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\begin{document}

\title{Outcome Comparison of KTP laser and CO2 laser excision for Laryngeal
papillomatosis -- A Systematic Review}



\author[1]{Jimin Yang}%
\author[2]{Zhongcheng Xie}%
\affil[1]{Department of Otolaryngology, Head and Neck Surgery, West China Hospital, Sichuan University}%
\affil[2]{Clinical Anatomy \& Reproductive Medicine Application Institute}%


\vspace{-1em}



  
  \date{May 28, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: CO2 laser and the 532-nm potassium titanyl phosphate laser
(KTP) were developed to treat Laryngeal papillomatosis (LP); however,
the difference in their outcomes remains unclear. Methods: A systematic
review was conducted through a comprehensive search of three databases.
Results: Overall, the cure rates were 87.25\% in the KTP group and
75.98\% in the CO2 group (p<0.05). The complications rates were
significantly different between the two groups (p\textless{}0.0001). In
addition, there was no significant difference between the recurrence
rates of the CO2 group and the KTP group (10\% vs 9.8\%). The risks of
bias were 13.1\selectlanguage{ngerman}±1.45 and 13.6±1.52 for CO2 group and KTP group
respectively, which indicated the fair quality of evidence. Conclusions:
The available fair-quality evidence suggested that KTP laser excision
may be a better choice for LP. Following evaluations on the benefits of
the two surgical techniques with more high-quality randomized controlled
studies are needed.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Abstract}

\textbf{Background} : CO\textsubscript{2} laser and the 532-nm potassium
titanyl phosphate laser (KTP) were developed to treat Laryngeal
papillomatosis (LP); however, the difference in their outcomes remains
unclear.

\textbf{Methods} : A systematic review was conducted through a
comprehensive search of three databases.

\textbf{Results} : Overall, the cure rates were 87.25\% in the KTP group
and 75.98\% in the CO\textsubscript{2} group (p<0.05). The
complications rates were significantly different between the two groups
(p\textless{}0.0001). In addition, there was no significant difference
between the recurrence rates of the CO\textsubscript{2} group and the
KTP group (10\% vs 9.8\%). The risks of bias were 13.1\selectlanguage{ngerman}±1.45 and
13.6±1.52 for CO\textsubscript{2} group and KTP group respectively,
which indicated the fair quality of evidence.

\textbf{Conclusions} : The available fair-quality evidence suggested
that KTP laser excision may be a better choice for LP. Following
evaluations on the benefits of the two surgical techniques with more
high-quality randomized controlled studies are needed.

\textbf{Keywords} : Laryngeal papillomatosis; Recurrent respiratory
papillomatosis; 532-nm potassium titanyl phosphate laser; CO2 laser;
Systematic Review

\textbf{Key points:}

\begin{enumerate}
\tightlist
\item
  CO\textsubscript{2} and KTP laser were developed to treat LP, but the
  differences in their outcomes have not been systematically summarized.
\item
  This review was conducted through three databases involving 283
  related studies, and 15 of them met the inclusion criteria.
\item
  KTP laser might result in a superior outcome and lower postoperative
  complication rate than CO2 laser for LP.
\item
  HPV positive rate, remission rate, and clearance rate for LP are
  suggested to be reported in future studies.
\item
  High-quality randomized controlled studies are needed to further
  evaluate the benefits of the two surgical techniques.
\end{enumerate}

\textbf{Introduction}

Laryngeal papillomatosis (LP) is a benign tumor that can involve the
whole respiratory tract and upper digestive tract\textsuperscript{1}. It
is also termed as recurrent respiratory papillomatosis(RRP) due to its
high recurrence rate postoperatively and multiple surgeries are
frequently required\textsuperscript{2}. In general, LP can be divided
into juvenile-onset and adult-onset LP\textsuperscript{3}. The reported
incidence rate is 0.17 and 0.54 per 100 000 people for juvenile-onset
and adult-onset LP, respectively\textsuperscript{4}. Its morphological
characteristics appeared with many abnormal exophytic projections, one
of which is composed of a center of connective tissue covered with
squamous epithelium\textsuperscript{5,6}. Although benign, LP is chronic
and can significantly influence on life style due to requiring multiple
operations and significant financial impact, scarring, airway
obstruction, hoarseness, and rare but the potential for malignant
transformation\textsuperscript{4,7,8}.

