The preliminary literature search produced 147 citations. After filtering the search according to inclusion criteria, 69 titles and abstracts were screened for relevance. After screening, a total of 21 articles were included in this review. The selected articles include: ten randomized controlled trials, four prospective single-arm trials, four case series, two case report(s), and an expert opinion. Table 2 presents the treatment regimen and clinical outcomes of studies involving intralesional 5-FU monotherapy and intralesional 5-FU with adjuvant corticosteroid therapy.
Intralesional 5-FU Monotherapy
Gupta and Kalra treated 24 consecutive patients with 50–150 mg intralesional injections of 50 mg/ml of 5-FU using 1-week injection intervals for a total of 16 injections. Clinical evaluation by a single observer was done at treatment, cessation of treatment, and the follow-up period. Excellent flattening was seen in 33.3% of patients, and more than 70% patients reported decreased itching, pain, and discharge. Side effects of treatment included pain and hyperpigmentation in all 24 patients as well as ulceration in 1 patient. There were no reoccurrences in patients who were followed up at 3–6 months .
In a similar study, Nanda and Reddy studied the effects of 5-FU in 28 patients with keloids on the chest, shoulder, upper arms, back, and additional locations. Eight patients had previously failed to respond to triamcinolone acetonide (TAC) 40 mg/cc injections every 3 weeks. Weekly intralesional injections of 0.5–2 ml of 50 mg/ml 5-FU per session were administered for no more than 12 weeks. There was good improvement in 71.4% patients and excellent improvement in 7.1% patients. Follow-up at 24 weeks revealed no recurrences. Adverse effects included pain in 100%, ulceration in 21.4%, and burning in 7.1% of patients .
Kontochristopoulus et al. also investigated the effects of intralesional 5-FU in 20 patients with keloid lesions on various locations including the chest, back, extremities, and earlobes. Eleven patients had previously failed treatment with steroid injections, silicone gels, surgical excision, and cryotherapy. Weekly intralesional injections of 0.2–0.4 ml/cm2 of 50 mg/ml 5-FU were administered over an average of seven sessions. Forty percent of patients had good improvement, and 5% had excellent improvement. At 52-week follow-up, 47% demonstrated reoccurrence. All patients experienced pain and transient hyperpigmentation, and six patients had superficial ulceration .
Goldan et al. utilized 5-FU injections to treat a 67-year-old female with facial HTSs and keloids following dermabrasian facial resurfacing. The patient had achieved only mild improvement with previous treatments including acyclovir, prednisone, fucidic acid, fexofenadine, betamethasone, and local silicone sheets with intralesional methylprednisolone acetate. Serial intralesional injections of 50 mg/ml 5-FU in six sessions over 3 months produced significant improvement of post-dermabrasian HTSs and keloids, with noticeably smaller, softer scars and less erythema. Local anesthesia with 1% lidocaine was administered prior to injections, and silicone sheets were applied following treatment. The patient experienced few side effects throughout the treatment and complete resolution of pain and pruritus .
Haurani et al. evaluated the effects of excision followed by intralesional 5-FU in 32 patients with keloid lesions and 21 patients with HTSs. All had previously failed corticosteroid therapy, and many failed other conventional treatments. Scars were administered 50 mg/ml 5-FU intralesional injections every 2–4 weeks with a total dose of 500 mg. Additionally, keloids were excised 2 weeks prior to the start of intralesional series. Patients were assessed upon scar symptom questionnaire and scar volume. Fair or good improvement was noted in 27% of patients, and 63% experienced excellent improvement. Nineteen percent of patients experienced reoccurrence of lesions at 1-year follow-up .
