PHARMACOLOGY

2-week intervals. No serious ocular or systemic adverse events were identified throughout 24 weeks of follow-up, with the exception of a mild elevation of mean systolic and diastolic blood pressure measurements. By 24 weeks, the mean VA letter score increased by 14 letters in the study eyes and the mean central retinal thickness (CCT)

as measured by optical coherence tomography (OCT) decreased by 112 m.26

Cleary et al.27 conducted a large, retrospective study involving 112 eyes of patients with neovascular AMD, including choroidal neovascular membranes, pigment epithelial detachment, and macular hemorrhage. The median follow-up was 5 months. Intravitreal bevacizumab­ was found to be an effective treatment, resulting in improved vision and foveal anatomy at 6 months and even lasting up to 9 months of follow-up. The authors emphasized that 60% of patients who received only one injection maintained improved or stable vision at 6 months.

In another retrospective review of 118 eyes with neovascular AMD, VA improved by more than 15 ETDRS letters in 22.8% of eyes and stabilized in a further 65.2%. Only 11.9% lost 15 letters or more of vision. The mean VA improved from a Snellen equivalent of 6/30 to 6/24 at 1 month, and this improvement was maintained at 6 months. The mean macular thickness decreased by 87 m, with a reduction in intraretinal and subretinal fluid and pigment epithelial detachment. Classic and predominantly classic CNV groups showed a greater improvement in vision, whereas the occult CNV group showed the least visual improvement after treatment.28

A prospective, open-label, nonrandomized clinical study of 60 eyes with subfoveal CNV that were treated with intravitreal bevacizumab with over 12 months of follow-up showed significant anatomical and functional improvement. The mean VA improved from 45.7 letters at baseline to 53.1 letters at 12 months, and 92.2% of eyes lost fewer than 15 letters. The mean CRT decreased from 327.4 m at baseline to 227.8 m.29 Examples of the employment of bevacizumab in the management of neovascular AMD are illustrated in Figures 32.1 and 32.2.

One study compared visual outcomes and macular thickness changes associated with primary and secondary bevacizumab therapy for CNV. Eighteen eyes received primary bevacizumab treatment and 20 eyes received pegaptanib (Macugen) as initial treatment followed by bevacizumab therapy. The mean VA improvement and mean decrease in retinal thickness in the primary bevacizumab treatment cohort were better than the secondary bevacizumab treatment group. Primary bevacizumab therapy resulted in significantly greater visual improvement and a larger mean decrease in retinal thickness than secondary bevacizumab treatment at 3 and 6 months.30 The change in retinal thickness is often best demonstrated on OCT, as illustrated in Figure 32.3.

DIABETIC RETINOPATHY

The chronic hyperglycemia of diabetes mellitus and wide areas of ischemic retina results in activation of VEGF and increases its synthesis. The upregulation in VEGF is associated with neovascularization in PDR as well as with diabetic macular edema (DME). Studies show that intravitreal bevacizumab resulted in marked regression of retinal neovascularization in patients with PDR and previous panretinal phototherapy, and rapid resolution of vitreous hemorrhage. It also achieved short-term reduction of fluorescein leakage from persistent active neovascularization and improved vision in patients with diabetic retinopathy.31 Pretreatment of bevacizumab before vitrectomy is also effective in preventing bleeding during surgical dissection of fibrovascular membrane. The optimal time for preoperative injection is apparently 48–72 hours, and vitrectomy after 7 days can be associated with strong fibrosis and adhesion of fibrovascular membrane, resulting in some surgical complications.32

Primary intravitreal bevacizumab at doses of 1.25–2.5 mg seems to provide stability or improvement in patients with DME.An interventional retrospective multicenter study demonstrated that 41.1% eyes remained stable, 55.1% improved ≥2 ETDRS lines of best corrected VA (BCVA), and 3.8% decreased ≥2 ETDRS lines of BCVA. Mean central macular thickness (CMT) at baseline as measured by OCT was 387.0 ± 182.8 m and it decreased to a mean of 275.7 ± 108.3 after 6 months of follow-up.33

A randomized phase II clinical trial comparing photocoagulation and intravitreal injection of 1.25–2.5 mg in the treatment of DME demonstrated that bevacizumab can reduce DME in some eyes. It was found to achieve a greater reduction in central subfield thickness (CST) at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between the two doses.34

RETINAL VEIN OCCLUSION (RVO)

Currently, increasing data support the role of intravitreal bevacizumab as an effective treatment for patients with macular edema secondary to RVO. Multiple injections seem to be necessary in order to achieve visual stabilization and macular changes. The effect of a single injection seems to last 6–8 weeks. The most common treatment protocol is two to three injections over the first 5–6 months. Patients who had minimal or no response to laser therapy appeared to benefit from bevacizumab.35 A prospective study in patients with branch RVO (BRVO) found that intravitreal injections of bevacizumab 1.25 or 2.5 mg improved BCVA by 5.1 and 4.8 lines, respectively, after 6 months of repeated injections. There was also a decrease in CMT.36 A combined (BRVO and CRVO) prospective study followed 29 eyes. Three intravitreal injections of 1 mg bevacizumab (0.04 ml) were administered at 4-week intervals; further

