Review

A systematic review evaluating the efficacy and safety of

a combination of ablative treatment and self administered
treatment versus ablative treatment alone for external
anogenital warts
Cheng Feng1, MD, Wei Li2, MD, PhD, Xiaojun Wang1, MD, Hailin Zhang1, MD,
Loubin Si1, MD, Zhixiong Chen1, MD and Ming Bai1, MD

1
Department of Plastic Surgery, Peking Abstract
Union Medical College Hospital, Chinese Background External anogenital warts are proliferative lesions. Till now, there is no
Academy of Medical Sciences & Peking
consensus on the standard treatment of external anogenital warts. The combination of
Union Medical College, Beijing, China, and
2
Cancer Center, Beijing Ditan Hospital,
ablative therapy and self-administered treatment has been reported to achieve sustained
Capital Medical University, Beijing, China complete clearance than ablative therapy. The aim of this review was to compare the
efficacy on achieving complete clearance of warts between the combination of ablative
Correspondence therapy with self-administered therapy and ablative therapy alone.
Ming Bai, MD
Methods We conducted a systematic review to evaluate the efficacy and safety of the
Peking Union Medical College Hospital
(Dongdan campus)
combination of ablative therapy and self-administered treatment for external anogenital
No.1 Shuaifuyuan Wangfujing Dongcheng warts. The Cochrane Central Register of Controlled Trials, Medline, Embase and Science
District Citation Index Expanded, China National Knowledge Infrastructure and Wanfang were
Beijing 100730 searched.
China
Results Of 1138 initially identified publications, 37 studies in English and Chinese were
E-mail: majaca@sina.com
included. The combination of ablative therapy and self-administered treatment therapy
showed significantly high complete clearance rates at 4, 8, 12, or 24 weeks after
Conflict of interest: None.
treatment compared to ablative therapy alone. In a subgroup analysis based on the treatment
Funding source: None. duration of imiquimod cream therapy, 4 and 8 weeks of imiquimod 5% cream plus CO2 laser
produced similar efficacy on clearance. The combination therapy is tolerable for patients.
Conclusions In conclusion, this review provided evidence to support the use of the
doi: 10.1111/ijd.14863 combination of ablative therapy and self-administered treatment for external anogenital
warts to maintain sustained clearance.

mainly include ablative therapy (e.g. laser ablation, cryoablation,

Introduction
External anogenital warts (EAGWs) are proliferative lesions,
generally caused by “low risk” human papillomavirus (HPV)
types 6 and 11.1 The overall incidence of EAGWs has been
reported as ranging from 160 to 289 per 100,000 individuals,
with a median of 194.5 per 100,000.2 EAGWs, including both
external genital warts and external perianal warts, usually occur
on the coronal sulcus, frenulum, penis, scrotum, vulva, clitoris,
urethral meatus, introitus, perianal areas, and perineal areas.
The presence of EAGWs would bring about negative impact on
quality of life of patients, such as the impact on sexuality and
feelings of shame, guilt, and anxiety.3
Until now, there is no consensus on the standard treatment of
EAGWs. Generally speaking, the common treatments can be
divided into two categories: provider-administered treatment and
self-administered treatment. The provider-administered treatments
microwave ablation, and electrosurgery) and non-ablative therapy
(e.g. trichloroacetic acid).4 The self-administered treatments
mainly include imiquimod, podophyllotoxin, and polyphenon E. The
ablative therapy can lead to rapid clinical efficacy on visible lesions,
however, it has poor efficacy on maintaining complete clearance
and carries high risk of recurrence.5 The self-administered treat-
ments can be helpful for achieving sustained clearance and reduc-
ing recurrence but usually need a long time.6,7 Therefore, the
combination of ablative treatment and adjuvant self-administered
treatment is appealing. The rationale for the combination therapy
on EAGWs is that adjuvant self-administered treatment can
achieve local control on subclinical warts based on the destruction
of all visible warts caused by ablative therapy.8
There are some systematic reviews on the treatment of
EAGWs that have been published, and most of them focused
on monotherapy on warts, such as intralesional 1

