Bevacizumab vs Mitomycin C in Phacotrabeculectomy
GFS (trabeculectomy) is still the mainstay of surgical management of glaucoma. When glaucoma is associated with visually significant cataract, GFS can be combined with cataract extraction and intraocular lens implantation to treat these coexistent conditions. However, combining GFS with phacoemulsification (combined surgery) may not yield the same reduction of IOP as trabeculectomy alone. Hence, it has become routine practice to augment glaucoma-filtering surgery with pharmacological agents that reduce the wound-healing response and prolong the survival of the resultant bleb.
The most important reason for failure of GFS is wound-healing response, which is mainly mediated by fibroblast proliferation, migration, and contraction. This leads to postoperative scarring in the filtering tract, bleb, and subconjunctival tissue, preventing aqueous outflow. Most of the currently used adjuncts that modulate wound healing target fibroblast activity with antimetabolites, predominantly 5-fluorouracil and MMC, and are effective at limiting the scarring process. However, these agents can cause extensive cell death and apoptosis, resulting in complications such as severe postoperative hypotony, bleb leaks, and endophthalmitis. Khaw et al have splendidly summarized the various agents that have been used to modulate wound healing after glaucoma surgery. Most notably, a major phase III randomized multicentric clinical trial undertaken to evaluate the role of CAT 152, a humanized monoclonal antibody to TGF-β2 failed to show any significant effect in preventing bleb failure over a 12-month follow-up period. Many others such as ribozymes, Paclitaxel, p21(WAF-1/Cip-1), Interferon α, and MMP inhibitors penicillamine and fibrostatin-c have been investigated but are not yet available for routine clinical use. Hence, the search continues for an ideal pharmacological agent to modulate the subconjunctival wound-healing response with an acceptable safety profile to benefit routine application.
Angiogenesis, which allows for early migration of inflammatory cells and fibroblasts into the wound and the release of key mitogenic cytokines such as fibroblast growth factor, is a critical component of the wound-healing process. It is essential for granulation tissue formation during the process of any wound healing. VEGF has been proven to be the single most important agent responsible for physiological and pathologic angiogenesis. Anti-VEGF agents have been used successfully in the treatment of various posterior segment pathologies such as choroidal neovascular membranes, diabetic eye disease, and vascular occlusions. In fact, anti-VEGF agents have brought about a major change in ocular therapeutics and are at the heart of a tremendous amount of research to expand their applications in various ocular disease processes.
Blocking VEGF can be a strong wound-modulating agent that is of potential use as an adjunct in GFS. Memarzadeh et al recently published the results of a trial using bevacizumab compared with 5-fluorouracil as an antifibrotic agent in trabeculectomy in a rabbit model and concluded that administration of multiple postoperative subconjunctival injections of bevacizumab is associated with improved trabeculectomy bleb survival. Bevacizumab may thus be a useful agent for improving success and limiting scar tissue formation after trabeculectomy.
Safety concerns regarding the systemic and local toxicity of intraocular use of bevacizumab have been encouraging, with very few investigators reporting serious systemic adverse events. The short-term viability of bevacizumab-augmented single-site phacotrabeculectomy was seen clinically by a functioning filtering bleb and a reduced IOP in our study. The clinical safety and tolerability was shown by the absence of widespread signs of local toxicity or of intraocular inflammation and by the lack of any systemic adverse effects for the patient.
In this study, there were no significant differences in IOP among the study groups at 1 week and 6 months after treatment. All groups showed a significant reduction in IOP compared with baseline, and the number of AGM per person also reduced significantly. However, the ScB group had more patients who fell in the category of complete success with no treatment failure, compared with the other 2 groups. These results suggest higher efficacy of ScB compared with the other groups. However, the small sample size does not allow such conclusions from this study and merely hints at future possibilities of this new approach. A much larger sample with a better study design would be required to establish the therapeutic supremacy of one drug over another.
The bleb characteristic comparison between the groups showed that the ScB group had higher and more avascular blebs compared with the other groups at 1 month after treatment. However, this difference did not persist at the 6-month follow-up. The main concern was the gradual increase in vascularity of blebs that received bevacizumab over the 6-month follow-up. This may lead to bleb failure in the future and a study with a longer follow-up is required to ascertain long-term efficacy.