Currently, no definite treatment modality for LP is yet available,
clinical management of LP is mainly rely on repeated careful surgical
resections with preservation of non-infected
tissue\textsuperscript{9,10}. Besides, the treatment for LP in clinical
is still frustrating on account of unpredictable outcomes, the tendency
for recurrence, and intractable complicates\textsuperscript{11,12}.
Effective prevention of complicates is one of the main targets for
treatments, which could be the important criteria for evaluating
treatment methods\textsuperscript{2,3,13}. Surgical excision in the
operating room under general anesthesia is the traditional management
method\textsuperscript{1,14,15}. Powered by advanced technology, a
direct laryngoscopic approach started in the
20\textsuperscript{th}century\textsuperscript{16,17}. Afterwards, with
the development of the carbon dioxide (CO\textsubscript{2}) laser in the
1960s, it quickly became popular in laryngology but multiple
complications, such as thermal injury, significantly limited its
applications\textsuperscript{1,18,19}. Subsequently, the 585-nm pulsed
dye laser (PDL) was first introduced in 2001 to manage PL with a fiber
delivery system of absorbable energy\textsuperscript{20,21}. However,
bleeding caused by PDL and its extremely short pulse width blocked the
further application of this technology\textsuperscript{2,22,23}.
Furthermore, adjuvant antiviral drugs have been administrated and
studied for increasing therapeutic effects in recent years, but their
therapeutic effects have not been confirmed\textsuperscript{24--26}.

In the past thirty years, photoangiolytic laser-the 532-nm potassium
titanyl phosphate laser (KTP), has been widely applied in office-based
laryngeal surgical procedures\textsuperscript{27--29}. Many studies have
been reported successful treatment of multiple vocal diseases, such as
papilloma, varix, polyp, Reinke edema, vocal process granuloma, ectasia,
and glottal dysplasia\textsuperscript{29}. The angiolytic properties of
KTP shrink lesions through photothermolysis and the laser energy can be
absorbed by hemoglobin\textsuperscript{10,30,31}. With those advantages,
KTP laser seems to be the promising modality of LP treatment. However,
in China(and neighboring countries), the CO\textsubscript{2} laser is
being used as the first-choice modality for LP applied by most
hospitals. To date, there was no consensus or comparison study on which
laser is better for LP therapy.

This review aims to evaluate and compare the cure, complications, and
recurrence rates of CO\textsubscript{2} and KTP lasers for LP. We
hypothesized that KTP laser could yield comparatively better outcomes
than CO\textsubscript{2} laser for LP.

\textbf{Method}

The study was performed according to PRISMA\textsuperscript{32} and the
check list was presented in Appendix S1.

\emph{2.1. Eligibility Criteria}

Clinical studies with reported or published data were involved (e.g.,
review papers were not included). We considered all research
demonstrating the prognosis of RRP after KTP laser and
CO\textsubscript{2} laser excision. Abstracts and conference proceedings
were excluded due to the lack of comprehensive studies from these
sources. In order to perform comprehensive research, no restrictions
existed on language or country of publication.

\emph{2.2. Search Strategy}

PubMed, EMBASE, Cochrane library, and WOS were used to conduct a
systematic review of the published literature and searched up until
December 31st, 2020 (from January 1st, 1900). The search terms were
(Papilloma* or Papilloma Virus or Papillomatosis or Papillomatoses) and
(Laryngeal* or throat or larynx or throttle) and
(CO\textsubscript{2}laser* or KTP laser* or potassium titanyl phosphate
laser) (Search Strategy for PubMed, Appendix S2). Reference lists of
previously published reviews and studies in these reviews were
researched in this work to make sure all the related studies were
involved.

\emph{2.3. Study Selection}

After deleting the same studies from different databases, two reviewers
(XXX and XXX) assessed the titles and abstracts of initial papers
independently and decided on the final inclusion eligibility. After
then, the two reviewers identified the full text of all possibly
relevant records. All the differences were solved by consensus.

