31 Modification of wound healing in glaucoma drainage surgery

Background

Glaucoma drainage surgery has a pivotal role in the management of glaucoma. In the developing world, it is the mainstay of treatment and in richer countries it is used in aggressive disease and where other therapies fail.

The most common procedure performed is trabeculectomy, a guarded filtration procedure. In older Europeans with primary open angle glaucoma, trabeculectomy has a success rate of at least 80%, and in individuals undergoing surgery early in the clinical course without extensive prior use of medical therapy the results are even better.1

However, it is clear that there are groups of patients with a poorer prognosis for surgery. Risk factors for failure of glaucoma drainage surgery include young age (particularly children), black African ethnic origin, prior medical therapy with adrenergic agents and pilocarpine, previous failed glaucoma drainage surgery, aphakia and previous cataract surgery, uveitis, angle recession glaucoma (secondary to trauma) and anterior segment neovascularisation.2 These factors are thought to be additive. In an effort to improve results, especially where risk of failure is increased, investigators have studied the use of antiproliferative agents to inhibit postoperative scarring in the sub-conjunctival space.

Postoperative corticosteroids have been clearly shown to improve results after surgery and are used routinely. In their relatively small RCT, Starita et al.3 showed a significantly better success rate with postoperative topical steroids that persisted at both 5 and 10-year follow up.

Beta radiation was first used for glaucoma drainage surgery over 60 years ago but has not gained widespread use.4 The use of 5-fluorouracil, given as multiple postoperative injections, was first described in 19845 while mitomycin C as a peroperative topical application was first described by Chen et al. in 1990,6 who reported using it in a case series going back to 1981. Subsequently, intraoperative 5-fluorouracil and mitomycin C have been widely, although variably, used.7,8

Question

Do postoperative injections of 5-fluorouracil improve results in high-risk glaucoma drainage surgery, primary glaucoma drainage surgery or combined cataract and glaucoma drainage surgery?

The evidence

A systematic review by Wormald et al. has addressed these questions.9 A total of nine trials were found, but most were not of high quality. The main outcomes examined were “clinical failure” (i.e. the need to repeat surgery due to loss of intraocular pressure control) and mean postoperative intraocular pressure at one year. A requirement for the use of medical therapy was not a definition of failure.

For cases with a high risk of failure, the review found data from two studies with a total of 239 participants: a large multi-centre study and a smaller study.10,11 The smaller study11 showed a considerably larger effect. Patients who had undergone previous failed glaucoma drainage surgery or cataract extraction were included. The main exclusion criterion was prior exposure to 5-fluorouracil. The data suggested a 60% reduction in the risk of failure: from 43% to 19%. The relative risk (RR) estimate was 0·4 (95% CI

0·16–0·90). The summary number needed to treat (NNT) estimate was four cases (95% CI 3–8). Mean intraocular pressure (IOP) was only reported in the smaller study, where there was a 16 mmHg lower mean IOP in treated subjects.

For primary trabeculectomy, which was defined as an initial surgical procedure in subjects with uncontrolled open angle glaucoma, the systematic review found two studies with a total of 112 participants using the dosing regimen as originally described12,13 and two studies using a less intensive regimen with a total of 120 randomised subjects.14,15 The systematic review found a reduction in risk of failure from 18% to 3%, which represents a 76% reduction in risk. The RR estimate was 0·24 (95% CI 0·08–0·74). The summary

NNT estimate was five cases (95% CI 3–12). The constituent trials in the systematic review were small and produced no statistically significant results. The mean postoperative intraocular pressure was 5 mmHg lower in the subjects treated with 5-fluorouracil. The trial by Chaudhry et al. demonstrated no significant difference in success rates (defined as IOP <21 mmHg on no medications in this study) or degree of IOP reduction.15

For combined cataract extraction and glaucoma drainage surgery, a total of 142 subjects were randomised in three trials.16–18 The point estimate of relative risk reduction was 0·42, equivalent to a 58% reduction in the risk of failure. However, the confidence intervals are very broad and firm conclusions cannot be drawn. This is primarily because there was a very low failure rate in both arms of each study. The mean postoperative IOP was significantly lower in two of the studies.16,18 However, the mean IOP values were very different in the three studies so a pooled estimate was not available.

Question

What are the adverse effects of postoperative 5-fluorouracil?

