Intravitreal Bevacizumab for the Management
`of Choroidal Neovascularization in
`Age-related Macular Degeneration
`
`ZIAD F. BASHSHUR, MD, ALI BAZARBACHI, MD, ALEXANDRE SCHAKAL, MD,
`ZEINA A. HADDAD, MD, CHRISTELLE P. EL HAIBI, MS,
`AND BAHA’ N. NOUREDDIN, MD
`
`● PURPOSE: To investigate the efficacy and safety of
`intravitreal bevacizumab for managing choroidal neovas-
`cularization (CNV) due to age-related macular degener-
`ation (AMD).
`● DESIGN: Prospective interventional case series.
`● METHODS: Seventeen eyes of 17 patients with subfo-
`veal CNV due to AMD participated in this study at the
`American University of Beirut Ophthalmology Clinics.
`All patients had failed, refused, or were not eligible for
`photodynamic therapy. All eyes received a baseline eye
`examination, which included best-corrected visual acuity
`(BCVA), dilated fundus examination, ocular coherence
`tomography (OCT) imaging, and fluorescein angiogra-
`phy. An intravitreal injection of bevacizumab (2.5 mg/
`0.1 ml) was given at baseline and followed by two additional
`injections at four-week intervals. BCVA, OCT, and fluo-
`rescein angiography were repeated four weeks after each
`injection. Main outcome measures were improvement in
`BCVA and central retinal thickness (CRT).
`● RESULTS: Mean baseline BCVA was 20/252 (median
`20/200), and baseline CRT was 362 ␮m (median 350
`␮m). Improvement in VA and CRT occurred by the
`fourth week. At 12 weeks, mean BCVA was 20/76 (P <
`.001) and median BCVA was 20/50 (P < .001). Both
`mean and median CRT decreased to 211 ␮m (P < .001).
`Thirteen (76%) of 17 eyes had total resolution of
`subretinal fluid, and four eyes (24%) had BCVA better
`than 20/50. No systemic or ocular side effects were noted
`at any time.
`● CONCLUSION: Eyes with CNV due to AMD treated
`with intravitreal bevacizumab had marked anatomic and
`
`See accompanying Editorial on page 141.
`Accepted for publication Feb 24, 2006.
`From the Department of Ophthalmology (Z.F.B., Z.A.H., C.P.E.,
`B.N.N.), and Department of Internal Medicine (A.B.), American Uni-
`versity of Beirut, and Department of Ophthalmology, Hotel Dieu de
`France (St Joseph University) (A.S.), Beirut, Lebanon.
`Inquiries to Ziad Bashshur, MD, American University of Beirut
`Medical Center, PO Box 11-0236/B11, Beirut, Lebanon; e-mail: zb00@
`aub.edu.lb
`
`visual improvement. Further studies are necessary to
`confirm the long-term efficacy and safety of this treat-
`ment.
`(Am J Ophthalmol 2006;142:1–9. © 2006 by
`Elsevier Inc. All rights reserved.)
`
`A GE-RELATED MACULAR DEGENERATION (AMD) IS A
`
`leading cause of legal blindness in the industrial-
`ized world.1 Although neovascular AMD is less
`prevalent than atrophic AMD, it accounts for most cases
`with severe visual loss from AMD.1–3 Vascular endothelial
`growth factor (VEGF) has been implicated in the choroi-
`dal neovascularization (CNV) of AMD.4 VEGF helps
`promote endothelial cell growth and increases vascular
`permeability.4,5
`Standard treatment options for CNV include argon laser
`photocoagulation and photodynamic therapy (PDT) using
`verteporfin. The Macular Photocoagulation Study showed
`that well-defined or “classic” subfoveal CNV was amenable
`to argon laser photocoagulation.6 –9 However, this proce-
`dure results in irreversible photoreceptor injury that usu-
`ally causes a central scotoma.9 Later, large multicenter
`studies showed that PDT was effective in decreasing the
`probability of moderate and severe visual loss from pre-
`dominantly classic subfoveal CNV.10 –12 Although PDT
`was designed to minimize damage to the retina and retinal
`vessels, a patient may continue to lose vision before
`stabilizing.11,12
`In December 2004, the US Food and Drug Administra-
`tion approved intravitreal injection of pegaptanib, a 28-
`base anti-VEGF aptamer, for the management of CNV.
