovascular membranes (See Figure 3). In theory, by attacking each of these three areas—VEGF with
`anti-VEGF agents, inflammation with corticosteroids, and vascular permeability with photodynamic therapy—we have a better
`chance of arresting the pathologic process altogether, if not at least for a longer period of time.
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`The published data support the theory and, in general, combination therapy appears to provide a comparable visual result with a
`longer duration of effect when compared to anti-VEGF therapy alone.
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`Combination therapy is also effective for managing most anti-VEGF treatment failures. A variety of combination therapies have
`been utilized for anti-VEGF treatment failures and in some cases as primary therapy. Most "double therapies" combine an anti-
`VEGF agent with Visudyne, and there is data supporting efficacy for this approach. Most investigators are utilizing a triple-
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`therapy regimen with anti-VEGF, photodynamic therapy and corticosteroid.
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`Amounts of anti-VEGF drug vary, but most commonly used are Avastin 1.25 mg/0.05 cc or Lucentis 0.3 mg/ 0.05 cc.
`Dexamethasone is the most commonly used corticosteroid at a dose of 6 mg/0.05 cc. These volumes allow completion of the
`procedure without a concomitant limited vitrectomy and appear to be effective.
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`While not approved for reimbursement by the Centers for Medicare & Medicare Services, many use a protocol of reduced
`fluence by lowering the power density by 50 percent or reducing the duration of treatment. Since combination therapy adds the
`use of Visudyne to the treatment protocol, the reported 1 to 4 percent risk of acute vision loss with photodynamic therapy must
`be disclosed to the patient.
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`For most retinal specialists, it is this risk that limits the use of combination therapy for primary treatment, particularly in those with
`relatively preserved visual acuity (>20/200) and a large fibrovascular PED or RAP (retinal angiomatous proliferation) lesions
`(since an RPE tear may be more likely to occur in these patients). Examples of resistant cases responding to combination
`therapy are shown in Figure 4.
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`Role of Corticosteroids
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`As noted above, dexamethasone is the most commonly used corticosteroid in combination "triple therapy." Unpreserved
`triamcinolone acetate may still be useful in select cases. I consider an intravireal triamcinolone acetate injection as an alternate
`to dexamethasone for triple therapy in patients who: 1) have a history of improvement with IVTA in the past; 2) are not known
`corticosteroid responders; 3) are pseudophakic; or 4) have evidence for vitreous inflammation on clinical examination. While wet
`AMD is likely the result of multiple factors, as shown in Figure 4, in some patients, one factor may predominate over another, and
`thus longer acting corticosteroids such as TA may play a more critical role in the treatment of select patients. Some clinicians still
`utilize combination therapy with IVTA and Visudyne and this may still be appropriate in select cases.
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`In rare cases I have used a treat-and-observe protocol with IVTA alone for managing pseudophakic patients with wet AMD. A
`new formulation of IVTA has recently been released by Alcon, and Allergan now has a sustained-release unpreserved
`formulation awaiting approval. The use of the formulation in wet AMD should be explored.
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`Other Treatment Options
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`Other treatment options are still available for wet AMD, although anti-VEGF therapy has greatly curtailed their use.
`Transpupillary Thermotherapy (TTT) is still reimbursed by CMS for the treatment of wet AMD. The TTT4CNV clinical trial,
`however, did not find a significant difference between TTT and sham (47 percent vs. 43 percent, respectively). While the results
`of the submacular surgery trial (SST) as well as a larger meta-analysis of additional studies argue against the use of surgery in
`patients with wet AMD, surgical excision of CNV is still utilized in select patients, particularly those who have failed anti-VEGF
`therapy and have a more clearly defined subretinal (type I) rather than sub-RPE (type II) lesion. Type I lesions are typically found
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`in non-AMD patients.
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`In select AMD patients surgery may be considered for treatment failures, particularly those with extensive subretinal fluid, recent
`but severe vision loss and a small lesion relative to the area of involvement. Submacular hemorrhages associated with wet AMD
`are still pneumatically displaced in the office or, in the OR with subretinal TPA in select cases. Focal radiation therapy with an
`intravitreal probe (Epi-Rad90 Ophthalmic System, NeoVista, Fremont, Calif.) has now been utilized alone and in combination
`with Avastin. A significant visual improvement was reported for a small cohort of patients, but its use as rescue therapy awaits
`formal investigation.
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`Role of NSAIDs
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`There is now evidence that non-steroidal anti-inflammatory drops may suppress VEGF activity and inhibit choroidal
`neovascularization. Additional studies are required to determine if NSAIDs are useful as adjunctive therapy in the management
`of choroidal neovascularization.
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`Prognosis of Treatment Failures
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`An empiric observation of treatment failures suggests a worst prognosis for visual acuity. Many of these patients have a fibrotic
`element associated with the choroidal neovascular membrane and have undergone unsuccessful treatment for a long period of
`time. In my small series of 13 patients who failed Avastin prior to the availability of Lucentis, all had 20/200 or worse visual
`acuity.
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`Diagram for Treatment Failures
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`Managing treatment failures requires both a creative and consistent approach and the major strategies are summarized in Figure
`5. Using the most potent currently available anti-VEGF agents, stabilization of vision and edema can be achieved in about 95
`percent with a treat-and-observe or treat-and-extend protocol. The minority, 5 percent, are treatment failures and continue to
`experience leakage, growth or progressive vision loss.
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`When these lesions are associated with relatively poor vision (<20/200), and there is a poor response to the initial treatment
`protocol, prompt treatment with combination therapy should be considered. If the vision is relatively preserved (>20/200) and the
`lesion is small, continued monotherapy may be reasonable, although for lifestyle reasons, combination therapy may be selected
`by the patient if frequent injections have become a burden. When combination therapy is successful, maintenance treatment
`may still be required with periodic anti-VEGF injections given as needed.
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`Recognizing an anti-VEGF treatment failure early on may improve outcomes. Having a clear definition of treatment failure—
`persistent fluid on OCT no longer responsive to anti-VEGF injections—will help you identify these patients. Following consistent
`"treat and observe" or "treat and extend" protocols may also reduce failure rates. Informing patients of the off-label and unproven
`nature of some rescue therapies is critical. When possible, enroll treatment failures in clinical trials to help us determine which
`treatment options may be best for these patients.
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`Dr. Gallemore is an assistant clinical professor of ophthalmology at Jules Stein Eye Institute, UCLA School of Medicine. He is
`also the director and founder of the Retina Macula Institute, Torrance and Los Angeles, Calif. Contact him at (310) 944-9393
`(phone); fax: (310) 944-3393 or e-mail: Retina2000@yahoo. com.
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`12. Combination Therapy: Lucentis (Ranibizumab Injection) and Xibrom (Bromfenac Ophthalmic Solution) 0.09% in the
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`Vis Sci, ARVO Abstracts, 2008 (in press).
`13. Amrite AC, Kompella UB.Celecoxib inhibits proliferation of retinal pigment epithelial and choroid-retinal endothelial
`cells by a cyclooxygenase-2-independent mechanism. J Pharmacol Exp Ther. 2008 Feb;324(2: 749-58. Epub 2007 Nov
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