The evidence

The systematic review considered adverse effects for all trials. Use of postoperative 5-fluorouracil was associated with a significantly increased risk of postoperative wound leak with a point estimate of risk 1·7 (95% CI 1·04–2·64). Hypotony was only found in the cases undergoing primary trabeculectomy, with a significantly increased risk in subjects treated with 5-fluorouracil. The point estimate was 7·4 (95% CI 1·2–45·0) with a number needed to harm (NNH) of 56 subjects (95% CI 24–518). No cases of endophthalmitis were reported in any trial. Expulsive haemorrhage was only reported in one trial with no difference between the treated and control subjects.19 There was no convincing evidence that 5-fluorouracil increased the risk of a shallow anterior chamber, although the event rate was low. The risk of corneal epithelial toxicity is increased by treatment with 5-fluorouracil. The point estimate of risk was 6·2 (95% CI 3·9–9·7). Postoperative cataract was reported by Chaudhry,15 which found this in 16% of treated eyes compared with 3% of control eyes. Despite this being a large effect, it was not statistically significant.

Comment

The routine use of a course of injections of 5-FU is less frequent now. Additional ad hoc injections for an apparently

failing bleb are quite commonly practised in some clinics although there is no good evidence to support its use.

There is a major gap in the evidence with regard to any attempt to measure patient-orientated outcomes. Frequent postoperative sub-conjunctival injections are potentially unpleasant for patients and the keratopathy associated with 5-FU is painful. It is probably because of this that clinicians now prefer to use 5-FU or mitomycin peroperatively.

None of the trials have sufficient long-term follow up to provide evidence of the risk of longer term complications such as hypotony secondary to late leakage from a thin walled bleb and endophthalmitis.

Question

Does intraoperative 5-fluorouracil improve results in primary glaucoma drainage surgery compared with surgery without an antimetabolite?

The evidence

To date, data are only available for primary glaucoma drainage surgery. There is no published systematic review but three published trials were found: two from Africa, by Egbert et al.20 and Yorston and Khaw.21 and Khaw and one from the United Kingdom by Leyland et al.22 Success was defined in all trials by intraocular pressure criteria of antiglaucoma drugs. In Africa, this is an essential requirement due to inherent problems in treating glaucoma medically.23

The Egbert et al. study20 reported short-term follow up, with a minimum of 90 days of follow up required for inclusion. A significant effect of 5-fluorouracil was reported with a failure rate of 13% for 5-fluorouracil and 45% for controls (defined as an IOP >21 mmHg). Of 61 eligible eyes, 55 were included in the analysis (24 after 5-fluorouracil and 31 controls). Case selection was mixed; only 75% had primary open angle glaucoma (POAG) and were undergoing a first procedure for glaucoma. The trial showed a clear advantage for the use of 5-fluorouracil, although given the small sample size, eclectic case selection and short follow up, the results can not be considered definitive.

Yorston and Khaw21 performed a randomised controlled trial of 5-fluorouracil versus standard trabeculectomy in Kenya. Of 68 patients with POAG, 56 (85%) were followed for a minimum of six months and 30 followed for two or more years (44%). A significant effect of 5-fluorouracil was found with 88·8% of 5-fluorouracil subjects and 70·6% of controls having an IOP <22 mmHg at two years. At six months, the mean postoperative IOPs were 16·9 mmHg (5-fluorouracil) and 17·4 (controls). Complications were similar in both groups, with subsequent cataract being the most important complication. The effect of 5-fluorouracil

seems to be a prolongation of success in this population rather than a lower IOP. The authors commented on an increased incidence of cystic blebs (which may predispose to postoperative infection) in the 5-fluorouracil group in the early postoperative period, but this effect diminished with time. The authors estimated that the cost of 5-fluorouracil was £1·25 per failure prevented (NNT 6). For both African studies, loss to follow up was significant, which may limit the conclusions that can be drawn.

Leyland et al.’s study was performed on subjects undergoing a first glaucoma drainage surgery where the risk of failure was not considered to be particularly high. There were no significant differences between the treated and control groups, although the study had limited power (approximately 20%) to detect a 10% difference in success rate between the two groups as the success rate was high in both arms.22

Question

What are the adverse effects of intraoperative 5- fluorouracil?

