Compared therapeutic efficacy between intralesional bleomycin and cryotherapy for common warts: A randomized clinical trial
Published Web Locationhttps://doi.org/10.5070/D362g0g3mj
Compared therapeutic efficacy between intralesional bleomycin and cryotherapy for common warts: A randomized clinical trial1. Dermatology department, Bouali University Hospital, Ardabil University of Medical Sciences, Ardabil, Iran2. Faculty of
medicine, Ardabil University of Medical Sciences, Ardabil, Iran 3. PHS department, Karolinska Institute, Stockholm, Sweden
H Adalatkhah MD1, H Khalilollahi MD1, N Amini2, H Sadeghi-Bazargani MD MPH3
Dermatology Online Journal 13 (3): 4
In spite of many available studies on bleomycin and cryotherapy in treating warts, little head to head research is done to compare efficacy of these treatments. Our aim was to compare the therapeutic effects of intralesional bleomycin and cryotherapy on common warts of the hands and feet. In this clinical trial 44 patients above 12 years of age referred to the dermatology clinic of Bouali University Hospital were enrolled. The patients were required to have warts on at least two symmetric limbs (hands or feet). The warts located on right and left limbs of each patient were examined and counted. Each patient received both cryotherapy and intralesional bleomycin on his or her warts. The two treatment types were randomly allocated to either right sided or left sided warts. Each patient was evaluated at 2 week intervals and retreated if necessary up to three times. Data were analyzed by SPSS 11 and EPI Info 2002 statistical packages. The mean number of warts was 5.2 on upper limbs and 4.6 on lower limbs. In 86.4 percent of the cases all warts on the limb side treated by intralesional bleomycin were cleared compared with 68.2 % for cryotherapy (P<0.05). Relative risk for the effect of bleomycin compared to cryotherapy in this regard was 1.27 (1<RR<1.6). We found bleomycin to have a clearance rate equal to 87.6 percent of warts, compared to 72.3 percent by cryotherapy. Relative risk for therapeutic effect of bleomycin compared to cryotherapy in this regard was 1.23 (1.11<RR<1.33).Conclusion: Intralesional bleomycin is more effective than cryotherapy in treating warts on hands and feet.
Human papilloma viruses have been identified as the cause of cutaneous and genital warts. Furthermore, HPV DNA can also be detected in certain malignant epithelial tumors such as cervical carcinoma and cutaneous squamous cell cancer [1, 2, 3]. Many people around the world have experienced or will experience HPV infection during their life. The prevalence of viral warts in European countries has been reported to be between 3 and 20 percent . In an Iranian study the prevalence was 15 percent among those aged 12-16 years and 25 percent of the participants had a positive history of common warts . Some studies have suggested spontaneous wart clearance rates equal to 23 percent at 2 months, 30 percent at 3 months and 65-78 percent at 2 years . However, many patients present for medical treatment.
Different types of warts and those at different sites may need different treatments. There is no single treatment that is 100 percent effective; several types of treatment may be combined. Intralesional bleomycin therapy has been used in the treatment of viral warts since the 1970s . Since then many studies have found bleomycin to be effective in treating warts [7-17]. Cryotherapy is one of the most common treatments for warts [18, 19, 20, 21, 22]. Although both of these treatments are painful and need combined local anesthetics, bleomycin may be more available and easily accessible in peripheral practices in many countries. In spite of many available studies on bleomycin and cryotherapy in treating warts, little research has been done to compare the efficacy of these treatments in similar settings and individuals. Our aim was to compare the therapeutic effects of intralesional bleomycin and cryotherapy on common warts of the hands and feet.
Materials and methods
Setting and design: The study was conducted in Ardabil, a northwestern province of Iran. In this clinical trial, study patients referred to the dermatology clinic of Bouali University Hospital who had warts on at least two symmetric limbs (hands or feet) were enrolled if they were above 12 years old. Differentiation of warts from callosities or corns in some doubtful cases was done after gentle paring. Pregnant women and patients younger than 12 were excluded from the study. Other exclusion criteria included any intention to get pregnant in the near future and history of vascular diseases such as Raynaud's phenomenon, systemic sclerosis, livedo reticularis, and chilblains. Most patients (44 of 52) continued participation and randomly received one of the two treatments to be tested on each limb. None of the patients had previous treatment prior to our study.
The warts located on right/left limbs of each patient were examined and counted to form two groups of right sided and left sided warts. Each patient received both treatments on his or her warts. The two treatment types were randomly allocated to either right sided or left sided warts.
A graphical wart map was prepared for each patient and location of warts along with data regarding wart size and type of treatment were recorded on this. Other data were collected through a structured questionnaire after an interview and medical examination by a dermatologist.
Treatment and assessment: Bleomycin sulfate (BLEO-S: Nippon Kayaku CO.LTD, Japan) was diluted up to a 0.5 mg/ml concentration. After adding 2 percent lidocaine this was injected into the lesion using an insulin syringe. This concurrent injection method has been shown to be suitable by previous studies and we chose it as our choice to provide a concurrent acceptable anesthesia. Injection was continued until each wart blanched.
Cryotherapy: Cryotherapy with a spray gun (Cryal Jet: Cortex technology CE, Denmark) was done using nozzles of suitable size. The spray gun was held perpendicular to the wart at a distance of 1-2 cm. The wart was sprayed until the ice-ball formation had spread from the center to include the edge of the wart and a 1-mm margin.