\emph{2.5. Risk of Bias/Quality Assessment}

Thanks to the abundance of non-randomized studies showing in the
available literature, two independent reviewers (XXX and XXX) critically
appraised all the eligible studies with Methodological Index for
Nonrandomized Studies (MINORS) to assess the quality of included
studies. A senior reviewer made the final decision on the assessment if
a consensus was not achieved and supervised the entire process. The
MINORS instrument contains 12 items: 4 for comparative studies and 8 for
noncomparative studies. A score of 0 (not reported), 1 (reported but
inadequate), or 2 (reported and adequate) was given for each item,
resulting in an ideal maximum score of twenty-four for comparative
studies and sixteen for noncomparative studies. For non-randomized
studies, the methodologic quality was assessed as follows: 0 to 5, very
low quality of evidence; 6 to 10, low quality; 11 to 15, fair quality;
16, good quality. The outcomes of the risk-of-bias and quality
assessment provided the confidence level for the conclusions to be drawn
from this review.

\emph{2.6. Data Synthesis and Analysis}

We analyzed the following characteristics in this study: number of
patients, study design, evidence level, quality of study, inclusion and
exclusion criteria, and outcomes used for the evaluation of the
surgery/treatment effectiveness. The demographic and clinical outcome
data were presented in the form of mean±standard deviation. Thus, we
collected and calculated the number of various rates from studies, such
as cure rate (defined as no papilloma for five years based on the
previous study\textsuperscript{33}), and gained the overall rare of KTP/
CO\textsubscript{2} laser therapy for LP to compare their therapeutic
effects. The P-value for a continuous variable was calculated using a
t-test, and the Fisher exact test was conducted for the categorical
variable. P-value\textless{}0.05 was considered statistically
significant in this study. To further assess the robustness of the
complete results of the primary outcome, the sample size was calculated
based on the cure rate at the final follow-up. By conducting a two-tail
t-test of 80\% power (1 -- b) and a 0.05 level of significance using G
power software, an estimated sample size of 58 patients per group was
required. When a published work lacked sufficient details, we attempted
to contact the authors of those research to acquire the necessary
information.

\textbf{3. Results}

\emph{3.1. Results of the Search}

We identified 283 unique abstracts. Of these abstracts, fifty-one of
them were fully assessed and 15 passed all eligibility criteria. Figure
1 presents the reasons for full-text article exclusions.

\emph{3.2. Description of Studies and Study Characteristics}

The 15 studies that passed all eligibility criteria came out between
1900 and 2020 (Table 1); 12 of the studies were published in
English\textsuperscript{12,30,42,43,34--41}, two of them published in
Chinese\textsuperscript{10,44}, and one published in
Spanish\textsuperscript{1}, including 5 studies in KTP
group\textsuperscript{10,30,34,35,44} and 10 articles in
CO\textsubscript{2} group\textsuperscript{1,12,36--43}. These studies
totally involved 612 patients with LP and 2120 surgeries treated with
CO\textsubscript{2} laser/KTP laser, including 102 KTP cases and 510
CO\textsubscript{2} cases separately. There are 8 retrospective
studies\textsuperscript{1,12,36--38,40,42,43} with only 2 prospective
works\textsuperscript{39,41} in CO\textsubscript{2} group, while KTP
group contains 2 retrospective\textsuperscript{10,44} and 3 prospective
studies\textsuperscript{30,34,35}. Besides, the patient population
selected in studies is different and most studies recruited patients
with recurrent laryngeal/respiratory papillomatosis, while others
included inverted papilloma\textsuperscript{30}, laryngeal
papilloma\textsuperscript{1,38,42,44}, juvenile-onset
RRP\textsuperscript{39} (Table 1). All studies included males and
females with a higher percentage of males (Mele: 65.61\% and 66.25\% for
KTP and CO\textsubscript{2} respectively), and there was no differences
between the gender percentages of the two groups (p\selectlanguage{english}>0.05) (Table 2).
However, significant difference existed between the average age of KTP
and CO\textsubscript{2} group (p\selectlanguage{english}<0.001) before surgery (Table 2).
Besides, sample sizes ranged between 3 and 244 (median 39).
Specifically, the sample sizes for the CO\textsubscript{2} group and KTP
group were 3-222 and 9-39, respectively. The evidence levels of all the
studies were classified as level D. All studies accessed samples from
outpatient departments.