In a study of 44 patients with keloid lesions, Saha and Mukhopadhyay compared intralesional 5-FU to 40 mg/ml TAC injections (RCT control). Weekly 50-mg/ml intralesional 5-FU was administered over an average of five sessions. Seventeen of 20 patients (85%) in the 5-FU group achieved fair to excellent flattening of lesions. Thirty-five percent of patients experienced reoccurrence of lesions at 6 months post-treatment. Both treatment regimens were equally effective in reducing keloid volume, but the side effects were noticeably worse in the 5-FU group, with 95% experiencing extreme pain and 65% experiencing superficial ulcerations .
In a similar manner, Khare and Patil compared intralesional 5-FU plus excision in 28 patients to intralesional TAC (control) in 24 patients with ear keloids. Patients in the treatment group received 50–150 mg/ml 5-FU intralesional injections following excision. Ninety-six percent of patients in the treatment group demonstrated reduced keloid size at the end of 1 year. Fewer instances of recurrences occurred in the treatment group (4%) as compared to the control group (22%). Side effects of therapy included superficial necrosis in three patients, partial wound dehiscence in two patients, and local infection in one patient .
Prabhu et al. also compared the efficacy of weekly intralesional injections of 50 mg/ml 5-FU versus 40 mg/ml TAC (control) in 30 patients with keloids for 4 weeks. Interestingly, good to excellent flattening of keloid size was seen in 64% of patients in patients receiving 5-FU versus 87% in patients receiving TAC monotherapy, and the difference was statistically significant. More complications were encountered in the 5-FU group and included ulceration in one patient, pruritus in one patient, and pain in one patient, but this distinction was not statistically significant .
Intralesional 5-FU/TAC Combination
In a series of observations involving more than 1000 patients over 9 years, Fitzpatrick recorded the use of 5-FU with and without different adjuvant therapies for the treatment of various scar types including keloids. All patients received intralesional injections of 50 mg/ml 5-FU without ever exceeding 100 mg per treatment. Initially, patients received 5-FU monotherapy once monthly, which was found to be ineffective. With added time and experience, Fitzpatrick reported reduced pain and overall better outcomes with once-weekly injections (on average) of a mixture of 45 mg/ml 5-FU in combination with 1 mg/ml of TAC .
Manuskiatti and Fitzpatrick conducted a study involving ten patients with previously untreated median sternotomy HTSs and keloids. In a single study, several management options were compared by separating lesions into five segments: laser radiation with 585-nm pulsed-dye laser (PDL), TAC, intralesional 5-FU, and intralesional TAC in combination with 5-FU (5-FU/TAC), and untreated control. In 5-FU sections, intralesional injections of 50 mg/ml 5-FU were administered every 2 weeks for the first eight treatments and every 4 weeks for the last two treatments. All treated segments demonstrated significant improvement; however, no method demonstrated superiority over the others. Intralesional 5-FU and 5-FU/TAC demonstrated significant lesion flattening as compared with baseline by week 8. Scar erythema was reduced at week 16 and week 24 with 5-FU and 5-FU/TAC, respectively, compared to baseline. Scar pliability was increased at week 8 with 5-FU/TAC and by week 16 with 5-FU monotherapy. Subjects receiving 5-FU revealed 70% with fair improvement and 30% with good improvement on self-assessments at 32 weeks. All patients who received 5-FU with or without adjuvant treatment noted pain and burning. One patient on 5-FU/TAC developed superficial ulceration .
Apikan and Goodman also investigated 5-FU in combination with betamethasone acetate (BA) and betamethasone sodium phosphate (BSP) in two patients with keloid scars. A mixture of 1.6 ml of 50 mg/ml 5-FU with 0.4 ml of 3 mg/ml of BA and 3.9 mg/ml of BSP was injected every 2 weeks for 1 year. The study demonstrated a reduction in keloid size and minimal side effects with no recurrences at 1-year follow-up. Side effects included hyperpigmentation in both patients .
