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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 18  |  Issue : 1  |  Page : 7-12

Intraoperative infiltration against topical application of 5-fluorouracil in pterygium treatment


Department of Ophthalmology, Zagazig University Hospital, Zagazig, Egypt

Date of Submission11-Jun-2016
Date of Acceptance25-Dec-2016
Date of Web Publication6-Mar-2017

Correspondence Address:
Basem M Ibrahim
Department of Ophthalmology, University Hospital, Zagazig - 44519
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-9173.201625

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  Abstract 

Purpose The aim of this study was to compare the efficacy and safety of intraoperative infiltration versus topical application of 5-fluorouracil (5-FU) as an adjuvant drug in pterygium treatment.
Design The study design was a prospective interventional comparative case series.
Patients and methods A total of 100 consecutive cases of pterygia in 95 patients (64 primary and 36 recurrent) were subjected to pterygium excision with the bare sclera technique. The cases were equally divided into two groups (A and B) according to the method of application of the adjuvant 5-fluorouracil (5-FU). Group A included fifty eyes and received intraoperative infiltration of 0.5 ml of 5-FU (50 mg/ml) at the end of the surgical procedure. Group B included fifty eyes and received intraoperative topical application of 5-FU (50 mg/ml) for 5 min during the surgical procedure. Postoperative follow-up was carried out at days 1, 7 and 14, and monthly thereafter for at least 6 months. Postoperative regrowth of fibrovascular tissue crossing the limbus was defined as recurrence. Data were evaluated and statistically analyzed.
Results All the pterygia were in a nasal location and all the treated pterygia extended 2 mm or more into the cornea. Postoperatively, pterygium recurrence was observed in 14% in group A and 20% in group B, a statistically insignificant difference (P>0.05). With regard to postoperative complications, the difference was also statistically nonsignificant (P>0.05).
Conclusion Infiltration of 5-FU rather than topical application as an adjuvant to pterygium surgery is easy, time saving, and does not necessitate copious irrigation with saline as with topical application with comparable results and postoperative complications.

Keywords: 5-fluorouracil, infiltration, pterygium


How to cite this article:
Ibrahim BM, Nada WM. Intraoperative infiltration against topical application of 5-fluorouracil in pterygium treatment. Delta J Ophthalmol 2017;18:7-12

How to cite this URL:
Ibrahim BM, Nada WM. Intraoperative infiltration against topical application of 5-fluorouracil in pterygium treatment. Delta J Ophthalmol [serial online] 2017 [cited 2017 Jun 25];18:7-12. Available from: http://www.djo.eg.net/text.asp?2017/18/1/7/201625


  Introduction Top


Pterygium is a common ocular disorder described as a fibrovascular growth of the conjunctiva with corneal extension with different reported prevalence rates ranging from 0.3 to 29% in different parts of the world [1].

Environmental factors have been anticipated in various studies, such as chronic irritation, ultraviolet light exposure, and inflammation. In contrast, antiapoptotic mechanisms, growth factors, extracellular matrix remodeling, cytokines, genetic components, viral infections, and immunological mechanisms have been proposed recently in the pathogenesis of the disease [2],[3],[4],[5].

Regardless of its unacceptable cosmetic appearance for many people particularly when inflamed or fleshy, pterygium may affect vision by its astigmatic effect or by encroaching into the visual axis and may be also a cause of ocular irritation [6].

Surgical excision is the treatment of choice for pterygium. However, simple excision (bare sclera technique) has a high recurrence rate, which could be up to 40% in some cases [6]; this necessitates additional therapy to decrease the recurrence rate, such as conjunctival autograft, β-radiation, and antimetabolites (mitomycin-C and 5-FU) [7],[8].

5-FU is a pyrimidine analogue with a chemical structure related to thymine and uracil. Its active metabolite, 5-fluoro-deoxyuridine 5-monophosphate (FdU-MP), inhibits thymidylate synthetase and the incorporation of thymidine into DNA. 5-FU also interferes with RNA and ribosomal RNA synthesis and promotes apoptosis in Tenon’s capsule fibroblasts. It was shown that a 5-min exposure to 5-FU results in growth arrest of cultured Tenon’s fibroblasts [9].