In both study groups, patients were visited every 15 days up to a maximum of three times and repeated the treatment if required. A wart was considered cleared if it completely resolved; otherwise it was considered as a failure. The wart treatment was done by one dermatologist and the final evaluation after 6 weeks was the responsibility of another dermatologist.
Statistics: Data were entered into the computer and analyzed by SPSS version 11 and Epi-Info 2002 statistical packages. One way ANOVA and t test were used to compare the means of quantities among the subgroups and Chi-square test was undertaken to compare the proportions. A p-value less than 0.05 percent was considered as demonstrating statistical significance. The desired outcome in this clinical trial was complete resolution of warts by 6 weeks after initial treatment. The relative risk of bleomycin treatment compared to cryotherapy was calculated along with its 95 percent confidence interval by means of Epi-Info 2002 statistical package. If relative risk was greater than one and its confidence interval didn't include this value, bleomycin could be assumed as more effective than cryotherapy. Otherwise it was considered as less effective or similarly effective as cryotherapy. The confidence interval calculation was based on the Taylor series approach using the following formula at which Re is considered as the probability of having a positive treatment result for bleomycin and Ru is considered as the probability of having a positive treatment result for cryotherapy :
Ethics: The study was approved by ethical committee of Ardabil University of Medical Sciences. Written consent was taken from all participants.
Females constituted 52.3 percent of participants and 47.7 percent were males. Mean age of participants was 20.2 ± 6.9 years. Mean number of warts on upper limbs was 5.2 and on lower limbs was 4.6. Distribution of warts on upper and lower limbs was statistically similar between study groups.
In 86.4 percent of the cases, all warts on the limb side treated by bleomycin were cleared compared with 68.2 percent for cryotherapy. The difference was statistically significant (Table 1). Relative risk for effect of bleomycin compared to cryotherapy was 1.27.
Mean percent of number of warts cleared on each limb was 76.1 for cryotherapy and 91.8 for intralesional bleomycin. The difference was found to be statistically significant (p <0.05). Bleomycin was shown to be more effective both in males and females as well as both upper and lower limbs (p <0.05). Figure 1 presents a comparison of this rate in males and females.
Bleomycin was found to be more effective when the comparison was made between the total numbers of warts cleared by each treatment (Table 2).
Only five cases of significant adverse complications were encountered, three of which belonged to bleomycin. Minor complications were not recorded.
Superior efficacy in wart clearing was shown in our study with intralesional bleomycin vs. cryotherapy. We used a 0.5mg/ml concentration of bleomycin in this study. It has been shown by Hayes that a 0.5 mg/ml concentration is as effective as 1 mg/ml . Numerous reports have been published on the use of intralesional bleomycin for the treatment of recalcitrant warts with clearance rates ranging from 14 to 99 percent. The majority of the data suggest that bleomycin is effective in over two-thirds of the reported cases with minimal side effects . However, in a systematic review by Gibbs no consistent evidence was found for the efficacy of intralesional bleomycin .
In our study the clearance rate for intralesional bleomycin therapy was 87.6 percent, and in 86.4 percent of patients all the warts treated with bleomycin were cleared. The clearance rate for intralesional bleomycin from previous studies are given in Table 3 [8, 11, 15, 17, 23, 26].
We found cryotherapy to have a wart clearance rate equal to 72.3 percent. And in 68.2 percent of patients all the warts treated with cryotherapy were cleared. In a study by Ahmed et al. clearance rates at 3 months were 47 percent with cryotherapy with cotton wool bud and 44 percent in the cryospray group. Cryotherapy with liquid nitrogen for hand and foot warts in another study was equally effective when applied with a cotton wool bud or by means of a spray . In a study by Berth-Jones et al., the clearance rate was 57 percent for the single freeze technique, and 62 percent for the double freeze technique. That study found that the use of a double freeze-thaw cycle confers little or no advantage over a single freeze in the treatment of hand warts, but may be considerably more effective for plantar warts . In Bourke's study, the clearance rate was 66 percent in the group treated weekly, 47 percent in the group treated every 2 weeks, and 30 percent in those treated every 3 weeks. However, it was concluded that the clearance percent is related to the number of treatments received, and independent of the interval between treatments . Connolly et al. had found in their study that a 10-second sustained freeze was more effective in cryotherapy of viral warts but carried a significantly greater morbidity in terms of pain and blistering .
As we can see from the above mentioned studies, most of the trials of cryotherapy studied different regimens rather than comparing cryotherapy with other treatments or placebo . Although there is more controversy about its efficacy, most of the studies show lower cure rates for cryotherapy when compared with other studies done on bleomycin. No published study was found to compare the efficacy of bleomycin with cryotherapy on the same patients or the same study group. In our study we found that bleomycin had 1.23 times more clearance efficacy than cryotherapy. Pain is the main problem both in cryotherapy and intralesional bleomycin; analgesia is helpful in both groups. Pain management seems to be easier for bleomycin and the pain period is shorter compared with the pain and discomfort that may continue for several hours after cryotherapy. Considering the good tolerance and efficacy of intralesional bleomycin, some researchers suggest the posssiblity of using it for non-recalcitrant warts . The current cost of bleomycin therapy is less than cryotherapy in Iran and perhaps other countries as well. Bleomycin therapy also requires less equipment than cryotherapy.
Intralesional bleomycin is more effective than cryotherapy in treating warts on hands and feet.
Acknowledgment:We are thankful to Ardabil University of medical sciences for financially supporting this research. We thank also Dr.Shaker for his kind executive help in conducting the research.
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