The evidence

No excess complications were reported in the Egbert et al. or the Leyland et al. study, although a non-significant increase in bleb leaks was reported in the former study (four of 24 eyes v two of 31 eyes). Yorston and Khaw reported an excess of shallow anterior chambers in the early postoperative period, with thin walled drainage blebs at three months, but no numbers were reported. There were no cases of hypotony reported, but hypotony appears to be rare in Africans.24

Comment

So far there have been few trials and no systematic review providing a summary of the evidence for this fairly common practice. Some surgeons are happy to use topical 5- FU in primary trabeculectomy without excess risk factors for failure although the trade off of risk and benefit for this practice is not certain.

One further large trial will soon be completed in the UK and two others have been completed in Chile and Singapore but have not yet been published. A Cochrane systematic review is also near completion.

Question

Does intraoperative mitomycin C improve results in highrisk glaucoma drainage surgery, primary glaucoma drainage surgery and combined cataract and glaucoma drainage surgery?

The evidence

This question has been addressed in a Cochrane review by Wilkins et al.25 The review included 11 trials covering 698 subjects. As for the review on postoperative 5- fluorouracil, the main outcome measurements were the proportion of successful cases (unsuccessful cases defined by uncontrolled intraocular pressure or repeat surgery).

For subjects with a high risk of failure, there were four trials with 193 subjects.26–29 Two trials included high-risk subjects and one included subjects undergoing combined glaucoma and cataract extraction who were already at high risk of surgical failure due to previous failed surgery. One trial specifically included subjects with secondary glaucomas. The trials showed a significantly reduced risk of failure at 12 months: summary odds ratio (OR) 0·32, 95% CI 0·2–0·53. The summary NNT estimate was 3 (95% CI 2–4). Three trials reported IOP data; the summary mean IOP difference was 5·31 mmHg (95% CI 3·85–6·76 mmHg).

Three trials were found for combined cataract extraction and glaucoma surgery.30–32 A total of 167 participants were randomised. No benefit of mitomycin C was found. For IOP two trials reported significantly lower IOP and one did not. The combined result suggested a mean difference in IOP reduction of 3·34 mmHg (95% CI 2·51–4·16 mmHg).

For primary trabeculectomy a total of 338 participants undergoing a first glaucoma surgical procedure were randomised in four trials.33–36 In the largest trial,36 subjects were randomised to placebo or to one of three dosing regimens of mitomycin C (0·2 mg/ml for two minutes, 0·2 mg/ml for four minutes or 0·4 mg/ml for two minutes). A summary OR of 0·29 (95% CI 0·16–0·53) was found. The summary NNT estimate was five (95% CI 4–8). Two trials reported IOP data at 12 months. The pooled estimate was a mean difference of 5·41 mmHg (95% CI 3·48–7·34 mmHg).

Question

What are the adverse effects of intraoperative mitomycin C?

The evidence

From data in the review, mitomycin C was associated only with an excess risk of cataract and the NNH was 15.25

Robin et al.’s trial found an increased risk of cataract with longer mitomycin C treatment times.36 Specifically, use of mitomycin C was not associated with an increased rate of endophthalmitis, hypotony, wound leak or shallow anterior chamber. However, the event rates of these complications were low.

Comment

The majority of trials in this review25 were not judged to be of high quality though there were more better quality studies than in the 5-FU review.

The absence of effect in triple procedures is explained by the fact that IOPs were low in many patients entering the trials. Drainage was performed to reduce the risk of postoperative IOP spikes although this was not measured as an outcome.

Many recognise the increasing incidence of hypotony, wound leak and endophthalmitis as important late complications of the use of mitomycin C although none of the trials have long enough follow up to address these important issues. Retrospective studies have quantified the risks but active surveillance is needed to monitor this problem prospectively.

Question

What are the comparative effects of mitomycin C and 5-fluorouracil in the modification of wound healing after glaucoma surgery?

The evidence

There is no systematic review but there are five randomised controlled trials comparing mitomycin C and 5-FU in adults and one in paediatric glaucoma. Two trials dealt with patients at high risk of failure, one with pseudophakic patients, one with black West African patients and two with primary trabeculectomy.

The first comparative trial was by Kitazawa et al.,37 in which 32 patients had one eye randomised either to mitomycin C 0·2 mg/ml applied during surgery or 10 postoperative injections of 5-fluorouracil over two weeks.

All eyes had a poor surgical prognosis; follow up was between seven and 12 months. Eighty-eight per cent of eyes treated with mitomycin C compared to 47% of eyes treated with 5-FU achieved an IOP less than 20 mmHg. Corneal complications were more common in the 5-FU group while other complications were similar in both groups.