Davidson et al. conducted a retrospective review of 94 patients with 102 keloids. Keloids were separated into three treatment groups including: 5-FU/TAC without excision (52 subjects), 5-FU/TAC with excision (24 subjects), and TAC treatment with excision (26 subjects). A 3:1 concentration of 37.5 mg/ml of 5-FU and 10 mg/ml of TAC was mixed, and 0.1 ml of solution per centimeter of lesion was injected. Excisional patients were given injections 2, 4, and 6 weeks after surgery, and non-excisional patients were administered injections every 4 weeks. A statistically significant reduction in keloid size was seen with 5FU/TAC regimens (92%) as compared to TAC alone (73%). Patients with keloids treated with 5-FU experienced pain and pruritus .
Khan et al. enrolled 150 patients to receive either intralesional 0.25 ml of 40 mg/ml TAC diluted with 0.75 ml normal saline or 0.9 ml of 50 mg/ml of 5-FU mixed with 0.1 ml of 40 mg/ml TAC. There was significant improvement with 5-FU/TAC compared to TAC monotherapy, with 63 5-FU/TAC patients (84%) having good to excellent results compared to 51 TAC patients (68%). There were no instances of scar recurrence at 6-month follow-up. Eighteen patients (24%) who were administered TAC alone and six patients (8%) who were given 5-FU/TAC experienced complications .
Mutalik and Patwardhan studied 30 patients with HTSs and keloids and administrated intralesional injections of 50 mg/ml 5-FU. TAC 40 mg/ml was added in a 1:1 ratio for lesions with inflammation or firm induration. Patients were instructed to use sodium fusidate or mupirocin for 5 days following treatment and follow-up in 4 weeks; 67% of patients showed complete flattening of keloids with a mean of four injections. A quarter of these patients who improved with therapy developed reoccurrence of lesions at 1-year follow-up. Side effects included transient hyperpigmentation with 5-FU. Infection and hypopigmentation were seen in a few patients who received concomitant steroids .
Intralesional 5-FU/TAC and Lasers
Fitzpatrick also recounted successful treatment of scars with pronounced erythema using pretreatment with PDL therapy. In a 45-year-old female with HTSs and keloids following plastic surgery to the face, Fitzpatrick administered intralesional injections of 45 mg/ml 5-FU and 1 mg/ml of TAC over 20 treatment sessions. Follow-up use of PDL (6.25 J/cm2) demonstrated complete resolution of HTSs and keloids .
Alsilian et al. used lasers in combination with intralesional 5-FU/TAC for the treatment of keloids and HTSs. Sixty-nine patients were divided into three groups receiving different therapies: TAC 10 mg/ml injected at weekly intervals for 8 weeks, TAC + 5-FU 0.1 ml of 40 mg/ml TAC added to 0.9 ml of 5-FU 50 mg/ml injected weekly for 8 weeks, and 5-FU/TAC serial injections for 8 weeks, combined with 585 PDL 5–7 J/cm2 at the 1st, 4th, and 8th weeks. Statistically significant improvement was found in patients receiving 5-FU/TAC and 5-FU/TAC + PDL in contrast to TAC monotherapy. Average flattening of the lesion was 50% in the TAC group, 77% in the 5-FU/TAC group, and 79% in the 5-FU/TAC + PDL groups. Patients in all three groups complained of pain associated with injections. Steroid atrophy and telangiectasia was seen with TAC monotherapy .
Darougheh et al. randomized 40 HTSs and keloid patients to receive either TAC alone or 5-FU/TAC. Weekly intralesional injections of 10 mg TAC or a mixture of 4 mg TAC and 45 mg 5-FU were given for a total of eight treatments. There were statistically significant reductions in length, width, height, erythema, induration, and pruritus in both groups, with greater improvement in the 5-FU/TAC group. Greater than 50% improvement was reported in 20% of the TAC group versus 55% in the 5-FU/TAC group. Trained observers also reported greater improvement in the 5-FU/TAC group; however, this difference was not statistically significant. Adverse events included pain, atrophy, and telangiectasia in those receiving steroids. Interestingly, the 5-FU/TAC group demonstrated no adverse effects besides injection pain .
