5-fu for problematic scarring: a review of the literature

Summary

Keloids and hypertrophic scars represent a common complaint for plastic surgeons. These scars often leave patients with severe morbidity due to their resistance to therapy. A variety of therapeutic options exist, yet none seem to offer a permanent solution, and scars frequently reoccur. The antineoplastic drug 5-fluorouracil (5-FU) has been shown to inhibit fibroblast proliferation in vitro and has been used as a treatment modality for these pathologic and problematic scars. We present a review of literature on treatment protocols, and on the efficacy and safety profile of this drug in the treatment of problematic scarring in terms of size reduction and symptom resolution. Current evidence suggests that 5-FU is effective in treating keloids and hypertrophic scars, but further research must be done to correlate therapeutic response with the age of the scar. In addition, larger randomized control trials must be conducted with longer follow up periods to assess recurrence rates with better accuracy.

Introduction

Hypertrophic scars and keloids represent a challenging problem for the patient and the plastic surgeon due to the difficulty in controlling such scars, as well as high recurrence rates.

These scars result from excessive fibrous tissue deposition in the context of abnormal wound healing. They usually leave the patient with a severe impairment in quality of life by altering psychological, physical and social wellbeing, as well as cause significant distress to the treating physician. The prevalence of hypertrophic scars and keloids cannot be accurately determined as multiple factors play a role, such as ethnicity, age, location of the wound and mechanism of injury; however it ranges from 30 to 90%.¹ Scar formation is a normal physiologic response to penetrating skin injuries in adults, however; it is the prolonged inflammatory phase of wound healing and the excessive deposition of type 1 and type 3 collagen along with fibronectin by fibroblasts that cause hypertrophic scars and keloids.^2,3

It is important to pursue the treatment of such problematic scars due to severe psychological stress related to the appearance or even the injury that resulted in the formation of the scar. Moreover, these scars are symptomatic most of the time, with pain, pruritus and pressure being the most common complaints reported by patients.⁴

In general, both types of scars are treated with the same therapeutic options, yet it is important to differentiate between the two. Hypertrophic scars and keloids can be differentiated based on their clinical course and appearance. Excessive fibrosis is thought to result from deregulated cellular proliferation. Keloids represent extra collagen deposition at the scar site, and growth continues well beyond the confines of the wound. Hypertrophic scars are also raised above the skin, however they increase in size and remain within the confines of the wound, not invading adjacent tissue.⁵ Such scars can present anywhere on the body but they most commonly occur on the face, ear lobes, arms, shoulders, back and chest. Therapeutic intervention to deal with such problematic scars includes massage therapy and pressure garments, silicone gel sheeting, intralesional steroid injections, laser therapy and radiotherapy.^2,6

Chemotherapeutic drug use for hypertrophic scars and keloids has also been used to treat recurrent and intractable scars.⁷ 5-fluorouracil is a fluorinated pyrimidine analog that acts as an anti-metabolic agent, inhibiting thymidylate synthase and interfering with RNA synthesis. The rationale for using 5-fluorouracil stems from a study conducted by Neil et al., which showed a dose-dependent inhibition of fibroblast proliferation and decrease in collagen synthesis.⁸ Through inhibition of these rapidly proliferating cells, scar degradation is stimulated. In our review, we will evaluate the efficacy of using 5-fluorouracil as a single agent or in combination with other treatment modalities on reducing the morbidity and recurrence rates of these problematic scars.

Methods

In order to obtain all available published data on the treatment of hypertrophic scars and keloids, a broad literature search in PubMed, Medline and Google scholar was performed.

Search terms included 5-FU, fluorouracil, problematic scars, hypertrophic scars and keloids, and they were used in different combinations. We limited our search to include papers published between the years 2000 and 2017. We included reports on randomized control trials and prospective clinical trials involving the use of 5-FU as a single agent or combined with a maximum of two other agents. Only citations in English and on human subjects were included in this study.

Results

The literature review yielded 83 citations. After filtering and screening through these citations, 57 titles, abstracts and letters to the editor were screened for relevance. Studies that involved several simultaneous therapies on the same scar were not included. In total, 8 articles were included in this review.

