Bevacizumab (Avastin®)
Bevacizumab (Avastin®)
Bevacizumab (Avastin®, Genentech, Roche) is a recombinant, humanized, monoclonal immunoglobulin G1 antibody (149 kD) that binds to and inhibits the biologic activity of all isoforms of human VEGF.
This molecule has 2 antigen-binding domains (ranibizumab has 1).
In 2004, the FDA approved bevacizumab for use in patients with metastatic colorectal cancer.
It has received additional approval for use in patients with non–small-cell lung cancer and those with metastatic breast cancer(78-81).
Though not formally studied or approved for any intraocular disease, Rosenfeld’s pioneering work and the unavailability of a related ocular drug, ranibizumab, led to rapid and wide use of bevacizumab all over the world(82, 83).
Using bevacizumab as an intravitreal injection to treat neovascular AMD is off-label at this time, however many ophthalmologists, appropriately offer intravitreal bevacizumab to AMD patients based on multiple forms of evidence: results from several retrospective case series, extrapolation from the magnitude of the outcomes reported with ranibizumab, the structural similarity between ranibizumab and bevacizumab, the individual, and the natural history of the disease if left untreated(84).
In the human retina, it is unclear if the molecule of bevacizumab fully distributes within the retinal layers or if localized inhibition of VEGF in the vitreous and inner retina is responsible for the clinical effects associated with administration(85-87).
There are also theories that the larger size of bevacizumab relative to ranibizumab may result in bevacizumab not clearing as quickly from the eye, potentially resulting in longer duration of activity.
To the knowledge of this author, this claim has not been confirmed(84).
Full antibodies generally have longer systemic half-lives than antibody fragments.
Therefore, it is assumed that the half-life of bevacizumab in the eye and in the circulation is longer than that of ranibizumab after intravitreal injection.
Different half-lives for these 2 drugs may have implications for different dosing frequencies and different systemic toxicities(78, 86-91).
Experimental and clinical studies
Experimental and clinical studies
Following the initial successful administration of this drug in the management of exudative AMD in May 2005, numerous case series were published illustrating the effectiveness of this treatment in a high proportion of patients(92).
Almost all of the evidence supporting the use on neovascular AMD comes from off-label usage in short-term uncontrolled clinical case series, which suggests that intravitreal administration is apparently locally and systemically well tolerated and is associated with vision stabilization or improvement in most treated eyes(85, 86, 87, 91, 94).
One of the earlier large retrospective case series in the literature included 81 consecutive eyes
(79 patients) with subfoveal choroidal neovascularization treated with 1.25 mg (0.05 cc) intravitreal bevacizumab, at baseline and 1 month later if morphologic changes attributable to the CNV persisted (subretinal fluid, pigment epithelial detachment, retinal thickening).
Seventy-eight percent had prior treatment with pegaptanib, photodynamic therapy (PDT), or both.
After one IVB injection, 30 of 81 eyes had resolution of their subretinal fluid. At 2 months, 50% demonstrated resolution of leakage.
The mean best corrected visual acuity (BCVA) improved from 20/200 to 20/125 at week 8
(p < 0.0001)(91).
Spaide et al. in a subsequent study evaluated 266 eyes, 70% of which had prior treatment for exudative AMD (PDT or pegaptanib).
At the 3-month follow-up (data available for 141 patients) 38.3% patients improved by 2 or more Snellen lines.
Mean BCVA improved from 20/184 to 20/109 at 3 months (p<0.001).
Central retinal thickness measured by OCT improved over 3 months from a mean of 340 microns to a mean of 213 microns (p<0.001)(95).
A greater visual acuity effect has been reported in naïve eyes compared to those that have received previous treatment, for example in a study of 50 eyes (48 patients) treated with bevacizumab for exudative AMD found that naïve eyes responded more favorably than previously treated eyes.
Six of the 14 (43%) of naïve eyes gained 3 lines or more of vision versus 17% of eyes that had undergone prior treatment.
The naïve group’s mean visual acuity improved from 20/160 at baseline to 20/63 (p<0.001) at week 24(96).
Such visual acuity gains were not reported with PDT or pegaptanib treatment and were comparable to the results of the phase III studies of ranibizumab.