`Although pegaptanib-treated eyes continued to lose vision
`during the first year of the trial, they fared better than
`controls.13,14 Another anti-VEGF agent currently in phase
`III clinical trials for neovascular AMD is ranibizumab, a
`chemically modified product of bevacizumab that is affin-
`ity-matured to have higher affinity for VEGF (Miller J,
`unpublished data, presented at American Society of Retina
`Specialists Annual Meeting, July 2005). Bevacizumab is a
`humanized monoclonal antibody that inhibits all isoforms
`
`0002-9394/06/$32.00
`doi:10.1016/j.ajo.2006.02.037
`
`© 2006 BY ELSEVIER INC. ALL RIGHTS RESERVED.
`
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`of VEGF and is approved for treatment of colorectal
`cancer.15 Recently, bevacizumab was used to treat CNV
`due to AMD. Michels and associates16 showed that intra-
`venous bevacizumab administered in two or three infusions
`at a dose of 5 mg/kg every two weeks decreased central retinal
`thickness (CRT) and improved vision. Later, Rosenfeld and
`associates17 presented a case report of a single eye that had
`improved CRT and visual acuity four weeks after an intrav-
`itreal injection of 1.25 mg of bevacizumab.
`We treated 17 eyes with CNV due to AMD with
`intravitreal bevacizumab. We report on the anatomic and
`visual acuity results after 12 weeks of follow-up.
`
`METHODS
`
`STARTING AUGUST 2005, EYES WITH SUBFOVEAL CNV DUE
`to AMD were considered for intravitreal bevacizumab.
`Patients were offered this treatment if they were not
`eligible for PDT, refused PDT, or had not responded to
`PDT. Eyes not eligible for PDT were those with minimally
`classic CNV greater than four disk areas or those with
`CNV that is more than 50% obscured by blood. Nonre-
`sponse to PDT was considered if the subfoveal CNV
`continued to grow with loss of visual acuity after three
`sessions. Eyes with occult CNV were also considered for
`treatment if there was evidence of subretinal hemorrhages
`on fundus examination or the patient noted recent de-
`crease in visual acuity over the past 12 weeks. The hospital
`administration at the American University of Beirut Med-
`ical Center gave permission for the use of intravitreal
`bevacizumab as a compassionate treatment in a situation
`that would otherwise result in severe visual
`loss. All
`patients who were considered for intravitreal bevacizumab
`treatment had a thorough discussion about the possible
`benefits and complications. All patients signed a consent
`form for the off-label intravitreal injection of bevacizumab.
`The study was in adherence to the tenets of the Declara-
`tion of Helsinki.
`Initial examination included best-corrected visual acuity
`(BCVA) using Snellen acuity charts, slit-lamp examina-
`tion of the anterior segment, dilated fundus examination,
`and fluorescein angiography. Eyes with better than 20/50
`visual acuity were not considered for treatment. Baseline
`1-mm CRT was measured for all eyes using ocular coher-
`ence tomography (OCT) macular retinal mapping (Stratus
`OCT, Carl Zeiss Meditec, Dublin, California, USA). This
`map was created from six consecutive slow diagonal 6-mm
`scans that intersected at the fovea. Retinal thickness was
`measured automatically by the OCT software, and this was
`the distance between the vitreoretinal interface and the
`anterior surface of the retinal pigment epithelium. Because
`AMD patients may have difficulty fixating, the fundus
`image generated by the OCT machine during the proce-
`dure was used to center the scan at the fovea for each
`
`FIGURE 1. Ocular coherence tomography (OCT) scans and
`central retinal thickness (CRT) measurements for an eye with
`subfoveal choroidal neovascularization (CNV) due to age-
`related macular degeneration (AMD) that had complete reso-
`lution of subretinal fluid after the first intravitreal injection of
`bevacizumab. (Top) Baseline CRT is 236 ␮m with a visual
`acuity of 20/50. (Middle) One week after injection, CRT is
`184 ␮m. (Bottom) Four weeks after injection, CRT is 187 ␮m
`with visual acuity of 20/50. OCT at eight and 12 weeks
`remained unchanged, but visual acuity was 20/40.