A

B

Figure 32.2  (A) Late fluorescein angiography photograph (13 minutes) of an 85-year-old female with age-related macular degeneration. A large juxtrafoveal choroidal neovascularization lesion is illustrated with petaloid macular edema. (B) Same lesion 2 months after two bevacizumab injections. The leakage has decreased dramatically.

retreatment was based on OCT findings. CRT significantly decreased 1 day after the first injection, and three injections reduced macular edema to 328 m CRT from an average baseline of 558 m (range 353–928 m) and improved BCVA to 20/50 (from a baseline of 20/100). Fluorescein angiography (FA) showed no evidence of increased avascular zones.37

Another prospective study on patients with CRVO revealed a mean ETDRS letter gain 13.92 letters ± sd of 14.4 from baseline to 6 months. The mean CRT decreased from 535 ± sd of 148 m at baseline to 323 ± 116 m at 6-month follow-up. Ischemic CRVO was associated with significantly lower VA than nonischemic CRVO, although the VA gain was similar in both groups.38

UVEITIC CYSTOID MACULAR EDEMA (CME)

Intravitreal bevacizumab seems to be an effective treatment in the management of refractory inflammatory CME. One study demonstrated a reduction in CRT with a mean foveal thickness reduction of 127.2 m at 4 weeks: 4 out of 10 patients had concurrent improvement in VA, which was unchanged in the other 6. The authors noted that the effect is transient and that reinjections may be necessary.39

A

B

Figure 32.3  (A) Optical coherence tomography of a 72-year-old male with advanced (neovascular) age-related macular degeneration in the left eye with severe cystic macular edema. (B) Same section after two bevacizumab intravitreal injections. Complete resolution of the edema is illustrated. There was also improvement in visual acuity of 6 ETDRS letters.

eyes and remained the same in 25%. Leakage from the myopic CNV on FA decreased in 87.5% of eyes while the CNV area on FA and the foveal thickness on OCT images decreased significantly after the treatment.40

RETINOPATHY OF PREMATURITY (ROP)

Retinopathy of prematurity is a disease characterized by incomplete vascularization of the peripheral retina leading to retinal neovascularization. Standard therapy has consisted of ablation of the peripheral retina once threshold disease is reached.

There are no controlled studies on treatment of ROP with bevacizumab and data are limited to a number of case reports in which intravitreal bevacizumab (0.4–0.75 mg) was used in combination with indirect laser photocoagulation treatment in severe cases of ROP with zone 1 involvement with or without plus disease. Treatment resulted in ROP regression, prompt resolution of plus signs, and neovascular proliferation with regression of the vascular component of the fibrovascular membrane and acute fibrosis. There is currently an open-label phase I/II trial for babies with stage III–V ROP who are otherwise untreatable with laser or cryotherapy. Notably, due to bevacizumab’s potential side-effects in this young age, this treatment should first be evaluated in well-controlled studies and after careful consideration.41–43

also reported as a treatment of foveal detachment in idiopathic perifoveal telangiectasia (IPT). The OCT images showed marked reversal of the foveal detachment after the injection, with restoration of foveal depression in all eyes. The vision of all treated eyes improved and remained unchanged up until the last follow-up visit.45

NEOVASCULAR GLAUCOMA (NVG)

NVG is a condition that results from iris rubeosis in response to ischemia of the posterior retina. It can be the expression of advanced diabetic retinopathy, RVO, ocular ischemic syndrome, and other ischemic disease of the retina.

Intravitreal bevacizumab effectively stabilized iris neovascularization activity (with regression following one injection) and controlled intraocular pressure (IOP) in patients with iris neovascularization alone and early-stage NVG without angle closure (71% had normalization of IOP 21 mmHg). Intravitreal bevacizumab cannot control IOP in advanced NVG, but may be used adjunctively to improve subsequent surgical results.46 Bevacizumab was also reported to give similar results by intracameral injection. In this study patients with iritic neovascularization secondary to proliferative retinal vasculopathies received 1.25 mg bevacizumab intracamerally. All 15 patients with neovascularization demonstrated reduction in leakage of the neovascularization within 3 weeks of the injection, as observed on slit-lamp photography and FA. IOP was controlled with maximum medical therapy in 8 of 9 eyes, thereby reducing the need for glaucoma surgery. VA improved from a median of hand motions to 20/200.47

OTHERS

Intravitreal bevacizumab was found to improve or maintain vision and reduce hemorrhage and retinal edema in cases of radiation retinopathy related to plaque radiation therapy.48,49

Intravitreal injection of bevacizumab, although safe, is still controversial in its efficacy in patients with postoperative CME.50,51

