Dermatologic Therapy, Vol. 00, 2016, 00–00 C 2016 Wiley Periodicals, Inc.

V
DOI:10.1111/12356
DERMATOLOGIC THERAPY
ISSN 1396-0296

ORIGINAL PAPERS

Safety and effectiveness of

cantharidin–podophylotoxin–
salicylic acid in the treatment of
recalcitrant plantar warts
 pez Lo
Daniel Lo ndez†,
 pez*, Juan Manuel Vilar Ferna

Marta Elena Losa Iglesias‡, Carlos Alvarez Castro*,
§
Carlos Romero Morales , Marıa Matilde Garcıa Sanchez*,
¶
& Ricardo Becerro de Bengoa Vallejo
*Research, Health and Podiatry Unit, Department of Health Sciences,
Faculty of Nursing and Podiatry, Universidade da Corun ~ a, Spain,
†Modeling, Optimization and Statistical Inference Research Group,
Universidade da Corun ~ a, Spain, ‡Faculty of Health Sciences, Universidad
Rey Juan Carlos, Spain, §Faculty of Health, Exercise and Sport, European
University of Madrid, Villaviciosa de Odon, Madrid, Spain and ¶School of
Nursing, Physiotherapy and Podiatry, Universidad Complutense de Madrid,
Spain

ABSTRACT: The aim of our study was to evaluate the efficacy and safety of topical
cantharidin–podophylotoxin–salicylic acid (CPS) treatment of recalcitrant plantar warts (RPW).
This study was carried out in a health center in the city of A Corun ~ a (Spain) between January
and December 2013. A total of 75 patients completed all the stages of the research process.
Information related to treatment with CPS and adverse effects was abstracted from medical
records. Of 93 potential patients identified, 75 had at least one follow-up visit or telephone
call after treatment and were included in this study. Patients experienced an average of 5.4
visits until complete resolution of their plantar wart occurred, although CPS was not applied
at every visit. Fifty-four patients required one application to eliminate the wart and 21
patients required two applications/patient. Seventy-seven percent of patients experienced
blistering – an expected therapeutic side effect. All patients experienced some form of an
adverse event, the most common being pain (81.3%) and significant blistering (15%). Other
side effects were rare (18.7%) and included pruritus, possible mild infection, significant

Address correspondence and reprint requests to: Daniel Lo  pez Lo

 pez, Universidade da Corun ~ a, Unidade de Investigacio
 n Sau de
e Podoloxıa, Departamento de Ciencias da Sau  de, Campus Universitario de Esteiro s/n, 15403 Ferrol (Espan~ a), or email:
daniellopez@udc.es
Conflict of interest: The authors did not receive any financial assistance from or have any personal relationships with other peo-
ple or organizations that could inappropriately influence (bias) their work.
Author Contributions: All authors: concept, design, analyses, interpretation of data, drafting of manuscript or revising it critically
for important intellectual content.

1
 pez Lo
Lo pez et al.

irritation, and bleeding. All patients reported treatment, supporting our results that CPS is a
safe and efficacious treatment modality for RPW and should be considered when symptomatic
infection necessitates treatment.