`
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`FIGURE 2. Fluorescein angiographic changes in choroidal
`neovascularization (CNV) for the eye in Figure 1 after the first
`intravitreal injection of bevacizumab. Early-phase (Top left)
`and late-phase (Top right) angiograms before treatment show
`occult CNV. (Bottom) Late-phase angiogram four weeks after
`treatment with resolution of late leakage. Follow-up angiogra-
`phy at eight and 12 weeks continued to show no leakage.
`
`mycin eye ointment (Alcon, Puurs, Belgium) was instilled
`in the treated eye, and a light patch was applied. Patients
`were instructed to unpatch the eye the next day and use
`topical ciprofloxacin (Alcon, Puurs, Belgium) three times
`a day for three days.
`injection of bevacizumab was
`A similar intravitreal
`administered to all eyes at four and eight weeks of
`follow-up even if there was total resolution of subretinal
`fluid and retinal pigment epithelial detachment.
`Patients were examined at one week and four weeks after
`each injection. BCVA was measured at each visit along with
`slit-lamp examination of the anterior segment and dilated
`fundus examination. OCT and fluorescein angiography
`were repeated at least at the four-week follow-up. Ocular
`side effects that were monitored were decrease in vision,
`rise in intraocular pressure, cataract formation, inflamma-
`tion, bacterial endophthalmitis, retinal detachment, vitre-
`ous hemorrhage, and changes on fundus examination or
`fluorescein angiography.
`The main outcome measures were improvement in
`visual acuity and decrease in CRT. Snellen acuities were
`converted to the logarithm of the minimum angle of
`resolution (logMAR) to facilitate statistical analysis. The
`paired Student t-test was used to compare the mean visual
`acuity and CRT at weeks four to 12 after treatment with
`mean baseline measurements. Similarly, the paired Wil-
`
`examination. All OCT examinations at baseline and at
`follow-up were done by the same person (A.S.).
`All patients had blood pressure measurements at every
`visit. They were also monitored for symptoms of possible
`thromboembolic events.
`The hospital pharmacy divided a 100-mg (4-ml) vial of
`bevacizumab (Genentech Inc, San Francisco, California,
`USA) into 20 1-ml syringes using aseptic techniques and
`under a laminar flow hood. Therefore, each syringe contained
`5 mg, or 0.2 ml, of bevacizumab. The syringes were stored at
`4°C for no longer than 14 days. After that time, remaining
`syringes were discarded because sterility could not be consid-
`ered without further sterility testing.18 No stability testing was
`done to determine if bevacizumab remained stable in polypro-
`pylene syringes during the 14-day period.
`The eye to be treated was prepared with 5% povidone-
`iodine solution. Anesthesia was administered as a subcon-
`junctival injection of lidocaine 2% in the inferotemporal
`quadrant approximately 3 to 4 mm from the limbus. Enough
`anesthetic was injected to form a small bleb in the area where
`the intravitreal injection was to be given. Using a 30-gauge
`needle, 0.1 ml (2.5 mg) bevacizumab was injected intrav-
`itreally through the pars plana 3.5 mm from the limbus. If
`the intraocular pressure was greater than 25 mm Hg or the
`optic nerve head was not adequately perfused 20 minutes
`after the injection, a paracentesis was performed. Tobra-
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`coxon signed rank test was applied to compare the median
`visual acuity and CRT at weeks four to 12 with median
`baseline values. The level of statistical significance was set
`at P ⬍ .05 with a 95% confidence interval.
`
`RESULTS
`
`IN AUGUST 2005, 17 EYES OF 17 PATIENTS RECEIVED INTRA-
`vitreal bevacizumab. There were five women and 12 men.
