5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts
Condition: Ectropion; Skin Neoplasms
MeSH terms: Skin Neoplasms; Ectropion
Study type: Interventional
Phase: Phase 2

Summary: 
      Full thickness skin grafts are an essential tool in surgery around the eyelids for
      reconstruction or rehabilitation following injury or surgery. Common conditions where skin
      grafts are needed include cicatricial ectropion, restoration of eyelid function after tumor
      removal, burns to the eyelids, or trauma. Early complications, occurring in the first 2 weeks
      after surgery, are rare: wound dehiscence, necrosis, infection, bleeding, partial or complete
      graft failure. However, late postoperative complications generally categorized as "scarring"
      (including graft hypertrophy and contraction, keloid formation, and hypo/hyper pigmentation)
      can limit the success and acceptability of the procedure by patients. Scars form following
      any insult to the deep dermis as a result of wound healing. Factors such as age, skin type,
      racial pigmentation, genetics, and sex may influence fibroblast proliferation as part of the
      healing response, resulting in a suboptimal result. Graft contraction is perhaps the most
      worrisome result, since it can result in failure of the initial surgery and may require
      additional surgery to correct. Many treatments have been used to manage these complications:
      corticosteroid injection, cryotherapy, pressure therapy, radiotherapy, laser therapy,
      silicone based products, and antimetabolite therapy. One such antimetabolite, 5-fluorouracil
      (5-FU), has been used over the last 15 years as an adjunct or primary treatment to modulate
      wound healing and scar formation. Other studies have demonstrated safety for cutaneous and
      subcutaneous injection in the periocular region. However, no controlled studies exist. This
      prospective, randomized, and double-blinded clinical study will evaluate the use and benefit
      of 5-FU versus saline in patients undergoing skin grafting for periocular reconstruction. The
      decision for the need for skin grafting will be at the discretion of the attending surgeon
      and will be made separate from enrollment in the study. Surgery will be performed as
      indicated. The study medication or placebo (normal saline) will be administered 2-3 weeks
      after surgery and then every 2-3 weeks afterwards for up to a total of 4 injections. After
      the injections, regular scheduled follow-up will be at 3, 6, and 12 months post-op. Outcomes
      at each study visit (up to 12 months post-operatively) include graft size, color, contour,
      and complications between study treatment group and placebo group.
    

Detailed description: 
      In oculofacial surgery, full thickness skin grafts are a fundamental tool used to restore
      function to the eyelid. This can be required after removal of skin cancer, correction of
      eyelid malposition such as cicatricial eyelid ectropion (the eyelid edge is pulled away from
      the eye), retraction (the eyelid is pulled lower than normal, exposing more of the eye to the
      air), scar formation (such as a medial pulling or web), or trauma with loss of tissue. These
      conditions affect patients of all ages, ranging from newborns to nonagenarians. Skin grafting
      in the periorbital area is relatively safe, although complications may arise. The most common
      and challenging complication scarring and graft shrinkage. This can lead to requiring
      additional surgery to add additional skin or to improve the appearance of the graft. In
      addition to the morbidity of another surgery, some patients have limited or no additional
      skin available (e.g. young patients, burn patients). The eyelid skin is the thinnest of the
      body, so only thin skin can be used as donor material. However, the amount of skin available
      for this purpose is very little.

      There are limited options for preventing graft shrinkage and scarring in this situation. The
      oldest and most commonly used technique is injection of steroid medication. Steroids decrease
      proliferation of a fibroblast cells, which create collagen and glycosaminoglycan, two
      proteins created by the body that contract and cause graft shrinkage. Data in literature
      shows that one form of steroid, triamcinolone, is effective for this purpose. However, there
      is a risk of embolization of this solid steroid material that care rarely cause blindness. In
      addition, in the periocular area, steroids can elevate eye (intraocular) pressure (that can
      cause glaucoma in some cases) and accelerate the formation of cataracts.

      Another medication used for this purpose is 5-fluorouracil (5-FU). This is an antimetabolite
      (a drug that inhibits another chemical that is part of normal processes) that works by
      irreversibly inhibiting the enzyme thymidylate synthetase resulting in impaired DNA
      synthesis. This reduces fibroblast proliferation and inhibits collagen type 1 production
      which is a key protein in scar formation. This medication is commonly used in ophthalmology
      after glaucoma filtration surgery. In this usage, it is injected under the conjunctiva to
      prevent scarring around the surgical site.

      There have been two retrospective studies that have investigated the safety and efficacy of
      5-FU injected in periorbital skin grafts with or without Kenalog. The first (Massry 2011)
      used post-operative injections of a 50:50 mixture of 5-FU and triamcinolone for correction of
      medial canthal webs. In 2 patients, they found it to be safe and effective. The author noted
      he has used it previously for other scar management cases and was "very pleased with the
      results and [had] negligible side-effect[s]." The same author performed another study using
      5-FU for skin grafts. This study evaluated 19 patients who had skin grafts for various
      purposes and were injected following surgery (similar to our protocol). This study
      demonstrated safety of the injection, with no cases of complication. The author concluded
      that the 5-FU is effective with "minimal scarring, high patient and surgeon satisfaction, and
      few complications." However, there was no comparison group to truly evaluate the effect. With
      only two retrospective studies by the same author, there is no strong evidence that it is
      effective, although safety has been demonstrated.

      The investigators therefore propose a randomized controlled prospective study to evaluate the
      outcomes of periocular skin grafts with or without the use of 5-FU injected in the
      post-operative period. Patients will be recruited from the investigators' practices who need
      full thickness skin grafts for reconstruction after cancer removal, pre-existing scarring,
      eyelid malposition, or trauma. Patients will be introduced to the study, and will come back
      for detailed explanation and consent. The injection medication will be prepared by the Mass
      Eye and Ear Research Pharmacy and labeled for this double-blinded study. Injections will be
      given 2-3 weeks after surgery and up to 4 times (also every 2-3 weeks). Measurements and
      photographs of the skin graft will be taken at each visit (following injections, at 3, 6, and
      12 months) to monitor for complications. Patients will be followed for at least 12 months.

      If effective, this medication could change the post-operative management of skin grafts,
      reduce complications and reoperations.
    

Intervention name(s): 5-Fluorouracil; Normal saline
Intervention type(s): Drug; Other
Intervention description(s): Treatment medication; Placebo
Other intervention name(s): 5-FU; Saline
Intervention MeSH terms: Fluorouracil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Skin graft; 5-Fluorouracil; Periocular reconstruction