Figure 18.1 Bevacizumab (Avastin: Genentech, South San Francisco, CA) was first introduced and was the first antiangiogenic agent approved by the U.S. Food and Drug Administration (FDA) to inhibit tumor growth.

Pharmacokinetics studies of intravitreal bevacizumab in rabbit models have shown that after an injection of 1.25 mg bevacizumab, a peak concentration of free bevacizumab (400 μg/mL) is achieved in the vitreous humor. Vitreous concentrations decline with a half-life of 4.32 days, but concentrations ≥10 μg/mL were maintained in the vitreous for 30 days. A peak concentration in the aqueous humor reached at day 3 after drug administration. Low concentrations were detected in the serum after intravitreal injection and in the aqueous humor of the fellow eye (39). In another study done in macaques, the aqueous humor and serum bevacizumab concentration were measured after intravitreal bevacizumab injection. At day 1, a peak in the aqueous humor was observed while the peak concentration in the serum was at 1 week. VEGF levels returned to preinjection concentrations after 42 days (40). In humans treated with intravitreal bevacizumab, a study showed decrease in VEGF concentration within 7 days of treatment (41).

SANA (Systemic Avastin for Neovascular AMD) was the first prospective study in patients with exudative AMD treated with intravenous bevacizumab. Eighteen patients with subfoveal CNV were enrolled in an open-label study in which bevacizumab 5 mg/kg was injected intravenously every 2 weeks for two or three infusions. VA improved from 54 letters (Snellen VA 20/80) at baseline to 68 letters (Snellen VA 20/40) at 24 weeks, an increase of 14 letters (P ≤ 0.001). Additionally, retinal thickness decreased from 392 to 280 μm at week 24. Adverse events occurred in 18.5% of the patients. At week 3, increased blood pressure was observed and controlled with antihypertensive drugs (36,42). Additionally, bevacizumab was also associated with increased risk of venous thromboembolism in cancer patients (43). Intravenous bevacizumab improved VA and decreased retinal thickness as early as 1 week after therapy; however, its potential systemic side effects outweighed its benefits.

The first anti-VEGF drug designed for intraocular use in the treatment of AMD was pegaptanib sodium (Macugen). Pegaptanib is a 28-base RNA oligonucleotide ligand or aptamer that binds to human VEGF₁₆₅ with high specificity and affinity. Pegaptanib showed efficacy for the treatment of AMD; however, the VISION study concluded that intravitreal pegaptanib injection at 6-week intervals stabilized vision in 70% of cases and improved it in only 6% (44,45).

In 2006, phase III clinical trials, MARINA and ANCHOR, demonstrated that the use of anti-VEGF ranibizumab (Lucentis, Genentech, Inc. South San Francisco, CA) promoted VA improvement in patients with neovascular AMD, stabilizing vision in 95% of patients and improving VA between 7.2 and 11.3 letters in 30% to 40% of patients (46,47). While these trials were still in progress, Rosenfeld et al. (48) showed that bevacizumab could also lead to VA improvement at a considerably lower cost and became the first to report the use of intravitreal bevacizumab for the treatment of exudative AMD to minimize the risk of systemic treatment (48). Consequently, bevacizumab was and is used worldwide by clinicians for the treatment of neovascular AMD. Exudative AMD is the most common indication for intravitreal bevacizumab. However, the use of bevacizumab developed in the absence of formal protocols. Many papers, including retrospective and prospective studies, uncontrolled case series, and uncontrolled randomized trials, have shown improvement in VA as well as decrease in macular thickness after treatment.

Subsequently, intravitreal injection of bevacizumab achieved worldwide success because of its safety profile, availability, short-term effects, and low cost compared to other anti-VEGF drugs. Since ranibizumab and bevacizumab are derived from the same monoclonal antibody and have a similar mechanism of action, it was suggested that they have similar efficacy and safety in treating AMD. Despite the lack of large-scale clinical trials, bevacizumab is the most commonly used treatment in the United States for exudative AMD (49). In an analysis of 222,886 Medicare beneficiaries from 2008, 146,276 (64.4%) received bevacizumab and 80,929 (35.6%) received ranibizumab (49).