The use of bevacizumab (by intravitreal injection and by local application to the conjunctiva or cornea) is also being investigated for a number of other ocular diseases. There are several small studies and case reports on the use of bevacizumab as an adjuvant treatment during pterygium and glaucoma surgery and in severe cases of corneal neovascularization, especially before corneal transplantation. The efficacy of this regimen is still controversial.

of >11% at 3 weeks in 43% of bevacizumab-treated eyes and in 28% of eyes treated with laser alone, and in 50% and 37% of eyes, respectively, at 6 weeks. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes.33 In a second study, intravitreal bevacizumab treatment of patients with DME yielded better visual outcome than laser photocoagulation. No further beneficial effect of intravitreal triamcinolone could be demonstrated. Finally, intravitreal bevacizumab remarkably augmented the short-term response to scatter panretinal laser photocoagulation.54

As mentioned above, the use of bevacizumab is adjuvant to the laser photocoagulation in cases of RVO. Patients who had minimal or no response to laser therapy appeared to benefit more from bevacizumab.35

In severe cases of NVG, the use of bevacizumab as adjuvant to antiglaucomatotic agents or as previtrectomy treatment (in cases of vitreous hemorrhage) was found beneficial and achieved better results.46

The use of bevacizumab for the rest of the above-mentioned indications is currently reserved as a last resort in severe cases where other approved, standard therapy failed to yield results.

CONTRAINDICATIONS

There are no absolute contraindications to local treatment with bevacizumab given as intravitreal injection. Due to its related side-effects, however, there are some relative contraindications. For instance, it is wise to withhold treatment in patients who had suffered a cardiovascular event or cerebrovascular event during the previous year.55

Bevacizumab has been shown to be teratogenic in rabbits when administered in doses that approximate the human dose on an mg/kg basis. For that reason, it is not recommended during pregnancy. It is not known whether bevacizumab is secreted in human milk. Because human IgG1 is secreted into human milk, the potential for absorption and harm to the infant after ingestion is unknown. Women should be advised to discontinue nursing during treatment with bevacizumab. Because physeal dysplasia was observed in juvenile cynomolgus monkeys with open growth plates (although this effect was found to be partially reversible upon cessation of treatment) it is less favored in treating children.

Systemic use of bevacizumab is also contraindicated around major surgery (because of impairing wound healing), or if severe systemic side-effects appear (e.g., significant increase in blood pressure).14

In a prospective, randomized, controlled clinical study that compared intravitreal bevacizumab therapy versus photodynamic therapy (PDT) plus intravitreal triamcinolone for neovascular AMD, treatment with bevacizumab was found to be more beneficial. Patients treated with bevacizumab improved by 2.2 ETDRS lines at 6 months of follow-up. Eyes treated in the PDT plus intravitreal triamcinolone arm had a stable mean VA at month 6 compared with baseline. It should be noted that the reduction in CRT was not significantly different between both groups (as demonstrated on OCT).52

A prospective randomized study compared verteporfin PDT with intravitreal bevacizumab for the management of predominantly classic CNV associated with AMD in 62 eyes. At the 6-month follow-up, the mean BCVA and greatest linear dimension were significantly better in the bevacizumab group compared to the standard PDT group.53 Currently, the phase III study, Comparison of AMD Treatment Trial (CATT), supported by the National Eye Institute of the National Institutes of Health (USA), is being conducted to compare the efficacy of bevacizumab with ranibizumab in the management of neovascular AMD.

Intravitreal bevacizumab injection was found more beneficial than focal photocoagulation in cases of DME. There was a CST reduction

Reports in the literature indicate that repeated intravitreal injections of either 1.25 or 2.5 mg bevacizumab are reasonably safe and well tolerated. Ocular complications include transient corneal abrasion (0.2%), chemosis (0.2%), subconjunctival hemorrhage (0.03%), lens injury (0.1%), bacterial endophthalmitis (0.01–0.16%), tractional retinal detachments (0.04–0.16%), uveitis (0.09%), rhegmatogenous retinal detachment (0.02%), and vitreous hemorrhage (0.02%). Notably, these adverse events are related to the injection procedure and are in the expected range for any intravitreal injections.56,57

Ocular adverse events possibly related to bevacizumab include episodes of inflammation (0.14%), cataract progression (0.01%), acute vision loss (0.07%), central retinal artery occlusion (0.01%), new or progressive subretinal hemorrhages (0.06%), and tears of the retinal pigment epithelium (0.06%). Inflammation usually occurs 2–7 days after the injection, and lasts no longer than 1 week. Cataract progression usually occurs in a patient with a pre-existing mature cataract.55 It should be borne in mind that bevacizumab injections cause a pre­ dictable, probably volume-related, rise in IOP of about 20 mmHg during the first 3 minutes after injection (from a baseline mean IOP of 15.17 mmHg to a mean of 36.27 mmHg). This is followed by a spontaneous decrease to a mean of 24.56 mmHg at 10 minutes after