\emph{3.3. Surgical techniques}

The most important point for surgical techniques is laser setting. We
found that 10 studies reported the relative information of laser
setting, while the other 5 did not. Additionally, laser settings from
each work were inconsistent with each other. In the
CO\textsubscript{2}group, the laser setting on the energy was ranged
from 2-30W reported by 6 works, while the frequency of laser was between
100 and 300Hz presented by two studies. As for KTP laser, the energy
setting was within the scope of 6-8W, which is more accurate than that
of CO\textsubscript{2} laser between different literature. Meanwhile,
the frequency of KTP laser was 2 Hz reported by two studies.
Furthermore, most CO\textsubscript{2} laser excision surgeries for LP
were conducted in the operation room under general anesthesia, while the
majority of KTP laser excision surgeries were performed under local
anesthesia.

\emph{3.4. Indications and Contradictions}

All the studies involved in this review have explicitly reported that
patients were diagnosed with LP or RRP, which was confirmed by their
pathological specimens and treated with CO\textsubscript{2} laser/KTP
laser excision. On the other hand, contradictions varied from study to
study. Patients treated with adjunctive therapies, such as the HPV
vaccine, were excluded from this study. In addition, serious cases with
systemic metastases, such as lung, were also excluded. Moreover,
patients were treated with not only CO\textsubscript{2} laser/KTP laser
but also with other techniques at the same time point, such as PDL laser
and microblade excision, were no involved. The age and gender were not
limited to a specific scope.

\emph{3.5. Clinical outcomes}

Overall, the cure rates were 87.25\% (89 of 102) in the KTP group and
75.98\% (389 of 512) in the CO\textsubscript{2} group (Table 3). The
cure rates were significantly different between the two groups (p=
0.0127). In addition, the recurrence rates were 9.80\% (10 of 102) in
the KTP group and 10\% (34 of 340) in the CO\textsubscript{2} group.
There was no significant difference between the recurrence rates of the
CO\textsubscript{2} group and the KTP group. Other clinical outcomes,
such as death rate, remission rate, clearance rate, effective rate, and
HPV-detected rate, cannot be compared between the two groups in this
study due to those parameters were rare reported in both groups.

\emph{3.6. Complications rates}

The complications rates were 2.32\% (2 of 86) in the KTP group and
17.71\% (88 of 497) in the CO\textsubscript{2} group (Table 3). The
complications rates were significantly different between the two groups
(p\textless{}0.0001). In the KTP group, only two complications were
reported that webbing was formed in front of the vocal fissure, causing
hoarseness but did not affect breathing\textsuperscript{44}. As for
CO\textsubscript{2} laser, a great number of complications occurred,
including mucosal tears, tooth injuries, laryngeal edema, scarring,
stenosis, and web formation (most were anterior glottic web), and
delayed soft tissue complications (i.e. functionally debilitating scar
formation with consecutive voice disorders or airway
stenosis)\textsuperscript{1,12,38,40--42}. These complications relied on
the invasiveness of papilloma, the instrumentation used during surgery,
and the experience of the surgeon\textsuperscript{12}.

\emph{3.7. Risk of Bias Assessment}

The MINORS scores of the five prospective cases in the KTP group
averaged 13.1 (SD, 1.45; range, 11-15) (Appendix S3), suggesting the
fair quality of evidence. The scores of the 10 prospective studies in
the CO\textsubscript{2} group averaged 13.6 (SD, 1.52; range, 12-15),
suggesting the fair quality of evidence. No statistical difference
existed between the MINOR scores of the abovementioned two groups
(p\selectlanguage{english}>0.05).

\textbf{Discussion:}

This systematic review reported 15 studies totally involving 612
patients with LP treated with CO\textsubscript{2} laser or KTP laser and
2120 surgeries, including 102 KTP cases from 5 studies and 510
CO\textsubscript{2} cases from 10 studies separately. Both
CO\textsubscript{2} and KTP groups were improved postoperatively in
clinical outcomes. Compared with the CO\textsubscript{2} group, the KTP
group showed significantly better results in cure rate and had a lower
postoperative complication rate. To the best of our knowledge, this work
is the first study that systematically and comprehensively compares the
clinical outcomes of CO\textsubscript{2} and KTP lasers for LP.

