Antifibrotics and Wound Healing in Glaucoma Surgery

SURVEY OF OPHTHALMOLOGY

VOLUME 48 • NUMBER 3 • MAY–JUNE 2003

DIAGNOSTIC AND SURGICAL TECHNIQUES MARCO ZARBIN AND DAVID CHU, EDITORS

Antifibrotics and Wound Healing in Glaucoma Surgery Paul J. Lama, MD, and Robert D. Fechtner, MD Glaucoma Division, New Jersey Medical School, Newark, New Jersey, USA

Abstract. When medical and laser therapy fail to control intraocular pressure, glaucoma filtration surgery needs to be performed. Glaucoma surgery is unique in that its success is linked to interruption of the wound-healing response in order to maintain patency of the new filtration pathway. In this article we will review the wound-healing pathway and the pharmacologic interventions that have been employed clinically and experimentally to interrupt wound healing, particularly steroids and the antifibrotic agents 5-fluorouracil and mitomycin C. A review of the published literature looking at use of these agents to enhance success as well as the associated complications are presented, critiqued, and interpreted in order to put the studies in proper perspective. Future directions and recommendations regarding use of these agents are available and an introduction to newer wound modulating agents such as antitransforming growth factor beta 2 is presented. (Surv Ophthalmol 48:314–346, 2003. 쑖 2003 by Elsevier Inc. All rights reserved.) Key words. 5-fluorouracil lectomy • wound healing

•

complications

•

glaucoma surgery

•

mitomycin C

•

trabecu-

Wound Healing Pathway

Unlike many other types of surgery in which complete healing of tissue with restoration of normal architecture would be a desirable outcome, glaucoma surgery seeks to achieve incomplete healing to allow aqueous humor to escape the eye. A completely healed trabeculectomy is a failed trabeculectomy. The use of antifibrotic agents to improve the success of glaucoma surgery has become common practice, and the benefits provided by these agents are accompanied by unique complications. In this article, we will review the data regarding the use of these adjuncts to glaucoma surgery.

Injury to tissue following physical trauma, whether surgical, chemical, or radiation-induced, results in a sequence of biologic events leading to repair. Repair involves two distinct processes: replacement and regeneration. Replacement results in scar tissue formation in lieu of restoration of the normal epithelial and stromal architecture. In contrast, regeneration results in restoration of the original architecture leaving no trace of injury. Complete regeneration can occur when the structural framework remains intact. Tissues capable of complete regeneration include 314

쑖 2003 by Elsevier Inc. All rights reserved.

0039-6257/03/$–see front matter doi: 10.1016/S0039-6257(03)00038-9

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

315

Fig. 1. Flow chart of the wound healing pathway. (Reprinted from The Glaucomas, ed 2, 1996, with permission of Mosby).

the kidney, liver, and glandular organs. Most tissue injury, however, results in a variable degree of replacement of damaged cells by scar tissue formation in addition to regeneration of lost, damaged, and dead cells. The conjunctiva shares many features of repair with skin.

Healing of surgical skin wounds is often considered the prototype repair process that involves both replacement and regeneration (Fig. 1).87 The initial processes involved in healing are inflammation and coagulation, leading to a cascade of biological events including cellular, hormonal, and growth factor

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Surv Ophthalmol 48 (3) May–June 2003

release. These ultimately lead to repair and scar tissue formation. With injury to vascular tissue, leakage of plasma proteins and blood cells occurs. Clotting factor activation leads to conversion of fibrinogen to fibrin. Platelet aggregation occurs at the site of endothelial cell damage, which exposes subendothelial collagen. Platelets play a critical role in wound healing not only because thrombin assembly occurs on the surface but also because platelets release mitogens and platelet derived growth factor (PDGF). Clots as well as hormones released during vascular injury, such as histamine, serotonin, prostaglandins, kinins, and leukotrienes, lead to cellular migration of neutrophils, monocytes, and macrophages as well as fibroblasts. Neutrophils are recruited to the site of injury through the action of proteases released during degranulation lyse and then phagocytose debris. Endothelial cell growth factors (ECGF) are released by epithelial cells, and interleukin-1 (IL-1) is released by macrophages. The white blood cell response is followed by fibroblast and endothelial cell migration, which clinically appears as red granulation tissue. Depending upon the intensity of the wound-healing response, fibroblasts may be present as early as 24 hours after injury. Fibroblasts produce collagen, elastin, and mucopolysaccharides. Collagen cross-linking as well as myofibroblast transformation leads to collagen supercoil formation, which is also accompanied by dehydration, leading to dense scar tissue formation. Remodeling over time is responsible for the evolution of clinical manifestations of a cicatrix. Racial and genetic factors play integral roles in determining the degree and physical appearance of scar tissue. Healing of ocular surgical wounds follows a similar cascade. In theory, one can modulate the woundhealing response by interfering with the multitude of cellular and humoral factors involved in the pathway. Genetic predisposition cannot be altered at this time. However, avoiding unnecessary trauma through gentle handling of tissue during surgery can influence the degree of inflammation and scar tissue formation. Current pharmacologic interventions that modulate the wound-healing pathway can be described by the mechanism of action and by the phase of the wound-healing response a particular agent interrupts. Classification of these agents is thus simplified if we categorize the healing pathway into four main phases: coagulative, inflammatory, proliferative, and post-proliferative remodeling. Steroids, for example, interrupt the inflammatory phase whereas 5fluorouracil interrupts the proliferative phase.

Effect of IOP-Lowering Drugs on Wound Healing It has been shown that chronic use of topical antiglaucoma agents, especially adrenergic agonists,

LAMA AND FECHTNER

results in long-term morphologic effects on the conjunctiva and Tenon’s capsule.13,99 Specifically, subclinical conjunctival inflammation associated with an increased number of conjunctival inflammatory cells and fibroblasts has been noted.14 Such histologic changes may prime the post-surgical fibroblastic response resulting in increased fibrosis, thus increasing the risk of bleb failure following trabeculectomy. The greatest adverse effect was reportedly induced by triple topical therapy consisting of a beta-blocker, a miotic, and an adrenergic agonist.15 Broadway and colleagues16 prospectively investigated whether preoperative treatment with corticosteroids can reverse the histologic changes and improve bleb survival after trabeculectomy. One month prior to surgery, 30 patients scheduled for trabeculectomy underwent biopsy of the inferior conjunctiva, had their sympathomimetic agents discontinued, and began treatment with 1% fluoromethalone QID. At the time of surgery two additional biopsy specimens were removed, one from the superior bulbar conjunctiva and one from the inferior bulbar conjunctiva. All biopsy specimens were evaluated quantitatively with respect to inflammatory cell and fibroblast numbers. These investigators demonstrated that pretreatment with topical fluoromethalone can successfully reduce the number of inflammatory cells and fibroblasts. They further analyzed the outcome of first trabeculectomy in 16 of these patients with a matched control group of 16 patients who did not undergo preoperative conditioning of the conjunctiva with topical steroids and found that such pretreatment improved trabeculectomy outcome as defined by IOP less than 21 mm Hg without medication. There was an 81% success rate at 12 months in the pretreated group as compared to 50% in the control group. The survival curves suggest that pretreatment with steroids improves chances for early filtration success. Because bleb survival may be adversely affected by topical glaucoma therapy and because a substantial proportion of newly diagnosed glaucoma patients eventually require filtering surgery to control intraocular pressure, this observation has led to the suggestion that glaucoma surgery should be offered as initial therapy. Indeed, though beyond the scope of this review, a multicenter, randomized, prospective clinical trial comparing surgical and clinical outcome of initial trabeculectomy versus conventional medical management followed by trabeculectomy surgery if necessary has been underway since the mid 1990s and may help answer this question (CIGTS, Collaborative Initial Glaucoma Treatment Study). Interim results have been recently published.67 The data indicate that although initial surgery affords, on

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ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

the average, slightly better IOP control, it is equivalent to aggressive initial medical therapy in preventing glaucomatous visual field progression. Patients in the surgery-first group also had an initial greater reduction in visual acuity, which was likely due to a higher incidence of development of visually significant cataracts.

Anti-inflammatory Agents Anti-inflammatory agents have long been part of the strategy for modulating inflammation and wound healing in the eye. Steroid hormones can be viewed as the prototype. Steroidal hormones are naturally produced by the adrenal gland. There are three major classes of steroidal hormones: glucocorticoids, mineralocorticoids, and the sex steroids. The glucocorticoids are the class of hormones involved in inhibiting inflammation and wound healing. STEROIDAL AGENTS

The mechanism of action of both natural and synthetic glucocorticoids is through binding to specific intracellular receptors upon entering target tissues. The macromolecular complex thus formed is transported into the nucleus and ultimately leads to alteration of gene expression. Pharmacologically, glucocorticoids affect a wide number of physiological processes. Binding to glucocorticoid receptors leads to both metabolic and catabolic changes (e.g., glucose, insulin, protein, and fat metabolism) in addition to the well-known immunomodulatory and anti-inflammatory effects. Inhibition of inflammation and wound healing by glucocorticoids is largely mediated via suppression of leukocyte concentration, distribution, and function as well as their effects on vascular permeability. A single dose of steroids results in reduction of neutrophils at the inflammatory site and shifts lymphocytes, monocytes, and basophils out of the circulation and into lymphoid tissue. This dose also results in inhibition of leukocyte and tissue macrophage function. The ability of these cells to respond to antigens and mitogens is severely limited. Macrophage function is especially impaired, preventing phagocytosis as well as release of enzymes (i.e., collagenase and plasminogen activator) and growth factors (e.g., interleukins). Steroidal hormones also inhibit phospholipase and block conversion of membrane phospholipids to arachidonic acid. Such blockade leads to inhibition of prostaglandin as well as leukotriene synthesis. Leukotrienes are potent leukocyte chemotactic factors as well as promoters of vascular permeability. Corticosteroids can also reduce vascular permeability through inhibition of the activity of kinins and reduction in the

amount of histamine released by basophils. Reduction in vascular permeability leads to less leakage of serum and clotting factors and hence formation of clot and fibrin. Thus, steroid-mediated inhibition of leukocyte concentration and function as well as vascular permeability leads to less local tissue disruption, reduction in amounts and activities of mitogens and growth factors, and clot and fibrin production. The end result is a diminution of fibroblastic activity with inhibition of wound healing. Synthetic steroids are classified by potency as compared to cortisol. Hydrocortisone is pharmacologically equivalent to cortisol. Prednisone, prednisolone, methylprednisolone, and dexamethasone are progressively more potent (Table 1). The potency of topical ocular corticosteroids depends additionally upon the ability of the agent to penetrate tissue, which depends upon lipid solubility. For example, the acetate form of prednisolone penetrates the cornea far better than the phosphate form as a result of its biphasic solubility as compared to the water solubility of the phosphates. Thus, for control of intraocular inflammation, prednisolone acetate is superior to prednisolone phosphate. However, for local conjunctival control of inflammation the phosphate form should in theory be equipotent to the acetate form. Topical ocular corticosteroids are used routinely following virtually any major or minor ocular surgical procedure. Although it seems intuitive that topical steroids would be beneficial in improving trabeculectomy success rates, there was little evidence before the 1980s to support this notion. Furthermore, there was considerable controversy as to whether additional systemic treatment was beneficial. Starita et al investigated the effects of topical and systemic steroids in a randomized prospective trial.112 In their study 68 eyes of 54 patients were divided into three treatment groups. Group 1 received no steroids; group 2 received topical prednisolone acetate 1%; and group 3 received the same as group 2 plus oral prednisone. They concluded that topical steroids were beneficial

TABLE 1

Relative Potency and Intraocular Anti-inflammatory Activity of Corticosteroids Corticosteroid Dexamethasone Methylprednisolone Prednisone or Prednisolone Hydrocortisone

Equivalent Dose (Oral) 0.75 mg 4 mg 5 mg 20 mg

Prednisolone acetate, dexamethasone alcohol ⬎ prednisolone phosphate, dexamethasone phosphate, rimexalone, loteprednol ⬎ medrysone.

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Surv Ophthalmol 48 (3) May–June 2003

in treating postoperative inflammation and significantly improved trabeculectomy outcome as compared to the regimen without topical steroids. However, systemic prednisone did not provide any additional benefit over topical steroids. Mean followup times were 20.4 months in group 1, 18.3 months in group 2, and 18.5 months in group 3. Subsequently, long-term follow-up was provided for some of these patients. At 5 years, 58 eyes of 45 of these patients were evaluable, an equal number from each group was lost to follow-up. The mean intraocular pressure (IOP) in steroid-treated patients was 14.5 ⫾ 1.8 mm Hg and 19.3 ⫾ 2.1 mm Hg in the group without steroids. Although there was a statistically significant difference in success rates between groups 1 and 2 and between groups 1 and 3, there was no statistically significant difference between the two steroid-treated groups (groups 2 and 3). Using visual field and optic disk criteria, 94% of the steroid-treated patients were considered stable as compared to 43% of those patients in the group without steroid treatment. Thin cystic blebs were more frequently found in the steroid-treated patients. Using a two-tailed t-test, the occurrence of thin cystic blebs in the entire study population was associated with lower IOP and a higher success rate as well as fewer medications.89 At 10 years, there were 46 eyes that remained evaluable. The results still demonstrated a clear advantage in the steroid-treated group in terms of IOP control, visual field, and optic disk parameters.6 This study provided the first clear demonstration of the benefit of topical steroids in trabeculectomy. The lack of additional benefit from oral steroids was further supported in a prospective study by Azuara-Blanco et al.8 They performed a prospective randomized double-masked placebo controlled trial comparing outcome of trabeculectomy in patients given 50 mg of oral prednisone BID for 3 days in the perioperative period as compared to placebo. The probability of success at 9 months, as defined by IOP ⱕ 15 mm Hg with no more than one antiglaucoma medication, was 63.0% in the prednisone group and 65.6% in the control group. The use of oral prednisone in unselected patients appeared to confer no additional short-term benefit in surgical success following trabeculectomy. Topical corticosteroid use following trabeculectomy appears beneficial, but there has been no definitive consensus regarding specific dosing and duration of treatment. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDS) suppress the inflammatory response by blocking

LAMA AND FECHTNER

conversion of arachidonic acid to endoperoxides via inhibition of cylooxygenase.98 Endoperoxides are biochemical precursors of prostacyclin, thromboxane A2, and prostaglandins. NSAIDS also inhibit platelet function and aggregation. Platelets, thrombi, and the products of arachidonic acid metabolism are important stimulators of the inflammatory response and hence the wound-healing pathway. Although 1% prednisolone acetate is very effective in suppressing inflammation, this agent and other steroids may lead to the development of infection (especially keratitis) and cataracts. Because NSAIDS do not possess the same ocular toxicity profile as topical steroids can they potentially supplant steroids as the postoperative anti-inflammatory agents of choice following glaucoma filtering surgery? Kent and colleagues performed a randomized prospective trial comparing diclofenac with prednisolone acetate after trabeculectomy with mitomycin C.55 There were 14 patients randomized to diclofenac QID versus 12 patients randomized to 1% prednisolone acetate QID. At 6 months there was no statistically significant difference in outcome with respect to IOP control or complication rates. Although these results suggest that topical NSAIDS may be equivalent to steroids in suppressing inflammation following uncomplicated trabeculectomy, the number of patients was small, and follow-up was too short to formulate a meaningful conclusion.