One patient in the ScB group experienced local conjunctival necrosis without any long-term adverse events. This adverse event may be explained on the basis of avascular necrosis because of ScB. Intensive steroids prevented scarring and there was gradual conjunctival reepithelialization when the peak effect of bevacizumab declined. No toxic effects of bevacizumab were seen in the corneal epithelium or endothelium in our study and ScB had a relatively better safety profile compared with the other groups at the 6-month follow-up.
Grewal et al reported on the efficacy of a single postoperative injection of 1.25 mg/0.05 mL of bevacizumab in 12 glaucomatous eyes that underwent trabeculectomy. Ours was a controlled randomized double-blinded comparative efficacy study in contrast to the uncontrolled noncomparative open-label trial by Grewal et al. The preoperative mean IOP was greater in our study. The IOP at all time intervals was lower in the study by Grewal et al compared with ours. This may be explained on the basis of a higher preoperative mean IOP and a greater reduction in IOP following trabeculectomy alone compared with a combined single-site phacotrabeculectomy. The bleb characteristics of the 2 studies are not comparable because of the different bleb grading systems used. However, we are in concordance in terms of higher and more avascular blebs in the beginning and less cystic blebs with gradually increasing vascularization at 6 months when ScB is used as an adjunct. One major difference between the 2 studies is the multiple-dosing schedules of ScB used in our study compared with the single postoperative injection used in theirs. VEGF is upregulated as early as 3 days after the induction of wound healing and this expression lasts for at least 7 days. Studies have also shown that, in full-thickness skin wounds, VEGF messenger ribonucleic acid expression declines around day 13, and after 3 weeks it is no greater than normal. This warrants multiple injections to counteract the VEGF that accumulates during the first postoperative week following GFS. Hence, we injected bevacizumab at approximately 1 week after treatment to maintain the therapeutic concentration and ensure efficacy in wound modulation. Even Memarzadeh et al, in their rabbit model of ScB to reduce bleb fibrosis, have recommended multiple injections till postoperative day 14 to neutralize the VEGF produced in abundance during wound healing.
The use of bevacizumab in glaucoma is currently an off-label application, and several issues need to be addressed, such as dose, route of application, duration of action, and toxicity profile. These parameters may be altered in the future to improve the effect of bevacizumab-augmented phacotrabeculectomy.
To our knowledge, this is the first study evaluating the safety and efficacy of bevacizumab as an adjunct in phacotrabeculectomy, and the first randomized comparative study comparing bevacizumab with MMC in GFS. Previous reports have evaluated the efficacy of bevacizumab in trabeculectomy alone or in salvaging failing vascularized blebs. The success and failure of any procedure depend entirely upon the precise definitions used to define them. The clear-cut definitions used for defining success in terms of complete and qualified success gave more significance to the results in our study, rather than merely relying on mean IOP, which has many variables that determine it. The Indiana Bleb Assessment System enabled us to see that the blebs with bevacizumab gradually increased in vascularity over a 6-month period.
The major drawback of the study was the small sample size and short duration of follow-up. This makes it difficult to draw any meaningful conclusions for widespread application. The effect of bevacizumab on the corneal endothelium was also not evaluated because of lack of specular microscopy equipment. However, on the basis of the results of this pilot study, further studies to evaluate the safety and efficacy of ScB in preventing bleb failure are warranted.
In conclusion, this trial suggested that bevacizumab has good safety and efficacy in augmenting short-term results of combined phacotrabeculectomy in eyes with primary open-angle or angle-closure glaucoma associated with visually significant cataract. Bevacizumab in routine glaucoma filtration surgery may signify a paradigm shift in the surgical management of glaucoma. The sponge bevacizumab arm did as well as the MMC group but not as well as the subconjunctival arm. Hence, we recommend that future trials compare ScB with MMC or 5FU and not include sponge-soaked bevacizumab. Multiple injections of ScB in the early postoperative period may be required to maintain the long-term survival of these blebs.