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2 Review Combination treatment for external anogenital warts
immunotherapy,9 imiquimod,10 cantharidin treatment,11 laser
therapy and photodynamic therapies,12 and combined thera-
pies.3,13 However, till now, it is hard to identify the standard
treatment strategy with satisfying efficacy.
Recently, some studies have reported that the combination
treatment strategy can generate a more favorable clearance
rate than ablative treatment alone for EAGWs.7,8 However,
there is still lack of clear and compelling evidence to prove bet-
ter efficacy of the combination treatment. Therefore, we con-
ducted a well-designed review with the intention to provide the
best level of evidence for the role of the combination of ablative
treatment and self-administered treatment for treating EAGWs.
Methods
A systematic review was conducted evaluating the efficacy and
safety of the combination of ablative treatment with self-
administered treatment for EAGWs. We followed the
methodology of the ‘Cochrane Handbook’ for Systematic
Reviews of Interventions.14 This review was registered on
PROSPERO (no. CRD42018114807).
Electronic searches
We performed electronic searches in the following databases:
The Cochrane Central Register of Controlled Trials (CENTRAL),
Medline (via PubMed), Embase, and Science Citation Index
Expanded (Web of Science) on the August 7th and 8th, 2018.
We also identified relevant randomized clinical trials (RCTs) in
two of the most prevalent Chinese databases, which were
China National Knowledge Infrastructure (CNKI) and Wanfang.
The search strategies are shown in the Supplementary file.
Selection of studies
Two review authors (Cheng Feng and Xiaojun Wang)
independently asked for inclusion of all the titles and abstracts
of records retrieved from the search. Selected studies were
further screened by retrieving full texts. All RCTs which
compared the efficacy of the combination of ablative treatment
(laser therapy, cryotherapy, microwave ablation, or
electrocautery) with self-administered treatment (imiquimod,
podophyllotoxin, or polyphenon E) vs. ablative treatment alone
for EAGWs were included. Non-RCTs, reviews, case series,
letters to the editor, and non-human studies were excluded. The
language was limited to English and Chinese. Disagreements
were resolved by discussion. Consulting the third review author
was done when necessary.
Outcomes
The primary outcomes were complete clearance rates (CCR) at
4, 8, 12, and 24 weeks after treatment. Complete clearance
was defined as disappearance of all warts, including baseline
warts, any recurrent warts, and any new warts during follow-up.
The secondary outcome was adverse events.
International Journal of Dermatology 2020
Feng et al.
Data extraction and management
Two authors (Cheng Feng and Wei Li) independently extracted
the data from all included articles. Disagreements were
resolved by discussion. Consulting the third review author or
writing correspondence to the original investigators was done
when necessary. Basic study characteristics (the first author,
year of publication, sample size), demographic data of patients,
information of treated warts, information of treatment (e.g.
concentration, duration, dosage, and frequency), and outcomes
were recorded.
Intention-to-treat (ITT) analysis was performed whenever
possible for all included studies. ITT analysis was defined as
people being analyzed in each group to which they were
allocated at randomization, irrespective of whether they finished
treatment or were lost to follow-up. All missing data were
analyzed as treatment failure for all outcomes.13
Assessment of risk of bias
Two review authors (Hailin Zhang and Loubin Si) independently
assessed the risk of bias of each included trial following the
instructions given in the Cochrane Handbook for Systematic
Reviews of Interventions and methodological studies.14 The risk
of bias of all domains were classified as high, unclear, or low
risk of bias. Disagreements were resolved by discussion.
Consulting the third review author was done when necessary.
Data-analysis
We explored heterogeneity by the Chi2 test with significance set
at P < 0.10. In addition, we accessed the quantity of
heterogeneity by using the I2 statistic.
We performed meta-analysis whenever it was possible.
Otherwise, we provided narrative summary of the results. We
analyzed data using the software Review Manager 5.3.15 The
treatment efficacy was analyzed by using a random-effects
model.
Results
Results of the search
We retrieved a total of 1138 references and screened 760
records after excluding duplicates. Full text of 93 articles was
obtained. Finally, 37 RCTs7-8,16-50 were included in this review.
The search process is shown in Figure 1. Details of all included
RCTs are shown in Table S1.
The 37 RCTs included 3476 participants. All 37 RCTs
focused on the treatment of EAGWs. The sample size of stud-
ies ranged from 42 to 240 patients. This review focused on the
endpoints of CCR and adverse events. In the study by Schofer
et al.,18 the ablative therapy was defined as electrocautery, liq-
uid nitrogen, laser therapy, or surgery. However, 69% of
patients in the mono-ablative therapy group and 63% of patients
in the combined therapy group were treated by electrocautery.
Therefore, we roughly included the results of this study in the
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Feng et al.
Figure 1 Flow diagram of studies included
in the review
analysis of the comparison of electrocautery plus imiquimod 5%
cream vs. electrocautery alone.
Risk of bias
The results of assessment of risk of bias for each study are
shown in Fig. S1. For seven comparisons in the present review,
the risk of bias of included RCTs were shown in Table 1. Most
of included studies did not describe the methods of random
sequence generation, details of allocation concealment and
blinding, and thus have unclear risk of bias.
Efficacy
CO2 laser + imiquimod 5% cream vs. CO2 laser
Twenty-six RCTs16-17,19,22-28,31-35,39,41-50 compared the efficacy
of CO2 laser plus imiquimod 5% cream treatment with CO2
laser alone for treating EAGWs. However, they did not
ª 2020 the International Society of Dermatology
Combination treatment for external anogenital warts Review 3
contribute data to every outcome of interest. For each available
outcome, we performed subgroup analysis whenever possible.
Only one RCT26 examined the CCR at 4 and 8 weeks after
the treatment. The combination of CO2 laser and imiquimod 5%
cream treatment generated similar treatment efficacy on clear-
ance of EAGWs at both 4 and 8 weeks after treatment
(P > 0.05).
Twelve RCTs24,28,31-32,35,39,41,43-44,48,49 reported the CCR at
12 weeks after the treatment. The CO2 plus imiquimod 5%
cream therapy was associated with a significantly higher CCR,
compared to CO2 laser alone (RR 1.53, 95% CI 1.38–1.71,
I2 = 46%, Table 2, Fig. S2). We performed subgroup analysis
according to the duration of imiquimod 5% cream treatment
(Table 2, Fig. S3). The results showed that the CO2 laser plus
imiquimod 5% cream therapy with the duration of 4 weeks (RR
1.51, 95% CI 1.22–1.87, I2 = 28%), 8 weeks (RR 1.50, 95% CI
1.36–1.65, I2 = 0%), and 12 weeks (RR 2.29, 95% CI 0.87–
International Journal of Dermatology 2020
4 Review Combination treatment for external anogenital warts Feng et al.