Antifibrotics The trabeculectomy originally described by Cairns in 1968 has been the prototype glaucoma-filtering procedure performed over the last three decades. Despite modifications of the original technique and evolution of new laser and surgical filtering procedures, the trabeculectomy remains the most commonly performed glaucoma incisional surgical procedure. The success rate of glaucoma-filtering surgery unfortunately has been limited by postoperative scarring. Scarring most commonly occurs at the level of the episclera leading to flap fibrosis and eventual bleb failure. Whereas gentle handling of tissue, control of intraoperative bleeding, and use of postoperative anti-inflammatory agents leads to reduced fibroblastic activity, such maneuvers are usually insufficient to prevent scarring for the long term. Thus, use of antiproliferative agents to inhibit fibroblast replication and function would be significantly more effective in achieving early filtration as well as enhancing bleb survival. In the early 1980s, 5-fluorouracil and mitomycin C were found to be effective in inhibiting fibroblastic activity and have tremendously impacted the success rates of trabeculectomy.

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

319

Fig. 2. Inhibition of cell replication by various agents. G0 ⫽ resting phase; G1 ⫽ pre-DNA synthesis; S = DNA synthesis; G2 ⫽ RNA synthesis; M ⫽ mitosis; R ⫽ recruitment phase. (Reprinted from Textbook of Ocular Pharmacology, 1997, with permission of Lippincott Williams & Wilkins).

5-Fluorouracil 5-Fluorouracil (5-FU) is a chemotherapeutic agent that specifically mediates its antiproliferative effect by antagonizing pyrimidine metabolism, hence its classification as an antimetabolite. It initially undergoes anabolic transformation into ribosyl and deoxyribosyl nucleotide metabolites. Specifically, one of these metabolites, 5-fluoro-2′deoxyuridine 5′-phosphate (FdUMP), binds covalently to thymidylate synthetase and its cofactor N5,10-methylene tetrahydrofolate to form a ternary complex thereby interfering with a critical biochemical step in the synthesis of thymine nucleotides.35,95 This step results in inhibition of DNA synthesis and ultimately in cell death. The ribosylphosphate form of 5-FU may also be incorporated into mRNA leading to defective protein synthesis (Fig. 2).95 Experimentally, 5-FU has been demonstrated to be a very effective inhibitor of fibroblast growth. Khaw et al showed in vitro and in vivo that a 5-minute exposure results in growth arrest and may have a long lasting effect on cultured human Tenon’s fibroblasts.60 5-FU also specifically interferes with qualitative fibroblast functions such as collagen lattice contraction.78 It is particularly useful as an adjunct to inhibit wound healing during glaucoma surgery

as a result of the localized tissue effects, short halflife, ease of administration and dosing which can be titrated to the clinical response.122 Animal studies have demonstrated that adjunctive 5-FU following trabeculectomy results in decreased fibroblast proliferation and scarring with prolonged bleb survival as compared to no 5-FU.43 CLINICAL EVALUATION OF 5-FLUOROURACIL (TABLES 2 AND 3)

There have been numerous national single-site as well as multicenter studies demonstrating efficacy of 5-FU in augmenting the success rate of glaucoma surgery. There were significant interstudy differences in total dose, mean dose, mode of delivery (sponge vs. injections or both), patient selection, and study duration. Nevertheless, the cumulative data support a significant benefit in terms of bleb survival and clinical success as determined by IOP results in treated eyes compared with control eyes not receiving adjunctive 5-FU.1,2,4,5,10,22,28,32,33,38,40,44,45,49,64,68,75,77, 80,82,86,88,90,92,102,104,108,114,117,120,122,123,129 Heuer and colleagues performed a pilot study enrolling 104 eyes of 95 high-risk patients who underwent filtering surgery with subconjunctival 5-FU.45 The first 19 patients had 3 mg (0.3 cc at 10 mg/cc dilution) injected 180⬚

45

2

5

40

92

80

90

117

86

123

FFSS group

Araie et al

Goldenfeld et al

Ruderman et al

Ophir et al

Rothman et al

Tsai et al

Ren et al

WhitesideMichel et al

Reference

Heuer et al

Authors

20

Subgroup of 5-FU pilot study patients with neovascular glaucoma Prospective, randomized study in patients undergoing combined phacotrabeculectomy Consecutive, non-comparative case-series in patients with JOAG

Prospective, randomized study in primary trabeculectomy Prospective, randomized study in primary trabeculectomy Prospective, randomized study in primary trabeculectomy Retrospective study

Prospective, randomized study, in patients with history of cataract surgery or failed filter Prospective, non-randomized, mixed, POAG, secondary and refractory glaucoma

Pilot study, complicated, glaucomas, high-risk for failure, historical controls

Study Design

5 mg injections dose range between 15–45 mg

5 mg injections over first 2 postoperative weeks; mean dose 24.8 mg in 5-FU group

5 mg injections, 105 mg injections over 2 weeks

Mean dose 28.9 ⫾ 10 mg

4–6 5 mg injections

5 mg injections daily from post-op day 1–7

Mean dose, 36.8 ⫾ 19.7 mg in POAG group, 49.5 ⫾ 18.0 mg in secondary glaucoma group, 36.5 ⫾ 10.0 mg in refractory group 5 mg injections, 5 injections between day 1 and day 15

5 mg injections, 105 mg over 2 weeks

3 mg or 5 mg injections, 105 mg over 2 weeks

Dose

No difference in IOP control, number of glaucoma medications, or visual acuity between 5-FU and control group 95% had IOP ⬍ 20 without medications

IOP ⱕ 20 mm Hg in 96% in 5-FU group and 76% in control group IOP ⱕ 21 mm Hg without medications 72.3% in 5-FU group and 51.3% in control group Success rate at 5 years of 28% Median time to failure was 13.3 months

Success in 12/14 in 5-FU group and 3/12 in control group

IOP ⱕ 20 mm Hg in 94% of 5-FU group and 73% in control group

69% success with 5-FU as compared to 39% success with historical controls without 5-FU 49% success at 5 years in 5-FU group; 26% success rate in control group; [Add 1 and 3 year results] Kaplan–Meier 5-year probability of IOP ⬍ 16 mm Hg without medications was 55.2% with 5-FU and 0% without 5-FU

Outcome

Historical controls

Key Limitations

Surv Ophthalmol 48 (3) May–June 2003

74

34

52

41

26

62

362

213

104

No. of Eyes

Studies Using Post-operative Subconjunctival 5-Fluorouracil

TABLE 2

320 LAMA AND FECHTNER

10

75

114

102

Mora et al

Towler et al

Sidoti et al

4

Anand et al

Bell et al

32

Reference

Dietze et al

Authors

Retrospective study in patients undergoing primary trabeculectomy with lo-risk features

Prospective, non-randomized study, variable risk patient groups Retrospective series; patients with 1 or more risk-factors for failure Restrospective study; variable risk groups; low-risk-no risk factors, High-risk- 1 or more risk factors Retrospective, non-comparative case-series in uveitic glaucoma

Consecutive case-series

Study Design

50 mg/cc sponge application for 5 minutes

25 mg/cc sponge application for 5 minutes

25 mg/cc sponge application for 5 minutes 50 mg/cc sponge application for 5 minutes

50 mg/cc sponge application for 5 minutes 25 mg/cc sponge application for 5 minutes

Dose

Yes; IOP ⬎ 21 mm Hg given at 4–7 day intervals up to 4 weeks post-op Yes; Up to 7 injections Mean 2.2 ⫾ 1.6 injections

Yes; post-op days 1–21

No

No

No

Intraoperative 5-FU

Studies Using Intra-operative 5-FU with or without Post-operative Injections

TABLE 3

83% had IOP between 5 and 21 mm Hg

49% achieving target IOP without medications. Trend towards better IOP in lower-risk patients Mean IOP in high-risk patients not receiving post-op 5-FU was 15.3 ⫾ 2.1 mm Hg; Mean IOP in low-risk eyes receiving post-op 5-FU was 10.8 ⫾ 4.8 mm Hg IOP 20 mm Hg or less medications in 82% at 1 and 2 years and 67% at 5 years

84% had IOP ⱕ 21 reduction of at least 20% at 3 months

84% had IOP ⱕ 21 reduction of at least 20% at 3 months

Outcome

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY 321

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Surv Ophthalmol 48 (3) May–June 2003

from the surgical site via a tuberculin syringe attached to a 30-gauge needle at the conclusion of surgery and then daily for 14 days. However, due to the rapid progression to scarring in eyes undergoing filtering surgery with neovascular glaucoma (NVG) that received 3 mg injections, the protocol was revised for the remaining 76 patients to twice daily 5 mg injections for 7 days then once daily on days 8–14. The protocol revision and higher dosing level was justified based on the safety and tolerability of 10 mg subconjunctival injections of 5-FU for retinal detachments complicated by proliferative vitreoretinopathy. Moreover, because the half-life of aqueous 5-FU after subconjunctival injections in normal rabbit eyes was only 4 hours, the investigators felt that twice-daily dosing was most appropriate.11 The authors found a success rate of 69% with adjunctive subconjunctival 5-FU in aphakic eyes versus 39% with trabeculectomy alone (historical controls). In eyes with prior failed surgery, the success rate was 81% as compared to historical controls of 36–40% without 5-FU. Patients with NVG had the best comparative improvement with 5-FU with an overall success rate of 75% (n = 16) as compared to the 11% success rate in historical controls from the same institution performed by the same surgeons. The definition of success in this study was an IOP of less than 21 mm Hg with medications and less than 25 mm Hg without medications. Although useful for comparison, such criteria would not currently be considered successful endpoints. In fact, such cutoff levels would be unacceptable, as contemporary target pressures have shifted to the mid to low teens as glaucoma progression in eyes with moderate to advanced optic nerve damage appears proportionately higher in surgical eyes with higher levels of IOP.1 In spite of a major shift in what is clinically considered an acceptable target pressure, most studies continue to use 21 mm Hg as a cutoff for defining success. Some additional secondary endpoints are percent reduction in IOP (usually 20%) or need for further surgical intervention. Rockwood et al published a continuation of the original pilot study by Heuer that included an additional 60 patients who were enrolled subsequently. In total he reported the results in one eye of each of 155 patients. These investigators used cumulative life table analysis to assess surgical success rates at 1-, 2-, and 3-year intervals (Fig. 3). Most failures occurred within 8 months of surgery except for those with NVG failures; 50% of the failures occurred after only 2 weeks, and 70% of failures after only 2 months. Age and race did not affect outcomes. The most prevalent complications were corneal epithelial defects in 55.5% and conjunctival wound leaks in 36.8%. The high rate of wound leaks may be partially related to technical factors such as the use of large needles prior

LAMA AND FECHTNER

Fig. 3. Surgical success rates (%) reported by year from Rockwood et al.88 NVG = neovascular glaucoma.

to adoption of small vascular needles. The leaks that developed in the patients enrolled later in the study were found to be secondary to wound gape as a result of breakage or loosening of the 9-0 poly-glactin sutures. Nine of 99 (9%) aphakic eyes developed intraoperative and delayed postoperative nonexpulsive choroidal hemorrhage. No such hemorrhages occurred in phakic eyes.88 The original pilot studies used historical controls for comparison. Overall, there have been few randomized, controlled, prospective clinical trials evaluating 5-FU versus no 5-FU. Even between those studies with a prospective design, there was considerable variability, inasmuch as some enrolled both high- and low-risk patients, some were exclusively low-risk patients with uncomplicated primary glaucoma undergoing initial incisional surgery, or were exclusively high-risk patients with complicated glaucomas or had previous ocular surgery involving conjunctival manipulation. Total dose and mode of administration of 5-FU was not standardized. Furthermore, total number of patients enrolled in some of these studies were very small, thus limiting the strength of that particular study. Therefore, data from large well-designed prospective clinical studies would be most useful in providing more robust information. A landmark multicenter, randomized, prospective clinical study with 5-FU is the Fluorouracil Filtering Surgery Study (FFSS). The size of the study and the duration of follow-up make it deserving of detailed consideration. In this study 213 high-risk patients who had at least one failed filtering procedure but were phakic or who had undergone cataract surgery and were either aphakic or pseudophakic were randomized to trabeculectomy alone versus trabeculectomy with postoperative 5-FU. Those who were randomized to 5-FU received subconjunctival injections (5 mg/injection, 10 mg/ml concentration) administered 180⬚ from the filtering site twice daily for the first 7 postoperative days and then daily on days 8–14, totaling 105 mg. Injections were withheld only

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

if serious complications such as wound leakage occurred. Measurement outcomes included IOP, visual acuity, and visual fields. Complications were also assessed in each group. The last published report regarding this study was the 5-year follow-up report in 1996.2 Recruitment began in September 1985 and follow-up continued through December 1993. Failure was defined as a reoperation to control IOP pressure or an IOP greater than 21 mm Hg at or after the first-year examination. At the 5-year evaluation, 51% were classified as failures in the 5-FU group as compared to 74% in the control group. The greatest difference in success between the two groups was at 6 months. At that point the cumulative proportion of patients that did not require reoperation in the 5FU group was approximately 90% but was between 65–70% in the control group. The survival curves between the two groups continued to diverge albeit at a less steep slope until 18 months at which point the slopes were roughly parallel (Fig. 4). There were a number of preoperative factors that were found to critically influence trabeculectomy success rates. One of the most dramatic preoperative characteristics was time interval between last incisional surgery and trabeculectomy. Those with prior surgery within 30 days had an abysmal success rate

Fig. 4. Survival curves for trabeculectomy with 5-FU vs. no 5-FU. Note that in the 5-FU group early bleb survival is much greater than those blebs not supplemented with 5-FU but after 18 months the slopes of the survival curves are nearly parallel. Perioperative suppression of the fibroblastic response improves early bleb survival but continued wound healing activity results in a steady decline in bleb survival similar to the no 5-FU group. (Reprinted with permission of Elsevier Inc. from the American Journal of Ophthalmology.)