Discussion
GFS (trabeculectomy) is still the mainstay of surgical management of glaucoma. When glaucoma is associated with visually significant cataract, GFS can be combined with cataract extraction and intraocular lens implantation to treat these coexistent conditions. However, combining GFS with phacoemulsification (combined surgery) may not yield the same reduction of IOP as trabeculectomy alone. Hence, it has become routine practice to augment glaucoma-filtering surgery with pharmacological agents that reduce the wound-healing response and prolong the survival of the resultant bleb.
The most important reason for failure of GFS is wound-healing response, which is mainly mediated by fibroblast proliferation, migration, and contraction. This leads to postoperative scarring in the filtering tract, bleb, and subconjunctival tissue, preventing aqueous outflow. Most of the currently used adjuncts that modulate wound healing target fibroblast activity with antimetabolites, predominantly 5-fluorouracil and MMC, and are effective at limiting the scarring process. However, these agents can cause extensive cell death and apoptosis, resulting in complications such as severe postoperative hypotony, bleb leaks, and endophthalmitis. Khaw et al have splendidly summarized the various agents that have been used to modulate wound healing after glaucoma surgery. Most notably, a major phase III randomized multicentric clinical trial undertaken to evaluate the role of CAT 152, a humanized monoclonal antibody to TGF-β2 failed to show any significant effect in preventing bleb failure over a 12-month follow-up period. Many others such as ribozymes, Paclitaxel, p21(WAF-1/Cip-1), Interferon α, and MMP inhibitors penicillamine and fibrostatin-c have been investigated but are not yet available for routine clinical use. Hence, the search continues for an ideal pharmacological agent to modulate the subconjunctival wound-healing response with an acceptable safety profile to benefit routine application.
Angiogenesis, which allows for early migration of inflammatory cells and fibroblasts into the wound and the release of key mitogenic cytokines such as fibroblast growth factor, is a critical component of the wound-healing process. It is essential for granulation tissue formation during the process of any wound healing. VEGF has been proven to be the single most important agent responsible for physiological and pathologic angiogenesis. Anti-VEGF agents have been used successfully in the treatment of various posterior segment pathologies such as choroidal neovascular membranes, diabetic eye disease, and vascular occlusions. In fact, anti-VEGF agents have brought about a major change in ocular therapeutics and are at the heart of a tremendous amount of research to expand their applications in various ocular disease processes.
Blocking VEGF can be a strong wound-modulating agent that is of potential use as an adjunct in GFS. Memarzadeh et al recently published the results of a trial using bevacizumab compared with 5-fluorouracil as an antifibrotic agent in trabeculectomy in a rabbit model and concluded that administration of multiple postoperative subconjunctival injections of bevacizumab is associated with improved trabeculectomy bleb survival. Bevacizumab may thus be a useful agent for improving success and limiting scar tissue formation after trabeculectomy.
Safety concerns regarding the systemic and local toxicity of intraocular use of bevacizumab have been encouraging, with very few investigators reporting serious systemic adverse events. The short-term viability of bevacizumab-augmented single-site phacotrabeculectomy was seen clinically by a functioning filtering bleb and a reduced IOP in our study. The clinical safety and tolerability was shown by the absence of widespread signs of local toxicity or of intraocular inflammation and by the lack of any systemic adverse effects for the patient.
In this study, there were no significant differences in IOP among the study groups at 1 week and 6 months after treatment. All groups showed a significant reduction in IOP compared with baseline, and the number of AGM per person also reduced significantly. However, the ScB group had more patients who fell in the category of complete success with no treatment failure, compared with the other 2 groups. These results suggest higher efficacy of ScB compared with the other groups. However, the small sample size does not allow such conclusions from this study and merely hints at future possibilities of this new approach. A much larger sample with a better study design would be required to establish the therapeutic supremacy of one drug over another.
The bleb characteristic comparison between the groups showed that the ScB group had higher and more avascular blebs compared with the other groups at 1 month after treatment. However, this difference did not persist at the 6-month follow-up. The main concern was the gradual increase in vascularity of blebs that received bevacizumab over the 6-month follow-up. This may lead to bleb failure in the future and a study with a longer follow-up is required to ascertain long-term efficacy.