Although LP is a benign disease as mentioned above, it is frequently
associated with substantial morbidity and mortality\textsuperscript{4}.
Therefore, balancing treatment goals (voice preservation and disease
regression and/or restoration) with the morbidity and cost of the
treatment is required and should be seriously considered before
treatments\textsuperscript{7}. Recent studies have found that Human
papillomavirus (HPV, a DNA virus) is the cause of LP. Besides, pieces of
evidence suggested that more than 100 genotypes of HPV infecting
exist\textsuperscript{45--47}. For instance\selectlanguage{english},HPV-6 and HPV-11 result in
the low-risk and the most common LP; HPV-16 and HPV-18 play a high-risk
role but rarely happen\textsuperscript{48}. According to clinical cases
observed, two categories are divided depending on onset age. Juvenile
onset RRP (JoRRP) represents the onset age of patients less than 12
years old, while adult-onset RRP (AoRRP) more than 12 years
old\textsuperscript{5,8}. Most JoRRP is transmitted vertically during
pregnancy or acquired from a contaminated mother during delivering; as
for AoRRP, it is often sexually transmitted by oral
sex\textsuperscript{49}. Besides, a trimodal distribution has been
pointed out that 7, 35, and 64 years old are the peaking onset
ages\textsuperscript{50}. In spite of this, a bimodal distribution is
most acceptable by researchers\textsuperscript{5,49,51}. Based on the
information, a serial of anti-viral drugs was investigated for LP,
including the HPV vaccine, Interferon, Cidofovir, Bevacizumab,
Celecoxib, and so forth\textsuperscript{5,52}. For instance, the
meta-analysis of Rosenberg et al. found that the number of
surgeries/months was significantly reduced after long-term HPV
vaccination than before vaccination\textsuperscript{53}. These adjuvant
treatments may benefit patients with LP treated with surgical excision
and more studies are needed to assess the effects of combination KTP
laser surgery with adjuvant therapies.

In this review, we found that both KTP and CO\textsubscript{2} laser
groups demonstrated satisfactory outcomes for LP in the cure rate,
87.25\selectlanguage{english}% and 75.98\selectlanguage{english}% respectively. In addition, the cure rate of KTP
laser is significantly higher than that of CO\textsubscript{2} laser,
which demonstrated the main therapeutic effect of KTP laser is superior.
Another evaluation indicator is recurrence rate, but we found there no
difference between the two groups for LP treatment (9.8\selectlanguage{english}% vs 10\selectlanguage{english}%,
p=0.2967). Moreover, the safety outcome-complication rate of the KTP
group is 2.32\selectlanguage{english}%, which is considerably lower than that of
CO\textsubscript{2} laser (17.71\selectlanguage{english}%) (p\selectlanguage{english}<0.0001). Those findings strongly
support our hypothesis that KTP laser could yield comparatively better
outcomes than CO\textsubscript{2} laser for LP.

Several reasons may explain why KTP laser was superior to
CO\textsubscript{2} laser for LP according to literature. The
CO\textsubscript{2} laser was firstly used in the 1960s and it quickly
gained popularity for LP\textsuperscript{14,18}. Many therapeutic
options have been advocated for LP, such as microblade and PDL laser,
but surgical removal using CO\textsubscript{2} laser remains the most
important single treatment choice\textsuperscript{4,54,55}. Although the
10 600 nm wavelength of the CO\textsubscript{2} laser is well absorbed
by water in biological tissue and is suitable for fine surgical cutting,
its application to remove laryngeal lesions is not without
risk\textsuperscript{56,57}. Thermal injury, excessive resection, and
repeated surgeries may result in a loss of pliable vocal fold tissue,
fibrosis, and scar formation, which can significantly affect the quality
of voice and life\textsuperscript{34,58}.