However, those with longstanding exudative AMD have also been shown to improve with treatment.
One retrospective study in 48 eyes with exudative AMD for 5 months or longer (mean 17.9 months) showed that 25% of those improved at least 3 lines with bevacizumab intravitreous injection after a mean follow-up of 27 weeks(96).
In another prospective case series, Bashshur et al. injected 2.5 mg (0.1ml) of bevacizumab (twice the dose most frequently used) into the vitreous in 17 eyes with wet AMD patients and followed by two additional injections at four-week intervals.
Mean best-corrected visual acuity was 20/252 at baseline and 20/76 at week 12 (P < 0.001).
Mean central subfield retinal thickness also improved between baseline and week 12 in all 17 patients.
No systemic or ocular side effects were noted(85).
Safety
Safety
Data on the safety of intravitreal bevacizumab are more limited than data on ranibizumab or pegaptanib safety because there are no large, prospective, controlled safety studies with this treatment.
Local side-effects are similar to those found for the other anti-VEGF agents(98).
A safety retrospective study evaluating the side effects of intravitreal bevacizumab reviewed 1265 patients for 12 months, with 92 lost to follow-up.
Ocular complications included seven (0.16%) bacterial endophthalmitis, seven (0.16%) tractional retinal detachments, four (0.09%) uveitis, and a case (0.02%) of rhegmatogenous retinal detachment and another case (0.02%) of retinal detachment and vitreous hemorrhage(99).
In electrophysiological studies no negative side-effects were seen on the retina. In contrast, the results showed a recovery effect on photoreceptors even at the site of the CNV(100).
Most of the in vitro, ex vivo and in vivo experiments excluded short-term negative effects on ocular cells and histology(101, 102, 103, 104, 105).
A paper, however, discloses mitochondrial disruption in the inner segment of photoreceptors and apoptosis after high doses of intravitreal bevacizumab in the rabbit eye.
The electrophysiological investigation and light microscopy, in contrast appeared unaltered.
This suggests that potential side-effects on the cellular level cannot be detected with the present diagnostic tools in clinical practice(98, 106).
Intravenous use of bevacizumab in patients with colorectal cancer is associated with severe systemic side effects including arterial thromboembolism, gastrointestinal perforation, hemorrhage, hypertensive crisis and nephrotic syndrome.
Initial studies using this therapy intravenously for ocular disease in a healthier population did not find nearly the same risks(107, 108).
The dose of intravitreal bevacizumab is much lower (1/400th) of the dose used for intravenous treatment and has not been found to result in unexpected systemic side effects(92).
There are no studies adequately undertaken to identify rare systemic events.
In a 3-month retrospective study of bevacizumab treatment in 266 patients, 1 (0.4%) developed a nonfatal myocardial infarction after the third injection.
Two patients (0.8%) had apparent transient ischemic attacks (diagnosis was not definitive).
There were 2 deaths, one from myocardial infarction.
Nevertheless, that patient was a smoker with a history of emphysema.
It is important to consider, however, that this population (mean age, 80.3 years) is at risk for myocardial infraction regardless of treatment.
Any potential safety concerns remain unknown and waiting for randomized and controlled clinical trials.
Discussion
Discussion
The initial results of intravitreal bevacizumab for exudative AMD led to the acceptance of this off-label therapy by ophthalmologists around the world, assuming, based on case series evidence, that bevacizumab is at least almost as good as ranibizumab with respect to efficacy and safety.
Some ophthalmologists might recommend bevacizumab instead of ranibizumab, even when it is available and affordable to the patient, because of the concerns regarding the treatment costs(84, 92).
Intravitreal bevacizumab accounts for more than 50% of all anti-VEGF therapy delivered for exudative AMD in the United States(109).
The National Eye Institute is sponsoring a clinical trial to compare the safety and efficacy betwen bevacizumab and ranibizumab for the treatment of exudative AMD – CATT study.
This study and other prospective, controlled and randomized trials in several countries (IVAN-UK, VIBERA-Germany, MANTA-Austria, LUCAS-Norway, GEFAL-France) will provide the best level of evidence regarding the efficacy and safety of bevacizumab.
Some of these ongoing studies can give consistent information about the necessary dose-ranging and dosing-frequency to control AMD neovascularization.