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For concerns both cosmetic and functional, postsurgical or posttraumatic scarring can pose a challenge for physicians. But the antimetabolite 5-fluorouracil (5-FU) offers a versatile option for approaching this common problem. Given its proven and long-standing track record in oncology, off-label applications of 5-FU have expanded in recent years into orbital and adnexal efforts to modify keloids and hypertrophic scars.
How Scars Form
Visible scars develop through an exaggerated healing process, said Sean M. Blaydon, MD, an oculofacial plastic surgeon in private practice in Austin, Texas. Fibroblasts proliferate at the site of the injury, leading to the overproduction of collagen, followed by cross-linking and the loss of unidirectional alignment, giving the scar its ridgelike character. As the scar matures, the thickened area gradually subsides and flattens.
Fibrous tissue. Some wounds develop excessive fibrous tissue, as is the case with keloids or hypertrophic scarring. “Hypertrophic scarring may not be much of a concern for patients elsewhere on their bodies, but around the eyes and on the face, it’s hard to overlook,” said Dr. Blaydon. Ordinarily, the thin, highly vascularized periocular skin nurtures optimal healing and less prominent scars than elsewhere in the body, said Malena M. Amato, MD, an oculoplastic surgeon at the Kaiser Permanente Medical Center in Union City, Calif. And yet even a 2- to 3-mm scar following blepharoplasty is significant, she said, adding that factors influencing keloid or hypertrophic scar formation include genetics, race, sex, age, infection and type of injury.
Scar remodeling. In many cases, a scar will remodel over a period of about 10 weeks, or even up to a year, said Raymond S. Douglas, MD, PhD, associate professor of ophthalmology at the University of Michigan. “It will never appear as virgin tissue,” he said. But it will assume a modified, less-dense appearance.
In certain cases, the scarring response can become quite robust, said Dr. Douglas, explaining that it is always highly heterogeneous and unpredictable, especially after eyelid surgeries. But variable responses and poor surgical outcomes related to scarring have less to do with technique and more to do with biologic responses.
Additional triggers. At the site of previous traumas or surgeries, an infiltration of fibroblasts may lie in wait until there is another surgery or intervention. And the surgical scalpel may simply tip the balance toward an unfavorable result, said Dr. Douglas.
At first blush, scarring can appear to be a simple mechanical problem. “For example, it can affect the dynamic movement of the eyelid,” said Dr. Douglas, where a scar band may hold the eyelid to the bone, preventing movement. “But once you define the problem as more biological than mechanical, you can begin to think of innovative biologic modifiers. And 5-FU is a very safe example.”
5-FU works well for several reasons:
Fewer fibroblasts. Ophthalmologists were the first to recognize the antifibroblast activity of antimetabolites, Dr. Blaydon said. For instance, 5-FU was used as early as the 1980s to improve the results of trabeculectomy. “5-FU acts on a slightly different pathway than steroids do,” said Dr. Blaydon. “It inhibits DNA production and decreases the proliferation of the infiltrating fibroblasts in the area where you inject, ultimately lowering production of collagen and decreasing the density of the extracellular matrix.” The agent prompts a quicker resolution of the scar, said Dr. Douglas. “It allows the inflammatory process and repair to continue without massive, or further, infiltration of fibroblasts.”
Targeted attack. Unlike mitomycin- C, 5-FU only works on cells that are metabolically active and proliferating, said Dr. Douglas, instead of causing collateral damage to surrounding cells.1 And with fewer side effects, it’s possible to apply it to a greater variety of situations to reduce or dampen the severity of scars, he said. Although washout of the drug from the tissue occurs rapidly, the effects are long lasting, Dr. Douglas added.
Other benefits. Dr. Amato also appreciates having an alternative with a low side-effect profile. She started using 5-FU a couple of years ago in patients with hypertrophic scars on which she would previously have used triamcinolone. “I started seeing better or faster results,” she said, adding that it didn’t lead to hypopigmentation, fat atrophy and deposition of white precipitate at the injection site, which is more likely with Kenalog. Dr. Blaydon added that 5-FU is also more cost-effective than other antineoplastics, such as bleomycin and interferon.
Versatility in Clinical Practice
“I keep a bottle of 5-FU handy,” said Dr. Blaydon, “because I probably use it once a day. I’m even using it to treat small or unresolving chalazia.” However, he noted that a chalazion that is still recurrent after one injection “should be biopsied to rule out a masquerading neoplasm.”
Dr. Amato uses 5-FU in her cosmetic and reconstructive practice, both for recent and long-standing scars. For early postoperative or traumatic hypertrophic periocular scars, or for chronic chalazia, Dr. Amato performs a series of injections of 5-FU over a period of weeks. “With an advanced keloid, I excise it and do a postop injection about a month later. I might do a series of two or three injections.”