Lamping and Belking compared postoperative 5-FU injections and peroperative mitomycin C in patients who had previously undergone extracapsular cataract extraction and posterior chamber lens implantation.38 Eighty eyes in 74 patients were randomised and followed up for 12 months. IOPs were significantly lower in the mitomycin C group and there was no difference in complications.

Katz et al. compared postoperative 5-FU with intra-operative mitomycin in eyes at high risk of failure.39 Nineteen eyes in 19 patients were randomised to 5-FU compared with 20 eyes in 20 patients randomised to mitomycin C. They were

followed up for 26–38 months. Postoperative exclusions meant that the analysis was not intention to treat. Pressures were found to be significantly lower in the mitomycin C group. Complications were similar in both groups except for a more frequent occurrence of Tenon’s cysts in the mitomycin C group.

Researchers in all of these initial studies concluded that mitomycin C was as or more effective than postoperative 5-FU injections with similar or indeed fewer complications.

Kuldev Singh and colleagues went on to compare intraoperative 5-FU with mitomycin C in a West African population.40 These patients were undergoing a primary procedure without prolonged previous exposure to topical medications. The intervention was either 50 mg/ml 5-FU for five minutes or mitomycin C 0·5 mg/ml for 3·5 minutes, applied to the exposed sclera with a soaked sponge. One eye of each of the 85 patients was randomised and followed for at least four months (CI 4–19, mean 10 months). Mitomycin C achieved a significantly higher success rate (proportion of IOP <21 mmHg) and lower mean IOP though the difference in patients achieving an IOP of <15 mmHg was not significant. There was no reported difference in complication rates and a further paper reported that for longer term follow up of patients in this and another trial, there was no difference in risk of hypotony, which occurred in two of 101 participants.24

The same group went on to conduct a similar trial in California.41 The dose of 5-FU was the same but mitomycin C was applied for two minutes at a concentration of 0·4 mg/ml. One eye of 113 patients were randomised and followed for an average of 309 days for the 5-FU group and 339 days for the mitomycin C group. Predefined target IOPs were met a little more frequently in the mitomycin C group but did not reach statistical significance. Complications were again similar in both groups.

The most recent study reported was from Indiana.42 This also compared the two agents in primary trabeculectomy. One hundred and fifteen eyes of 103 patients were randomised in a double-masked manner either to 50 mg/ml 5-FU for five minutes or 0·2 mg mitomycin C for two minutes. Outcomes were measured at six and 12 months in terms of success defined by various different IOP cut-off points. None of the outcomes was statistically different at either time point. Complications occurred more frequently in the mitomycin C group but this was not satisfactory.

Comment

It seems somewhat counter intuitive that peroperative 5-FU seems to be as effective as mitomycin C in primary trabeculectomy while postoperative injections (overall a considerably higher dose) is less effective in eyes at higher baseline risk of failure. Dose and duration of application of

mitomycin C has tended to become less with the passage of time, perhaps because of the recognition of the much longer term complications now being reported. The trials have been conducted over more than a 10-year time span and there has been a noticeable improvement both in the standard of conduct and reporting of the trials over that period. As is so often observed, the size of the observed effect becomes less as the quality of the clinical experiments improve.

Question

Is beta radiation effective in improving the results of glaucoma drainage surgery?

Three trials were found that have examined the effect of beta radiation in improving the outcome of glaucoma drainage surgery. Two of these included white patients undergoing primary trabeculectomy and the other recruited Chinese subjects. Barnes et al. used 750 cGy just before surgery with 65 subjects.43 The mean IOP reduction was very similar in both treated and control subjects, success was achieved in 100% of treated subjects and 88% of control subjects (intraocular pressure <21 mmHg with or without medication). Mean reductions in IOP of 10·3 mmHg and 9·3 mmHg were found in treated and control subjects.

Rehman et al. used a very similar methodology in a similar patient population, except that treatment was applied on completion of surgery and it was double masked; 61 subjects were treated.44 The success rate was 100% in treated eyes and 95% in untreated eyes using the above criteria. For success without medication, the respective success rates were 90% and 86%. Complications were similarly prevalent in both groups in both trials.

Lai and Ho reported data from a Chinese population of 101 subjects with 1000 cGy applied on completion of surgery.45 They reported success rates of 90% in treated subjects and 74% in control subjects. This difference was found to be significant. No excess of complications were reported in the subjects treated with beta radiation, although follow up was limited to one year (personal communication). Mean IOP data were not available. All three trials were of reasonable quality.