323

with most failing within the first few months and all failing after slightly more than 12 months. Overall, the time interval between last incisional surgery and trabeculectomy was inversely proportional to failure rate. The number of prior surgical procedures was also an important factor influencing success rates. Those that had only one prior surgical procedure initially fared better than the rest, but after 5 years success rates were no better than those who had two procedures. Those with more than two prior surgical procedures, however, had the lowest success rates. Type of glaucoma was an important variable as well. Those with primary open-angle glaucoma (POAG) had better outcomes than all other types and those with secondary angle-closure glaucoma (SACG) had the worst outcome. Other preoperative variables that were found to significantly influence time to failure after trabeculectomy included: poor preoperative visual acuity, high preoperative IOP, self-reported Hispanic ethnicity, trabeculectomy performed in an inferior location as opposed to a superior location, and brown or hazel-colored eyes as compared to blue. Some of these observations might seem predictable. For example, patients with high preoperative IOP might have had worse outcomes as a result of appropriately shorter time-intervals between last incisional surgery and trabeculectomy. Observation of such eyes with very high IOP would pose too great a risk of optic nerve damage prompting early surgical intervention. Likewise, those with SACG are similarly more likely to have a higher preoperative IOP and a correspondingly shorter time-interval between last incisional surgery and trabeculectomy accounting for the greater failure rate observed in this group. Although, it is not entirely clear why inferior trabeculectomy location negatively influenced outcome, one explanation may be that because these eyes had severe scarring superiorly precluding trabeculectomy in that location such eyes had a greater potential for development of fibrosis and hence failure. Ethnic differences in success rates especially between whites and those of African origin (41 patients) may have been masked by the effects of confounding variables, which independently altered the wound healing response. Of the types of postoperative complications, the development of late bleb leaks were among the most serious. Patients in the 5-FU group had a greater risk of late bleb leaks, occurring in 9% as compared to a 2% rate in controls. Recent evolution of surgical techniques such as broad surface application of antiproliferative agents to promote diffuse rather than focal filtration may reduce the risk of this complication. In summary, the FFSS has demonstrated that 5-FU has a significant effect on improving trabeculectomy success rates over controls after 5 years. However, failure continues to occur at a steady and

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slow rate. Recent and/or multiple surgical trauma strongly accelerates postoperative fibrosis leading to enhanced scarring and filtration failure. Although 5FU improves bleb survival rates, there is an increased risk of late bleb leaks and late bleb infection. Araie et al published another large series with a total of 362 eyes of 263 patients. Of these, 263 received subconjunctival injections of 5-FU at a concentration of 50 mg/cc administered during the first 14 postoperative days. The mean administered dose was between 36.0 ⫾ 19.5 mg for patients diagnosed with POAG. Those with refractory glaucoma or secondary glaucoma as defined by the authors received 49.5 ⫾ 18.0 mg and 36.5 ⫾ 20.0 mg of 5-FU. The other 99 did not receive any injections. Follow-up was from 1–9 years. Kaplan–Meier life table statistics were employed to determine a 5-year survival rate. The probability of IOP control below 21 mm Hg with or without medication in the 5-FU group was 92.5% for POAG, 87.4% for secondary glaucoma, and 57.5% for refractory glaucoma. The probability of achieving the same results without medication was 58.2%, 54.8%, and 27.8%, respectively. The probability of achieving an IOP of 16 mm Hg or lower without medication, which would be a more typical contemporary IOP target, especially in patients with severe nerve damage, was 55.2%, 49.8%, and 24.5%, respectively. Thus, in this study those patients with successful surgery who can achieve IOP control without medication are also likely to be able to achieve IOP in the mid teens. The probability of success in the group without 5-FU was significantly lower for each subtype of glaucoma. The probability for an IOP below 16 mm Hg at the 5-year point was 0% without 5-FU in patients with POAG or refractory glaucoma and 12% in those with secondary glaucoma. There was a 38.8% incidence of corneal epithelial defects in the 5-FU group. All other complication rates were similar in both treatment groups.5 Goldenfeld reported the outcome of 62 patients with uncontrolled glaucoma undergoing their first incisional procedure who were randomized to five 5mg injections of 5-FU postoperatively beginning the first postoperative day up until day 15.40 All patients underwent limbal-based conjunctival flaps. All patients were followed for at least 1 year. Success was defined as IOP ⱕ 20 mm Hg. A successful outcome was found to occur in 30/32 (94%) of 5-FU-treated eyes and in 22/30 (73%) of control eyes. Hypotony (IOP ⬍ 5 mm Hg) with reduction of one line of Snellen acuity without macular biomicroscopic changes occurred in four 5-FU–treated patients and none of the control patients. Life table analysis revealed an initial large treatment advantage for the blebs in the 5-FU group in the first year. However, afterward the curves are essentially parallel between treatment

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and control groups indicating similar rates of subsequent failure. Similar survival curves have been described in other studies.90 This result implies that adjunctive 5FU use inhibits early fibrosis conferring early filtration and successful IOP control, however, late fibrosis and remodeling continues at similar rates in both groups, eventually leading to parallel rates of reduction of bleb survival. Ruderman and colleagues performed a randomized study of 26 patients with and without low dose 5-FU during filtering surgery. Those randomized to 5FU received a total of seven injections of 5 mg of 5-FU diluted to a concentration of 10 mg/ml beginning on postoperative day 1 and then daily. After 12 months 12/14 in the 5-FU group and 3/12 in the control group were considered successes. Mean postoperative IOP of the 5-FU group at 6–18 months was 14.4 ⫾ 1.4 mm Hg as compared to controls who had a mean IOP of 30.7 ⫾ 3.9 mm Hg during the same interval.92 Ophir and Ticho reported their findings in one eye of each of 41 patients randomized to 4–6 postoperative 5-FU injections (5 mg diluted to 10 mg/ml with saline) vs. no 5-FU (but no placebo injections). Follow-up was 17 or more months in each group. The IOP was 20 mm Hg or less in 96% of the 5-FU group but in only 76% of the control group. They reported transient punctate epithelial defects in 28% in the 5-FU group but did not alter the protocol. Although the small study size in some of the studies and lack of a placebo injection as a control may have reduced the overall validity of the results, the considerable and consistently observed differences in outcome demonstrate the clear advantage of wound modulation with 5-FU following glaucoma filtering surgery. Furthermore, because subconjunctival injections are unpleasant and may even be painful, a study patient may not find the possibility of randomization to placebo injections acceptable. Hence enrollment in masked trials with placebo injections would be very difficult. Thus, although placebo controlled trials are preferable from the perspective of a masked study design, certain clinical situations, such as with 5-FU injections, may not permit it.80 The results of the above studies indicate a treatment benefit with postoperative 5-FU injections in both high-risk as well as low-risk patients. In contrast to the original pilot study, the FFSS, and other studies that included high-risk patients, those that exclusively studied low risk patients used fewer total injections. The rationale was that such patients require fewer total doses because the potential for fibrosis was significantly less. Furthermore, such dose reduction would potentially lead to fewer complications, fewer side effects, less pain, and would be considerably more convenient to both patient and physician.

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

One of the longest follow-up studies of low-risk patients who underwent initial trabeculectomy with low-dose postoperative 5-FU was recently reported by Rothman et al, which is a continuation of the study originally reported by Liebmann in 1991.68 This study was a retrospective analysis of 52 consecutive patients who received postoperative 5-FU injections within the first two postoperative weeks and 74 control subjects who had trabeculectomy alone. The total dose was individualized at the surgeon’s discretion. A mean total dose of 28.9 ⫾ 10.0 mg was administered (range 10–55 mg). Mean follow-up for all patients was 58.1 ⫾ 44.1 months (range 1.1–159.9 months) and for successful eyes was 55.9 ⫾ 47.1 months (range 7.6–159.9 months). The 5-year success rates with and without medicines were 77.8% in the 5-FU group and 62.2% in the control group. The complete success rates (IOP ⬍ 21 mm Hg without medications) were lower in both groups, 72.3% and 51.3%, respectively. Those in the 5-FU group were also using fewer medications as compared to control subjects, 0.7 ⫾ 1.1 medications versus 1.8 ⫾ 1.4 medications. Late bleb leaks occurred in 12 patients, and 10/12 had received 5-FU. Bleb-related infection occurred in 6.3% of patients but at a higher rate in those treated with 5-FU, 6/52 versus 2/74. Five of the six 5-FU–treated patients that developed infection had a late bleb leak. As compared to the 1991 report, the difference in success rates between 5-FU–treated and control patients at 9 years follow-up had narrowed considerably, underscoring the importance of long-term follow-up. In that report 100% of patients in the 5FU-treated group as compared to 78.9% of controls had successful IOP control at 2 years follow-up. In contrast the cumulative success at five years was 77.8% in the 5-FU group and 62.2% in the controls. Additionally, during the follow-up period 7 of 52 (13.5%) patients who had received 5-FU and a similar ratio of controls (11/74, 14.9%) required needle revision. Thus, as mentioned previously, 5-FU only appears to increase the likelihood of successful filtration in the first few years after surgery as a result of inhibition of fibroblast proliferation and function. Long-term success, however, continues to wane at a rate similar to controls who were not subjected to perioperative antimetabolites. This underappreciated but consistent observation suggests that continued uninhibited late fibrosis leads to bleb failure. In spite of the progressive decline in bleb survival in 5-FU-treated patients, there is still a greater risk of late bleb-related infection in this group as compared to untreated controls. Although inhibition of early fibrosis in low-risk patients requires significantly fewer injections as compared to the higher risk patients in the FFSS and

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other studies, the lower range of the dose-response curve had not been defined until recently. Chaudhry et al22 reported 1-year follow-up of 40 eyes of 40 low-risk patients undergoing primary trabeculectomy randomized to three 5-mg 5-FU injections or no injections and found no difference in IOP control between the two groups. Doses higher than 15 mg are thus likely necessary to achieve a threshold level of inhibition of fibroblasts in order to yield a successful outcome following trabeculectomy. 5-FLUOROURACIL AND COMBINED SURGERY

Glaucoma surgery combined with cataract surgery often leads to disappointing results from the perspective of IOP control. Use of antiproliferative agents would be potentially useful in augmenting bleb survival when filtering surgery is performed in conjunction with cataract surgery. Many investigators have reported results of combined surgery with adjunctive antifibrosis therapy. Many of these are small series, and none has the sample size or duration of follow-up as the FFSS. Hennis reported the effects of subconjunctival administration of 5-FU following combined extracapsular cataract extraction with trabeculectomy in 15 eyes of 15 patients as compared to a control group of 17 patients who did not receive any injections. The authors reported no difference in outcome between the two groups with respect to IOP, bleb appearance, or number of postoperative medications necessary to control IOP. These results, published more than 9 years ago, are less applicable to contemporary surgery in the U.S. because trabeculectomy is now most commonly performed in conjunction with small-incision phacoemulsification, a technique less traumatic than standard extracapsular cataract extraction. The total dose or biologic effectiveness of 5-FU therefore may not have been sufficient in Hennis’s study to overcome the fibroblastic response leading to failure of detection of a treatment benefit.44 Despite the apparent lack of benefit from 5-FU in extracapsular cataract extraction combined with trabeculectomy, with less traumatic small incision surgery (phacoemulsification) and a correspondingly lower stimulus for fibroblastic proliferative activity, it may be possible to identify a treatment effect if one actually exists in combined surgery with 5-FU. Gandolfi and Vecchi randomized 24 patients to combined clear cornea phacoemulsification and trabeculectomy to delayed low-dose postoperative 5-FU beginning on day 8 after surgery then weekly for 5 weeks versus no 5-FU. In contrast to Hennis’s results, 10 of 12 patients in the 5-FU group had an IOP ⱕ 15 mm Hg at 1 year as compared to only one of 12 in the no 5-FU group. Although this was a small study

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it indicated that there might be a treatment benefit. This result supports the concept that less traumatizing surgery would shift the operative risk for bleb failure to a lower risk category leading to improved success rates even with low dose antifibrotic.38 Ren et al reported the largest and longest randomized prospective trial of combined cataract surgery by phacoemulsification and trabeculectomy with or without 5-FU.86 A total of 74 patients were randomly assigned to combined surgery alone (36 patients) or to combined surgery with adjunctive postoperative 5FU (38 patients). The 5-FU group received 5.0 ⫾ 1.3 injections each containing 5 mg 5-FU for a mean total of 24.8 mg over the first 2 postoperative weeks. Surgical success was defined as an IOP less than or equal to 20 mm Hg on not more than 1 glaucoma medication and without the need for additional surgery. During an average follow-up of 45.3 ⫾ 25.0 months, both groups had a significant improvement in both postoperative IOP and visual acuity as compared to preoperative levels. The authors found no statistically significant difference between groups in terms of postoperative IOP, number of glaucoma medications, or final visual acuity. This is consistent with the initial report of this study published by O’Grady et al.77 Donoso and Rodriguez recently reported their results of a retrospective study comparing combined single-incision phacotrabeculectomy with adjuvant 5FU (n = 22) versus trabeculectomy with 5-FU followed at a later time with phacoemulsification (n = 18).33 Both groups had 5-FU, 50 mg/ml, administered intraoperatively directly to the scleral surface for a duration of 5 minutes via a cellulose sponge. The group that had sequential surgery underwent phacoemulsification after a mean of 6 months following trabeculectomy. The mean postoperative IOP did not differ between groups. Survival curves using criteria for success defined as IOP ⱕ 20 mm Hg without medication or more stringent criteria of IOP ⬍ 15 mm Hg without medication were similar in both groups. Therefore, sequential surgery appears to be equivalent to simultaneous combined surgery. In summary, multiple published studies have yielded inconclusive data with regard to IOP control and bleb survival following combined cataract and trabeculectomy with adjuvant 5-FU. Combined surgery introduces a number of additional surgical variables that may play a critical role in determining the outcome from the perspective of IOP control and bleb survival as compared to trabeculectomy alone. Such variables include the following: 1) surgical approach, namely, same-site combined versus separatesite, same-day combined, versus separate-site sequential combined; 2) mode of extraction—extracapsular versus phacoemulsification; 3) ultrasound duration

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during phacoemulsification; 4) presence of posterior synechiae or transpupillary membranes requiring intraoperative lysis or removal; 5) need for stretch pupilloplasty; 6) need for partial vitrectomy; and 7) postoperative manipulation. 5-FLUOROURACIL IN SECONDARY GLAUCOMA

The treatment of various secondary glaucomas, such as neovascular and uveitic glaucoma, present a challenge to the surgeon. Inflammatory and neovascular glaucoma are particularly difficult because the inflammatory response is a potent stimulator of fibroblasts, and resultant scarring limits the success rate of glaucoma filtering surgery. In the 5-FU era there have been few clinical trials specifically addressing the efficacy and safety of filtering surgery with this antimetabolite in patients with uveitis. Jampel retrospectively reviewed the records of 12 eyes of 10 adult patients with uveitic glaucoma who underwent trabeculectomy with 5-FU. After a median follow-up of 7.75 months, all had an IOP below 20 mm Hg, and 10 of 12 required no medication. The mean dose of 5-FU was 33 ⫾ 10 mg (range 20–55 mg). Pre- and postoperative use of systemic and topical steroids was the same, indicating that 5-FU did not influence the inflammatory response. Weinreb reported a reduction in the frequency and degree of uveitis in a series of 6 patients with uveitic glaucoma who underwent trabeculectomy with 5-FU; he suggested that 5-FU might have a beneficial effect on intraocular inflammation. This observation could not be substantiated by Jampel’s or subsequent studies. On theoretical grounds alone it is unclear why 5-FU should possess anti-inflammatory properties because this agent is a cell-cycle specific agent and is most effective in suppressing actively dividing cells not terminally differentiated noncycling cells such as aqueous leukocytes. Thus its effect on leukocyte activity at current subconjunctival doses is unknown.49 Patitsas reported the results of 21 eyes of 18 patients with intraocular inflammatory disease who underwent trabeculectomy with 5-FU. The dosages used were the same as the FFSS mentioned above. Seventy-one percent achieved an IOP of less than 21 mm Hg over a mean follow-up of 34 months. The success rates in phakic patients (9/10) was greater than in aphakis or pseudophakic (6/ 11) patients. Choroidal effusions, however, developed in 13/21 eyes. Choroidal hemorrhage, retinal detachment, and macular retinal pigment epithelial abnormalities associated with hypotony occurred in one eye each.82 The largest prospective study of 5-FU in filtering surgery in patients with uveitic glaucoma was reported recently by Towler et al.114 This study was an