In the beginning, there were many issues to resolve, such as retinal penetration, toxicity, and schedule for retreatment. A question of particular interest was whether intravitreal bevacizumab could penetrate the retina given its large size, but some reports concluded full retina penetration after injection (50). In fact, an animal study using confocal immunohistochemistry demonstrated full retinal thickness penetration 24 hours after intravitreal injection (51). With regard to toxicity, several experimental animal studies confirmed no retinal toxicity even at doses of 5 mg of intravitreal bevacizumab (52,53). Electrophysiologic and histologic studies have not demonstrated toxicity as well (52–56). Studies in patients with AMD have shown improvement in mf-ERG responses and its correlation with improvement in VA. Specifically, improvement in P1 amplitude was observed and correlated with decreased leakage on fluorescein angiography. These results may explain an increase in neural activity in the retina.

By 2006, level 1 evidence has supported the safety and efficacy of Lucentis. Level 1 evidence is evidence obtained from properly conducted well-designed, randomized, controlled trials (46,47). In the case of bevacizumab, no level 1 evidence existed until 2011. During this time, data were limited to case series and randomized controlled trials with small numbers of patients or short follow-up periods. El-Mollayes et al. (57) reviewed 571 articles involving bevacizumab use and AMD between 1997 and 2010 (57). Of these articles, only eight included at least 30 patients with AMD treated with bevacizumab for at least 12 months of follow-up (58–65). These studies were characterized by small number of patients (from 37–147 subjects), different concentrations of intravitreal bevacizumab (1.25, 2.5, and 1 mg), and different treatment protocols (three monthly injections followed by as-needed treatment or as-needed injections 4 or 8 weeks after the first injection). The studies reported an average number of 4.3 injections over 12 months, and best-corrected visual acuity (BCVA) improvement of 8 letters (from 39.9 letters at baseline to 47.95 letters by 12 months), additionally central retinal thickness improved from 375.2 to 249.9 μm by the end of 12 months (57).

It is important to understand that phase III trials enroll large number of patients to ensure enough strength of evidence with meaningful differences from active or control cases and to characterize safety profile of the treatment. The PDT trials, TAP and VIP, enrolled 948 patients. The VISION trial of pegaptanib enrolled 1,186 patients. MARINA enrolled 716 patients, and ANCHOR enrolled 423 patients. In the case of bevacizumab, phase III clinical trials had not been conducted, and the best evidence was a level 2 evidence obtained from well-designed controlled trials without randomization, series with or without intervention, and multicenter case–control studies, until 2010 and 2011 with ABC and CATT studies.

THE ABC AND CATT STUDIES

Presently, there are results and ongoing phase III, randomized clinical trials on bevacizumab in AMD. The ABC trial was conducted in Saudi Arabia. The CATT study (Comparison of AMD Treatments Trials), which compares intravitreal bevacizumab to ranibizumab, was conducted in the United States, and similar studies are being conducted in Germany (VIBERA), United Kingdom (IVAN), Austria (MANTA), Norway (LUCAS), and France (GEFAL).

The ABC trial reported the first level 1 evidence for the efficacy of bevacizumab in the treatment of neovascular AMD. The treatment schedule was based on an as-required strategy. In this prospective, randomized, multicenter, double-masked trial, more than 45% of patients treated with bevacizumab improved 10 or more letters while 32% of the patients treated with bevacizumab gained 15 or more letters from baseline VA. Mean VA increased 7.0 letters in the treatment group with a median of seven injections during a 54-week period. These results are comparable to those in the MARINA and ANCHOR studies, and the retreatment approach used was not a fixed monthly but an as-required one (66).

Limitations of the ABC trial are that it does not compare bevacizumab with ranibizumab and the number of patients enrolled is small. Bevacizumab remains not approved by the FDA for intraocular use, and this may have medicolegal implications

In 2011, CATT study (Comparison of Age-Related Macular Degeneration Treatment Trials) was published (67). It is a multicenter, single-blind, noninferiority trial that enrolled 1,208 patients with exudative AMD at 44 clinical centers. The patients were treated with 0.50 mg ranibizumab or 1.25 mg bevacizumab on either a monthly schedule or as needed with monthly evaluation. There were four study groups: ranibizumab every 28 days (ranibizumab monthly), bevacizumab every 28 days (bevacizumab monthly), ranibizumab only with active CNV (ranibizumab as needed), and bevacizumab only with active CNV (bevacizumab as needed). Every 28 days, an optical coherence tomography (OCT) was performed, and signs of active CNV were defined as decreased VA compared to previous examination, new or persistent hemorrhage, fluid seen on OCT, or dye leakage on fluorescein angiography.