Table 1 Risk of bias of included studies in seven therapy was significantly higher than that of MWA therapy alone
comparisons (RR 2.20, 95% CI 1.26–3.83, I2 = 73%, Table 1, Fig. S6).

Number Number of Number Cryoablation + imiquimod 5% cream vs. cryoablation

of included of Only two RCTs21,30 assessed the efficacy and safety of cryoab-
included studies included
lation plus imiquimod 5% cream treatment and cryoablation
studies with studies
with low unclear with high therapy for EAGWs. In these included studies, Chen et al.30
risk of risk of risk of concluded that the combination therapy had similar efficacy at
Comparisons bias bias bias 4 weeks (P = 0.051) and better efficacy at 8 weeks (P = 0.003)
on complete clearance of EAGWs. Ding et al.21 observed that
CO2 laser + imiquimod 5% 0 26 0
CCR at 24 weeks after the combined treatment was signifi-
cream vs. CO2 laser
Electrocautery + imiquimod 5% 0 2 1 cantly higher than that after cryoablation monotherapy
cream vs. electrocautery (P < 0.001).
MWA + imiquimod 5% cream 0 3 0
vs. MWA
Cryoablation + podophyllotoxin cream vs. cryoablation
Cryoablation + imiquimod 5% 0 2 0
Only one RCT29 was included. According to the authors, there
cream vs. cryoablation
Cryoablation + podophyllotoxin 0 0 1 was no statistical difference on CCR at 4 weeks (P = 0.141),
cream vs. cryoablation 8 weeks (P = 0.463), and 12 weeks (P = 0.672) after treat-
Cryoablation + sinecatechins 0 0 1 ment.
15% vs. cryoablation