As for KTP laser, it has both the cutting function of
CO\textsubscript{2} laser and the hemostatic effect of PDL laser, so its
application in laryngeal microsurgery has many advantages: (1) The
operation is significantly less destructive than the traditional
laryngeal laceration, without laryngeal laceration, and with less
tracheotomy ratio. In addition, KTP laser is more likely to preserve
postoperative laryngeal function, and the postoperative hospital stay
was short (less cost), requiring only 2 to 3 days\textsuperscript{44}.
(2) The accuracy and precision of the operation were improved by using a
KTP laser. The tumor boundary can be clearly seen under the microscope,
and the level of incision can be distinguished so that the lesion can be
completely removed while minimizing collateral
damage\textsuperscript{59}. (3) The fiber-based delivery of the KTP
laser with the technical advancement of distal-tip endoscopy enables
surgical procedures to be performed in-office settings under local
anesthesia, by which considerable time and medical expenses would be
saved\textsuperscript{31,35}. (4) The KTP laser has a good hemostatic
effect and allows the surgery to be performed in a bloodless manner.
Especially in children with laryngeal papilloma invading the
supraglottis, the tumor has a rich blood supply. Under this condition,
the KTP laser can be applied to its advantage, resulting in a clear
field and a well-defined cut, reducing collateral
damage\textsuperscript{5,53}.

This study had several limitations. Firstly, the available studies or
data about KTP laser used for LP were very limited (102 patients).
Whereas the cases number achieved the minimal sample number after
conducting a sample size estimation (58 in each group). Secondly, much
data collected by different studies are not consistent between KTP and
CO\textsubscript{2} groups. For example, HPV positive rate, remission
rate, and clearance rate for LP were always presented in the
CO\textsubscript{2} group but rarely appeared in the KTP
group\textsuperscript{1,40}, which made it impossible to compare those
parameters and may potentially influence the results of this study. We
recommend that future studies should report those data for patients with
LP as possible. In addition, the age difference (before surgery) between
CO\textsubscript{2} group and KTP group should be noted. But we believe
due to most studies in CO\textsubscript{2} group did not report the
detail age of patients (419/510 patients), the data of age from the two
groups was not representative and the difference should not be a serious
problem. Thirdly, high-quality comparative evidence is significantly
insufficient as most studies included were at level D. The MINORS scores
of these studies averaged 13.1 and 13.6 in the CO\textsubscript{2} group
and KTP group, respectively, demonstrated the fair quality of evidence.
Future research in the form of standard-evaluation prospective
multicenter randomized controlled studies is required.

\textbf{Conclusion:}

This systematic review demonstrated that the overall clinical outcomes
of KTP laser and CO\textsubscript{2} laser were good for LP and
indicated that KTP laser might result in a superior outcome and lower
postoperative complication rate than CO\textsubscript{2} laser. (Figure
2) In the future, more high-quality randomized controlled studies on the
long-term outcomes of these two techniques are needed to further
evaluate them.

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\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{TABLE 1}

Study List and Details

\textbf{Author}

\textbf{EL}

\textbf{Characteristics}

\textbf{Study}

\textbf{Lesions}

\textbf{Laser setting}

\textbf{Outcomes}

\textbf{Results}

\textbf{Findings}

\textbf{CO\textsubscript{2}}

Castillo et al

D

N/proc:29/NA Age:14 months old-84 years old Gender:10F/19M

Retrospective

Laryngeal Papillomatosis

3-6W continuous power 100-200Hz repeition rate

Complications HPV detected recurrence remission(No recurrence occurred
within two months) clearance(No recurrence occurred within three years)
cure(No recurrence occurred within five years)

n=3/29(10.4\%) n=22/29(75.8\%), mainly HPV6 and HPV11 n=13/29(44.8\%)
n=6/29(20.7\%) n=10/29(34.5\%) n=12/29(41.3\%)

Papillomatosis is characterised as a pathology with an unpredictable
course and with a low probability of malignancy. CO2 laser surgery has
meant a revolution in symptomatic treatment, but there is presently no
curative treatment

Dedo et al

D

N/proc:109/548 Age:NA Gender:43F/66M

Retrospective

Laryngeal Papillomatosis

NA

Compilcations: acute upper airway obstruction anterior glottic webbing
Remission Malignant Degeneration Death

n=2(1.8\%) n=9(8.1\%) n=45(41.3\%) n=3(2.7\%) n=0(0\%)