Katz et al. described intralesional 5-FU/TAC in combination laser therapy in a 75-year-old female who developed perioral, hypertrophic scarring following a phenol peel for perioral rhytides. She had previously received intralesional 5-FU/TAC therapies with no improvement. Katz et al. attempted 595-nm PDL (7–9 J/cm2, 7–10-mm spot size, 3–10-ms pulse width, with 21–55 pulses per treatment) followed by the 1450-nm diode laser (12–14 J/cm2, 6-mm spot size, 6–16 pulses per treatment). After each laser session, the patient was administered 10 mg/ml intralesional TAC and 50 mg/ml 5-FU. She experienced greater than 95% of aesthetic and functional improvement and no recurrence following ten treatment sessions. Side effects included temporary bruising .
Hatamipour et al. studied the effects of intralesional 5-FU with topical silicone in the prevention of keloids. Fifty patients with keloids of different sizes and varying durations were used to compare treatment with and without 5-FU. Any prior therapy was discontinued before enrollment. In the treatment group, keloids were excised, covered with topical silicone sheets, and administered a series of 50 mg/ml 5-FU intralesional injections at postsurgical days 7, 14, 28, and during the 2nd and 3rd months, with doses varying between 0.6 to 1 ml. The second group and controls received no 5-FU intralesional treatment; 75% of patients showed complete improvement versus 43% in the control group. Side effects included ulceration, burning, and pain at the injection site .
Uppal et al. studied 11 Afro-Caribbean patients with keloid scars on the earlobes, chest, or shoulders. Ten patients had previously received intralesional steroid treatment. Patients with bilateral earlobe keloids were randomized into control or treatment groups according to coin toss, and linear scars were split in half. Following excision, treatment lesions were given 50 mg/ml 5-FU intralesional injections in phosphate-buffered saline by a soaked sponge pledget for 5 min. Control lesions were exposed to phosphate-buffered saline alone. Greater clinical improvement by lower keloid scar scores was appreciated in treated lesions than controls by blinded observers .
Sadeghinia and Sadeghinia developed a novel approach to administer 5-FU named “5-FU tattooing.” The procedure of 5-FU tattooing includes anesthesia of lesions followed by dripping 1 ml of 50 mg/ml of 5-FU solution onto each centimeter area of the lesion. Forty punctures are made in the skin using a 27-gauge needle, and 1 ml of 5-FU solution was again dripped on the surface and covered in order to optimize absorption of 5-FU. The study involved 40 patients randomized into an intralesional TAC group or 5-FU tattooing group. Patients who received any other treatment type in the past 6 months were excluded from the study. Patients received therapy every 4 weeks for a total of 12 weeks. At the end of the study, both groups demonstrated a reduction in size, erythema, induration, and pruritus. More than double the number of patients receiving 5-FU achieved good to excellent patient satisfaction scores as compared to those in the TAC group (85% versus 40%, respectively). Greater overall improvement was also appreciated by observer assessment in the 5-FU group. Ninety-five percent of patients in the 5-FU group achieved good to excellent results, whereas only 50% in the TAC group achieved a good to excellent response .
Wilson et al. utilized botulinum toxin to enhance the inhibitory effect on fibroblasts. Following surgical excision, 80 patients with keloids were injected with intralesional 50 mg/ml 5-FU with 50 IU/ml botulinum toxin, using a total dose of less than 140 U. All patients were treatment failures with various other methods. The mean follow-up period was 19.6 months over which only 3.75% experienced recurrence. More than 80% of patients reported significant improvement and 12.5% conveyed at least slight improvement. Complications included pruritus, pain, and residual post-inflammatory hyperpigmentation. One patient experienced partial wound dehiscence during the postoperative period. Eleven patients (13.75%) experienced late widening of the scar, which resulted in corrective surgery at a later date in half .