Among the 1,161 patients who were alive 1 year after enrollment, VA was available for 1,105 (95.2%) patients. All four study groups showed VA improvement from baseline to 1 year, with most improvement during the first 6 months. At 1 year, bevacizumab was comparable to ranibizumab (99.2% confidence interval for the difference in the mean change in VA within –5 to +5 letters) when both were given monthly and when they were administered as needed. Additionally, ranibizumab given as needed was comparable to ranibizumab given monthly. When comparing bevacizumab administered as needed and bevacizumab administered monthly, the data were inconclusive. No inferiority or noninferiority was established in the two study groups. Ranibizumab administered as needed was comparable with bevacizumab given monthly. However, the comparison between ranibizumab administered monthly and bevacizumab given as needed was also inconclusive.

At 1 year, patients treated with ranibizumab monthly gained 8.5 letters, whereas ranibizumab administered as needed led to a gain of 6.8 letters. Additionally, patients treated with bevacizumab monthly gained 8.0 letters, whereas bevacizumab administered as needed led to a gain of 5.9 letters. The proportion of patients who did not show a decrease in VA of 15 letters or more from baseline was 94.4% in the group treated with ranibizumab monthly, 94% in the group treated with bevacizumab monthly, 95.4% in the group treated with ranibizumab as needed, and 91.5% in the group treated with bevacizumab as needed. The patients who gained at least 15 letters increased during the first 36 weeks in all four groups but did not differ at 1 year among the groups. Fixed monthly retreatment improved VA, and the differences were not significant in the ranibizumab group and inconclusive for the bevacizumab groups. In relation to the cost of treatment, the average cost per patient for the first year in the ranibizumab-monthly group was $23.500; in the ranibizumab as-needed group, the cost was $13.800; $595 in the bevacizumab-monthly group and $385 in the bevacizumab as-needed group (67).

The results from the ABC and CATT studies are based on 1-year follow-up and are encouraging; however, longer follow-ups are needed. Longer follow-ups may show surprising results. In the HORIZON study, patients who were treated on a monthly schedule during year 1 and afterward with an as-needed schedule show a decrease in median VA by five letters after 1 year and by an additional three letters after 2 years (68).

PROTOCOLS OF TREATMENT: RETREATMENT ALGORITHMS AND MAINTENANCE THERAPY

Fixed Monthly Injections

Initially, there was no clear consensus on retreatment strategies. In the MARINA and ANCHOR studies of ranibizumab, patients received monthly intravitreal injections during 2 years, so each patient received a total of 24 injections. Today, the fixed monthly ranibizumab retreatment schedule has not been widely accepted (46,47). Later, large clinical trials such as PIER, SAILOR, and EXCITE have evaluated less frequent retreatment strategies. Patients were at first treated with three monthly injections of ranibizumab, termed the “loading phase,” followed by a quarterly injection regimen. The results observed were positive but did not equal the MARINA and ANCHOR results. In fact, patients showed less mean gain in VA, and fewer patients experienced 15 or more letters of visual gain. Additionally, if after the loading phase there was a gain in VA, it was not maintained during the study (69–71). EXCITE, PIER, and SAILOR studies evaluated monthly maintenance therapy compared to reduced frequency schedule of injections and found that reduced schedule is insufficient for optimal monitoring of disease progression (70,71).

As-Required Injections

PrONTO study introduced a dosing regimen characterized by three consecutive monthly intravitreal injections followed by as-needed retreatment based upon signs of recurrence, ophthalmoscopy, OCT, or fluorescein angiography, called the as-needed or PRN protocol (72). It seems that the PRN dosing regimen is the most widely used today. Ranibizumab was used in PrONTO study, and the dosing regimen was OCT guided and variable. Patients received three monthly intravitreal injections, and retreatment was based upon loss of five letters of VA, new-onset hemorrhage or CNV, increase of central retinal thickness of more than 100 μm documented with OCT, or intraretinal fluid. The 2nd year of study added as retreatment criteria evidence of recurrent intraretinal, subretinal, or sub-RPE fluid (72,73). In the first year of PrONTO study, patients received an average of 5.6 injections of ranibizumab. The results of PrONTO study suggest that 70% of the patients treated with intravitreal ranibizumab showed resolution of edema within 1 month after the first injection, and 90% of the patients showed resolution of fluid after the loading phase (72).