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open, non-comparative prospective series of 50 eyes of 43 patients with uveitic glaucoma who underwent trabeculectomy with adjuvant 5-FU. None had IOP elevation detected prior to development of uveitis. The median time from diagnosis of uveitis to development of glaucoma was 5.5 years. In this study 5-FU was administered intraoperatively directly to the scleral bed via a soaked cellulose pledget. The concentration used was 25 mg/ml, and the duration of exposure was 5 minutes. Additional postoperative subconjunctival injections of 5-FU were given if the IOP was ⬎21 mm Hg postoperatively and was associated with poor bleb development. These were administered as 5 mg injections at 4–7 day intervals during the first 4 weeks of surgery. The authors reported a success rate of 82% of eyes at 1 and 2 years and 67% at 5 years postoperatively. Success was defined as “complete” when IOP was 20 mm Hg or less without medications or “partial” if medications were necessary to achieve that IOP. The number of patients that actually reached the 5-year mark was not reported. The range of follow-up was as long as 78 months with a median follow-up of 54 months. Five-year success rates were estimated by Kaplan– Meier survival statistics. As indicated earlier such extrapolation is potentially misleading as actual outcomes at 5 years may yield significantly different success rates. The analysis would be significantly more robust had most of this cohort actually reached the 5 year mark and had equivalent success rates as predicted by Kaplan–Meier survival analysis. There was no difference in success between those patients who had intraoperative 5-FU only or additional postoperative 5-FU. This result may be due to the fact that those who did not receive additional 5-FU were those with better early filtration. Although the results of trabeculectomy with 5-FU in patients with uveitic glaucoma appear encouraging, there are several important aspects of this study to consider. First, those patients who failed had at least one additional risk factor including aphakia, pseudophakia, or a history of previous surgery that required conjunctival incision and manipulation, or were of high-risk racial or ethnic origin. Indeed, 5/ 7 patients of African origin failed. Second, the study design mandated that the uveitis be under control at the time of surgery (not more than a 1⫹ aqueous cellular score). Thus, one would expect the prognosis of patients undergoing 5-FU augmented filtering surgery would be considerably worse when other risk factors or more active uveitis is present. Because the results of filtering surgery in historical controls with uveitic glaucoma are limited and no randomized prospective studies are available, it is difficult to assess the efficacy of this agent as compared to no adjunctive treatment. Currently, randomization to placebo or no treatment in such

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high-risk patients in the context of a clinical study would not be considered justifiable. 5-FLUOROURACIL IN NEOVASCULAR GLAUCOMA

Both proliferation of fibrovascular tissue into the trabecular meshwork and disruption of the blood– aqueous barrier are central pathophysiologic mechanisms leading to synechial angle closure in the development of neovascular glaucoma. This form of glaucoma is particularly difficult to manage and is associated with a poor prognosis not only as a result of refractory IOP elevation but also due to the underlying disease process leading to retinal destruction. The original 5-FU pilot study from the Bascom Palmer Eye Institute enrolled 34 patients with neovascular glaucoma. They underwent either posterior lip sclerectomy (18/34) or trabeculectomy (16/34) with 5-FU. Rockwood’s intermediate-term results reported an encouraging 68% success rate at 3 years using Kaplan–Meier life table analysis. Tsai reported the long-term results.117 The follow-up report by Tsai, however, was very discouraging with success rates plummeting by 5 years to only 28%. Specifically, 19/ 34 patients (56%) were considered surgical failures with a median time to failure after surgery of 13.3 months. Twelve of these eyes were characterized as failures as a result of loss of light perception. The cause of loss of light perception, whether due to uncontrolled IOP or progression of retinal disease, however, was not specified. Risk factors influencing bleb survival were age ⬍50 years and type-1 diabetes. The 1-year success rates for patients under age 50 was 23% and in type-1 diabetics median bleb survival was only 4.8 months as compared to 54.5 months in type-2 diabetics. Perhaps type-1 diabetics had a lower success rate and accelerated failure as a result of persistent neovascularization unresponsive to panretinal photocoagulation (PRP). Because of the retrospective nature of the study, the degree of regression of rubeosis could not be determined in those patients that received PRP. It is likely, however, that if complete regression of rubeosis were to occur, success rates in terms of IOP control would be similar regardless of whether the patient is a type-1 or type-2 diabetic. The strong age dependence may be explained by the fact that those under the age of 50 are more likely to be type-1 diabetics and because younger individuals are likely to have a greater propensity for aggressive wound healing. In summary, the longterm prognosis of 5-FU augmented filtering surgery in patients with neovascular glaucoma is dismal. Young patients with type-1 diabetes appear to be at particularly high risk of bleb failure. 5-FLUOROURACIL IN DEVELOPMENTAL GLAUCOMA

Developmental glaucoma is usually considered a surgical disease. In the era before antiproliferative

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adjunctive treatment, Simmons recommended performing full-thickness procedures in young glaucoma patients. He believed that guarded filtration surgery would have a very low success rate.104 However, with the favorable success rates over controls reported in certain high-risk patients who had 5-FU augmented surgery, it was appealing to consider the use of antiproliferative agents in this population. However, there have been few reports in the literature of filtering surgery in developmental or juvenile glaucoma augmented with 5-FU. Zalish reported a small case series involving four eyes of two patients with congenital glaucoma who had previously undergone at least one angle surgical procedure who subsequently underwent trabeculectomy with 5-FU. At 16.5 months the IOP was reported to be in the low teens with no evidence of disease progression by visual field or optic nerve head examinations.129 Whiteside-Michel reported the largest consecutive case-series of 20 eyes of 20 patients age 40 years or younger, most of whom had juvenile open angle glaucoma. The mean patient age was 26.8 ⫾ 9.7 with a range between 13 to 40 years of age. The patients received 5 mg 5-FU injections beginning the day of surgery administered 180⬚ away from the surgical site. A total of 15–45 mg of 5-FU was injected. After a mean follow-up of 31.1 ⫾ 17.3 months, the mean postoperative IOP was 10.5 ⫾ 4.0 mm Hg. Nineteen of twenty eyes had an IOP less than 20 mm Hg without medications. Serious complications occurred in 15% (3/20). Two had endophthalmitis and one had hypotony maculopathy. The majority of complications were typical corneal epithelial changes observed in other reported studies.123 Again, the small number of patients, lack of prospective, randomized, placebocontrolled studies limits the conclusions one can draw. Nevertheless, Whiteside-Michel observed that thin, avascular blebs had formed in some of the patients indicating that 5-FU administered to this age group can sufficiently inhibit fibroblast activity to cause such bleb morphology to develop. 5-FLUOROURACIL AND INTRAOPERATIVE ADMINISTRATION

Because subconjunctival injections of 5-FU can be very toxic to the corneal epithelium and because this mode of administration is also very time-consuming, uncomfortable, and inconvenient both to the patient and physician, alternative modes of delivery may be preferable. Gross was among the first to clinically study the efficacy and safety of a single dose of 5-FU applied via a cellulose sponge beneath the conjunctival flap. He published preliminary results after 3 months and reported an 84% success rate defined

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as an IOP of less than 21 mm Hg or a 20% reduction in IOP. His group also reported no cases of corneal epithelial defects.32 Experimental studies at Moorfields Eye Hospital suggested that single 5-minute exposures of intraoperative 5-FU at a concentration of 25 mg/ml has similar effects on subconjunctival fibroblasts compared to subconjunctival injections. These results were then tested clinically in 34 eyes of 33 glaucoma patients undergoing filtering surgery. The dosage and duration was the same as in the experimental study. The follow-up period ranged from 3–9 months. The preliminary results as reported by Lanigan et al64 revealed successful IOP control in all low/ moderate-risk eyes without significant corneal side toxicity. Three high-risk eyes failed. Two were complete failures and one required a topical beta-blocker. The authors concluded that low/moderate risk eyes undergoing filtering surgery augmented with single 5-minute exposures of 5-FU might result in successful bleb function and IOP control. Despite such promising preliminary data, is a single intraoperative exposure of 5-FU enough? In lowerrisk cases the results from prospective as well as retrospective trials suggests that single intraoperative 5-FU exposures may be sufficient in controlling pressure at least in the short-term, but in high-risk cases such exposures alone may be insufficient in providing IOP control following trabeculectomy.4,10,28,108,120 Anand et al and Bell et al reported the two largest series studying the effects on bleb survival and IOP control following single 5-minute applications of 5-FU during trabeculectomy. Anand’s group prospectively followed 76 eyes of 76 consecutive patients. They all received a single 5-minute intraoperative sponge application of 25 mg/ml of 5-FU during trabeculectomy. There were 31 eyes classified in the low-risk category and 45 eyes classified in the high-risk category. They used three criteria to judge success: 1) IOP ⬍ 21 mm Hg, 2) IOP ⬍ 21 mm Hg and IOP reduction of 30%, and 3) IOP ⬍ 15 mm Hg and IOP reduction of 30%. Using the first two criteria, there was no reported difference in success rates between the two risk groups at 6 or 12 months postoperatively. However, using the third criterion, the low-risk category fared significantly better than the high-risk group. This was statistically significant with a p-value of 0.033. Bell et al retrospectively reviewed a consecutive series of 45 eyes of 45 patients. All had at least one risk factor for subconjunctival fibrosis and surgical failure. During trabeculectomy all patients received a single 5-minute intraoperative exposure of 5-FU at a concentration of 25 mg/ml via a cellulose sponge. The mean follow-up was 24 months. Only 22 (49%) achieved IOP control without medications. There

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

was a trend toward better IOP control in lower-risk eyes as compared to high-risk eyes especially within the first 12–18 months. With longer follow-up the differences however, appeared to diminish. This result once again supports the observation that 5-FU, whether via intraoperative sponge or postoperative injection, can improve bleb survival within the first few years after filtering surgery through inhibition of early postoperative wound healing but cannot sustain the effect consistently over the long term. Furthermore, the greater the risk, the lower the likelihood of overcoming the early fibroblastic response and the greater the likelihood of early surgical failure. Even though high-risk eyes may be classified as successful when judged by less stringent criteria, attaining a target IOP in the mid-low teens in this subset is considerably less likely with intraoperative 5FU alone. Can supplementation with postoperative 5-FU injections enhance success rates in high-risk eyes following trabeculectomy with intraoperative sponge application of 5-FU? Mora et al75 retrospectively reviewed the outcomes of 140 eyes of 119 patients who underwent trabeculectomy with a 5minute intraoperative exposure of 5-FU (50 mg/ml) supplemented by postoperative 5-FU injections at the discretion of the surgeons. Injections, when given, were administered within the first 21 postoperative days. For the purpose of data analysis, all patients were categorized according to risk factors defined and outlined by the authors. A low-risk patient had no risk factors. Patients with one or more risk factors were categorized as high risk. More specifically, 50/ 61 (82%) high-risk eyes and 55/79 (70%) low-risk eyes received supplemental 5-FU injections. Success was judged and analyzed by three different criteria: 1) final IOP ⬍ 21 mm Hg, 2) final IOP ⬍ 21 mm Hg and ⬎30% reduction in IOP, and 3) final IOP ⬍ 15 mm Hg and ⬎30% reduction in IOP. Mean followup was 16.0 ⫾ 10.0 months (range 2–42 months). The authors concluded that there was no difference in outcome in terms of final IOP and success rate between high-risk and low-risk eyes. They also reported no difference in outcome between eyes that did or did not receive supplemental 5-FU injections. However, looking at the data more closely reveals that those high-risk eyes that did not receive postoperative 5-FU had the highest final mean IOP of 15.3 ⫾ 2.1 mm Hg. In contrast, low-risk eyes that received postoperative 5-FU injections had the lowest final mean IOP of 10.8 ⫾ 4.8 mm Hg. Furthermore, without medications the success rates dropped considerably in the high-risk group as a whole regardless of whether or not supplemental injections of 5-FU were administered. This trend was especially evident when success was defined by the most stringent criterion of final IOP ⬍ 15 mm Hg and ⬎30% reduction in IOP.

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Only 34% of the high-risk patients were able to achieve this target without medication. In contrast, 77% of low-risk patients using the same criterion were able to achieve this target without medication. This retrospective study thus illustrates that high-risk eyes are considerably less likely to achieve lower target IOP following trabeculectomy with intraoperative 5-FU regardless of whether supplemental postoperative 5-FU injections are administered. Low-risk patients fared best as a group even when judged by the most stringent criterion. Sidoti et al102 more recently reported the outcome of a smaller cohort of 41 low-risk patients who underwent trabeculectomy with intraoperative 5-FU (50 mg/ml) for 5 minutes followed by a variable number of 5-mg postoperative injections at the discretion of the surgeon. Using Kaplan–Meier life table analysis, the success rate at 15 months was 83%. Success was defined as 5 mm Hg ⬍ IOP ⬍ 21 mm Hg. The mean postoperative IOP was 12.1 ⫾ 4.3 mm Hg. In this lower risk group, only 2.2 ⫾ 1.6 (range 0–7) injections of 5 mg of 5-FU were administered postoperatively to achieve these results. Because single intraoperative exposures appear to be sufficient in low-risk groups, without a randomized prospective trial it is unclear whether 5-FU additionally administered postoperatively is of clear benefit in this cohort. However, it does illustrate that 5-FU administered intraoperatively can result in successful IOP control with fewer corneal complications (17% in this study) by reducing the requirements for postoperative subconjunctival injections. In summary, intraoperative 5-FU administration for 5 minutes is effective in achieving successful bleb function and IOP control in low-risk patients limiting the need to few if any postoperative supplemental 5FU injections and resulting in fewer reported corneal complications. This mode of administration is also simpler, less uncomfortable to the patient, and more convenient than 5-FU injections alone. However, the evidence at present suggests that high-risk patients are unlikely to achieve a successful outcome with this mode of administration alone or in combination with supplemental injections when success is judged by more strict criteria. Even in high-risk cases, however, the total supplemental doses given postoperatively are still far fewer than the doses administered in earlier trials such as the FFSS. It appears that for low-risk eyes, a single intraoperative exposure to 5-FU may be sufficient. The current standard is to administer 5-FU intraoperatively using a soaked sponge. Postoperative injections are administered and titrated as necessary based on bleb appearance. 5-FLUOROURACIL TOXICITY AND COMPLICATIONS

Corneal toxicity is the most commonly recognized form of 5-FU-related ocular toxicity. This result is

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really not very surprising as 5-FU is toxic to actively replicating tissue such as the corneal epithelium. 5FU has been shown experimentally in rabbits to decrease the mitotic rate and thymidine uptake of healing corneal epithelium.97 The frequency of epitheliopathy can be greater than two-thirds of all patients treated. This was very common in early studies with 5-FU with total doses approaching or exceeding 100 mg. Manifestations include punctate keratopathy, filamentary keratopathy, frank epithelial defects that can involve virtually the entire cornea, and whorl-like or striate melanokeratosis. These changes, although often resolving without long term loss of visual acuity, in some instances can lead to severe secondary complications such as bacterial corneal ulceration, corneal melting, and even perforation. The whorl-like melanokeratotic changes appear to occur with a considerably greater frequency in deeply pigmented eyes and tend to persist usually without visual sequelae. Concurrent use of topical corticosteroids, as is usually the case after filtering surgery, may potentiate such complications. Cessation of administration of 5-FU can expedite epithelial recovery. Those patients with underlying corneal epithelial pathology such as keratoconjunctivitis sicca, bullous keratopathy, or exposure keratopathy may be at especially high risk for development of such complications.61 Adjusting the 5-FU dose, however, can minimize toxicity while maintaining therapeutic effect. Weinreb advocated titrating the total number of 5-FU injections to the observed clinical response rather than using a fixed total dose administration protocol. By withholding 5-FU injections in eyes that had developed corneal toxicity such as filaments and epithelial defects, flat anterior chamber, or conjunctival wound leak, he reported a lower rate of 5-FU keratopathy and wound leak as compared to previously published studies without compromising filtering success rate.122 Thus, it is apparent that individual patients have variable biologic responses to the antiproliferative effects of this antimetabolite. Preoperative risk assessment can serve as a guide to the approximate dose necessary to achieve surgical success but should be adjusted according to the clinical response. Furthermore, injecting 5-FU using a no reflux technique as described by Traverso may also be helpful.115 Titrating the dose of administered injections is one method of minimizing toxicity; changing the delivery system may be even better. As described in detail above, intraoperative administration of 5-FU via a soaked cellulose sponge has dramatically reduced the corneal complication rate by reducing or eliminating the need for supplemental 5-FU injections. The risk of 5-FU–related corneal