`The average age was 68.3 years with a range of 59 to 78
`years. All eyes had subfoveal CNV due to AMD. Four eyes
`had poor response to PDT. Four eyes were not eligible for
`PDT because a minimally classic CNV was greater than
`four disk areas, and two eyes had more than 50% of the
`CNV covered by subretinal blood. None of these eyes had
`blood covering the fovea. The remainder of the patients
`refused PDT.
`All eyes tolerated the procedure with no complications.
`Mean baseline BCVA was 20/252 (median 20/200) and
`mean CRT was 362 ␮m (median 350 ␮m). At the
`four-week follow-up, mean and median BCVA improved
`to 20/105 (P ⬍ .001) and 20/80 (P ⫽ .001), respectively.
`Mean and median CRT at four weeks decreased to 279 ␮m
`(P ⬍ .001) and 282 ␮m (P ⬍ .001), respectively. Three
`(18%) of 17 eyes had complete resolution of subretinal
`fluid and retinal pigment epithelial detachment on OCT
`(Figures 1 and 2).
`Mean BCVA at eight weeks (four weeks after the second
`injection) improved to 20/79 (P ⬍ .001), and median BCVA
`was 20/50 (P ⬍ .001). In addition, mean CRT decreased to
`231 ␮m (P ⬍ .001), and median CRT decreased to 230 ␮m
`(P ⬍ .001). At the eighth week of follow-up, seven (41%) of
`17 eyes had total resolution of SRF and PED on OCT
`(Figures 3 and 4). This included the three eyes that had such
`a response after the first injection.
`Mean and median BCVA at 12 weeks (four weeks after
`the third injection) stabilized at 20/76 (P ⬍ .001) and
`20/50 (P ⬍ .001), respectively. Both mean and median
`CRT at 12 weeks decreased further to 211 ␮m. This was
`statistically better than mean baseline CRT (P ⬍ .001)
`and median baseline CRT (P ⬍ .001). Thirteen (76%) of
`17 eyes had total resolution of SRF and PED on OCT
`(Figures 5 and 6). Tables 1 and 2 summarize the visual
`acuity and CRT data over 12 weeks.
`After 12 weeks, all 17 eyes had improvement in CRT
`(Figure 7), and eight (47%) of 17 eyes had CRT equal to
`or less than 200 ␮m. Fifteen (88%) of 17 eyes had better
`BCVA at 12 weeks than baseline, whereas two eyes did not
`improve (Figure 8). Four (24%) of 17 eyes ended with
`BCVA better then 20/50. All 17 eyes had marked reduc-
`tion or absence of leakage from the CNV on angiography;
`however, the improvement on angiography did not occur
`as rapidly as that noted on OCT. We did not note any
`ocular side effects at any stage. There was no significant
`rise in intraocular pressure or progression of cataract.
`
`FIGURE 3. Ocular coherence tomography (OCT) scans and
`central retinal thickness (CRT) measurements for an eye with
`subfoveal choroidal neovascularization (CNV) due to age-related
`macular degeneration (AMD) that had complete resolution of
`subretinal fluid after the second intravitreal injection of bevaci-
`zumab. (Top) Baseline CRT is 328 ␮m with visual acuity of
`20/200. (Middle) Four weeks after the first injection, CRT is 209
`␮m with visual acuity of 20/80. (Bottom) Four weeks after second
`injection or after eight weeks total follow-up, CRT is 181 ␮m
`with visual acuity of 20/40. Follow-up OCT at 12 weeks contin-
`ued to show no subretinal fluid, and visual acuity remained 20/40.
`
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`FIGURE 4. Fluorescein angiographic changes in choroidal neovascularization (CNV) for the eye in Figure 3 after two intravitreal
`injections of bevacizumab. Early-phase (Top left) and late-phase (Top right) angiograms at baseline show classic CNV. Four weeks
`after the first injection, there is no change in the early-phase (Middle left) and late-phase (Middle right) angiograms. Four weeks
`after the second injection or after eight weeks of follow-up, there is considerable decrease in the size of the CNV in the early phase
`(Bottom left) and decreased leakage in the late phase (Bottom right). Angiography at 12 weeks remained unchanged.