In addition to treating existing scars, 5-FU can enhance outcomes in a variety of plastic surgeries:
Nasal surgery. After constructing a new bypass channel for tear outflow during endoscopic nasal surgery, said Dr. Douglas, the body tries to narrow that new opening. “One of the things we do to put time on our side is to add a pledget laden with 5-FU,” he said. “This slows down the biologic response, which would close the newly created opening.”
Eyelid scars. “Eyelid scars usually aren’t thick, but they’re important because they inhibit the movement of small, delicate structures,” said Dr. Douglas. “5-FU injections given at the first sign of contracture can help minimize scar tissue and dramatically improve eyelid function.”
Eyelid retraction. Another increasingly common use of 5-FU is for cicatricial eyelid retraction in orbit surgery, said Dr. Blaydon. “A patient might have midlamellar scarring to the orbital rim, for example.” Injecting 5-FU softens attachments of these subcutaneous soft-tissue cicatrices to underlying tissues. “Muscles that move the eye are not that strong,” said Dr. Douglas. “But they can be tethered and severely restricted via a scar band. Many times this injection will help those muscles from getting scarred back down to the bone after you release them.” The goal is to allow muscles to move within fat without the restriction of a scar. “It’s like walking in air, as opposed to walking through water.”
Notes on Timing
“The best use of 5-FU is within weeks or months of the surgery or injury,” said Dr. Blaydon, “ideally within about a week or two.” Even after the first treatment, the cicatrix is a little softer and more mobile, sometimes less fixated to underlying tissue and described as “less tight” by patients. “These improvements may continue over three to five treatments. One injection is probably not going to be enough to get the full effect.”
If it’s a thick scar, a few injections may be needed within the first week, Dr. Blaydon said. But more typically, he’ll give one the first week and then repeat injections every one or two weeks for a total of three or four treatments. “Usually I keep injecting until I feel I’m not getting any further improvement in the quality of the scar. If I don’t see continued improvement, I have patients massage the area and see them six to eight weeks later.”
Never too early. Some patients benefit from even earlier attention. “I had a patient today who had previous cosmetic surgery elsewhere and retraction of the lower eyelid,” said Dr. Amato. “I already know that she’s had problems with scarring in the past.” For patients such as this woman, a prophylactic approach to fibroblast production in the early postop period on a previously operated site may be beneficial, Dr. Amato said.
Never too late. And it’s often never too late, even for long-lasting scars, given their ability to continually remodel, said Dr. Douglas. “The scarring process is supposedly resolved in a year or two, but I’ve injected 5-FU after many years and it has provided some benefit.” Dr. Amato also recalled a patient with a three-year-old forehead scar, which achieved a 50 percent improvement following 5-FU injections.
Notes on Technique
For hypertrophic scars in the periocular region, Dr. Blaydon combines about 0.1 ml of Kenalog with 0.9 ml of 5-FU, injecting between 0.1 and 0.2 ml of the mixture into and under the scar. If the scar is fixated to deeper tissue, he sometimes performs subcision by using the tip of the hypodermic needle to help release the scar’s deeper attachment. “We’ve found that this mixture works better than either alone,” he said, adding that the steroid acts on a slightly different pathway, helping provide a strong inhibition of fibroblasts and a more regular pattern of collagen production. In addition, the smaller concentration of steroid lowers the risk of side effects.
Delivery methods. Although nanotechnology delivery is in the works, the current delivery method is injection. Dr. Douglas uses 5-FU in combination with a variety of carriers that are similar to hyaluronic acid in structure. “This helps the 5-FU stay in the body longer.” If a scar is very tight, Dr. Douglas sometimes uses 5-FU along with other forms of fillers to expand tissue and stretch a scar at the same time he is attempting to dissolve it. He also reconstitutes AlloDerm grafts in 2 ml of 5-FU before placing them during eyelid reconstructions, which helps inhibit scar formation from the outset. 2 “Those eyelids have an amazingly supple character unlike any I have seen,” he said.
Easing discomfort. Although there can be some temporary swelling and redness for two or three days, risks are minor, said Dr. Douglas. He uses a topical anesthetic cream to ease the burning sensation that lasts about 20 seconds after injection.
Drs. Amato, Blaydon and Douglas report no related financial interests.
1 Taban, M. et al. Presented in part at ASOPRS Fall Meeting, Atlanta, Nov. 12–13, 2008.
2 Chang, H. S. Ophthal Plast Reconstr Surg 2011;27(2):137–141.