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toxicity is positively correlated with use of postoperative supplemental 5-FU injections. Although a number of investigators have attempted to use biodegradable materials in animal models to deliver 5-FU intraoperatively,50,66 currently, application using a cellulose or merocel sponge is by far the most common and preferred intraoperative method of 5FU delivery. As will be discussed in considerably more detail in the mitomycin C section, late-onset endophthalmitis is a one of the most feared complications following glaucoma filtering surgery. The largest retrospective study reporting the incidence of late-onset blebrelated endophthalmitis was by Wolner et al.126 In this study, 229 consecutive trabeculectomies performed with adjunctive 5-FU were reviewed for development of endophthalmitis. After a mean of 25.9 ⫾ 17.4 months, 13 eyes (5.7%) of 11 patients developed late endophthalmitis. Interestingly, 9/96 (9.4%) who had trabeculectomies performed at the inferior limbus developed this complication, whereas only 4/133 (3.0%) who had surgery performed at the superior limbus developed it. As a consequence of this observation, one investigator then proceeded to specifically analyze the risk of endophthalmitis following trabeculectomy along the inferior limbus and reported an overall 11.9% risk of endophthalmitis following trabeculectomy performed at this site.20 The relative risk of inferiorly placed blebs over superiorly placed blebs has also been confirmed by other investigators. We now avoid this location for filters. Surgical techniques have continued to evolve during the time we have been gaining experience with antifibrotic agents. Some of the evolution has been a response to the biological effects of these drugs. Because 5-FU can lead to thin-walled low resistance blebs, use of this antimetabolite may potentially be very useful in eyes that require low IOP such as eyes of patients with normal tension glaucoma or those with advanced disease. Wilson and Steinmann performed a randomized, controlled trial to quantify the effect of 5-FU by comparing trabeculectomy enhanced with 5-FU with a full-thickness procedure and modified shell tamponade alone. One eye of each of 17 patients was randomized to either technique. The 5-FU trabeculectomy eyes had a remarkably low mean IOP of 6.94 mm Hg, 4 mm Hg lower than the eyes that had full-thickness procedures; however, low IOP is not achieved without complications. Patients in the 5-FU group had a significantly greater reduction in visual acuity postoperatively as compared to full-thickness surgery without 5-FU. The frequency of choroidal detachments was also greater in the 5-FU group but not found to be statistically significant. Although full-thickness procedures at one time were advocated in order to achieve a low-target IOP, guarded filtering

331

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

procedures enhanced with an antiproliferative may result in even lower target pressures through wound modulation. Such low target pressures however, incur a greater risk of complications related to hypotony. As a result of the potential risk of hypotony secondary to antiproliferative use, guarded flaps are now sutured more tightly and released sequentially via argon laser suture lysis or releasable sutures.125 5-FU can enhance the success of glaucoma-filtering surgery through antifibrosis. Early use at relatively high levels frequently resulted in corneal toxicity. This fact, combined with the inconvenience and discomfort associated with postoperative injections, left many surgeons not entirely satisfied with 5-FU. Thus, discovery of a new or development of an existing antiproliferative agent would be a welcome addition to the glaucoma patient.

Mitomycin C (Tables 4 and 5) Prior to the original pilot study using 5-FU supplementation after glaucoma surgery, Chen found that mitomycin C used in conjunction with filtering surgery was successful in enhancing bleb survival. However, in spite of this discovery, use of this agent with regularity did not commence until the early 1990s.23 Mitomycin C is an antibiotic agent with antiproliferative properties. It is derived from the soil fungus Streptomyces caespitosus. Its pharmacological effect is probably derived from all three quinone, carbamate, and aziridine groups that comprise the molecule. It undergoes metabolic activation via reduction into an alkylating agent that cross-links DNA, a process mediated by cytochrome P-450 reductase and which occurs most effectively in an hypoxic environment. Because it can interfere with any phase in the cell cycle, mitomycin C is classified as a cell cycle nonspecific alkylating agent (Fig. 2). Thus, it not only inhibits DNA replication, it also inhibits mitosis and

protein synthesis. Mitomycin C does not interfere with a metabolite critical in DNA, RNA, or proteinsynthesis; it is not an antimetabolite and thus it is incorrect to refer to it as such.96 From here on it will be identified as an antiproliferative or antifibroblastic agent. Mitomycin C is effective at increasing the success of glaucoma surgery through its inhibition of the proliferative phase of the wound-healing pathway, specifically through inhibition of fibroblast as well as endothelial cell growth and replication. It is much more potent than 5-FU and exposures to mitomycin C as compared to 5-FU administered via single topical intraoperative application are typically 100-fold less. (e.g., 50 mg/cc of 5-FU versus 0.5 mg/cc of mitomycin C). The differences in biological potency are also manifest by the contrasting physical characteristics typically observed between mitomycin C-augmented blebs and 5-FU-augmented blebs. The former appear thinner and more avascular than the latter. Experimental studies using animal models have demonstrated the differential effects of exposure to each antiproliferative on fibroblasts as well as endothelial cells. Khaw et al57,59 compared the effects on fibroblast outgrowth following 5-minute applications of 5FU (50 mg/ml), mitomycin C (0.4 mg/ml), or distilled water in rabbits undergoing full-thickness glaucoma-filtering surgery. They found that fibroblasts cultured from tissue samples obtained from rabbits treated with mitomycin C still evidenced growth inhibition at 1 month while fibroblasts from 5-FU-treated rabbits demonstrated full recovery of growth arrest after slightly over 7 days. Smith et al performed cell culture experiments using mouse 3t3 fibroblasts and capillary endothelial cells exposed to varying concentrations of 5-FU and mitomycin C. In their experiments they found that while both cell types were susceptible to mitomycin

TABLE 4

Studies Using Intraoperative Mitomycin C in Trabeculectomy Authors

Reference

No. of Eyes

Cheung et al

24

132

Perkins et al

83

68

Study Design

Success/Endpoint

Outcome

Key Limitations

Life table analysis

Complete success IOP ⬍ 21 no meds; qualified success IOP ⬍ 21 with meds; Failure-reoperation for IOP

High loss of follow-up by 3 years

Life table analysis

IOP ⬍ 21, 20% reduction

1 year, 63% 83% (132 eyes); 2 year, 63% 83% (132 eyes) 47% success at 3 years, 70% success with meds

High loss of follow-up by 3 years

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LAMA AND FECHTNER TABLE 5

Studies Using Intraoperative Mitomycin C in Combined Procedures Authors Reference

No. of Eyes

Cohen

25

72

Budenz

17

78

Carlson

19

29

100

197

Shin

Study Design Prospective, double-masked, placebo controlled Retrospective

Prospective, randomized, placebo controlled prospective, randomized MMC vs no MMC

Dose

Success/ Endpoint

Outcome

IOP lower at all timepoints in MMC group, more early bleb leaks in MMC MMC, 5-FU, IOP IOP significantly lower or no reduction from preop in all antifibrotic groups, MMC group was lower than 5FU but not lower than no antifibrotic IOP 3.0 mm Hg greater mean reduction IOP reduction in MMC group IOP No difference overall, but reduction subgroups African, American, IOP ⬎ 20 on max meds, or 2 or more meds preop did better with MMC

C, fibroblasts were far more sensitive to 5-FU than endothelial cells and concluded that 5-FU is toxic to fibroblasts but spares endothelial cells whereas mitomycin C is cytotoxic to both types.109 The fairly rapid recovery of fibroblasts in vitro following 5-FU exposure and the lesser degree of endothelial inhibition by 5-FU as compared to mitomycin C may account for the observed clinical differences in bleb vascularity between 5-FU– and mitomycin C-treated eyes. The prolonged potent antifibroblastic effects of mitomycin C makes it suitable as a single-use adjunct in glaucoma-filtering surgery especially in those eyes at high risk for failure. In 1983 Chen and co-workers were the first to use mitomycin C as adjunctive therapy in the management of severe refractory glaucoma. During the last decade, there have been numerous studies that assessed the success rate of mitomycin C-augmented glaucoma filtering surgery. The purpose of this section is to present and analyze the available clinical experience with mitomycin C as an adjunct to standard trabeculectomy in both low- and high-risk eyes for surgical failure. Medline search of all relevant English language publications revealed most studies to be retrospective in nature. Few were prospective in nature and even those that were were non-randomized and uncontrolled. Furthermore, the surgical approach (limbal vs. fornixbased), concentration of mitomycin C used; size, number, and type of sponge used for application; and duration of application was variable between and

Key Limitations

IOP

Retrospective

small sample size

within studies. Moreover, the ocular diagnoses, patient demographics, and risk factors were also variable. Most studies were also of relatively short duration many with only several months or up to a 1-year follow-up.62,71,85,105 In spite of all these variables the cumulative data indicate that mitomycin C significantly augments the success rate of filtering surgery in high-risk eyes as compared to controls as well as to historical data in which an antiproliferative was not used. The published studies with the longest follow-up were conducted by Cheung et al24 and Perkins et al (Table 4).83 Using Kaplan–Meier life table analysis, Cheung reported a success rate at three years of 88.7% ⫾ 4.0%. This number, however, represents a cumulative proportion of patients who did not require reoperation for control of pressure following trabeculectomy with mitomycin C; 132 eyes were included in the study; 118 had an IOP ⬎ 21 mm Hg. After 1 year of follow-up, the complete success rate (IOP ⬍ 21 mm Hg with no medications) was 62.7% and qualified success rate (with medications) was 83.1%. Of all 132 eyes that completed 1 year of followup, only a total of 76 completed 2 years. Only 12 subjects were available for evaluation at 3 years after surgery. By the end of the study, a total of 39 failed (24.2%) over a mean follow-up 20.7 months but 25/ 39 failed within the first year. A high number of early failures is expected since the fibroblastic response is greatest in the initial days to weeks following filtering surgery. However, fibrosis continues to occur even in

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

eyes with established successful early filtration. Thus, continued prospective follow-up is necessary in order to determine long-term success. Perkins and colleagues had fewer total patients (68) in the study and reported a 47% success at 3 years. Success was defined as IOP less than 21 mm Hg and a reduction of IOP by at least 20% without medications. With concurrent medication use, the success rate was up to 70%. Fifty-seven percent of patients had had previous surgery. As in Cheung’s study, only 12 patients completed 3 years of follow-up. Thus, these intermediate-term studies extrapolated from Kaplan–Meier survival data appear to arrive at a long-term success rate. It would be highly informative if prospective follow-up of larger cohorts supports these conclusions, which are based on extrapolation from life-table analyses. MITOMYCIN C AND COMBINED PROCEDURES

Because long-term outcome of trabeculectomy combined with cataract extraction may not be as favorable as primary trabeculectomy, it has become very common to routinely use antifibrotics during combined surgery. However, what is the evidence supporting use of these agents during primary combined surgery? Previously we have mentioned several studies that failed to unequivocally show a benefit with 5-FU during combined surgery. Does mitomycin C provide better IOP control? Our search identified only three trials in the English language literature that randomized patients to mitomycin C versus no mitomycin C or placebo. There was one retrospective study that compared patients who received mitomycin C versus 5-FU or no antifibrotic agent. Cohen et al25 performed a prospective, doublemasked, placebo-controlled trial evaluating 72 consecutive patients undergoing combined cataract and glaucoma surgery. One surgeon performed all cases, and all patients had at least one year of follow-up. At all intervals during the first year, IOP control in the mitomycin C group was significantly better, fewer medications were required to achieve the desired target IOP, and filtering blebs were larger. These results were achieved at the expense of an increase in bleb leaks early after surgery and a slightly lower but not statistically significant reduction in endothelial cell counts. Overall, the complication rate was low during the study interval. Budenz and colleagues retrospectively compared 78 patients who underwent phacotrabeculectomy with mitomycin C, or 5-FU, or no antifibrotic. They found that all groups achieved statistically significant lowering of IOP with fewer medicines. Those with adjunctive mitomycin C had a lower IOP as compared to those with 5-FU but interestingly not any lower

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than those with no antifibrotic. Since the authors did not comment on bleb appearance, the lack of a detectable difference in IOP between treatment groups may be at least partially explained by the potential IOP lowering effect of cataract surgery alone. Also, relatively short follow-up, low numbers of patients in each subgroup, and selection of less stringent success criteria may have led to failure of identification of a treatment difference between antiproliferative use and no antiproliferative use.17 Carlson et al reported a randomized, placebo-controlled, prospective study consisting of 29 patients. Visual acuity results were similar in both groups. However, IOP control at 1 year was on the average 3.0 mm Hg lower in the mitomycin C group. The mitomycin C group also required less frequent laser suture lysis (43% vs. 80%) and required fewer (0.7 vs. 2.0) sutures cut. However, one case of late endophthalmitis occurred in a patient treated with mitomycin C but who had an intact bleb.19 Shin et al reported the largest study to date, comprising 197 eyes of 197 patients, randomly assigning patients to mitomycin C versus no mitomycin C.100 These investigators found that mitomycin C did not improve filtration success rates of primary phacotrabeculectomy as compared to placebo in nonselected patients. However, in a select group of patients with any one of three independent prognostic risk factors (African–American origin, IOP ⬎ 20 mm Hg on a maximally tolerated regimen, and using at least two medications preoperatively), mitomycin C did significantly change filtration outcome. It appears therefore that in those patients with no risk factors for filtration failure and early stage glaucoma controlled on single-agent therapy, prognosis for successful combined surgery is high enough that a treatment difference could not be detected between adjunctive mitomycin C and no mitomycin C. A much larger study population would therefore be necessary in order to prove that such a treatment difference exists. However, the weight of the evidence presented above suggests a beneficial role of mitomycin C during combined cataract and glaucoma surgery, particularly in patients at high risk. MITOMYCIN C IN CHILDHOOD AND DEVELOPMENTAL GLAUCOMA (TABLE 6)

Children with congenital or developmental glaucomas who fail angle surgery require some form of external filtration (e.g., trabeculectomy, glaucoma drainage device implantation) or cilioablation. Because children and young adults have such an aggressive wound-healing response, standard filtration surgery is often unsuccessful. Hence, antifibrosis therapy to modulate wound healing may potentially

Retrospective 65% success at 18 months, maintained at 30 months Life table analysis (Kaplan–Meier)

All (8) with aphakia failed. 1 year success in others was 77%

No significant difference between groups

MMC group, 91% success at 1 and 5 years; Control, 91/5 at 1 year, 73% at 5 years IOP ⬍ 21 without meds ⫽ success, IOP ⬍ 21 with meds ⫽ qualified success

38 70 Mandal

21 9 Azuara-Blanco

127 Yalvac

44, JOAG, 33 Developmental

Case-control, age 15–40, life table analysis, trabeculectomy with MMC vs without 47 Jacobi

11

Trabeculectomy with MMC vs trabeculectomy without Case series; age under 17 who underwent trabeculectomy with MMC; life table analysis Retrospective chart review