All of the articles are either prospective studies or randomized control trials (Table I).

Table I. Studies using 5-FU as a monotherapy or combined with surgical excision.

5-FU treatment alone

Gupta and Kalra conducted a prospective study on 24 consecutive patients with an average of 1.62 keloids per patient. They used a protocol that involved administering 50-150mg/ml of 5-FU intralesionally on a weekly basis with a maximum of 16 injections per patient. They measured response to treatment by assessing the degree of scar flattening as observed clinically by an observer; at the beginning of the treatment, at the end of the treatment and during follow up. An excellent response to therapy was more than 75% flattening. 33.3% of their patients had excellent flattening and more than 70% had resolution of all accompanying symptoms such as pruritus and pain. Moreover, out of the 24 patients, 19 presented for follow up at 6 months after stopping the treatment. None had any signs of recurrence. Side effects to treatment were limited to pain and mild hyperpigmentation at the injection site. However, no local anaesthetic was used or mixed with the 5-FU solution and the hyperpigmentation eventually disappeared after cessation of treatment. Interestingly, they found a correlation between keloid age and response to treatment, with scars younger than 5 years demonstrating superior flattening to scars older than 5 years.⁹

Nanda and Reddy conducted a similar study that included 28 patients with a varied number of keloids on each patient. They injected 50mg/ml of 5-FU without lignocaine on a weekly basis for up to 12 weeks, with doses ranging from 0.5ml to 2ml. Assessing outcome was based on patient satisfaction, photographic records and observation by an independent observer. A 5-point scale was used to report response to treatment: no improvement; poor = up to 25% improvement; fair = 26% to 50% improvement; good = 51% to 75% improvement, and excellent = 76% to 100% improvement. 71% of the patients showed good response to treatment and 7.1% showed excellent response. No treatment failure was recorded. Major irritating symptoms reported included itching, pain, cosmetic reasons, and restriction of movement. 22 of these patients had complete resolution of symptoms and the rest reported good response.

During the follow up period of 24 weeks from the start of treatment, none showed recurrence of the scars or symptoms. Side effects were limited to pain at the injection site in 100%, ulceration in 21.4% and burning in 7.1%.10

Haurani et al. conducted a prospective study on patients with keloids and hypertrophic scars. Keloid patients underwent excision and post excision 5-FU injections; these will be discussed at a later point. 24 patients with hypertrophic scars, resistant to corticosteroid therapy, were injected with 50mg of 5-FU (50mg/ml) and 10mg of 1% lidocaine, once monthly for 10 consecutive months. Scar volume and symptom resolution were documented to assess response. Symptom resolution was based on patient questionnaires while scar volume was assessed using a vinyl polysiloxane mould both before and after injection with 5-FU. A 65% reduction in scar volume was noted in all patients at the end of the treatment. Moreover, 86% of patients had partial or complete resolution of symptoms, which included pruritus, pain and pressure. Two patients developed open wounds from the injections, which resulted in cessation of the treatment until wounds healed.¹¹

A similar study conducted by Kontochristopoulos et al. studied the efficacy of intralesional 5-FU in treating keloids in 20 patients. Eleven of these patients had previous failed therapies. Treatment consisted of injecting between 0.2-0.4ml/cm2 of 50mg/ml 5-FU on a weekly basis. Duration of the treatment varied between patients based on the location and number of keloids, with an average of seven sessions. 85% of the patients showed an improvement of more than 50%, determined as scar volume reduction and resolution of symptoms. At one-year follow up, 9 patients out of 12 (81.8%) with short lasting keloids, defined as less than or equal to two years, showed no signs of recurrence, while in 8 patients with long lasting keloids, defined as more than two years, 6 (66.7%) showed signs of relapse.