`
`Mean baseline arterial blood pressure was 138/86. At no
`time during follow-up did the blood pressure rise notice-
`ably above baseline. Also, no thromboembolic events were
`observed during the period of this study.
`
`DISCUSSION
`
`WE TREATED 17 EYES WITH CNV DUE TO AMD WITH INTRA-
`vitreal bevacizumab. After 12 weeks of follow-up, these
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`FIGURE 5. Ocular coherence tomography scans and central retinal thickness (CRT) measurements for an eye with subfoveal
`choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) that showed complete resolution of subretinal
`fluid after the third intravitreal injection of bevacizumab. (Top left) Baseline CRT is 549 ␮m with visual acuity of 20/200. (Top
`right) Four weeks after first injection, CRT is 406 ␮m with visual acuity still 20/200. (Bottom left) Four weeks after second
`injection or at eight weeks, CRT is 311 ␮m and visual acuity is 20/70. (Bottom left) Four weeks after third injection or at 12 weeks,
`CRT is 209 ␮m and visual acuity is 20/70.
`
`eyes showed marked improvement in visual acuity and
`CRT. There were no untoward effects even after three
`injections using 2.5 mg. It may be that bevacizumab is less
`immunogenic than ranibizumab. With ranibizumab, the
`dose-limiting toxicity was intraocular inflammation and
`the maximum tolerated dose was 0.5 mg.19 Although mean
`CRT improved after each injection, there was no appre-
`ciable improvement in mean BCVA after the second
`injection. Perhaps photoreceptor damage from the CNV
`limited further visual improvement.
`The efficacy of intravitreal bevacizumab for the treat-
`ment of CNV due to AMD raises the question about its
`mechanism of action. Bevacizumab inhibits all isoforms of
`VEGF by blocking its interaction with membrane-bound
`tyrosine kinase receptors VEGFR-1 and VEGFR-2.20,21
`This would block activation of the intracellular tyrosine
`kinase, which would inhibit VEGF-induced cell prolifera-
`tion, survival, permeability, nitric oxide production, mi-
`gration, and tissue factor production.5 Animal studies
`
`suggested that the bevacizumab molecule was too large to
`cross the retina into the subretinal space.22 However, the
`results from this series and the report by Rosenfeld and
`associates17 confirm the effect of intravitreal bevacizumab
`on CNV. One possibility is that this large molecule is able
`to cross a diseased retina more readily. Another possibility
`is that bevacizumab inhibits VEGF in the vitreous, the
`surface of the retina, or inside the retina, which may be
`enough to prevent further growth and leakage from the
`CNV. Finally, results of the animal studies may not apply
`to the human eye, and bevacizumab is able to cross the
`retina.
`There are several potential adverse effects associated
`with the systemic use of VEGF inhibitors, such as in-
`creased risk for thromboembolic events, hypertension,
`epistaxis, hemoptysis, proteinuria, delayed wound healing
`after surgery, and impaired reproductive function.16,21 Vi-
`sual loss in the fellow eye may occur by inhibiting VEGF,
`which would cause regression of the choriocapillaris.23
`
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`FIGURE 6. Fluorescein angiographic changes in the choroidal neovascularization (CNV) for the eye in Figure 5 after the three
`intravitreal injections of bevacizumab. Early-phase (Top left) and late-phase (Top right) angiograms at baseline. Early-phase (Middle
`left) and late-phase (Middle right) angiograms four weeks after the first injection. Early-phase (Bottom left) and late-phase (Bottom
`right) angiograms four weeks after the third injection or at the 12 weeks of follow-up.
`
`Intravitreal administration of bevacizumab would help
`avoid these adverse events and allow a direct targeting of
`choroidal neovascularization by the antibody. The intrav-
`itreal route also allows for the use of a much lower dose of
`the agent compared with the intravenous approach (total
`
`dose of 2.5 mg vs 5 mg/kg dose used intravenously).