Treatment of LP with CO2 laser followed by podophyllum painting
represents a clear advance over traditional mechanical methods of
papilloma removal when voice quality, remission rate, and especially
incidence of complications, and occurrences of death are considered

Dedo et al

D

N/proc:244/548 Age:NA Gender:81F/163M

Retrospective

Respiratory Papillomas

20 W continuous power 0.2 seconds to continuous exposure time 1 to 2 mm
spot siz

Compilcations: anterior glottic webbing Remission Clearance Cure
Malignant Transformation Death

n=68(27\%) n=93(37.3\%) n=15(6.1\%) n=43(17.2\%) n=4(1.6\%) n=0(0\%)

A true cure with elimination of all human papilloma viruses
(particularly types 6 and 11) will not be achieved until a uniformly
effective vaccine or antiviral and immunomodulating agents are developed

Holler et al

D

N/proc:6/90 Age:3-17 years old Gender:6M

Prospective

Juvenile-onset Recurrent Respiratory Papillomastosis

NA

Jitter\% Shimmer\% NHR\% CAPE-V

4.57 14.66 0.31 60

the data demonstrate a correlation of worsening voice quality with
increased exposure to the CO2 laser

Koji et al

D

N/proc:9/14 Age:30-56 years old Gender:5M/4F

Prospective validation

Recurrent Respiratory Papillomastosis

2-3w continuous or super pluse power

Recurrence

n=3/9(33.3\%)

CO2 TNFLS is feasible as an in-office surgery for patients with
laryngopharyngeal pathologies. The therapeutic outcome is as expected
with advantage of low patient burden and easy to repeat.

Hu et al

D

N/proc:6/10 Age:NA Gender:NA

Retrospective

Recurrent Respiratory Papillomastosis

5w power in super pulse with 0.05s on and 0.01s off

Complication Incomplete sugery Introlerance

N=0/10 N=2/10 N=1/10

With meticulous patient selection, office-based laryngeal surgery
performed using a carbon dioxide laser appears to be a feasible
treatment option for various types of vocal lesions.

Preuss et al

D

N/proc:64/137 Age:NA Gender:NA

Retrospective

Recurrent Respiratory Papillomastosis

25 W

Complications: glottic webs, scar temporary laryngeal edema airway fire
Recurrence, Malignant transformation, Secondary airway carcinoma

n=4/64(6\%) n=2/64 n=0/64 n=3(4\%)

Laser microsurgery is the preferential treatment modality due to the low
rate of severe scarring and a lower tracheostomy rate as compared with
laryngeal microsurgery with cold instruments.

Robb

D

N/proc:5/11 Age:2.5-23 years old Gender:4F/7M

Retrospective

Recurrent Laryngeal Papilloma

10-30w in intermittent or plused

Complications Remission(more than 1 year) Intractable airway obstruction

n=0/11 n=5/11 n=2/11

What the laser has to offer over other modalities, is the ability
frequently to treat the paediatric larynx, with little risk of
post-operative oedema or bleeding, reduced hospital in-patient stay, and
only mild discomfort. However, even using frequent laser treatment, a
small number of severely affected children will require tracheotomy for
incipient or overt respiratory obstruction

Saleh

D

N/proc:3/NA Age:1-7 years old Gender:NA

Retrospective

Recurrent Laryngeal Papillomatosis

8-10w power

Complications

n=0/3

NA

Mattot et al

D

N/proc:37/595 Age:1-56 years old Gender:11F/26M

Retrospective

Laryngeal Papillomatosis

NA

Complications: carcinoma of larynx bronchial papillomata Remission

n=1/37 n=0/37 n=13/37(35\%)

The number of operations per year does not correlate with eventual
remission

\textbf{KTP}

Burns et al

D

N/proc: 37/55 Age: 23-73 years old Gender: 16F/21M

Prospective Uncontrolled

recurrent laryngeal papillomatosis

15 ms pulse width 5.25--7.5 J/pulse 2 Hz repetition rate 20--80 J/cm2
fluence

Complications \textgreater{}90 regression(4-12weeks) 75\%-89\% and
15\%-74\% regression

N:0/51 n=28/35 n=4/35 to 3/35

KTP laser procedure is useful and safe for recurrent papillomatosis. The
majority of patients had \textgreater{}90\% of lesion regression at 4 to
12weeks postoperative