They concluded that an association exists between duration of keloids and recurrence after treatment with 5-FU.¹²

Prabhu et al. conducted a randomized control trial on 30 patients with keloids and hypertrophic scars. They were randomized into two groups of 15 patients: group A received 50mg/ml of 5-FU with up to 2ml used; group B received 40mg/ml of triamcinolone acetonide (TAC) with a maximum dose of up to 2ml. The intralesional injections were scheduled on a weekly basis for up to four weeks, with a follow up period of six months, on a monthly basis. Treatment outcome was assessed based on scar volume reduction, which was measured at baseline and later at the end of the treatment using Vernier’s calipers. In the 5-FU group, mean reduction in scar volume was 57.21% with a standard deviation of 16.21, while mean reduction in the TAC group was 71.23% with a standard deviation of 18.01. This difference in volume reduction was considerably greater in the TAC group, with a P-value of 0.0402 showing statistical significance.¹³

Saha and Mukhopadhyay conducted a similar randomized controlled trial in order to compare the effect of intralesional 5-FU with intralesional TAC on keloids. 44 patients were randomized into two groups, one receiving intralesional 5-FU and the other intralesional TAC. Injections took place on a weekly basis for a total of 6 weeks. Patients were treated with 50mg/ml 5-FU and 40mg/ml TAC with a maximum volume injected in both groups, not exceeding 2ml. Reduction in scar volume, presence of itch and pain before and after treatment and side effects of treatment were evaluated. Volume reduction was based on the objective assessment of the same observer taking into consideration flattening, decrease in length and width. All patients in the two groups showed some degree of improvement in terms of volume reduction. 65% of patients in the 5-FU group showed reduction of volume between 51%-100% while 68% of the TAC group patients showed a similar percentage of volume reduction. Both groups demonstrated resolution of pruritus soon after treatment began. However, the 5-FU group demonstrated significantly more adverse effects than the TAC group. 95% of patients receiving 5-FU experienced pain upon injection that persisted up to 4 hours after injection. Moreover, 65% presented with superficial ulcerations after 2-3 injections.

This was not observed in the TAC group. At one-year follow up, both groups showed similar recurrence rates of between 35%-37%.14

5-FU injection post excision

Uppal et al. were one of the first to combine keloid excision with 5-FU in the treatment of problematic scars. They conducted a clinical trial on 8 patients with keloids, during which they excised the scar under local anesthesia and divided the wound in half. One half was exposed to a 5-FU soaked sponge pledget for 5 minutes then irrigated with saline. The other half acted as controls and were exposed to a sponge pledget soaked with phosphate buffered saline. The wounds were then closed primarily with interrupted 5-0 nylon sutures. Assessment was based on a modified Vancouver score in order to incorporate symptoms such as pruritus and pain, and was performed by a blinded observer. Follow up was done monthly up to 6 months post excision. All the scars were healed at 6 months and showed significantly lower scar score compared to the control.¹⁵

Haurani’s study also consisted of excision of keloids and a 5-FU injection protocol post injection. Injections started 2 weeks post excision and then monthly for up to 10 treatments. 50mg of 5-FU and 10ml of 1% lidocaine was injected during each monthly visit. Response to treatment was based on a scar symptom questionnaire and vinyl polysiloxane mold to assess reduction in scar volume. 35 patients enrolled in the study and all of them had previously failed corticosteroid therapy. 32 patients completed the treatment and were followed up for 1 year; median scar volume at baseline after excision was 0.39 ± 0.17cm3. At the end of the ¹⁰ treatment sessions the median scar volume was 0.43 ± 0.23cm³ and at one-year follow up the median volume was 0.66 ± 0.25cm³. Comparison between the volumes post excision and post treatment and at one-year follow up showed no statistical significance. Furthermore, 20 out of 32 patients complained about pain, pruritus, pressure and irritation from clothing. At one-year follow up, 63% of these patients reported complete resolution of these symptoms and 27% reported partial resolution.¹¹