0.4 mg/ml for 3 minutes

Outcome Success/Endpoint Dose Study Design No. of Eyes Reference Authors

Studies Using Mitomycin in Juvenile Glaucoma

TABLE 6

Very small sample

Surv Ophthalmol 48 (3) May–June 2003 Key Limitations

334

LAMA AND FECHTNER

improve the success of filtering surgery. Several small series have been reported. Jacobi et al performed a case control study of 11 eyes of 11 patients aged 15–40 years who underwent mitomycin C-augmented trabeculectomy compared to those who did not receive an antifibrotic agent. Using cumulative lifetable analysis, they found that mitomycin C patients had a 1-year success rate of 91%, which remained the same at 5 years whereas in the control group the success rate at 1 year was also 91% but decreased to 73% at 5 years follow-up. Success here was defined as IOP ⬍ 21 mm Hg on no medications (complete) or with mediations (qualified). These investigators found a significant increase in complications in the mitomycin C group as a result of overfiltration, for example, persistent hypotony, shallow anterior chamber, and choroidal detachments, as compared to controls. The unusually good results reported in this series should be viewed with caution in view of its small size.47 Yalvac studied patients 15–40 years of age who had juvenile open-angle glaucoma (44 eyes of 44 patients) and developmental glaucoma (36 eyes of 36 patients) and divided each group into two subgroups. One had standard trabeculectomy alone, and the other had trabeculectomy with 0.4 mg/cc mitomycin C applied for three minutes intraoperatively. Although the mitomycin C groups appeared to fare better in terms of IOP control, statistically there was no significant difference. This result may be simply due to small sample size and relatively short followup.9,127 Azuara-Blanco and colleagues studied 21 patients under the age of 17 who underwent trabeculectomy with mitomycin C. The two most common ocular diagnoses were trabeculodysgenesis (n ⫽ 6) and aphakia (n ⫽ 8). Interestingly all patients with aphakia failed after a mean follow-up of 14.7 months whereas in the phakic patients, the probability of success at 1 year using Kaplan–Meier life-table analysis was 76.9%. Aphakia has been identified as a risk factor in other studies.25 Mandal reviewed the charts of all patients with developmental glaucoma who underwent trabeculectomy with mitomycin C over a 5-year interval. A total of 38 eyes of 29 patients were found, and 34 had primary congenital glaucoma. The remainder had Axenfeld-Rieger anomaly and/or aniridia. They used Kaplan–Meier survival curves and found the probability of success to be 65% at 18 months, which was maintained at 30 months. Over the follow-up interval no cases of endophthalmitis were recorded.70 Freedman’s group found that children less than 1 year of age had a significantly lower probability of success as compared to those older than 1 year of age (73% vs. 30%, respectively). Similarly, those who were aphakic also had a worse prognosis as compared

335

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY TABLE 7

Studies Using Mitomycin with Drainage Devices Authors

Reference

No. of Eyes

Cantor

82

25

Study Design

Dose

Outcome

Prospective randomized, masked, controlled, MMC vs placebo with double plate Molteno

MMC 0.4 mg/ml for 2 minutes, vs BSS

No difference with respect to IOP or percent change from baseline IOP

to those who were phakic (64% vs. 29%, respectively). Postoperative supplementation with 5-FU in addition to intraoperative mitomycin C did not improve the success rate.37 In terms of complications, Sidoti found a 17% risk of endophthalmitis in a group of 29 eyes of 29 consecutive patients with pediatric glaucoma who underwent trabeculectomy with mitomycin C. They used a higher concentration (0.5 mg/cc) as compared to the other groups. Success rates at 12-, 24-, and 36-month intervals were 82%, 59%, and 59%, respectively. As in the other studies, life-table analyses were used to estimate probability of success.101 In summary, the cumulative data from the series above suggest a generally lower success rate in the pediatric population with developmental glaucoma undergoing filtering surgery with adjunctive mitomycin C as compared to adults. Furthermore, the prognosis appears to be especially poor in children under the age of 1 or who are aphakic. This result is consistent with the more robust wound-healing response that presumably occurs in children. Specific biological factors to explain the reason for the higher failure rate remains to be elucidated. With respect to complications, there also may be a higher than anticipated risk of endophthalmitis, but the numbers at present are too small to make definitive conclusions. MITOMYCIN C AND GLAUCOMA DRAINAGE DEVICES (TABLE 7)

Previous discussion has centered on the use of antifibrotic agents with trabeculectomy. Glaucoma drainage devices (GDD) are very useful in the surgical management of complicated glaucoma and in eyes with scarred conjunctiva from previous filtering or other ocular surgeries. The mechanism of filtration in an eye with a GDD is through the fibrous capsule that surrounds the plate. The degree of filtration is, to a certain degree, proportional to the overall surface area of the capsule surrounding the plate. Plates with larger surface areas have broader capsules and thus a greater surface area available for filtration. Capsular walls surrounding GDD, however, are considerably thicker than the bleb walls for trabeculectomies,

Key Limitations Small sample size

and thus the resistance to flow is greater. It would appear then that application of antifibrotics may lead to thinner capsular walls and enhanced filtration thereby improving surgical success rates. Cantor’s group performed a prospective, randomized, masked, controlled trial of mitomycin C 0.4 mg/ ml applied for 2 minutes vs. balanced salt solution in 25 consecutive patients undergoing implantation of a double-plate Molteno.18 Their conclusion was that adjunctive mitomycin C was no better than placebo with respect to IOP or percent change from baseline IOP. Other prospective studies were essentially consecutive series of patients that were compared to historical controls.7,65 With the exception of Perkin’s study,84 which reported an increased likelihood of a 2–3-year period of medication-free IOP control as compared to 5-FU or placebo, overall, the small amount of evidence suggests that addition of mitomycin C may not alter outcome with respect to IOP control in patients undergoing GDD implantation. COMPLICATIONS RELATED TO MITOMYCIN C

As a result of its biological potency as an antifibrotic agent with prolonged cytological toxicity occurring following its administration, mitomycin C is associated with development of potentially severe side effects and complications as compared to 5-FU. Thus, the biological activity of mitomycin C can be much like a double-edged sword. Mitomycin C administration during filtering surgery often leads to development of thin-walled, avascular blebs. Such blebs are associated with enhanced transconjunctival filtration as a result of lowered resistance through the bleb wall as compared to thicker-walled blebs. However, thin, avascular blebs often lead to focal bleb leaks. It has been shown that mitomycin C–augmented filtering surgery more often leads to thin-walled avascular blebs and more often results in the development of such late-onset focal bleb leaks, as much as three times more frequently than 5-FU blebs.41 Such bleb characteristics and morphology appear to be strongly associated with the subsequent development of endophthalmitis.110 Thus, it is not surprising that blebrelated endophthalmitis appears to be higher in

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those eyes augmented with antiproliferative agents. The largest retrospective analysis looking at such complications reviewed the results of 609 eyes that underwent filtering surgery with mitomycin C alone or combined with cataract extraction/IOL implantation.42 Greenfield et al reported 13 cases of late endophthalmitis, five of which were associated with blebs located inferiorly. Because mitomycin C blebs tend to be thinner and at higher risk for leaks, is there a difference between the rates of development of endophthalmitis between mitomycin C– and 5-FU–augmented eyes? Thus far, the differences in rates of development have been comparable between antiproliferatives when such comparisons were reported. Higginbotham et al reported a similar rate of development of endophthalmitis between mitomycin C– and 5-FU– augmented blebs.46 The reason for similar complication rates is likely related to the low frequency of occurrence of endophthalmitis during the short intervals studied and, thus, too few patients for analysis (about 1%/year overall). Moreover, because bleb morphology continues to evolve over time leading to late occurrences of bleb leaks, long-term follow-up of a very large number of patients is necessary before differences in risk can be statistically identified between each antiproliferative agent. One can only speculate at this time that mitomycin blebs may be at higher risk for development of endophthalmitis. A large prospective study would help answer this question but would take years to perform. A multicenter clinical trial in which data are collected prospectively to analyze the risk of subsequent development of endophthalmitis is currently underway. A compromise would be to perform a large, multicenter, retrospective study with thousands of eyes analyzed. Although such a study would introduce biases associated with retrospective analysis, it would nevertheless yield much more robust data than are presently available regarding antiproliferatives and other risk factors in the development of endophthalmitis without the length of time required for a prospective trial. Jampel and colleagues recently published a multicenter case-control study.52 The 131 cases of bleb-related infection in their report represent the largest series of cases published to date. They found that factors associated with an increased risk of bleb-related infection are full-thickness procedures, intraoperative mitomycin C, and episodic or continuous antibiotic use postoperatively. The latter observation supports the widely accepted dictum that prophylactic antibiotic use for prolonged periods of time may lead to emergence of resistant and potentially more virulent strains of bacteria resulting in an increased risk of late infection. The authors suggest that prophylactic antibiotics be restricted to a

LAMA AND FECHTNER

brief period postoperatively (5–7 days) to kill bacteria that may have been introduced into the eye during the normal course of surgery. It also appears that eyes undergoing filtration surgery in conjunction with cataract surgery are at lower risk for such infection. This finding has been noted previously but has never been systematically investigated. One can speculate that because filtering surgery combined with cataract surgery is often performed via a fornix-based approach the corresponding blebs tend to be more diffuse rather than thin-walled and cystic. Such blebs are less prone to development of leaks that can facilitate passage of bacteria through the conjunctiva. Thin-walled ischemic mitomycin C blebs lead to low outflow resistance and subsequent overfiltration. Overfiltration may then lead to development of hypotony. The incidence of hypotony maculopathy indeed became more widespread since antiproliferative agents came into use during glaucoma surgery. The consequences of hypotony are well known and include development of choroidal effusions or in some cases hemorrhage, maculopathy, shallowing of the anterior chamber, corneal decompensation, disruption of the blood–aqueous barrier, and cataract formation. Hypotony maculopathy following glaucoma-filtering surgery was reported first in 1955 by Dellaporta.30 The term hypotony maculopathy was coined by Gass in 1972 who suggested that the condition was caused by contraction of the elastic sclera resulting in chorioretinal folds.39 Naumann and Volcker described the histopathologic characteristics of uveal and retinal edema in acute and persistent hypotony. The posterior choroid becomes thickened in acute hypotony followed by peripheral choroidal detachment. Folds in Bruch’s membrane, as well as the retina, follow secondary to the increased choroidal volume.118 Hypotony maculopathy after 5-FU trabeculectomy has been reported. However, the literature regarding this complication specifically with 5-FU is scant. Stamper111 reported the features of 8 eyes of 6 patients who underwent trabeculectomy with postoperative 5-FU injections and developed hypotony with maculopathy. He found that young myopic individuals are more prone to development of associated maculopathy and visual acuity loss as compared to older individuals. The mean age in the maculopathy group was 50, whereas the mean age was 74 years in those with hypotony but without maculopathy. Although not proven, he suggested that the reason for the increased risk of development of hypotony maculopathy in myopes may be related to differences in axial length. Eyes with longer axial lengths may have less scleral rigidity and hence are more prone to wrinkling.

ANTIFIBROTICS AND WOUND HEALING IN GLAUCOMA SURGERY

The reported rates of occurrence of hypotony maculopathy after mitomycin C trabeculectomy have ranged widely. In a retrospective study by Zacharia et al, 52 eyes of 48 patients underwent trabeculectomy with 0.4 mg/cc of mitomycin with application times ranging from 3.5 to 7 minutes.128 They reported a 1 in 3 incidence of hypotony defined as an IOP of less than 5 mm Hg. Seven of these 17 eyes (14%) developed maculopathy and required revision surgery to correct the hypotony. This occurrence was the highest reported of all the published series available. More than half of hypotonous eyes lost two or more lines of Snellen visual acuity as compared to 14.3% of non-hypotonous eyes. The authors also found a statistically significant association between longer application time and hypotony. The lowest reported rate of hypotony to date is 1.3% and is from Suner et al in a series of 699 procedures performed over a 3-year period.113 His group attributed this lower rate to a mini-flap safety-valve incision with dimensions of 2.5 × 1.0 mm that was dissected 1 mm anterior to clear cornea prior to fistulization and titration of flap closure to the desired IOP prior to completion of surgery. He used MMC 0.5 mg/cc with a duration of 5 minutes. Although Zacharia’s cohort of patients was approximately 14 times smaller than Suner’s group and a larger sample may partially explain a reduced percentage of patients with maculopathy independent of surgical technique, modification in flap design strongly supports the concept of prevention by altering surgical technique in reducing postoperative complications. Prior to this publication there were no data suggesting that differences in flap design or closure influenced the development of hypotony with or without maculopathy. Whereas bleb leaks, endophthalmitis, and hypotony with associated maculopathy are the more common important toxicities related to antiproliferative agent use, there have been anecdotal reports of other important but less often reported toxicities associated with mitomycin C use in conjunction with glaucoma filtering surgery. Akova reported two cases of scleromalacia in pediatric patients who received 0.4 mg/cc mitomycin C for 5 minutes. Both had previous surgery. The scleromalacia was localized and nonprogressive. No surgical intervention was necessary to reinforce the sclera.3 Although scleromalacia associated with mitomycin C use has been reported in adults when used adjunctively following pterygium excision to prevent regrowth, there have been no reports (English language Medline search) of this complication associated with glaucoma surgery. The most plausible explanation is that in glaucoma surgery MMC is administered as a one-time application and thoroughly irrigated promptly afterwards. In

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contrast, after pterygium surgery patients were instructed to instill mitomycin C drops up to 4 times daily for 7–14 days and in some cases up to 28 days. Such dosing apparently resulted in rising cumulative tissue levels leading to severe toxicity with devastating ocular complications. Scleral and corneal melting with perforation, corneal edema, scleral calcification, iritis, corectopia, sudden onset mature cataract, and intractable pain were reported in a case series of 10 patients who received mitomycin C following pterygium excision.91 In 5 eyes visual acuity remained 20/200 or less. Since publication of that article, mitomycin C following pterygium excision fell out of favor and is currently rarely used to prevent pterygium recurrence. Fourman reported a case series of 5 patients who developed scleritis associated with mitomycin C use 3–24 weeks following inferior trabeculectomy.36 Corneal endothelial toxicity and mitomycin C use has not been extensively studied in the clinical literature. In fact, few studies have reported the effects of mitomycin C on the corneal endothelium independent of other variables such as cataract surgery, which is also known to affect the corneal endothelial cell count. Sihota and co-workers, however, specifically compared the effects of mitomycin C with no antiproliferative agent on the corneal endothelium prospectively after routine filtering surgery. They found that as compared to no antifibrotic use, mitomycin C usage during trabeculectomy resulted in approximately 10–11% greater endothelial cell loss (3.73 ⫾ 2.73% as compared to 13.9 ⫾ 4.69% and 14.52 ⫾ 7.8% with 0.2 mg/cc and 0.4 mg/cc, respectively).103 Mitomycin C has been an effective antifibrotic adjunct with glaucoma surgery. However, there is a growing concern that we have created an epidemic of hypotony, leaky ischemic blebs, and eyes at increased risk for endophthalmitis.121

Mitomycin C Versus 5-Fluorouracil Because mitomycin C is more potent than 5-FU and has longer lasting effects on cultured fibroblasts, clinicians tend to favor mitomycin C over 5-FU in especially complicated, difficult-to-control glaucomas. Notwithstanding these differences, there have been few clinical trials specifically designed to compare the two antifibrotics directly. In a randomized prospective clinical trial, Katz and co-workers compared single intraoperative mitomycin C application (0.5 mg/ml for 5 minutes) with postoperative 5-FU injections (5 mg injections daily for the first week after surgery and three injections during the second week) in a total of 39 eyes of 39 patients. All patients were considered high risk with pseudophakes and

