Purpose
To evaluate the safety and tolerability of ranibizumab given via subconjunctival injection in patients with primary pterygium undergoing pterygium surgery with autograft placement.
Design
Prospective, open-label pilot study.
Methods
Setting: Single-center, academic practice. Study Population: Ten patients with primary pterygia. bservational Procedure: Subconjunctival ranibizumab (0.5 mg/0.05 mL) administered at the limbus, adjacent to pterygium either 3 days prior to surgery (Group 1, n = 5) or at the time of surgery (Group 2, n = 5). Patients prospectively followed for 6 months after injection. Main Outcome Measures: Safety and tolerability of subconjunctival ranibizumab as determined by patient reporting, clinical examination, and masked observer interpretation of slit-lamp photographs.
Results
The median age at presentation was 59 years (range 33 to 71 years); 60% of patients were male. Five patients were randomly assigned to be injected with 0.05 mg ranibizumab via subconjunctival injection 3 days prior to surgery; an additional 5 patients were injected with ranibizumab at the time of surgery. All 10 patients tolerated the injection well. The conjunctival autograft remained intact in the 9 patients whose grafts were secured with sutures. There was dehiscence of the autograft in the 1 patient whose graft was secured with fibrin glue. No other safety concerns arose after 6 months of follow-up. Three pterygium recurrences were noted at 6 months (all patients in Group 1). All remaining patients had a normal surgical bed appearance.
Conclusions
The data from this small pilot study suggest that 1 subconjunctival injection of ranibizumab in conjunction with pterygium surgery is well tolerated.
Blockade of vascular endothelial growth factor (VEGF) with bevacizumab (Avastin; Genentech, Inc, San Francisco, California, USA) and ranibizumab (Lucentis; Genentech, Inc, San Francisco, California, USA) has been a successful treatment in decreasing visual morbidity associated with abnormal vascular conditions of the choroid and retina. More recently, topical anti-VEGF agents have been used to treat abnormal vascular conditions of the cornea. Vascularization from conditions such as chemical injury, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, interstitial keratitis, postinfectious keratitis, and corneal graft failure has been shown to regress with the use of topical and subconjunctival bevacizumab. Two groups have evaluated the use of bevacizumab in patients with abnormal corneal neovascularization attributable to pterygium. One group administered topical bevacizumab (25 mg/mL, 4 times daily for 3 weeks) to a patient with an impending recurrent pterygium and noted prominent regression of vessels after treatment. Another study evaluated the use of 2 subconjunctival bevacizumab injections (2.5 mg/0.1 mL) in 5 patients with recurrent pterygia and did not note regression of the abnormal vessels. No studies have evaluated the use of anti-VEGF agents as a surgical adjunct to pterygium removal.
The pathogenesis behind pterygia formation is not well understood. Different factors postulated to play a role include ultraviolet radiation and chronic irritation. More recently, inflammatory and immunologic factors have been thought to contribute to pterygium growth. Several studies have evaluated the role of VEGF in pterygium pathogenesis and have demonstrated elevated levels in pterygium tissue as compared to normal conjunctivae. Given the potential role of VEGF in pterygium growth, we sought to evaluate the use of an anti-VEGF inhibitor as an adjunct to pterygium excision. By inhibiting the action of VEGF, we postulated that this treatment may provide a beneficial effect in reducing pterygium recurrence following excision. In this open-label, phase I clinical trial, we aimed to assess the safety and tolerability of 1 subconjuctivally administered injection of ranibizumab (0.5 mg/0.05 mL) as an adjunct treatment to pterygium excision.
Methods
Study Population
Ten patients with primary pterygia who met the standard pterygium excision criteria (encroachment into the visual axis, severe induced astigmatism, or foreign body sensation unresponsive to medical therapy) were recruited to participate in the study. Inclusion criteria included ability to provide written informed consent and comply with assessments for the full duration of the study and age greater than 18 years. Exclusion criteria included disease-related factors such as recurrent pterygia or prior glaucoma surgery in the region of the pterygium, and patient-related factors such as pregnancy, women seeking to become pregnant, and lactating women.
Injection and Surgical Information
Patients were assigned to receive 1 subconjunctival injection 3 days prior to surgery (Group 1) or 1 injection at the time of surgery (Group 2). Patients in Group 1 received an injection at the slit lamp using an eyelid speculum and after application of anesthetic, povidine-iodine 5%, and antibiotic drops. Ranibizumab (0.5 mg/0.05 mL) was administered subconjunctivally adjacent to the abnormal vessels at the limbus in the superior nasal quadrant. Patients in Group 2 received an injection at the end of the pterygium excision surgery in a similar location. The ranibizumab injection was given at these 2 different time points as we planned a secondary analysis to compare ranibizumab, VEGF, and VEGF receptor levels in the pterygium tissue of the 2 groups. However, we arbitrarily chose a gap of 3 days between the injections of the 2 groups as the pharmacokinetics of subconjunctival anti-VEGF agents have not been elucidated and we did not know how long ranibizumab would exert its effect.