A further study by O’Donoghue et al.46 compared beta radiation with postoperative 5-fluorouracil injections in high-risk subjects. Follow up was short, for a minimum of eight months and 70 subjects were studied. Success rates of 76% for the subjects treated with beta radiation and 79% for the subjects treated with 5-fluorouracil were reported (IOP >21 mmHg without medications). There was a trend for the subjects treated with beta radiation to have more favourable bleb morphology, while corneal toxicity was more common

in the subjects treated with 5-fluorouracil (88% v 7%). Again, no patient-orientated outcome was reported but it might be supposed that those without injections had a less traumatic experience.

Comment

Beta radiation seems to be a relatively cheap and simple alternative to antimetabolites but when comparing costs, the process of safely storing the radioactive source needs to be taken into account. Neither mitomycin C nor 5-FU are very costly. There may be specific advantages for use of these treatments in the developing world and there is an ongoing trial addressing this question in South Africa.

It may be that adverse outcomes are less severe after beta radiation compared to mitomycin C, but this study has not yet been done. Follow up would need to be long term to capture late adverse events.

Implications for practice

The evidence base for the modification of wound healing in glaucoma surgery is relatively well populated with trials though it remains hard to be clear about the trade-off between risk and benefit in the different risk groups. Everyone’s ideal is to achieve a successful procedure first time round but the enthusiasm to achieve this must be tempered by the awareness of late complications. So far, we lack sufficient quantifiable estimates of risk and benefit for the different agents in use. It is interesting that more recent studies suggest that the clinical effectiveness of 5-FU and mitomycin C is not very different, while most of the reports of late complications relate to mitomycin C.

The evidence presented here can be used to guide clinicians to make the best judgement about choice of treatment for individual patients. This will always need to be a carefully balanced and properly informed choice for both patient and clinician.

Implications for research

In cell culture, there are enormous differences between 5-FU and mitomycin C. The latter is far more toxic, although 5-FU is also a poison.

Wound healing research has identified key growth factors in the healing of trabeculectomy drainage blebs, particularly transforming growth factor beta. Monoclonal antibodies to this have now been commercially produced and the results of a phase I/IIa trial are encouraging.47 Clearly the costs of producing such an agent will be high, but if it can be shown to reduce long-term complications safely, while

preserving or improving effectiveness, then savings may accrue with time.

Glaucoma is a long-term disease and therefore effectiveness studies have to address long-term safety and effectiveness. We found only one study in this review that managed 10-year outcomes.3 This may need to become a minimum aim in future research.

References

1.Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmology 1994;112(11):1446–54.

2.Ritch R, Shields MB et al. The Glaucomas. St Louis: Mosby, 1996.

3.Starita RJ, Fellman RL, Spaeth GL, Poryzees EM, Greenidge KC, Traverso CE. Shortand long-term effects of postoperative corticosteroids on trabeculectomy. Ophthalmology 1985;92(7):938–46.

4.Iliff CE. Surgical control of glaucoma in the negro. Am J Ophthalmol 1944;27:731–8.

5.Heuer DK, Parrish RK 2nd, Gressel MG, Hodapp E, Palmberg PF, Anderson DR. 5-fluoruracil and glaucoma filtering surgery. II. A pilot study. Ophthalmology 1984;91(4):384–94.

6.Chen CW, Huang HT, Bair JS, Lee CC. Trabeculectomy with simultaneous topical application of mitomycin C in refractory glaucoma. J Ocul Pharmacol 1990;6(3):175–82.

7.Chen PP, Yamamoto T, Sawada A, Parrish RK 2nd, Kitazawa Y. Use of antifibrosis agents and glaucoma drainage surgery in the American and Japanese Glaucoma Societies. J Glaucoma 1997;6(3):192–6.

8.Edmunds B, Thompson JR, Salmon JF, Wormald RP. The National Survey of Trabeculectomy. II. Variations in operative technique and outcome. Eye 2001;15(4):441–8.

9.Wormald R, Wilkins MR, Bance C. Post operative 5-fluorouracil for glaucoma surgery (Cochrane Review). In: Cochrane Collaboration: Cochrane Library. Issue 2. Oxford: Update Software, 2003.