KEYWORDS: cantharidin, foot disease, warts

Introduction the study. Exclusion criteria included: immuno-

compromised patients, pregnancy or breastfeed-
Viral warts are cutaneous and mucous membra- ing, use of medications, known sensitivity to any
nous lesions caused by human papillomavirus (1), of the components of the study solution, and
and are a common dermatological disease affecting dermatologic conditions at the site of treatment
approximately 7–24% of the general population application, such as eczema and psoriasis. Par-
(2–5). Studies have shown a significant portion of ticipants with unrealistic expectations or fear in
common warts (40–60%) resolve spontaneously relation to the treatment potential and those
within 2 years (6,7); however, the remaining 40–60% unable to tolerate, the refusal to sign an
require medical or surgical intervention (8). informed consent form, and the inability to
Unfortunately, approximately one-third do not understand and carry out the instructions in the
resolve and become recalcitrant despite repeated study were also excluded.
treatments. This can cause the patients physical
embarrassment and psychological distress and also Procedure
present a therapeutic challenge even for specialists
The measurements were carried out by a single
such as dermatologists (9–12).
physician who followed the technique described
There are few controlled studies that focus
by Becerro de Bengoa Vallejo et al. (18,19) and
specifically on the treatment of plantar warts
before applying the formula, the zone is washed
(13–18), and even fewer studies on the treatment
and disinfected. The keratin layer covering the
of recalcitrant plantar warts (RPW) (19). It has
wart is debrided to expose the RPW with a scalpel
recently been reported that the topical proprie-
handle and a number 15 blade. The topical prepa-
tary formulation consisting of 1% cantharidin,
ration was comprised of 1% cantharidin, 5%
5% podophyllotoxin, and 30% salicylic acid
podophyllotoxin, 30% salicylic acid, and 2 mL of
(CPS) has achieved complete clearance of RPW
in 100% of patients (19). This is a high cure rate
compared to other treatments (20–22) but it’s a
preliminary study. Despite its regular clinical use
(23) and reported safety (24), inadequate data
currently exist to modify the FDA status of can-
tharidin or reassure institutions of its safety (25).
The goal of the current study is to evaluate the
efficacy and safety of topical CPS treatment of
RPW and further characterize its safety profile by
assessing the adverse events experienced by a
large group of patients treated with CPS.

Materials and methods

Design and sample
The study consisted of a descriptive observatio-
nal study conducted in a health center, between
January 2013 and December 2013. The selection
of study participants was conducted by a non-
randomized and consecutive sampling method
to 93 patients in the age range of 7–62 years, of
which 75 gave consent and were enrolled into FIG. 1. Plantar aspect of the heel showing blister drained

2
 Efficacy and safety of CPS treatment of RPW

flexible collodion. This preparation was applied

with a swab to the RPW without surpassing the
margins of the lesion and the solution was
allowed to dry on the area for a few seconds.
The patient returned for examination at 24–48
hours, dressing removed (Fig. 1), the content of
the blister drained, and the area debrided with a
scalpel. This procedure resulted in the total
cleansing and elimination of the lesion (Fig. 2).
Subsequent ambulatory treatment was based
on topical application ointments in order to pre-
vent infection of the lesion, and on the use of a
bandage for subsequent protection.
After 15 or 20 days, if the zone was completely
healed and there were no remaining signs of the
RPW, the patient was discharged. A control visit
at six months confirmed the definitive resolution FIG. 2. The perilesional zone after being debrided with a
scalpel
of the lesion. In cases where RPW clinical signs
persisted after 15 or 20 days, a second applica-
tion was carried out. bles: age, weight, height, and BMI Independent
t-tests were used to determine significant differ-
Ethical considerations ences. Statistical calculations were performed
using the statistical package SPSS Statistics 19
The research was approved by the Research and (IBM) considering significant results with a
Ethics Committee of the Universidade da Corun ~a p value <0.01.
(Spain); record number: CE 18/2013. All volunteers
gave written informed consent before inclusion in
the study. In addition, the ethical standards for Results
experimentation in humans as described in the
A total of 75 patients of less than 65 years of age
Declaration of Helsinki (World Medical Assembly)
completed the research course. The sample ana-
and the Council of Europe Convention on human
lyzed included 34 (45.3%) males and 41 (54.7%)
rights consent and biomedicine, the Universal
females between 7 and 62 years of age.
Declaration of UNESCO on the human genome
Socio-demographic characteristics of the study
and human rights and appropriate national or
participants are shown in Table 1. In general, par-
institutional bodies were followed.
ticipants had normal weight (BMI 5 21.73 kg/m2).
At the beginning of the study, the patients had
Statistical analysis
a total of 126 RPW in different limited areas of
A descriptive analysis of the variables included the feet, 54 of which (72%) were located in the
in the study was performed. The mean, standard forefoot, 8 (10.7%) in the mid-foot, and 13
deviation (SD), and maximum and minimum (17.3%) in the rearfoot zones. The average dura-
values were calculated for the quantitative varia- tion of the lesion was 24.80 6 3.06 months, with

Table 1. Sociodemographic characteristics of the participants.

