Yazdanfar A. et al. Dermatol Surg 2008; 34: 656-659

1. Treatment of common warts with an intralesional Mixture of 5-Fluorouracil, Lidocaine, and Epinephrine: A prospective Placebo-controlled, Double-Blind Randomized Trial. Yazdanfar A. et al. Dermatol Surg 2008; 34: 656-659

2. Introduction • warts are benign epithelial neoplasms of the skin and mucous membranes due to humanpapilloma virus infections. • incidence of 10% in children and young adults. Prevalence in Hamedan in Western Iran of 5,2% • treatments: liquin nitrogen, topically applied acids, chemical and thermal cauthery, virucidal agents, cantharadin application, photodynamic therapy, electrosurgery, intralesional bleomycin, Co2 laser ablation. • 5-fluorouracil is na antimetabolite which has been used topically for the treatment of common warts. The authors performed this study to evaluate combination of intralesional 5-FU-lidocaine-epinephrine.

3. Materials and methods • prospective, double blind, placebo-controlled, randomized trial including 40 patients consulting at a referral dermatology centre in the city of Hamedan, Iran. • inclusion criteria: at least 18, with at least 2 symetric common warts, acceptable pretreatment laboratory studies (FBC, liveer and renal function, urinalysis, negative pregnancy test), no history of allergy to fluorouracil, lidocaine or epinephrine, one month treatment-free period • exclusion criteria: pregnancy (also if planned), lactation, chronic renal failure, abnormal liver function tests, abnroaml FBC. Plantar and periungal warts were excluded from this study.

4. informed consent approved by the Institutional Review Board and Ethics Committee of Sina Hospital and Hamedan University of Medical Sciences, Hamedan, Iran. • patients were barred during the study from receiving other treatments for their warts. • a pair of lesions was selected arbitrarily. The lesions were photographed and measured. The warts were randomized in two treatment groups, with one wart on each patient receiving intralesional 5-FU, LA, E and the other side receiving intralesional normal saline, • Patients, physicians and nurses participating in the study were blinded.

5. -The active solution: -4mL of 50mg/mL 5-FU -1mL mixture of 20mg/mL lidocaine and 0, 0125 mg/mL epinephrine. • The solution was injected intradermally with a Mantoux needle until the entire lesion lesion seemed to puff up. Patients received up to four injections at weekly intervals and were followed at 1 and 6 months after the final injection.

6. Pain was evaluated on a visual analog scale along a 10cm horizontal line, with more than 3cm considered moderate to severe pain. • Assessment: Complete response: no visible wart, Partial response: more than 50% reduction in size, No response: less than 50% reduction in size. FBC and blood chemistry tests were repeated after completion of treatment. • Data tabulation and statistical analyses were performed using computer software (SPSS, SPSS inc, Chicago). To evaluate the differences between both groups, authors utlised the chi-square test. A p value below ,05 was considered statistically significant.

7. Results • -34 patients (22men) (68 verruca) completed the study. -the 6 who defaulted waas for job relocation or scheduling conficts -age 19 +/- 4,5 years (15-38), follow-up period ranged from 4-10 months • Response rates: Table 1 • Recurrence Rates: -3 out of 22 lesions with complete response under 5-FU, L, E -2 out of 12 lesions with complete response under placebo (not statistically different)

8. From Table 1 (number of lesions respnding in both treatment groups) Complete response: -5FU 22 (64.7%) -Placebo 12 (35.3%) p smaller than 0.05 Partial response: -5FU 6 (17.6%) -Placebo 7 (20.6%) p not significant No response: -5FU 6 (17.6%) -Placebo 15 (44.1%) p smaller than 0.05% Total 5FU 34, placebo 34

9. Pain. Table 2. Although the incidence of moderate to severe pain was higher in the 5-FU + LE group compared to the placebo group, the differences were not statistically significant • LAB changes: none • cutaneous reactions. Local cutaneous reactions differed significantly between the two groups. They were confined to the treatment site and consisted (for 5-Fu, L, E) of erythema and edema (6 warts)), hypopigmentation (n=6), hypopigmentation (n=1), ulceration and necrosis (n=4), scarring (n=2. • In the placebo group 3 sites has erythema and edema and one had hypopigmentation.

10. From Table 2 (Pain after each of the 4 injections(n=34 +34)=visual scale (VAS more than 3=moderate to severe pain)) • Injection 1 5FU 14 (41.2%), placebo 12 (35.3%) p=.527 • Injection 2 5FU 12 (35.3%), placebo 11 (32.4%) p=.665 • Injection 3 5FU 12 (38.2%), placebo 10 (29.4%) p=.257 • Injection 4 5FU 11 (32.4%), placebo 10 (29.4%) p=.705

11. Discussion • -5FU is an antimetabolite who arrests the cell cycle. It was studied in the 70’s and 80’s and shown to be more of a historical interest, but these studies are limited by heterogeneity of methods and designs. • -Intralesional 5-FU + LE has the following advantages over topical 5-FU: -higher drug concentrations -less painful

12. -82.3% of response (64.7% complete response, 17.6% partial response) in 5-FU group and 55.9% in the placebo group. -[the complete response is lower in the placebo group 35.3%] -otherwise the higher response rate could be explained by: -injecting saline could have an effect by immune response to local trauma or central nervous-mediated effects -The 5-FU injected on the other side could stimulate memory T-cells. Note that 5-FU for chemotherapy concentration for solid tumours is 300-100 mg/m2. In the study it is around 2-6mg which is 150 times less.

13. previous studies with 5-FU, L, E obtained a response rate of 88% (70% complete response) in 76 patients with a total of 315 warts. Adverse effects included (in addition to this study) scarring. • used in treatment of keloids and condylomata accuminata with severe pain. L reduces this so that it becomes non statistically significantly different from intralsional saline.

14. Conclusion • 5FU, L, E intralesional injection of warts is safe and highly effective. • Studies with a higher number of patients as well as the study of the periungal and planatr warts is warranted.