10.Fluorouracil Filtering Surgery Study Group. Fluorouracil Filtering Surgery Study one-year follow-up. The Fluorouracil Filtering Surgery Study Group. Am J Ophthalmol 1989;108(6):625–35.

11.Ruderman JM, Welch DB, Smith MF, Shoch DE. A randomized study of 5-fluorouracil and filtration surgery. Am J Ophthalmol 1987; 104(3):218–24.

12.Ophir A, Ticho U. A randomized study of trabeculectomy and subconjunctival administration of fluorouracil in primary glaucomas.

Arch Ophthalmology 1992;110(8):1072–5.

13.Goldenfeld M, Krupin T, Ruderman JM et al. 5-Fluorouracil in initial trabeculectomy. A prospective, randomized, multicenter study.

Ophthalmology 1994;101:1024–9.

14.Loftfield K, Ball SF. 5-FU in primary trabeculectomy: a randomised trial. Invest Ophthalmol Vis Sci 1991;32(4):745.

15.Chaudhry IA, Pasha MA, O’Connor DJ, Weitzman ML, Caprioli J. Randomized, controlled study of low-dose 5-fluorouracil in primary trabeculectomy. Am J Ophthalmol 2000;130(6):700–3.

16.O’Grady JM, Juzych MS, Dhin DH, Lemon LC, Swendris RP. Trabeculectomy, phacoemulsification, and posterior chamber lens implantation with and without 5-fluorouracil. Am J Ophthalmol 1993;116(5):594–9.

17.Wong PC, Ruderman JM, Krupin T et al. 5-Fluorouracil after primary combined filtration surgery. Am J Ophthalmol 1994;117(2):149–54.

18.Gandolfi SA, Vecchi M. 5-Fluorouracil in Combined Trabeculectomy and Clear-cornea Phacoemulsification with Posterior Chamber Intraocular Lens Implantation. Ophthalmology 1997;104:181–6.

19.Fluorouracil Filtering Surgery Study Group. Risk factors for suprachoroidal hemorrhage after filtering surgery. The Fluorouracil Filtering Surgery Study Group. Am J Ophthalmol 1992;113(5):501–7.

20.Egbert PR, Williams AS, Singh K, Dadzie P, Egbert TB. A prospective trial of intraoperative fluorouracil during trabeculectomy in a black population. Am J Ophthalmol 1993;116(5):612–16.

21.Yorston D, Khaw PT. A randomised trial of the effect of intraoperative 5-FU on the outcome of trabeculectomy in east Africa. Br J Ophthalmol 2001;85(9):1028–30.

22.Leyland M, Bloom P, Zinicola E, McAlister J, Rassam S, Migdal C. Single intraoperative application of 5-Fluorouracil versus placebo in low-risk trabeculectomy surgery: a randomized trial. J Glaucoma 2001;10(6):452–7.

23.Schwab L, Steinkuller PG. Surgical treatment of open angle glaucoma is preferable to medical management in Africa. Soc Sci Med 1983;17(22):1723–7.

24.Singh K, Byrd S, Egbert PR, Budenz D. Risk of hypotony after primary trabeculectomy with antifibrotic agents in a black west African population. J Glaucoma 1998;7(2):82–5.

25.Wilkins MR, Indar A, Wormald R. Intra-operative mitomycin C for glaucoma surgery. In: Cochrane Collaboration. Cochrane Library. Issue 2. Oxford: Update Software, 2003.

26.Turacli E, Gunduz K, Aktan G, Tamer C. A comparative clinical trial of mitomycin C and cyclosporin A in trabeculectomy. Eur J Ophthalmol 1996;6(4):398–401.

27.Wu L, Yin J. The effect of mitomycin C on the filtration surgery of glaucoma with poor prognosis. Chung Hua Yen Ko Tsa (Chinese J Ophthalmol) 1996;32(1):32–4.

28.Andreanos D, Georgopoulos GT, Vergados J, Papaconstantinou D, Liokis N, Theodossiadis P. Clinical evaluation of the effect of mitomycin-C in re-operation for primary open angle glaucoma. Eur J Ophthalmol 1997;7(1):49–54.

29.Shin DH, Kim YY, Sheth N et al. The role of adjunctive mitomycin C in secondary glaucoma triple procedure as compared to primary glaucoma triple procedure. Ophthalmology 1998;105(4):740–5.

30.Shin DH, Simone PA, Song MS et al. Adjunctive subconjunctival mitomycin C in glaucoma triple procedure. Ophthalmology 1995; 102(10):1550–8.