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aphakes comprising the largest group. There were only three of African–American origin in each group. The mean follow-up was 32.0 ⫾ 2.8 months. Of the mitomycin C-treated eyes, 81.3% had IOP less than or equal to 12 mm Hg compared with 26.7% of eyes in the 5-FU group. The mitomycin C group on average required 0.5 ⫾ 0.8 medications compared with 1.6 ⫾ 1.3 medications in the 5-FU group. Late postoperative complications (⬎3 months after surgery) were similar in both groups.54 Lamping and Belkin63 specifically compared adjunctive 5-FU with mitomycin C in 80 eyes of 74 pseudophakes with posterior chamber lens implants undergoing trabeculectomy. After 12 months, the mean IOP in the mitomycin C group was 12.8 ⫾ 5.5 mm Hg as compared with 14.8 ⫾ 3.8 mm Hg in the 5-FU group. The mitomycin C group, as in the study by Katz, also required fewer medications (0.6 vs. 1.05 medications). A study performed by Oh and colleagues consisted of both an animal experimental arm as well as a human arm. They performed a prospective study comparing outcomes of filtering surgery in pigmented rabbits and in 55 eyes of 40 patients treated with mitomycin C (0.2 mg/ml or 0.4 mg/ml), 5-FU (50 mg/ml), or balanced salt solution. Bleb survival in the rabbits was positively correlated with the potency and concentration of antiproliferative agent used. In the human arm, there was no difference between mitomycin C and 5-FU at 3 months, but there was a statistically significant difference at 6 months. This study was limited by the fact that it was a 6-month follow-up study.79 Smith retrospectively compared the outcomes of 73 eyes of 63 patients who underwent initial trabeculectomy with mitomycin C 0.2 mg/ml for 3–5 minutes or 5-FU 50 mg/ml for 5 minutes. Both groups had similar preoperative IOP. At an average follow-up of 20.9 months the mean postoperative IOPs were 10.2 ⫾ 3.6 mm Hg and 9.7 ⫾ 3.4 mm Hg in the mitomycin C groups and 5-FU groups, respectively. Thus, they found essentially no difference in IOP lowering between the two groups. Complication rates were also similar with four bleb leaks occurring in the mitomycin group and three in the 5-FU group.107 Recently Singh et al published a randomized prospective trial comparing 5-FU 50 mg/cc for 5 minutes with mitomycin C 0.4 mg/cc for 2 minutes in primary trabeculectomy. There were 108 patients enrolled in the study with 17 surgeons participating. Mean follow-up was less than one year for both the 5-FU (about 10 months) and the mitomycin C (about 11 months) patients. They found no differences in terms of success rates, early and late complications, number of medications used at last follow-up, and visual acuity. However, these were primary trabeculectomies with a lower risk for failure. The participation

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of multiple surgeons, each using his or her individual technique, makes these results more generalizable to the broader population of surgeons performing trabeculectomy with antifibrotic agents. However, the unmasked study design and the relatively few numbers of surgeries performed by each surgeon limits the strength of the study. Furthermore, the length of follow-up is relatively short, and one hopes the investigators will continue to follow these patients.106 In spite of the differences in biological potency, there appears to be conflicting data regarding comparative success rates of mitomycin C and 5-FU. The studies, like most glaucoma surgery studies, have several limitations including short duration, study designs subject to potential bias, difficulty masking, and small sample size. Furthermore, individual surgical technique in single-surgeon studies may make applicability of the results to the general population more limited. Despite these limitations, recommendations must be established for use of these adjuncts based on available evidence (see the following section).

Other Anti-Scarring Agents: Old and New Whereas antiproliferative agents inhibit scarring through direct inhibition of fibroblast proliferation and function, there have been limited studies published evaluating drugs that inhibit collagen secretion and cross-linking. These agents thus inhibit scarring later in the wound healing pathway than do 5-FU and mitomycin C. β-aminoproprionitrile (BAPN), D-penicillamine, and colchicine are all inhibitors of collagen cross-linking. BAPN specifically inhibits lysyl oxidase. This enzyme catalyzes oxidative deamination of the epsilon-amino group of lysine and hydroxylysine to the corresponding aldehyde. This is the initial step in collagen cross-linking. Moorhead et al studied the effects of topical application of BAPN after glaucoma filtering surgery. In a series of 21 patients, they reported a mean IOP of 22 mm Hg or less in 18 patients at 3-month follow-up.74 Unfortunately, with the advent of 5-FU, there has been no long-term study determining the long-term efficacy of this agent. D-penicillamine, an agent that has been approved for the management of progressive systemic sclerosis, similarly inhibits collagen maturation by interfering with lysine-derived aldehydes rendering them unavailable for cross-linkage. It also blocks extracellular secretion of collagen.76 Available data are limited to animal studies in albino rabbits or cynomolgous monkeys.12,72,73 There are no published human clinical trials in the literature regarding this agent. Additionally, there are no published abstracts or clinical trials regarding the use of colchicine, a mitotic spindle toxin that can inhibit fibroblast function as well as collagen synthesis. Colchicine has

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been used to treat a variety of medical conditions associated with pathologic fibrosis such as idiopathic pulmonary fibrosis and cirrhosis.34,56,119 Inhibition of collagen synthesis appears to be related, at least in part, to inhibition of secretion of collagen, a microtubule-mediated cell function, rather than genetic inhibition of collagen mRNA synthesis.34 Despite a dearth of clinical data, the efficacy of these drugs alone as single agents is likely to be limited since they act at the end of the wound healing pathway. Thus, a relatively strong stimulus for fibroblast proliferation and collagen production can easily overwhelm the pharmacological capabilities of these agents. It is possible, however, that they could benefit when used in addition to 5-FU or mitomycin C.

Other Antiproliferative Agents DAUNORUBICIN

Daunorubicin is an anthracycline antibiotic derived from Streptomyces peucetius var caesius. Pharmacologically this agent, through intercalation, leads to blockade of both DNA and RNA synthesis and causes DNA strand scission. It also binds to membranes altering fluid and ion transport and generates semi-quinone and oxygen free radicals.15Clinically, daunorubicin is primarily used in the management of acute myelogenous leukemia. However, there have been a few published clinical trials in the ophthalmic literature evaluating this agent adjunctively as an antiscarring agent in conjunction with glaucoma surgery. Demailly and Kretz31 performed a randomized, prospective, unmasked clinical trial comparing the efficacy and safety of daunoubicin with 5-FU after filtering surgery in patients with primary open-angle glaucoma. There were 27 eyes of 25 patients in the study. Fourteen eyes of 13 patients were in the 5-FU group and 13 eyes of 12 patients in the daunorubicin group. A total of 10 subconjunctival 5-FU injections were administered (50 mg) in the 5-FU group and a single preoperative subconjunctival injection of daunorubicin was administered in the other group. Using Kaplan–Meier analysis, they reported a survival probability of 79% in the 5-FU group and 68% in the daunorubicin group. Actual follow-up was short averaging 7–8 months in each group. Although the authors reported a lower frequency of corneal complications with daunorubicin, the results lacked sufficient power given the small cohort of patients in each group. Furthermore, the daunorubicin group only received a single injection as compared to the 5FU group. Thus, on a milligram-to-milligram basis daunorubicin may actually more toxic to the cornea then 5-FU. Since publication of this report, there has been little clinical evidence supporting the use of

daunorubicin adjunctively to improve bleb survival after glaucoma-filtering surgery. BLEOMYCIN

Bleomycin is also derived from a soil fungus (Streptomyces verticillus). Bleomycin inhibits cell replication and survival through DNA binding. Following free radical generation, single- and double- strand breaks occur leading to inhibition of DNA synthesis. Bleomycin has been studied in an animal model of glaucoma surgery in conjunction with electrical stimulation.93 The dosage of bleomycin used was 10 µg/ml applied topically intraoperatively and washed with 50 ml of balanced saline analogous to current administration of an antiproliferative agent. The authors interestingly found that the combination of electrical stimulation and bleomycin was more effective then either alone in terms of bleb survival after filtering surgery in pigmented rabbits. Although it is unclear exactly how electrical stimulation enhances the fibroblast inhibitory effect of bleomycin, one may speculate that the electrical pulse facilitates bleomycin entry into the cell through changes in membrane permeability secondary to changes in polarity. Electrical stimulation may also potentiate generation of toxic free radicals leading to enhanced toxicity of cycling fibroblasts. No studies were found in the English language literature evaluating bleomycin in the context of human glaucoma filtering surgery.

Growth Factor Inhibitors Both 5-FU and mitomycin C are useful in inhibiting fibroblast growth and replication and thus improving surgical success rates when used adjunctively during or following filtration surgery. However, the complications from use of these agents can be very severe because such agents cause widespread fibroblast cytotoxicity and apoptosis. Optimally, one would like to inhibit postoperative scarring without the inherent risks of antiproliferative therapy such as thin leaking blebs, hypotony, or endophthalmitis. Differences in aqueous concentration of metabolites and growth factors between successful and failed blebs have been identified, and may lead to novel therapeutic approaches that would exploit such differences.48,51 One potential alternative approach may be use of specific growth factor inhibitors. This is not a new concept in medicine. Hormonal as well as growth factor suppression and immune modulation, without direct cytotoxicity, have been utilized in the treatment of breast cancer, melanoma, renal cell carcinoma, as well as endocrine tumors. Over the past seven years there has been increasing interest in growth factor inhibition to modulate ocular scarring.

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Khaw and co-workers demonstrated in vitro that epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1), which are known to be present in aqueous humor and at the surgical wound site after filtering surgery, could stimulate fibroblast proliferation, migration, and collagen production.58 Salas-Prato et al found that both PDGF and bFGF induced proliferation of human Tenon’s capsule fibroblasts can be successfully inhibited by rapamycin, a macrolide antibiotic with potent immunosuppressive properties, without any experimental evidence of cytotoxicity.94 Unfortunately, there are no published animal or human trials that indicate that this agent is clinically useful in preventing scarring following trabeculectomy. There has been accumulating evidence however, that TGF-β isoforms play a more integral role in ocular wound healing as compared to other aqueous and tissue growth factors. Transforming growth factor-β1, -β2, and -β3 are members of a family of multifunctional polypeptides that exhibit regulatory actions on the differentiation, growth, and other functions of diverse cell types. TGF-β1 and -β2 can induce epithelial cell proliferation, stimulation of mesenchymal cell growth, and induction of extracellular matrix protein synthesis. Both are equipotent with regard to these functions. Khaw and co-workers demonstrated that TGF-β1 could stimulate fibroblast proliferation in vitro to a much greater degree and at significantly lower concentrations compared with EGF, bFGF, and IGF-1. However, of the three isoforms, TGF-β2 is the major isoform present in the eye, and its overproduction has been linked to the development of fibrosis and scarring in the eye. Its strong scar-promoting effect is partially related to its ability to stimulate the proliferation and migration of human Tenon’s capsule fibroblasts and enhancement of contraction of collagen gels caused by these fibroblasts.27 TGF-β2 has been detected in vitreous aspirates of eyes of patients with retinal detachments and is found in especially high concentrations in those eyes with proliferative vitreoretinopathy.26 Although TGF-β2 is present in aqueous of normal individuals, levels have been found to be significantly higher in glaucomatous eyes.81,124 Tripathi et al also demonstrated that the percentage of intrinsically active TGF-β2 in aqueous of eyes with glaucoma was significantly greater than that in normal subjects.116 In fact, aqueous humor from patients with primary open angle glaucoma can increase fibroblast proliferation by 60% as compared with aqueous humor of normals.53 With the recent development of specific blocking antibodies, blockade of TGF-β2 activity may successfully inhibit scarring in vivo without the toxic ocular

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side effects of antiproliferative agents. Logan et al were able to demonstrate in a rat experimental model of brain injury that glial scarring can be successfully inhibited by recombinant human monoclonal antibody to transforming growth factor-β2 (CAT-152; Cambridge Antibody Technology). In their experiment this antibody reduced levels of fibronectin and laminin immunoreactivity, as well as macrophage and microglial cell counts. Reactive astrocytes were also significantly reduced in number and did not organize into the expected glial membrane around the fibrous scar.69 With this background, Khaw’s lab proceeded to study CAT-152 as an adjunct for glaucoma-filtering surgery.27 Their experiment had three main premises: 1) to determine the effects of CAT-152 on human Tenon’s fibroblasts, 2) to evaluate the safety and tolerance of subconjunctival administration of CAT-152, and 3) to investigate the effects of subconjunctival CAT-152 using an animal model of aggressive subconjunctival scarring after glaucoma-filtering surgery. In vitro administration of CAT-152 significantly reduced fibroblast proliferation, cell numbers were far lower as compared to control antibody treatment. It also significantly inhibited migration of and reduced human Tenon’s fibroblast-mediated collagen contraction as compared with the control antibody. In the in vivo animal study one eye of each of 72 female New Zealand rabbits were randomized to 100 µl subconjunctival injections of CAT-152 dissolved in phosphate buffered saline (PBS) (1.0 mg/ml or 0.1 mg/ ml), null antibody (1.0 mg/ml), or PBS. The injections were administered on day-0 before filtration surgery, immediately after surgery, and then on days 1, 2, 3, and 7 after surgery. All injections including null antibody and PBS caused early chemosis that resolved by day 7. No significant difference in conjunctival vascularity was noted among any of the injections. Furthermore, there was no evidence of intraocular inflammation in the aqueous or vitreous following injections. Histologically, control eyes had densely packed layers of collagen and fibroblasts in comparison to CAT-152 treated eyes, which had much looser architecture and visible evidence of subconjunctival bleb formation. In comparison to a rabbit eye treated with mitomycin C, CAT-152-treated eyes did not demonstrate any evidence of destruction of the conjunctival cytoarchitecture. There was, however, a significant reduction in fibroblast number. With respect to bleb morphology, treatment with CAT-152 was associated with elevated, diffuse, fleshyappearing blebs as compared to the scarred controlinjected blebs. Bleb survival was also significantly improved in rabbits treated with CAT-152. At day 30, bleb failure was present in only two rabbits (33%)

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treated with CAT-152 but was present in five rabbits (83%) undergoing control treatments. On the average CAT-152 increased bleb survival by five days. Although this result may not seem so significant, the rabbit model is one of aggressive conjunctival scarring, and an agent which can suppress the wound-healing response clinically and histologically in this animal is likely to be very effective in humans. In summary, CAT-152 effectively inhibited TGF-β2-mediated conjunctival scarring activity in vitro, was clinically safe, nontoxic, and well-tolerated after in vivo subconjunctival administration, and significantly improved glaucoma filtering surgery outcome in an animal model of aggressive conjunctival scarring as compared to control eyes. Importantly, CAT-152 effectively reduced fibroblast number and activity without histological evidence of disruption of the cytoarchitecture. Thus, as compared to antiproliferative agents, CAT-152 administration may be a gentler more physiological method of modulating the wound healing response. Such a promising animal study has led this group of investigators to propose a protocol for human use. Although it appears to be histologically safer, direct comparison of this monoclonal antibody with 5-FU and mitomycin C in terms of efficacy of prolonging bleb survival will be necessary.