Cryoablation + sinecatechins 15% vs. cryoablation

MWA, microwave ablation.
6.00, I2 = 89%) generated similar efficacy (P = 0.69) on achiev-
ing complete clearance of EAGWs at 12 weeks after treatment.
The results of CCR at 24 weeks after treatment correspond
to the meta-analysis of six RCTs16,22,33,46-47,50. There was sig-
nificantly higher CCR at 24 weeks after the combination of CO2
laser with imiquimod 5% cream treatment than CO2 laser alone
(RR 1.90, 95% CI 1.42–2.53, I2 = 73%, Table 2, Fig. S4). The
results of subgroup analysis of duration of imiquimod 5% cream
treatment are shown in Table 2 and Figure S5. There was no
significant difference (P = 0.53) between the efficacy of imiqui-
mod 5% cream treatment of 8 weeks (RR 2.49, 95% CI 1.71–
3.61, I2 = 0%) and 12 weeks (RR 2.06, 95% CI 1.30–3.26,
I2 = 66%) on complete clearance of EAGWs.
Electrocautery + imiquimod 5% cream vs. electrocautery
One RCT18 compared the efficacy and safety of electrocautery
plus imiquimod 5% cream therapy with electrocautery therapy
and reported CCR at 12 weeks after treatment. The results
showed that treatment efficacy of two different treatments was
similar (P = 0.171).
Two RCTs38,40 reported CCR at 24 weeks after treatment.
The combined therapy generated significantly high rates of
complete clearance (RR 1.62, 95% CI 1.33–1.97, I2 = 0%,
Table 2, Fig. S6) on EAGWs, compared to ablative therapy
alone.
MWA + imiquimod 5% cream vs. MWA
Three RCTs20,36,37 compared the efficacy between the MWA
plus imiquimod 5% cream treatment and MWA. The pooled
results showed that CCR at 24 weeks after the combination
One RCT8 reported that cryoablation plus sinecatechins 15%
have similar CCR at 8 weeks with that after cryoablation
(P = 0.694).
Adverse events
For adverse events, data extracted from original articles did not
allow us to perform meta-analysis. So, here, we only made a
narrative summary of adverse events reported in all 37 included
studies. The adverse events in both combined treatment group
and ablative treatment group mainly included mild or moderate
erythema, edema, burning, itching, erosion, pain, and ulcera-
tion. No significant difference of rates of adverse events was
reported between the combination treatment group and ablative
treatment group. Most adverse events occurred 2–4 weeks after
the initiation of treatment. For prognosis, most adverse events
were self-limited and would resolve spontaneously. Sometimes,
symptomatic treatment and dose reduction of drug can be
needed. Additionally, discontinuation of drug and blinded medi-
cation were reported in some articles, and details are shown in
Table 3.
Discussion
This systematic review indicated that the combination of abla-
tive therapy and self-administered therapy had better efficacy
on achieving complete clearance of EAGWs compared to abla-
tive therapy alone. Both the combination treatment and ablative
monotherapy were tolerated. For the comparison of CO2
laser + imiquimod 5% cream vs. CO2 laser alone, 4 and
8 weeks of imiquimod 5% cream treatment produced similar
clinical effect on maintaining complete clearance. For the com-
parison of cryoablation + podophyllotoxin cream vs. cryoablation

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Feng et al. Combination treatment for external anogenital warts Review 5

Table 2 Results of meta-analyses of CCR

Patients underwent Patients underwent Number of

Analyses combination treatment ablative treatment RR, 95% CI I2 studies

CO2 laser + imiquimod 5% cream vs. CO2 laser

1. CCR at 12 weeks after treatment 586 584 1.53, 1.38–1.71 46% 12
1.1 Subgroup analysis
1. 4 weeks of imiquimod 5% cream 90 90 1.51, 1.22–1.87 28% 2
2. 8 weeks of imiquimod 5% cream 368 367 1.50, 1.36–1.65 0% 7
75 74 2.29, 0.87–6.00 89% 2
2. CCR at 24 weeks after treatment 235 234 1.90,1.42–2.53 73% 6
2.1 Subgroup analysis
1. 8 weeks of imiquimod 5% cream 70 70 2.49, 1.71–3.61 0% 2
2. 12 weeks of imiquimod 5% cream 82 82 2.06, 1.30–3.26 66% 2
Electrocautery + imiquimod 5% cream vs. electrocautery
CCR at 24 weeks after treatment 90 88 1.62,1.33–1.97 0% 2
MWA + imiquimod 5% cream vs. MWA
CCR at 24 weeks after treatment 119 115 2.20, 1.26–3.83 73% 3

CCR, compete clearance rate, 95% CI, 95% confidence interval.

Table 3 Discontinuation of drug and blinded medication reported in included articles