Hung et al

D

N/proc: 16/79 Age: 23-73 years old Gender: 6F/10M

Prospective

Recurrent respiratory papillomatosis

30--50 ms pulse width 7--8 W 2 Hz repetition rate

Complications VHI-10: (1) before operation; (2) after the first
operation; (3) after 2 to 5 repeated in-office or in-hospital
procedures; (4) after 6 to 10 procedures CPPs: (1) before operation; (2)
after the first operation; (3) after 2 to 5 repeated in-office or
in-hospital procedures; (4) after 6 to 10 procedures GRB: (1) before
operation; (2) after the first operation; (3) after 2 to 5 repeated
in-office or in-hospital procedures; (4) after 6 to 10 procedures

NA (1) 28.3; (2)12.0; (3)10.1; (4)11.0 (1) 6.8; (2)10.5; (3)10.9;
(4)11.3 (1) 5.0; (2)2.4; (3)2.4; (4)1.4

KTP laser can be an effective tool for managing RRP. Voice quality can
be well preserved even after a dozen KTP laser procedures

Kaluskar et al

D

N/proc: 9/NA Age: 39-58 years old Gender: 2F/7M

Prospective Uncontrolled

Inverted papilloma of the nose and paranasal sinuses

8 W of power in continuous mode at least 80\% calibration

Compilcations Recurrence (1 year)

n=0/9 n=1/9

KTP laser is a good option in view of the low rates of recurrerice and
the minimal postoperative morbidity

Wei et al

D

N/proc:18/33 Age:12-68 years old Gender:F3/M15

Retrospective

Recurrence Laryngeal Papilloma

6w of power

Complications Cure Effective(tumour remission rate\textgreater{}50\%)
Ineffective(tumour remission rate\textless{}50\%)

n=0 n=11/17 n=3/17 n=3/17

KTP laser is safe and effective in the treatment of recurrent laryngeal
papilloma

Liu et al

D

N/proc:22/NA Age:3-60 years old Gender:NA

Retrospective

Laryngeal Papilloma

NA

Complications Cure Recuurence

n=2/22 n=19/22 n=3/22

KTP laser treatment is less destructive and it has high accuracy and
precision, also with good hemostatic effect

\textbf{Table 1.} Study List and Details

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{TABLE 2}

Study Characteristics at Preoperation

\textbf{Outcome}

\textbf{KTP laser\textsuperscript{a}}

\textbf{Patients, n}

\textbf{CO\textsubscript{2} laser\textsuperscript{a}}

\textbf{Patients, n}

\textbf{P value\textsuperscript{b}}

Age

49.83+-7.05

91

34.83+-7.36

85

\selectlanguage{english}\textbf{<0.001}

Male

65.61\% (292 of 445)

445

66.25\% (53 of 80)

80

\selectlanguage{english}>0.05

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textsuperscript{a} Values are presented as mean +- SD.
\textsuperscript{b} Between group KTP and group CO\textsubscript{2}.
Bold indicates P\textless{}0.05.

\textbf{Table 2.} Study Characteristics at Pre-operation

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{TABLE 3}

Clinical outcome comparsions

\textbf{Outcome}

\textbf{KTP laser}

\textbf{Surgery, n}

\textbf{CO\textsubscript{2} laser}

\textbf{Surgery, n}

\textbf{P value\textsuperscript{a}}

Cure

87.25\% (89 of 102)

102

75.98\% (389 of 512)

512

\textbf{0.0127}

Complications

2.32\% (2 of 86)

86

17.71\% (88 of 497)

497

\textbf{\textless{}0.0001}

Recurrence

9.80\% (10 of 102)

102

10\% (34 of 340)

340

0.2967

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textsuperscript{a} Between group CO\textsubscript{2} and group KTP.
\textbf{Bold} indicates P\textless{}0.05.

\textbf{Table 3.} Clinical outcome comparisons

Appendix S1 Check list

Appendix S2 Search Strategy

Appendix S3 MINIOR score

\textbf{Figure legends}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1} . PRISMA flow diagram.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2} Comparison of KTP and CO\textsubscript{2} laser for LP\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