The ABC trial used a loading phase and then an as-required retreatment schedule, based on criteria for retreatment: subretinal fluid on OCT, new hemorrhage, CNV, decreased vision by five or more letters with new intraretinal fluid on OCT, and injections performed at six weekly intervals. By using this retreatment schedule, the results of ABC trial showed that after 54 weeks, 32% of participants receiving bevacizumab gained 15 or more letters of VA, the results are comparable to those in the MARINA and ANCHOR studies (66).

The CATT study compared ranibizumab and bevacizumab using monthly and as-required retreatment schedules (67). In this study, bevacizumab administered monthly led to a gain of 8.0 letters at 12 months, and bevacizumab administered as-required led to a gain of 5.9 letters. Similarly, ranibizumab administered monthly led to a gain of 8.5 letters at 12 months, and ranibizumab in as-required schedule led to a gain of 6.8 letters. It is clear that a monthly retreatment schedule showed greater gain in VA, but the differences were “inconclusive” for the bevacizumab groups and were not significant for the ranibizumab groups. These studies follow up patients for 12 months, but other studies with longer follow-ups, such as HORIZON and SUSTAIN, have shown that significant visual gain is achieved with monthly injections and the as-required schedule is not as effective as the monthly fixed schedule.

Treat and Extend

Other retreatment schedules are used, in order to minimize the number of injections and visits to the hospital. In the treat-and-extend schedule, the patients are treated with monthly injections until macula is dry and without fluid seen with OCT. The follow-up between injections is lengthened by 1 to 2 weeks until recurrence of fluid is observed. If recurrent fluid is detected on a follow-up visit, the treatment interval is reduced to the previous interval. Treatment schedule is variable and subject to change at every visit, but the time between visits in individualized based on each patient’s response to treatment (74–76).

Combination Therapy

The findings of PrONTO study revealed that 70% of patients show resolution of macular edema within 1 month of intravitreal ranibizumab, and after the loading phase, 90% of patients show resolution of all fluid (72). However, in some patients, bevacizumab or ranibizumab may be insufficient to resolve neovascularization associated with AMD. Patients either may be refractory to these treatment modalities or may develop resistance to therapy. One study reported that resistance to bevacizumab is observed in 6 out of 59 eyes with 14 months of follow-up and after median number of 8 injections (77). Several factors may be involved in the resistance of treatment with bevacizumab. For instance, the development of neutralizing antibodies against bevacizumab molecule was confirmed in serum of patients treated with intravitreal injections (78). Additionally, inflammation and hypoxia may play a role in this resistance probably due to an independent pathway that may stimulate CNV formation through release of proangiogenic factors (79). An increased number of macrophages have been observed in excised human CNV treated with intravitreal bevacizumab (80). There is evidence that the basement membrane of endothelial cells persist after their death, acting as a scaffold for regrowth of CNV (81). Consequently, it has been suggested that combining treatments with different mechanisms of action may result beneficial (82). One of the combination therapies suggested is verteporfin PDT in combination with anti-VEGF (84). This treatment strategy may reduce the number of treatments required. Some studies have shown that combining PDT with bevacizumab stabilized VA, decreased the number of injections per year, and decreased pigment epithelium detachment (84–87). Also anti-VEGF therapy may be combined with macular radiation therapy, and it can be delivered through an external device on the sclera or through an internal device after pars plana vitrectomy (88). Also, severe submacular hemorrhage cases may be treated with vitrectomy and coapplication of subretinal injection of rtPA and bevacizumab followed by intravitreal fluid–gas exchange and after the procedure repeated postoperative intravitreal injections of anti-VEGF (89). However, large-scale, multicenter, double-blind studies are necessary to confirm combination therapy’s efficacy and safety.

Treatment Every 2 Weeks

The majority of patients benefit from a monthly treatment schedule, but some eyes will show no improvement and signs of CNV getting worse (90). In a recent study, authors create a mathematical model that predicts, by increasing the number of bevacizumab injections from monthly to every 14 days, the resulting trough levels of VEGF-binding activity of bevacizumab and other anti-VEGF molecules. They found that bevacizumab administered every 14 days showed a binding activity to be 6.5-fold higher, and they conclude that the theoretical increase in trough binding levels when anti-VEGF drugs are dosed every 2 weeks may benefit patients who show response to treatment within 2 weeks but rebound with increased macular thickness after a month (91).