Treatment strategy Study Events Related treatment group Patients

CO2 laser + imiquimod 5% He Xiaoyan 2008 Drug discontinuation CO2 laser + imiquimod 5% cream group 9 (9/57, 16%)
cream vs. CO2 laser Xiang Qing 2008 Drug discontinuation CO2 laser + imiquimod 5% cream group 7 (7/29, 24%)
Zhang Chunmei 2008 Drug discontinuation CO2 laser + imiquimod 5% cream group NA
Huang Fuxiang 2010 Drug discontinuation CO2 laser + imiquimod 5% cream group 6 (6/35, 17%)
Wu Hanguang 2010 Drug discontinuation CO2 laser + imiquimod 5% cream group 3 (3/48, 6%)
Li Jianming 2018 Drug discontinuation CO2 laser + imiquimod 5% cream group NA
Electrocautery + imiquimod 5% Helmut Scho€fer 2006 Drug discontinuation Electrocautery + imiquimod 5% cream 4 (4/103, 4%)
cream vs. electrocautery group
Xu Ping 2011 Drug discontinuation Electrocautery + imiquimod 5% cream NA
group
MWA + imiquimod 5% cream vs. Shen Hui 2011 Drug discontinuation MWA + imiquimod 5% cream group NA
MWA
Cryoablation + imiquimod 5% Chen Heng 2009 Drug discontinuation Cryoablation + imiquimod 5% cream NA
cream vs. cryoablation group
Cryoablation + podophyllotoxin R J C Gilson 2009 Stop of blinded Cryoablation + podophyllotoxin cream 13 (13/74,
cream vs. cryoablation medication group 18%)
R J C Gilson 2009 Stop of blinded Cryoablation group 4 (4/75, 5%)
medication

MWA, microwave ablation; NA, not available.

and cryoablation + sinecatechins 15% vs. cryoablation, the
results showed no significant difference on clearance rate. How-
ever, for these two comparisons, only one RCT was included,
which can lead to a high level of bias on efficacy assessment.
The rationale of the combination of ablative therapy and self-
administered treatment can be explained as follows: the ablative
therapy is a destructive therapy that can achieve fast efficacy
on warts, with high recurrence rate, because the ablative ther-
apy just removes the visible warts without eliminating underlying
HPV infection. The self-administered treatment can control sub-
clinical warts, which are likely to present near the primary
lesion, enhance immunological function and maintain efficacy.
Therefore, sustained complete clearance would be promised in
the combination treatment strategy.
There are several limitations in this review. The risk of bias
of most of the included studies in this review is unclear,
because they provided limited information about random
sequence generation, allocation concealment, and blinding.
Meta-analysis and related subgroup analyses of some compar-
isons were not possible because of the relatively small number
of included RCTs. Some studies did not provide detailed basic
characteristics of enrolled patients, and we were not sure about

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6 Review Combination treatment for external anogenital warts
some important clinical information. For some specific subsets
of the population, such as immunocompromised patients and
immunocompetent patients, the clinical efficacy would be differ-
ent, and it is appropriate to report the efficacy for different sub-
sets of population separately. Another limit of our review is that
most of included studies enrolled both untreated EAGWs and
recurrent EAGWs. However, the treatment on recurrent EAGWs
would be more difficult than primary EAGWs.
There are some implications for future researches. Clear
statements of randomization method, blinding, and allocation
method are highly recommended. Future research studies
should display detailed basic characteristics of patients. Further
research is recommended to focus on specific population (e.g.
immunocompromised patients and immunocompetent patients;
female or male) and specific warts (e.g. primary warts or recur-
rent warts).
Conclusions
In conclusion, the results of this review provided evidence to
support the use of the combination of ablative therapy and self-
administered treatment for EAGWs. The combination therapy is
tolerable for patients with EAGWs. In the future, more high-
quality RCTs are needed to conduct conclusions with a high
level of evidence and provide guidance for clinical treatment.
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Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Figure S1. Results of assessment of risk of bias for each
included study
Figure S2. Forest plot of comparison: CO2 laser + imiquimod
5% cream vs. CO2 laser; Outcome: complete clearance rate at
12 weeks after treatment
Figure S3. Forest plot of comparison: CO2 laser + imiquimod
5% cream vs. CO2 laser; Outcome: Complete clearance rate at
12 weeks after treatment; Subgroups: The duration of
imiquimod 5% cream treatment
Figure S4. Forest plot of comparison: CO2 laser + imiquimod
5% cream vs. CO2 laser; Outcome: complete clearance rate at
24 weeks after treatment
Figure S5. Forest plot of comparison: CO2 laser + imiquimod
5% cream vs. CO2 laser; Outcome: Complete clearance rate at
24 weeks after treatment; Subgroups: The duration of
imiquimod 5% cream treatment
Figure S6. Forest plot of comparison:
electrocautery + imiquimod 5% cream vs. electrocautery;
Outcome: complete clearance rate at 24 weeks after treatment
Figure S7. Forest plot of comparison: MWA + imiquimod 5%
cream vs. MWA; Outcome: complete clearance rate at
24 weeks after treatment
Table S1. Basic characteristics of included studies
International Journal of Dermatology 2020