One patient in the ScB group experienced local conjunctival necrosis without any long-term adverse events. This adverse event may be explained on the basis of avascular necrosis because of ScB. Intensive steroids prevented scarring and there was gradual conjunctival reepithelialization when the peak effect of bevacizumab declined. No toxic effects of bevacizumab were seen in the corneal epithelium or endothelium in our study and ScB had a relatively better safety profile compared with the other groups at the 6-month follow-up.
Grewal et al reported on the efficacy of a single postoperative injection of 1.25 mg/0.05 mL of bevacizumab in 12 glaucomatous eyes that underwent trabeculectomy. Ours was a controlled randomized double-blinded comparative efficacy study in contrast to the uncontrolled noncomparative open-label trial by Grewal et al. The preoperative mean IOP was greater in our study. The IOP at all time intervals was lower in the study by Grewal et al compared with ours. This may be explained on the basis of a higher preoperative mean IOP and a greater reduction in IOP following trabeculectomy alone compared with a combined single-site phacotrabeculectomy. The bleb characteristics of the 2 studies are not comparable because of the different bleb grading systems used. However, we are in concordance in terms of higher and more avascular blebs in the beginning and less cystic blebs with gradually increasing vascularization at 6 months when ScB is used as an adjunct. One major difference between the 2 studies is the multiple-dosing schedules of ScB used in our study compared with the single postoperative injection used in theirs. VEGF is upregulated as early as 3 days after the induction of wound healing and this expression lasts for at least 7 days. Studies have also shown that, in full-thickness skin wounds, VEGF messenger ribonucleic acid expression declines around day 13, and after 3 weeks it is no greater than normal. This warrants multiple injections to counteract the VEGF that accumulates during the first postoperative week following GFS. Hence, we injected bevacizumab at approximately 1 week after treatment to maintain the therapeutic concentration and ensure efficacy in wound modulation. Even Memarzadeh et al, in their rabbit model of ScB to reduce bleb fibrosis, have recommended multiple injections till postoperative day 14 to neutralize the VEGF produced in abundance during wound healing.
The use of bevacizumab in glaucoma is currently an off-label application, and several issues need to be addressed, such as dose, route of application, duration of action, and toxicity profile. These parameters may be altered in the future to improve the effect of bevacizumab-augmented phacotrabeculectomy.
To our knowledge, this is the first study evaluating the safety and efficacy of bevacizumab as an adjunct in phacotrabeculectomy, and the first randomized comparative study comparing bevacizumab with MMC in GFS. Previous reports have evaluated the efficacy of bevacizumab in trabeculectomy alone or in salvaging failing vascularized blebs. The success and failure of any procedure depend entirely upon the precise definitions used to define them. The clear-cut definitions used for defining success in terms of complete and qualified success gave more significance to the results in our study, rather than merely relying on mean IOP, which has many variables that determine it. The Indiana Bleb Assessment System enabled us to see that the blebs with bevacizumab gradually increased in vascularity over a 6-month period.
The major drawback of the study was the small sample size and short duration of follow-up. This makes it difficult to draw any meaningful conclusions for widespread application. The effect of bevacizumab on the corneal endothelium was also not evaluated because of lack of specular microscopy equipment. However, on the basis of the results of this pilot study, further studies to evaluate the safety and efficacy of ScB in preventing bleb failure are warranted.
In conclusion, this trial suggested that bevacizumab has good safety and efficacy in augmenting short-term results of combined phacotrabeculectomy in eyes with primary open-angle or angle-closure glaucoma associated with visually significant cataract. Bevacizumab in routine glaucoma filtration surgery may signify a paradigm shift in the surgical management of glaucoma. The sponge bevacizumab arm did as well as the MMC group but not as well as the subconjunctival arm. Hence, we recommend that future trials compare ScB with MMC or 5FU and not include sponge-soaked bevacizumab. Multiple injections of ScB in the early postoperative period may be required to maintain the long-term survival of these blebs.
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