31.Cohen JS, Greff LJ, Novack GD, Wind BE. A placebo-controlled, double-masked evaluation of mitomycin C in combined glaucoma and cataract procedures. Ophthalmology 1996;103(11):1934–42.

32.Carlson DW, Alward WL, Barad JP, Zimmerman MB, Carney BL. A randomized study of mitomycin augmentation in combined phacoemulsification and trabeculectomy. Ophthalmology 1997;104(4): 719–24.

33.Costa VP, Comegno PE, Vasconcelos JP, Malta RF, Jose NK. Low-dose mitomycin C trabeculectomy in patients with advanced glaucoma. J Glaucoma 1996;5(3):193–9.

34.Szymanski A, Gierek-Lapinska A, Koziak M, Gierek-Ciaciura S. A fluorophotometric study of corneal endothelium after trabeculectomy using different concentrations of Mitomycin-C. Int Ophthalmol 1996;20(1–3):95–9.

35.Martini E, Laffi GL, Sprovieri C, Scorolli L. Low-dosage mitomycin C as an adjunct to trabeculectomy. A prospective controlled study. Eur J Ophthalmol 1997;7(1):40–8.

36.Robin AL, Ramakrishnan R, Krishnadas R et al. A Long-term DoseResponse Study of Mitomycin in Glaucoma Filtration Surgery. Arch Ophthalmol 1997;115:969–74.

37.Kitazawa Y, Kawase K, Matsushita H, Minobe M. Trabeculectomy with mitomycin. A comparative study with fluorouracil. Arch Ophthalmol 1991;109(12):1693–8.

38.Lamping KA, Belkin JK. 5-Fluoruracil and mitomycin in pseudophakic patients. Ophthalmology 1995;102(1):70–5.

39.Katz GJ, Higginbotham EJ, Lichter PR et al. Mitomycin C versus 5- fluorouracil in high-risk glaucoma filtering surgery. Extended follow up. Ophthalmology 1995;102(9):1263–9.

40.Singh K, Egbert PR, Byrd S et al. Trabeculectomy with intraoperative 5- fluororacil versus mitomycin C. Am J Ophthalmol 1997;123(1):48–53.

41.Singh K, Mehta K, Shaikh NM et al. Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil. Prospective randomised clinical trial. Ophthalmology 2000;107(12):2305–9.

42.WuDunn D, Cantor LB, Palanca-Capistrano AM et al. A prospective randomised controlled trial comparing intraoperative 5-fluorouracil versus mitomycin C in primary trabeculectomy. Am J Ophthalmol 2002;134:521–8.

43.Barnes RM, Mora JS, Best SJ et al. Beta radiation as an adjunct to lowrisk trabeculectomy. Clin Exp Ophthalmol 2000;28(4):259–62.

Age-related cataract remains the commonest cause of blindness throughout the world and cataract surgery forms the major surgical workload of eye departments. Recent advances in surgical technique, equipment and intraocular lenses have significantly affected the way surgery is being performed. This section presents the evidence available on some important aspects of cataract surgery, with the objective of assessing the degree to which modern cataract surgical practice is based on high quality evidence from randomised controlled trials (RCTs). The findings of recent RCTs on cataract surgery found in the Cochrane Eyes and Vision Group register and published systematic reviews of trials are described.

Clinical assessments of different cataract surgical techniques are described in Chapter 32. Evidence for any benefit of phacoemulsification over extracapsular cataract extraction is discussed. The effect of different viscoelastics, incisions, phacoemulsification techniques and incision closure techniques are described. Chapter 33 looks at

studies of intraocular lens biocompatibility. The areas investigated are the influence of intraocular lens type on anterior chamber inflammation, surface cytology, anterior capsule reaction, lens implant decentration, posterior capsule opacification and postoperative vision. Chapter 34 evaluates the evidence of whether the use of multifocal intraocular lenses offers benefits over the current standard treatment of monofocal intraocular lens implantation. RCTs examining the perioperative management of cataract surgery are described in Chapter 35. This chapter sets out the evidence available in the following areas: prevention and treatment of cystoid macular oedema, prevention and treatment of endophthalmitis, and postoperative anti-inflammatory treatment.

Throughout this section gaps in the evidence are highlighted. It is apparent that standardised and objective outcome measures are required to improve the quality of future RCTs. The implications for future research are also addressed.