Recommendations Although use of antiproliferative agents during or following filtering surgery has been shown to improve surgical success rates through wound modulation, there is considerable toxicity associated with these agents that may lead to serious ocular morbidity and visual loss. It is thus imperative that all physicians who intend to perform glaucoma-filtering surgery with these adjuncts have thorough knowledge and understanding of all aspects of these agents to maximize patient safety and limit the risk of development of serious ocular sequelae. As with all surgical procedures, appropriate patient selection and preoperative evaluation cannot be overstated. Assessment of risk factors that predispose to aggressive postoperative scarring can help guide the surgeon towards appropriate antiproliferative selection, concentration, and duration of exposure. Proper selection may not only improve success rate but may also limit complications related to antiproliferative use. Such preoperative assessment can be facilitated by means of assigning a risk score to each patient based on clinical and demographic criteria (Table 8). Although the following weights attributed to each demographic or clinical situation have not been scientifically validated and thus are arbitrary scores, they nevertheless may serve as a helpful model

TABLE 8

Risk of Bleb Failure Patient and Ocular Factors Age ⬍50 ⬎80 Race (African Origin or Dark-Skinned Race) Prior surgery involving 1 superior quadrant Prior surgery involving both superior quadrants Chronic blepharoconjunctivitis including conjunctivitis medicamentosa Uveitis Mild Moderate Severe Neovascularization-active

Risk Score 1 ⫺1 2 1 3 1 1 3 5 5

to assist in making a decision regarding choice of antiproliferative therapy. Using this model, one might, for a score of ⫺1 to ⫹1 consider 5-FU, for a score of ⫹1 to ⫹4 consider mitomycin C. We recommend a shorter exposure or lower concentration of mitomycin C for a score of ⫹1, and a higher concentration and/or prolonged exposures for higher scores. For high-risk patients with a score of ⫹5 or greater, consider a glaucoma drainage device. Given the potential complications following mitomycin C administration, it may be prudent to avoid this agent in performing combined procedures in low-risk patients. One may even argue to forego combined surgery and instead perform clear cornea phacoemulsification without trabeculectomy because cataract surgery alone may lower IOP significantly. However, this effect is felt to be proportionally less with increasing severity of glaucoma.21 With modern small-incision phacoemulsification techniques performed by experienced surgeons, we believe that the likelihood of a potentially sight threatening pressure spike is probably low enough to justify cataract surgery alone in low-risk patients with mild disease. Intraoperative handling and use of these agents is essential in preventing potential complications to the patient as well as chemical hazards to the surgeon, assistant, and operating room staff. Thus, administration, timing of exposure, and disposal of antiproliferative should be meticulous. Tissue not intended for contact, such as the edges of the conjunctiva should be covered or held with blunt tissue forceps away from the antiproliferative-soaked sponges. Following exposure of a desired duration, the sponges should be removed and the operative field copiously irrigated with 30–50 cc of balanced salt solution. All instruments used in handling the antiproliferative

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should be set apart from the operative field for the remainder of the surgery. Unused antiproliferative and contaminated sponges should be disposed of in appropriate chemotherapy hazard containers as dictated by OSHA rules and regulations. Although steroids have been shown to be important in modulating the wound healing response after glaucoma-filtering surgery, the optimal dosing regimen, duration of treatment, and need for pretreatment are unknown. Our clinical approach however, is to recommend aggressive treatment with topical 1% prednisolone acetate postoperatively until all intraocular inflammation has subsided. This is followed by taper at a rate commensurate with the rate of resolution of external signs of inflammation, e.g., conjunctival injection. Once all intraocular inflammation has resolved, one may use a milder steroid with less corneal penetration. Although we do not routinely prescribe preoperative steroid treatment in the absence of clinical signs of inflammation, we do advocate discontinuation of sympathomimetics and any topical non-glaucoma medications when possible. When we can identify a glaucoma medication that is causing hyperemia, we often discontinue this agent preoperatively as well. Pretreatment with topical steroids should be strongly considered if obvious external signs of active inflammation are simultaneously present. Because antiproliferative agent use impairs wound healing, excess aqueous filtration as a result of too little scleral flap resistance in the early postoperative period may result in sustained hypotony. It should be understood that antiproliferative agents do not cause hypotony but will maintain hypotony. Thus, to avoid the associated complications of hypotony, the size of the ostium should be proportional to the size of the flap and should be made anteriorly into clear cornea to create a valve-like effect. Intraoperative assessment of flow and tension is imperative. Particularly, chamber depth and tension at equilibrium (the point at which all flow around the flap ceases as evidenced by non-wetting of a cellulose sponge at the sides of the flap) should be assessed. If anterior chamber depth is shallow and the eye is very soft and extremely deformable, then flow is too brisk. Additional sutures are then placed intraoperatively to raise flap resistance to the desired level. Postoperative sequential laser suture lysis or removal of releasable sutures if necessary will allow for a more controlled reduction in IOP. On the other hand, if resistance to flow is high as determined by a firm globe at equilibrium, then the ostium is either too small, too anterior, or both and should be enlarged. Gentle cautery to shrink the tissue at the sides of the flap may be another option to augment flow and lower the resistance to a desired level.

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Antiproliferative agents are critical adjuncts in augmenting filtering surgery success rate, however, they can also lead to serious complications and are thus potential double-edged swords. Meticulous surgical technique and judicious use of these agents to modulate wound healing following trabeculectomy can lead to a desired surgical outcome while limiting the risk of serious ocular morbidity.

Implications LONG-TERM SURVIVAL CURVES

Although adjunctive use of antiproliferative agents in glaucoma surgery has been shown to improve bleb survival, close scrutiny of the data reveals that the results are not ideal. Aside from methodological differences between studies including criteria defining success, many of the studies were of short duration with relatively few patients. Moreover, few patients were actually followed for three years or longer. In view of this limitation, the authors used Kaplan– Meier survival curves to estimate long-term probability of success. The cumulative data from such survival curves indicate that the greatest benefit from antifibrosis is within the first 6 months. During this time interval, those patients who did not receive adjunctive antiproliferative agents had a steep decline in bleb survival. However, patients in the noantiproliferative cohort whose blebs continued to function after the first year had survival curves that gradually approached the slopes of those that had antiproliferative therapy. What are the implications of this observation? 1. Antiproliferative therapy in the perioperative period suppresses fibroblastic activity facilitating the establishment of early filtration. 2. The effects of perioperative antiproliferative agents may not be sustained for the long-term. This situation is analogous to cancer chemotherapy in which induction chemotherapy is administered resulting in a clinical remission only to be followed by a late relapse due to proliferation of residual undetected cancer cells. Thus, the aim of wound modulation in glaucoma surgery is not only to suppress the initial fibroblastic proliferative activity but also to produce a sustained “remission” of fibroblastic function in order to prolong bleb survival thereby maintaining long-term IOP control. COMBINATION CHEMOTHERAPY TO INCREASE EARLY BLEB SURVIVAL

It is clear that our present antiproliferative therapy, which involves use of two classes of wound modulating agents, steroids and antiproliferative agents, in

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the perioperative period, may not be enough. Although there appears to be a progressive dose-response curve to escalating doses of antiproliferative therapy, the potential complication rate of such high doses is unacceptably high. Development of new wound-modulating agents may augment early filtration success by enhancing fibroblastic inhibition beyond that which can be achieved by our current regimen. Such expansion of our anti-wound healing armamentarium may lead to evolution of multidrug treatment strategies. Furthermore, with combination antiproliferative therapy the overall risk of serious ocular toxicity may actually be lowered. This is because with multi-drug regimens the eye may be spared higher doses of antiproliferative agents that are potentially the most toxic, and combining agents with different mechanisms of action may result in non-overlapping toxicities. Growth factor inhibitors such as anti-TGFβ-2 may be potentially useful adjuncts. Anti-TGFβ-2 antibodies have already been evaluated experimentally in a rabbit model and shown to prolong bleb survival over controls (no antiproliferative agent). A human clinical trial testing this new modality is underway.

suppress fibroblastic activity and re-induce a “fibroblastic remission”, or supplemental antiproliferative agents alone. Prompt intervention following recognition of early signs of bleb failure may prolong bleb survival and hence alter the survival rates of filtering blebs. LONG-TERM ANTIPROLIFERATIVE ACTIVITY

As mentioned above, perioperative fibroblast inhibition alone is often not sufficient in providing long-term remission of fibroblastic activity, thus accounting for a steady progressive decline in bleb survival. In fact, it has been demonstrated that fibroblasts that have been exposed to sublethal doses of mitomycin C or 5-FU may still critically influence growth and activity of untreated fibroblasts in the vicinity of treatment.29 Because wound maturation is a continuous process, long-term antifibroblastic therapy may be warranted in order to improve long-term bleb survival rates. The manner in which this may be achieved includes: chronic intermittent antiproliferative administration, growth factor inhibition, or gene therapy. The latter may be realized via activation of suppressor genes or through inhibition of promoters of fibroblast DNA or RNA synthesis.

CAREFUL FOLLOW-UP BLEB EVALUATION

Achieving target IOP following trabeculectomy is important but may lead to a false sense of security. Oftentimes the IOP may be low but the bleb may have physical characteristics that portend eventual failure. Such high-risk features include increased vascularity, progressive thickening of the bleb wall, and a paucity of microcysts. These findings are indicators that the healing response is quite active and if left unchecked, bleb failure will eventually occur. Close surveillance of the evolving morphologic features of the filtering bleb will provide clues regarding the status of the wound healing response and may provide the clinician with an opportunity for early intervention and rescue. EARLY WOUND INTERVENTION

Bleb encapsulation despite a “good IOP” may likely lead to eventual bleb failure. In order to prevent late failure, the underlying fibroblastic response will need to be suppressed aggressively. This is again analogous to the situation of a cancer patient whose surveillance markers indicate early cancer relapse prior to frank clinical manifestations of relapse. Such patients will require additional cycles of chemotherapy or other modalities to suppress growth of neoplastic cells. Similarly, the bleb exhibiting signs of early failure prior to IOP elevation will require intervention. Such intervention may include needling in combination with additional subconjunctival 5-FU or mitomycin C to

Summary The weight of the evidence from antifibrosis studies demonstrates that antiproliferative therapy is extremely useful in augmenting early filtering surgery success rates. However, long-term success rates of blebs supplemented with antiproliferative agents are not as promising as desired with survival curves that eventually parallel those blebs that did not receive antiproliferative therapy. Furthermore, variability between studies is great and multifactorial in origin. Patient demographics, duration and type of glaucoma, number of previous surgical procedures, method and dose of administration of antiproliferative agent, surgical technique, postoperative regimen, duration of follow-up, and criteria for success or failure are important variables that may affect reported outcome. Complications of glaucoma surgery are, as described above, often associated with the use of these agents. In order to achieve lower IOP we have increased the risk of hypotony and late infections. New approaches may allow modulation of wound healing with less of the toxicity associated with 5-FU and mitomycin C. However, with the currently available agents, meticulous surgical technique, judicious use of these agents, close bleb surveillance, early intervention, and multimodal therapy with long-term plans for suppression of fibroblastic activity may augment bleb survival rates and thus flatten the slope of the survival curve.

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Method of Literature Search

sification and trabeculectomy. Ophthalmology 104:719– 24, 1997 Caronia RM, Liebmann JM, Friedman R, et al: Trabeculectomy at the inferior limbus. Arch Ophthalmol 114:387– 91, 1996 Cashwell LF, Shields MB: Surgical management of coexisting cataract and glaucoma, in Ritch R, Krupin T, Shields MB (eds): The Glaucomas, Vol III. St. Louis, Mosby, 1996, ed 2, pp 1745–60 Chaudhry IA, Pasha MA, OConnor DJ, et al: Randomized, controlled study of low-dose 5-fluorouracil in primary trabeculectomy. Am J Ophthalmol 130:700–3, 2000 Chen CW, Huang HT, Sheu MM: Enhancement of IOP control effect of trabeculectomy by local application of anticancer drug. Acta Ophthalmol Scand 25:1487–91, 1986 Cheung JC, Wright MM, Murali S, Pederson JE: Intermediate-term outcome of variable dose mitomycin C filtering surgery. Ophthalmology 104:143–9, 1997 Cohen JS, Greff LJ, Novack GD, Wind BE: A placebo-controlled, double-masked evaluation of mitomycin C in combined glaucoma and cataract procedures. Ophthalmology 103:1934–42, 1996 Connor TB, Roberts AB, Sporn MB: Correlation of fibrosis and transforming growth factor-b type 2 levels in the eye. J Clin Invest 83:1661–6, 19 Cordeiro MF, Gay JA, Khaw PT: Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent. Invest Ophthalmol Vis Sci 40:2225–34, 1999 Cunliffe IA, Longstaff S: Intraoperative use of 5-fluorouracil in glaucoma filtering surgery. Acta Ophthalmol (Copenh) 71:739–43, 1993 Daniels JT, Occleston NL, Crowston JG, Khaw PT: Effects of antimetabolite induced cellular growth arrest on fibroblast– fibroblast interactions. Exp Eye Res 69:117–27, 1999 Dellaporta A: Fundus changes in postoperative hypotony. Am J Ophthalmology 40:781–5, 1955 Demailly P, Kretz G: Daunorubicin versus 5-fluoro-uracil in surgical treatment of primary open angle glaucoma: a prospective study. Int Ophthalmol 16:367–70, 1992 Dietze PJ, Feldman RM, Gross RL: Intraoperative application of 5-fluorouracil during trabeculectomy. Ophthalmic Surg 23:662–5, 1992 Donoso R, Rodriguez A: Combined versus sequential phacotrabeculectomy with intraoperative 5-fluorouracil. J Cataract Refract Surg 26:71–4, 2000 Entzian P, Schlaak M, Seitzer U, et al: Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. Lung 175:41–51, 1997 Falck FY, Skuta GL, Klein TB: Mitomycin versus 5-Fluorouracil antimetabolite therapy for glaucoma filtration surgery. Semin Ophthalmol 7:97, 1992 Fourman S: Scleritis after glaucoma filtering surgery with mitomycin C. Ophthalmology 102:1569–71, 1995 Freedman SF, McCormick K, Cox TA: Mitomycin C-augumented trabeculectomy with postoperative wound modulation in pediatric glaucoma. J AAPOS 3:117–24, 1999 Gandolfi SA, Vecchi M: 5-fluorouracil in combined trabeculectomy and clear-cornea phacoemulsification with posterior chamber intraocular lens implantation. A one-year randomized, controlled clinical trial. Ophthalmology 104:181–6, 1997 Gass JDM: Hypotony maculopathy, in Bellows JG (ed): Contemporary Ophthalmology. Baltimore, Williams and Wilkins, 1972, chap 34 Goldenfeld M, Krupin T, Ruderman JM, et al: 5-Fluorouracil in initial trabeculectomy. A prospective, randomized, multicenter study. Ophthalmology 101:1024–9, 1994 Greenfield DS, Liebmann JM, Jee J, Ritch R: Late-onset bleb leaks after glaucoma filtering surgery. Arch Ophthalmol 116:443–7, 1998 Greenfield DS, Suner IJ, Miller MP, et al: Endophthalmitis after filtering surgery with mitomycin. Arch Ophthalmol 114:943–9, 1996 Gressel MG, Parrish RK 2nd, Folberg R: 5-fluorouracil and glaucoma filtering surgery I. An animal model. Ophthalmology 91:378–83, 1984

Medline and Ovid were used to search literature from 1966 to 2002. Key words used were glaucoma, glaucoma filtering surgery, antimetabolites, 5-fluoruracil, mitomycin C. English language literature and English language abstracts of foreign literature were included in the search.

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Supported in part by unrestricted grants from Research to Prevent Blindness and The Glaucoma Research and Education Foundation. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Paul J. Lama, MD, Assistant Professor, Department of Ophthalmology, New Jersey Medical School, 90 Bergen Street, Suite 6100, Newark, NJ 07103