The surgical technique involved avulsing the pterygium off the cornea followed by application of a beaver blade and burr to the limbal region. A superior conjunctival autograft was harvested (in 10 patients) and secured in place with 10-0 nylon and 8-0 vicryl sutures (in 9 patients) or with fibrin glue (in 1 patient). Antifibrotic agents (eg, mitomycin C) were not used.
Data Collection
All data were obtained via prospective collection and entered into a standardized computerized database. The data collected included demographic characteristics, clinical examination findings prior to and after surgical intervention, and clinical photographs. Patients were seen prior to surgery, and were thereafter seen at 1 day, 1 week, 1 month, 3 months, and 6 months after surgery.
Main Outcome Measures
The primary outcome measures for safety and tolerability included the incidence and severity of ocular and systemic adverse events, as identified by subjective reporting, clinical examination, and masked observer slit-lamp photographs. Specifically, we looked for evidence of ischemia, necrosis, infection, and graft dehiscence at the surgical site. Secondary outcome measures included clinical results after surgery, specifically focusing on cosmesis and pterygium recurrence. The appearance of the surgical bed was graded according to Tseng’s criteria (grade 1 representing a normal appearance, grade 2 representing fine episcleral vessels without corneal extension, grade 3 representing episcleral vessels and fibrovascular tissue without corneal extension, and grade 4 representing fibrovascular tissue extending past the limbus).
Results
Study Population at Presentation
The Table summarizes patient and eye baseline characteristics. The patients were randomly assigned to receive the subconjunctival injection of ranibizumab either 3 days prior to surgery (n = 5) or at the time of surgery (n = 5). The median age at presentation was 59 years (range 33 to 71 years), with no difference in median age between the 2 groups (63 years for Group 1, 56 years for Group 2). Six of 10 patients were male; 5 of 10 pterygia were found in the right eye. Preoperative best-corrected visual acuity ranged from 20/25 to 20/100 ( Table ).
| Patient | Age | Gender | Eye | Group | Preoperative VA | Postoperative VA (6 Months) | Surgical Technique | Side Effects/Adverse Events | Grade a (6 Months) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 71 | F | OS | 1 | 20/100 | 20/50 b | Suture | None | 1 b |
| 2 | 63 | M | OD | 1 | 20/25 | 20/20 | Suture | None | 4 |
| 3 | 50 | M | OD | 1 | 20/40 | 20/30 | Suture | None | 4 |
| 4 | 45 | M | OD | 1 | 20/20 | 20/20 | Suture | None | 4 |
| 5 | 64 | F | OS | 1 | 20/30 | 20/30 | Suture | None | 1 |
| 6 | 35 | M | OS | 2 | 20/30 | 20/20 | Suture | None | 1 |
| 7 | 33 | F | OS | 2 | 20/20 | 20/20 | Fibrin glue | Graft dehiscence | 1 |
| 8 | 56 | F | OS | 2 | 20/40 | 20/25 | Suture | None | 1 |
| 9 | 67 | M | OD | 2 | 20/40 | 20/25 | Suture | None | 1 |
| 10 | 70 | M | OD | 2 | 20/25 | 20/25 | Suture | None | 1 |
a Grade of surgical bed using Tseng’s scoring method.
b Vision and grade at 3 months as patient lost to follow-up.
Safety and Tolerability
There were no systemic complications associated with the subconjunctival administration of ranibizumab. Regarding local complications, no necrosis, ischemia, or infection developed in the surgical bed area. The patient whose graft was secured with fibrin glue experienced graft retraction and dislocation, first noted 7 days after surgery ( Figure 1 ). This patient was observed and no further intervention was performed. The underlying scleral bed has remained avascular during the 6-month follow-up period with complete re-epithelialization of the surface. The conjunctival autograft in the 9 patients whose grafts were secured with sutures remained in position and no wound healing abnormalities were noted in the 6-months-postoperative period. In fact, at 1 week, the observed postoperative inflammation in the conjunctival autograft was less than in contemporary controls (ie, patients undergoing pterygium excision but who were not enrolled in this study) ( Figure 2 ). The quiescence in the conjunctival autograft was more pronounced in patients in Group 2 compared to patients in Group 1 ( Figures 2 and 3 ).