5-FU was found to be slightly superior to conjunctival autograft as an adjunctive therapy in the prevention of pterygium recurrence [10].

The use of mitomycin-C (MMC) as an adjunctive therapy for pterygium is a safe procedure, but needs some precautions such as long-term follow-up of these patients, good selection of patients, and controlled use of MMC [11].

No significant difference was found between 5-FU and low-dose MMC when used as an adjuvant after pterygium excision and conjunctival autograft. In one study, the recurrence rate in the MMC group was 11.8% compared with 8.7% in the 5-FU group [12].

Valezi and colleagues investigated the safety and efficacy of intraoperative infiltration rather than topical application of 5-FU for the prevention of recurrence after pterygium surgery. They concluded that intraoperative infiltration of 5-FU is safe and there is no statistically significant difference between the two modalities of application of 5-FU. The overall recurrence rate was 35.8% and occurred in 36.4% in recurrent and 35.7% in primary lesions [13].


  Patients and methods Top


This is a randomized prospective study of the outcome of pterygium surgery using intraoperative infiltration compared with topical application of 5-FU as an adjuvant drug in pterygium treatment. The study was carried out at the Ophthalmology Department, Zagazig University Hospitals, between March 2015 and January 2016. The study was approved by the Local Ethical Committee of Zagazig University. Written consent was obtained from the patients and included an explanation of the study.

A total of 100 consecutive cases of pterygia in 95 patients (64 primary and 36 recurrent) were surgically excised. The cases were equally divided into two groups (A and B) according to the method of application of the adjuvant 5-FU (50 mg/ml; Schumit 1967 Co., Ltd., Bangkok, Thailand, [Figure 1]): group A (50 eyes) in which intraoperative infiltration of 5-FU was used and group B (50 eyes) in which intraoperative topical application of 5-FU was used.
Figure 1 5-Fluorouracil ampoule

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Complete ocular examination was performed for each patient. Inclusion criteria were primary or recurrent pterygium that invaded more than 2 mm into the cornea in a patient older than 20 years. Exclusion criteria were external ocular diseases such as Sjogren syndrome and ocular rosacea.

All surgeries were performed by two surgeons and the same team of assistants and the surgical technique was the same in all patients.

Surgical technique

  1. Conjunctival topical anesthesia with Boxinate sodium 4% eye drops.
  2. Placement of a lid speculum.
  3. Subconjunctival injection of 0.5 ml of 2% lignocaine using a 25-G needle into the body of the pterygium.
  4. Partial superficial keratectomy with dissection of the pterygium from the cornea with Bard Parker no 15 surgical blade (Bard Parker Bensalem, Pennsylvania, United States).
  5. Conjunctiva and Tenon’s capsule dissection performed with spring action scissors.
  6. Complete resection, leaving 3 mm or more of bare sclera exposed, with minimal use of cautery.
  7. Group A: the episclera at the bare scleral bed and the surrounding conjunctiva and Tenon’s capsule was infiltrated using a 1 ml syringe and insulin needle (28 G) by 0.5 ml of 5-FU (50 mg/ml) ([Figure 2] and [Figure 3]). The cut conjunctival ends were anchored to the sclera in two separate points using braided synthetic absorbable 8–0 Vicryl (Ethicon Inc., Atraloc Vellberg, Germany).
    Figure 2 Surgical technique of 5-fluorouracil infiltration in group A

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    Figure 3 Surgical technique of 5-fluorouracil infiltration in group A

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  8. Group B: after excision of the pterygium, a Weck-cel sponge soaked in 50 mg/ml of 5-FU was applied to the bare scleral bed for 5 min. Then the eye was thoroughly washed with 20 ml of saline solution. The cut conjunctival ends were anchored to the sclera with 8-0 vicryl sutures.
  9. In both groups, 0.1% dexamethasone eye drops and antibiotic ointment were instilled at the end of surgery, followed by eye patching.