Khare and Patil conducted a prospective trial to assess the efficacy of 5-FU on ear keloids post excision. A control group received TAC injections twice weekly without excision. 28 patients underwent ear lobe keloid excision and a one-time injection of 5-FU with dosage ranging between 50-150mg. Patients were followed up on a monthly basis for the first 6 months and subsequently at 6 months. 27 out of the 28 patients showed excellent results at one-year follow up. Recurrence in the study group was significantly less than that of the control group: 3.57% and 21.9% respectively. However, the treatment group showed more side effects, with 3 patients developing necrosis at the injection site and another 2 suffering from wound dehiscence.¹⁶

Discussion

Scar formation is a normal part of wound healing. Fibroblasts are essential in producing the collagen responsible for providing strength for the healing scar. The pathogenesis of problematic scars, whether keloids or hypertrophic scars, arises from a disruption in this healing process.¹⁷

Several treatments for these scars are described in the literature, but none seem to have provided a permanent treatment for keloids and hypertrophic scars. The anti-metabolite 5-fluorouracil has been shown to inhibit fibroblast proliferation in a dose dependent manner, and with increasing dosages 5-FU induced cell cycle arrests at the G2/ M phase with eventual cell apoptosis.18 However, there is a lack of sufficient clinical trials with a large number of patients to assess efficacy, safety profile and recurrence rates when using 5-FU as a monotherapy for the treatment of problematic scars. Moreover, there doesn’t appear to be a standardized method for reporting the efficacy of scar treatment, as most trials rely on patient and observer scar scales and digital analysis of scar photographs. This issue was also evident in our review.^19,20 Assessing scar volume pre and post treatment seems to be a reliable option for standardizing response to treatment. However, a unified method for calculating the volume should be considered. In Haurani’s study, a vinyl polysiloxane mold was used while a Vernier’s caliper was employed in Prahbu et al.’s study. However, in Kontochristopoulos et al.’s study there was no clear indication on how the volume was measured. Finally in Khare and Patil’s study there was no clear definition for the excellent results reported for scar response post treatment.

The treatment protocols ranged from between 50mg/ml to 150mg/ml per visit, and the frequency of injections also varied, from once weekly to once monthly, with the longest treatment reaching 10 months in Haurani’s study. The use of 5-FU alone achieved good to excellent scar improvement in all the studies, with an average of 70% reduction in scar size after termination of treatment. 5-FU also resulted in an excellent resolution of symptoms with an average of 83% resolution of symptoms that were present at baseline. Moreover, there seems to be a correlation between the age of the scar being treated and therapeutic response, as was the case in Gupta and Kalra’s and Kontochristopoulos et al.’s studies.^9,12

In terms of recurrence, 5-FU therapy seems to have less recurrence rates than other conventional treatments. This could be attributed to the relatively short follow up periods in which it is difficult to draw conclusions regarding recurrence. In Kontochristopoulos et al.’s study, a correlation was found between the age of the keloid and relapse rate, with older keloids demonstrating a relatively high recurrence of 66.7%.

The kidneys excrete the metabolites of 5-FU, hence drug toxicity is related to intravenous dosing and not subcutaneous injections. No systemic side effects such as anaemia, thrombocytopenia, and leukopenia was observed in any of the studies.⁷ Nonetheless, there were no patients with chronic infections, immunocompromised or pregnant women in any of the studies.

The major side effects observed were pain at the injection site. However, this wasn’t observed in studies that used local anaesthetic with the injection. In addition, several patients also presented with superficial ulcerations that were successfully treated with fucidic acid cream. Overall, adverse reactions from intralesional 5-FU were easily controlled and didn’t contribute to any long-term morbidity for the patients. In the three studies that assessed the efficacy of 5-FU post excision of the keloids, most patients showed excellent response to the treatment in terms of volume reduction and symptom resolution. The highest recurrence rate was observed in Haurani et al.’s study, but they also had the highest number of patients in their trial.

Conclusion

Intralesional 5-FU has been shown to be a safe option for the treatment of problematic scars that have proved to be resistant to other forms of treatment. Side effects from the therapy can be easily avoided with adequate local anaesthesia and proper wound care. However, there should be standardized methods to document scar response to intralesional therapy. Finally, more studies should look at the correlation between scar age and response to intralesional treatments.