Total Group, Male, Female,

Mean 6 SD, Range, Mean 6 SD, Mean 6 SD, p value,
N5 75 Range, N 5 34 Range, N 5 41 Male vs. Female
Age, years 21.35 6 13.09 (7–62) 19.35 6 11.11 (7–49) 23.00 6 14.45 (7–62) 0.232
Weight (kg) 55.57 6 17.84 (23–94) 59.09 6 19.72 (29–94) 52.66 6 15.77 (23–86) 0.121
Height (cm) 157.71 6 16.82 (123–190) 161.62 6 19.34 (128–190) 154.46 6 13.83 (123–182) 0.076
BMI (kg/m2) 21.73 6 3.73 (11.07–31.23) 21.84 6 3.29 (15.91–29.01) 21.64 6 4.10 (11.07–31.23) 0.815
Number RPW 1.68 6 0.84 (1–5) 1.74 6 0.75 (1–3) 1.63 6 0.92 (1–5) 0.607

Abbreviations: BMI, body mass index; SD, standard deviation. In all the analyses, p < 0.01 (with a 99% confidence interval)
was considered statistically significant.

3
 pez Lo
Lo pez et al.
a confidence interval of 95% for the mean dura-
tion of 19.10 and 20.50 months. All patients had
received previous treatments.
All patients responded to CPS treatment and
experienced healed lesions with no major
adverse events. The most common adverse
events included pain (81.3%) and significant blis-
tering (15%). Other side effects were rare (18.7%)
and included pruritus, possible mild infection,
significant irritation, id reactions, and bleeding.
After the first treatment session, no patient
experienced pain when walking. All lesions dis-
appeared completely with a single application of
the topical CPS treatment in 54 patients (72%),
and after two treatment applications for 21
(28%) patients. All patients showed clinical heal-
ing within 8 weeks and the number of CPS appli-
cations required for the complete clearance of
RPW was 1.28 6 0.45 with the average number of
clinic visits needed for each patient until total
resolution of the lesion were 5.4 visits.
Treatment-related patient satisfaction was
assessed at the end of therapy using a ten point
visual analogue scale (VAS) where 1 represented
“not satisfied at all” and 10 referred to
“completely satisfied”. The average score was
9.13 6 0.74, indicating that all patients stated
that they would proceed again with the CPS
treatment if necessary.
Discussion
CPS is a widely used treatment for recalcitrant
warts that is advantageous because of its rapid
treatment time and lack of pain at the time of
application (19,26,27). Previous studies have
reported high satisfaction rates from both
patients and providers with its use (19,28). None-
theless, a lack of safety data has contributed to
an ambiguous FDA status (25).
Our study aimed to evaluate the efficacy and
safety of topical CPS treatment of RPW and fur-
ther characterize its safety profile in a large
group.
The results of the present study are the first to
demonstrate no major side effects with the use
of CPW for RPW, such as scarring, infection or
toxicity similar studies that report to be safe and
effective in molluscum, plantar wars and other
viral lesions (29,30).
The high patient/physician satisfaction rates
from this treatment support its use as a first-
choice RPW treatment.
4
Because techniques of CPS application vary
widely between practitioners (31) and different
application methods (occlusion or no occlusion,
duration of contact with CPS prior to washing it
off) may significantly influence the side effects
experienced. Thus, it may be beneficial to have a
specifi protocol established for application with
a known side effect profile.
There are several limitations to the study that
should be acknowledged. First, future studies
should compare CPS to vehicle in a double-
blinded, controlled fashion. A larger and more
diverse (individuals from various countries) sam-
ple size would be beneficial to improve the
strength of the study and identify more sub-
categories. This highlights the need for further
research on RPW, recognized as a public health
problem, and the need for continued research
into this common dermatologic challenge.
Conclusions
CPS is a safe and efficacious treatment modality
for RPW and should be considered when symp-
tomatic infection necessitates treatment.
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