Postoperatively, allpatients had instillation of antibiotic-steroid drops and ointment for 4 weeks. Follow-up visits were at postoperative days 1, 7, and 14, and monthly thereafter for at least 6 months. Recurrence was defined as the postoperative regrowth of fibrovascular tissue crossing the corneoscleral limbus. In addition, corneal epithelium regeneration was evaluated using fluorescein stain 2.5%.

Data on the distribution of recurrence of pterygium by sex, age, and type of injury in the evaluation periods were submitted to statistical analysis using unpaired t-test and χ2 −test. A P value less than 0.05 was considered significant.


  Results Top


A total of 100 eyes of 95 patients were studied. Fifty eyes of 48 patients were treated with 5-FU infiltration (32 male and 16 female), whereas 50 eyes of 47 patients were treated with topical application of 5-FU (33 male and 14 female). The mean age of the infiltration group (group A) was 42.8±10.3 years, whereas that for the topical application of 5-FU group (group B) was 44.6±11.2 years. No statistically significant differences were found between the two groups with regard to the sex using χ2 or age using unpaired t-test (P>0.05).

All the pterygia were in a nasal location. The mean follow-up period was 7.7±1.4 months in group A and 6.9±1.2 months in group B. Out of the 95 patients who started follow-up, 87 (91.6%) maintained follow-up to the end of the follow-up period.

All the treated pterygia extended 2 mm or more into the cornea. Postoperatively, pterygium recurrence was observed in 7 out of 50 eyes (14%) treated with 5-FU infiltration (group A) and in 10 out of 50 eyes (20%) treated with 5-FU topical application (group B). The difference in recurrence rate was statistically nonsignificant (P>0.05). During the follow-up period, recurrences were not observed early in the postoperative course. Most of the recurrences were detected after 2 months of surgery.

Inspection of preoperative data of eyes with recurrence of pterygium showed that 14 out of the seventeen eyes with recurrence were fleshy, three were inflammed, five were over 4 mm in size, whereas 12 were between 2 and 4 mm in size. [Table 1] shows the preoperative data of eyes that developed recurrence of the pterygium.
Table 1 Preoperative profile of eyes with pterygium recurrence in the two groups

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The operation time was statistically significantly lower in group A (10±3 min) than in group B (16±2.5 min) due to the extra time needed for the application of 5-FU and copious irrigation of its remnant in group B (P<0.05).

Complete regeneration of the corneal epithelium was faster in group A (mean: 2.1 days) than in group B (mean: 2.9 days), but the difference was statistically nonsignificant (P>0.05).

During the follow-up, superficial punctate keratopathy was noted in three (6%) eyes in group A and seven (14%) eyes in group B, mild scleromalacia was noted in one (2%) eye in group A and in none in group B, conjunctival granulomas were noted in one (2%) eye in group A and two (4%) eyes in group B, and delayed corneal re-epithelization (≥4 days) was noted in three (6%) eyes in group A and eight (16%) eyes in group B. The difference in postoperative complications was statistically nonsignificant (P>0.05) ([Table 2]).
Table 2 Complications of pterygium surgery in the two groups

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  Discussion Top


Pterygium is one of the most common corneal disorders encountered in Egypt possibly due to high exposure to ultraviolet light. Ultraviolet light exposure has been established as the most important risk factor in its development [14].

Pterygium has a high recurrence rate after simple excision unless adjunctive treatment is applied [15].

5-FU has been used as an intraoperative topical adjunct during pterygium surgery and by postoperative injections [16].

A mean follow-up period of at least 5–6 months for the detection of recurrence is recommended in most of the literature [17]. In this study, follow-up visits were maintained for at least 6 months to detect the actual recurrence rate after surgery.

In this study, there was no statistically significant difference in the recurrence rate with regard to sex, age, or type of lesion (primary or recurrent). The same was observed in another study [17].

In this study, the mean rate of recurrence in the 5-FU group was 17%, which is slightly higher than the 14% recurrence in the study by Akarsu et al. [17], who used combined intraoperative topical application for 3 min and postoperative injection of 25 mg/ml of 5-FU. It was also higher than the 11.4% recurrence rate observed by Bekibele et al. [10], who also used 5-min topical intraoperative application of 5-FU (50 mg/ml). However, it was lower than the recurrence rate reported by another study of Bekibele et al. [16], which was as high as 25.9% and was even higher than β-irradiation (22.5%) in their study.