SECONDARY EFFECTS

In chemotherapy treatments, systemic bevacizumab has been associated with an increased risk of thromboembolic events (43,92). In the case of AMD, intravitreal bevacizumab is administered at a dose of 1 to 2.5 mg that is 150 times less than the systemic chemotherapy dosage (93). Consequently, in relation to AMD, studies have shown no correlation between the number of bevacizumab injections and the incidence of adverse effects such as thromboembolic disease, new-onset hypertension, myocardial infarction, cerebrovascular accident, hemorrhage, and death (94). An international Internet survey of 70 centers in 12 countries reported on 7,113 injections given to 5,228 patients. The ocular adverse events observed included endophthalmitis in 0.01%, one case of traumatic lens injury (0.01%), and three cases of retinal detachment (0.04%). Potential drug-related ocular adverse events included intraocular inflammation (0.14%), acute vision loss (0.07%), nontraumatic cataract progression (0.01%), and central retinal artery occlusion (0.01%). Potential drug-related systemic adverse events included acute blood pressure rise (0.21%), stroke (0.07%), deep venous thrombosis (0.01%), transient ischemic attack (0.01%), and death (0.03%) (95). An analysis of eight studies reported the adverse events following intravitreal bevacizumab injection to be uveitis (0.11%), preretinal bleeding (0.11%), macular hole (0.11%), cataract (0.11%), RPE rip (0.014), endophthalmitis (0.6%), transient rise in intraocular pressure (0.86%), myocardial infarction (0.08%), and death (0.31%) (57).

Retrobulbar hemodynamics of 43 patients with AMD was examined with color Doppler ultrasonography after injection of 1.25 mg bevacizumab. Intravitreal bevacizumab induced a significant decrease in the peak systolic velocity and end-diastolic velocity and a significant rise in the resistive index of the central retinal artery and short posterior ciliary artery of the injected eye. Consequently, it seems that bevacizumab intravitreal injection significantly affects ocular hemodynamic parameters of both the injected and uninjected eyes (96). More studies are needed to understand the consequences of this observation.

SAFETY OF REPEATED INTRAVITREAL INJECTIONS

Fortunately, repeated intravitreal injections for an extended period of time show low incidence of ocular adverse events. It has been recommended that the injection technique used should avoid vitreal reflux, either by changing the needle gauge or injection technique (97). Also, the preparation of bevacizumab syringes should be done carefully, following aseptic guidelines.

PREPARATION

Bevacizumab for intravitreal administration has to be prepared from the intravenous chemotherapy formulation. The guidelines recommend preparation of individual syringes using aseptic technique and adequate sterilization procedures (98,99). Usually the syringes are prepared containing 0.12 mL (3 mg). Immediately prior to intravitreal injection, the plunger is advanced to 0.05 mL (Fig. 18.2). A study reported that syringes under 4°C show 10% degradation of the drug concentration at 3 months and 12% degradation when frozen in a syringe at −10°C (100). Other reports have described storage and reuse of a single vial for multiple doses under refrigeration with no ocular adverse events (101,102).

Patients must be informed about the risks and benefits of bevacizumab intravitreal injection, highlighting potential ophthalmic and systemic adverse events (103). Additionally, the American Academy of Ophthalmic Executives (AAOE) recommends consideration of FDA-approved drugs before off-label bevacizumab. Patients must sign an informed consent and should be aware of the off-label indication of intravitreal bevacizumab. Also patients should be instructed for symptoms that should be reported immediately (104).

NEEDLE GAUGE AND TECHNIQUE

Other complications described are temporary increase in intraocular pressure and reflux of bevacizumab with the formation of a subconjunctival bleb (105–107). Some ophthalmologists have adopted different intravitreal injection techniques in order to decrease the incidence of reflux taking into consideration intraocular pressure (108,109). Some patients may experience elevation of intraocular pressure 30 minutes after the injection.

Reflux of the drug may occur following an injection (107,110,111). To minimize the amount of reflux, authors have recommended an anterior chamber paracentesis immediately after an injection. The use of a “mercury bag” placed over the eye 20 minutes before injection may prevent bleb formation, ensuring that bevacizumab or any other intravitreal anti-VEGF remains in the vitreous. Small needle diameter, such as a 32-gauge needle, and an oblique injection technique may further minimize reflux after intravitreal injection (Figs. 18.3 and 18.4) (97,112).

CONCLUSION

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