`However,
`intravitreal
`injections pose several potential
`risks, including endophthalmitis, vitreous hemorrhage, and
`retinal detachment. Intravitreal bevacizumab itself may
`cause inflammation or ocular toxicity with repeated injec-
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`TABLE 1. Mean and Median Visual Acuity Over 12 Weeks for 17 Eyes With Choroidal
`Neovascularization Treated With Intravitreal Bevacizumab
`
`Number of Eyes
`(n ⫽ 17)
`
`Baseline
`Visual Acuity (Snellen)
`
`Week 4
`Visual Acuity (Snellen)
`
`Week 8
`Visual Acuity (Snellen)
`
`Week 12
`Visual Acuity (Snellen)
`
`Median (P value)*
`Mean (P value)†
`
`20/200
`20/252
`
`20/80 (0.001)
`20/105 (⬍0.001)
`
`20/50 (⬍0.001)
`20/79 (⬍0.001)
`
`20/50 (⬍0.001)
`20/76 (⬍0.001)
`
`*Paired Wilcoxon signed rank test.
`†Paired Student t test.
`
`TABLE 2. Mean and Median Central Retinal Thickness Over 12 Weeks for 17 Eyes With
`Choroidal Neovascularization Treated With Intravitreal Bevacizumab
`
`Number of Eyes
`(n ⫽ 17)
`
`Median (P value)*
`Mean (P value)†
`
`Baseline
`Central Retinal
`Thickness (␮m)
`
`350
`362
`
`Week 4
`Central Retinal
`Thickness (␮m)
`
`282 (⬍0.001)
`279 (⬍0.001)
`
`Week 8
`Central Retinal
`Thickness (␮m)
`
`230 (⬍0.001)
`231 (⬍0.001)
`
`Week 12
`Central Retinal
`Thickness (␮m)
`
`211 (⬍0.001)
`211 (⬍0.001)
`
`*Paired Wilcoxon signed rank test.
`†Paired Student t test.
`
`FIGURE 7. Scatter plot of baseline central retinal thickness
`(CRT) vs central macular thickness at 12 weeks for 17 eyes
`that received intravitreal bevacizumab for subfoveal choroidal
`neovascularization (CNV) due to age-related macular degener-
`ation (AMD). All points below the line imply improved final
`CRT.
`
`FIGURE 8. Scatter plot of baseline visual acuity vs visual
`acuity at 12 weeks (expressed in logMAR units) for 17 eyes
`that received intravitreal bevacizumab for subfoveal choroidal
`neovascularization (CNV) due to age-related macular degener-
`ation (AMD). All points below the line imply improved final
`visual acuity.
`
`tions. None of these side effects was observed in the 17
`treated eyes.
`Because of the small sample size and the short follow-up in
`this study, we cannot draw conclusions about the long-term
`efficacy and safety of intravitreal bevacizumab. Longer fol-
`low-up is necessary to determine the long-term safety of this
`treatment. We used 2.5 mg of bevacizumab, which is greater
`than that used by Rosenfeld and associates.17 Although no
`
`dose-ranging studies were done, we assumed a higher intrav-
`itreal concentration may allow greater VEGF inhibition and
`a greater availability in the subretinal space. We also decided
`on monthly injections mainly because other anti-VEGF trials
`(MARINA Study Group, unpublished data, presented at
`American Society of Retina Specialists Annual Meeting, July
`2005) utilized periodic intravitreal injections. We thought
`
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`these successive injections would lead to better VEGF inhi-
`bition, which may achieve regression of CNV in the short
`term, because VEGF is necessary for survival of immature
`blood vessels.23 Despite the longer half-life of bevacizumab
`compared with ranibizumab,24 bevacizumab has a lower affin-
`ity to VEGF25 and is a larger molecule that may achieve lower
`subretinal concentrations. Therefore, monthly intravitreal
`injections may achieve better CNV control. Of course, other
`studies are necessary to determine the ideal dose, number of
`injections, and frequency of injections. Further randomized
`trials should also compare intravitreal bevacizumab with
`other available anti-VEGF agents, such as pegaptanib sodium
`and ranibizumab.
`
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