A very high recurrence rate of 60% was reported by some authors using the bare sclera technique and intraoperative topical application of 5-FU, and they considered the drug to be ineffective [18]. However, it is known that the bare sclera technique yields poor results, in addition to the fact that 5-FU is a drug that is dose and time dependent. They used 5-FU at a concentration of only 10 mg/ml [18].

Akarsu and colleagues reported a recurrence rate of 14% when using 5-FU (25 mg/ml) in the intraoperative period of primary pterygium, in the form of application of sponges on the region of the bare sclera and also under the conjunctiva and Tenon’s capsule remaining in the nasal sector for 5 min, followed by weekly subconjunctival injection in individuals who began to show signs of recurrence. The authors recommend the use of this drug because they considered it to be effective and safe [17].

In contrast, other studies showed no statistically significant difference in the recurrence rate when comparing 5-FU with other adjuvant maneuvers for the treatment of pterygium such as mitomycin-C [19] or β-irradiation [16].

Valezi and colleagues investigated the safety and efficacy of intraoperative infiltration rather than topical application of 5-FU as an adjuvant drug in pterygium treatment. A volume of 0.2 ml of 5-FU was infiltrated at the end of the surgical procedure and the concentration used was 25 mg/ml. The patients had no serious intraoperative or postoperative complications observed during the follow-up period. The overall recurrence rate was 35.8% and occurred in 36.4% in recurrent and in 35.7% in primary lesions. They concluded that intraoperative infiltration of 5-FU was safe [13].

In the present study, 5-FU was used at a concentration of 50 mg/ml and the episclera at the bare scleral bed and the surrounding conjunctiva and Tenon’s capsule were infiltrated by a dose of 0.5 ml in group A and topical application of 50 mg/ml of 5-FU for 5 min in group B. Postoperatively, pterygium recurrence was observed in seven out of 50 eyes (14%) treated with 5-FU infiltration (group A) and 10 out of 50 eyes (20%) treated with 5-FU topical application (group B) with no statistically significant difference in postoperative complications between the two groups.

The larger dose, the higher concentration, and the wider area of infiltration of 5-FU in the present study in the infiltration group A as compared with the study by Valezi and colleagues may definitely have contributed to the lower recurrence rate in the present study (14%) as compared with study by Valezi et al. [13] (35.8%), with no added serious complications.

The operation time was statistically significantly lower in group A than in group B due to the extra time needed for the application of 5-FU and the copious irrigation of its remnant with saline in group B.

The inevitable soaking of the cornea for a relatively long time with 5-FU during topical application in group B may contribute to the higher incidence (although not significant) of corneal complications such as delayed corneal re-epithelization and superficial punctate keratopathy in this group. In contrast, in group A, controlled handling of 5-FU by precise infiltration of the targeted areas decreased the corneal exposure time to 5-FU drastically and consequently decreased corneal complications in group A.

The recurrence rate in the infiltration group A (14%) was lower than that in the topical application in group B (20%). However, it was statistically nonsignificant and the difference in postoperative complications was also statistically nonsignificant.


  Conclusion Top


Infiltration of 5-FU rather than topical application as an adjuvant to pterygium surgery is easy, safe, time saving, and decreased the corneal exposure time to 5-FU, with comparable results and postoperative complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Moran DJ, Hollows FC. Pterygium and ultraviolet radiation: a positive correlation. Br J Ophthalmol 1984; 68:343–346.  Back to cited text no. 1
    
2.
Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004; 23:195–228.  Back to cited text no. 2
    
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Di Girolamo N, Coroneo MT, Wakefield D. Active matrilysin (MMP-7) in human pterygia: potential role in angio-genesis. Invest Ophthalmol Vis Sci 2001; 42:1963–1968.  Back to cited text no. 3
    
