Fluorouracil Treatment of Problematic Scars – an Article Review

Updated 3/2017-- all links (except to my own posts) removed as many no longer active. and it was easier than checking each one. 

I’d like to review this Plastic & Reconstructive Surgery article on using fluorouracil for the treatment of keloids. The full reference (first article listed) is given below. First, a little background on keloids and hypertrophic scars.

Keloids and hypertrophic scars are challenging to treat. Both are benign growths of dense fibrous tissue that develop due to an abnormal healing response to a injury to the skin. A keloid by definition extends beyond the original borders of the wound or inflammatory response. A hypertrophic scar remains within the original boundary. Both are frequently symptomatic. Patients often report tenderness or pruritis.

There are many proposed mechanisms for abnormal scar formation. These include altered growth factor regulation, abnormal collagen turnover, familial genetic predisposition, and immune dysfunction. Although progress has been made in understanding scar pathophysiology, the exact pathogenesis is still unknown.

The response to any accepted scar treatment runs the gamut from minimal to complete. The most commonly used treatment modalities include intralesional steroid injection, surgical excision, cryotherapy, laser therapy, radiation therapy and the application of silicon gel sheets.

Most evidence for these modalities is based on smaller studies that employed little or no placebo control nor blinding of participants or researchers. As the authors of the first article (the one to be reviewed) point out:

Beyond the litany of treatment options, another obstacle in the scar literature is a lack of uniformity in reporting clinical results. This makes extrapolating from or comparing studies difficult. Many authors quantify treatment outcome using a visual appearance rating scale. Other outcome measurement options include symptom relief and direct scar size measurement. Qualitative descriptive scales are available for scars but are far from being widely accepted

And as the authors of the Medscape article point out:

A recent meta-analysis of 39 studies, representing 27 different treatments, reported a 70 percent chance of clinical improvement with any type of treatment.^[34]Therefore, it is possible that current treatments may not have any significant effect on clinical improvement. Based on emerging information on keloid pathophysiology, there is a need for further studies in order to develop better therapies for pathologic scarring.

Now for the article review. The authors stated that after noticing anecdotal reports suggesting low-dose intralesional fluorouracil could be used for treating undesirable scars, they decided to do a prospective case series. As noted above, we need prospective, well designed studies to truly define the best treatment of these scars.

Their method included both keloid and hypertrophic scar patients. Note the small number of patients in the study:

Keloid patients underwent excision followed by a series of treatments with intralesional 5-fluorouracil into the healing scar to prevent recurrence (n = 32).

The hypertrophic scar patients were treated with the same series of injections without scar excision to both control symptoms and improve scar appearance (n = 21).

The primary outcome measures were scar volume and a symptom questionnaire.

Patients were followed for 1 year after completing the injection treatments.

Only patients who had failed corticosteroid therapy were entered in the study. Some had failed other conventional treatments for abnormal scars (ie excision, radiation therapy, topical silicone, and/or pressure therapy). They did not include a control group because “we felt it was unethical to offer patients who had previous failed corticosteroid treatments the potential of the same treatment that did not help them the first time.” I’m not sure I agree with them as the control patients could have received “delayed” treatment in the interest of a better scientific study.

Treatment

Keloid Group (Group 1) patients had their scars excised and primary repair of the defects. Each patient received a total of 10 treatments at least a month apart. If any reaction or infection was identified, no treatment was performed at that visit. The patients returned weekly until the adverse reaction resolved at which time the injections were resumed.

Hypertrophic Scar Group (Group 2) patients did not require excision of the scar. Therefore injection treatment was started after the baseline documentation was obtained.

Baseline documentation included completion of a symptom questionnaire and vinyl polysiloxane molds. Symptom assessment and polyvinyl molds were repeated at the completion of the injection protocol (11 months after the baseline scar documentation) and again at the 1-year posttreatment follow-up

Because of the off-label use of 5-fluorouracil for the treatment of scars, time was spent explaining the indications, techniques, alternatives, benefits, and risks of the therapy. This was reinforced to the patients at each of the 10 injections in the treatment series.
Each treatment involved intralesional injection of 50 mg of 5-fluorouracil (50 mg/ml; American Pharmaceutical Partners, Inc., Schaumburg, Ill.) and 10 mg of lidocaine 1% (Hospira Worldwide, Schaumburg, Ill.).
For most of the scars, the medication was distributed evenly throughout the scar or the healing incision for the keloid group.
For large hypertrophic scars, the medication was injected into the most symptomatic part of the scar at that particular visit.
Treatments were continued until the maximum dose of 500 mg (10 injections) was reached.

Results
Their definition of recurrence was any visible evidence of scar growth. “It did not mean the scar returned to preexcision size or that the patient was dissatisfied with the result.”
In the keloid group, there were no recurrences during the course of the treatment, but there were six (6 / 32) at 1 year follow-up. This represents a success rate of greater than 80% at one year. The literature reports a success rate of 75 – 95 % for radiation combined with excision.
Of the hypertrophic scar patients, 86 percent had symptom improvement which was maintained for 1 year after treatment. More than one-third had complete resolution of the symptoms. Median scar volume reduction was 40 percent in this group.
I find this article interesting, but am not ready to begin using 5-fluorouracil prior to the tradition treatment courses. As the authors point out,

One weakness of the study is the length of follow-up. Although most studies do not report results longer than 1 year after treatment, it is clear that keloid recurrence can occur years later.

REFERENCE

Fluorouracil Treatment of Problematic Scars; Plastic and Reconstructive Surgery:Volume 123(1)January 2009pp 139-1485; Haurani, Mounir J. M.D.; Foreman, Kenneth M.D.; Yang, James J. Ph.D.; Siddiqui, Aamir M.D. (need subscription for access online)

Keloids: Pathophysiology and Management; Medscape Online Article, Posted 08/23/2007; David T. Robles MD PhD; Erin Moore; Michelle Draznin MD; Daniel Berg MD