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Van Setten G, Aspiotis M, Blalock TD, Grotendorst G, Schultz G. Connective tissue growth factor in pterygium: simultaneous presence with vascular endothelial growth factor − possible contributing factor to conjunctival scarring. Graefes Arch Clin Exp Ophthalmol 2003; 241:135–139.  Back to cited text no. 4
    
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Maini R, Collison DJ, Maidment JM, Davies PD, Wormstone IM. Pterygial derived fibroblasts express functionally active histamine and epidermal growth factor receptors. Exp Eye Res 2002; 74:237–244.  Back to cited text no. 5
    
6.
Ashaye AO. Ptrygium in Ibadan. West Afr J Med 1991; 10:232–243.  Back to cited text no. 6
    
7.
Amano SAU, Motoyama YAU, Oshika T, Eguchi S, Eguchi K. Comparative study of intra-operative mitomycin C and beta irradiation in pterygium surgery. Br J Ophthalmol 2000; 84:618–621.  Back to cited text no. 7
    
8.
Pikkel JAU, Porges YAU, Ophir A. Halting pterygium recurrence by postoperative 5-fluorouracil. Cornea 2001; 20:168–171.  Back to cited text no. 8
    
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Khaw PT, Sherwood MB, Mackay SLD. Five minute treatments with fluorouracil, floxuridine and mito-mycinhave long term effects on human Tenon’s capsule fibroblasts. Arch Ophthalmol 1992; 110:1150–1154.  Back to cited text no. 9
    
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Bekibele CO, Baiyeroju AM, Olusanya BA, Ashaye AO, Oluleye TS. Pterygium treatment using 5-FU as adjuvant treatment compared to conjunctiva autograft. Eye 2008; 22:31–34.  Back to cited text no. 10
    
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Raiskup F, Solomon A, Landau D, Ilsar M, Frucht-Pery J. Mitomycin C for pterygium: long term evaluation. Br J Ophthalmol 2004; 88:1425–1428.  Back to cited text no. 11
    
12.
Bekibele CO, Ashaye A, Olusanya B, Baiyeroju A, Fasina O, Ibrahim AO, Ogun O. 5-Fluorouracil versus mitomycin C as adjuncts to conjunctival autograft in preventing pterygium recurrence. Int Ophthalmol 2012; 32:3–8.  Back to cited text no. 12
    
13.
Valezi VG, Schellini SA, Viveiros MM, Padovani CR. Safety and efficacy of intraoperative 5-fluorouracil infiltration in pterygium treatment. Arq Bras Oftalmol 2009; 72:169–173.  Back to cited text no. 13
    
14.
Mackenzie FD, Hirst LW, Battistutta D, Green A. Risk analysis in the development of pterygia. Ophthalmology 1992; 99:1056–1061.  Back to cited text no. 14
    
15.
Pico G. Surgery for pterygium. In: Smith BC, Della Rocca RC, Nesi FA, Lishman RD, editors. Ophthalmic plastic and reconstructive surgery. St Louis, MO: Mosby; 1987. pp. 1416–1424.  Back to cited text no. 15
    
16.
Bekibele CO, Baiyeroju AM, Ajayi BGK. 5-Fluorouracil vs. beta-radiation in the prevention of pterygium recurrence. Int J Clin Pract 2004; 58:920–923.  Back to cited text no. 16
    
17.
Akarsu C, Taner P, Ergin A. 5-Fluorouracil as chemo adjuvant for primary pterygium surgery: preliminary report. Cornea 2003; 22:522–526.  Back to cited text no. 17
    
18.
Maldonado MJ, Cano-Parra J, Navea-Tejerina A, Cisneros AL, Vila E, Menezo JL. Inefficacy of low-dose intraoperative fluorouracil in the treatment of primary ptery-gium. Arch Ophthalmol 1995; 113:1356–1357.  Back to cited text no. 18
    
19.
Fernandes M, Sangwan VS, Bansal AK, Gangopadhyay N, Sridhar MS, Garg P et al. Outcome of pterygium surgery: analysis over 14 years. Eye 2005; 19:1182–1190.  Back to cited text no. 19
    


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