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\begin{document}

\title{Magnetic Resonance-High Intensity Focused Ultrasound (MR-HIFU) in
uterine fibroids management: An updated meta-analysis.}



\author[1]{Shilin Zheng}%
\author[2]{Yu Rong}%
\author[3]{Haiyun Zhu}%
\author[4]{Xiaoyu Zhang}%
\author[1]{Xuan Liu}%
\author[1]{Yun Wu}%
\author[5]{Meng Zhao}%
\affil[1]{Wuhan Third Hospital-Tongren Hospital of Wuhan University}%
\affil[2]{Guizhou Provincial People’s Hospital}%
\affil[3]{Linyi County People's Hospital}%
\affil[4]{Affiliated Hospital of Chifeng University}%
\affil[5]{First Affiliated Hospital of Nanjing Medical University}%


\vspace{-1em}



  
  \date{June 11, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Purpose: Magnetic Resonance-High Intensity Focused Ultrasound (MR-HIFU)
has revolutionized the treatment of Uterine fibroids. Usually, they are
associated with prolonged heavy bleeding during the menstrual period,
sacral pain, and increased frequency of UTIs, secondary dysmenorrhea,
constipation, and pregnancy-associated problems. It also impacts usual
activities, which lead to diminished quality of life and rising
healthcare costs. Generally, surgery is the only choice for uterine
fibroids; however, MR-HIFU is an entirely non-invasive novel therapy,
preferred in pregnancy desiring females. Excluding trials with stringent
treatment protocols that are no longer used, the efficacy of Magnetic
Resonance-High Intensity Focused Ultrasound (MRHIFU) therapy for uterine
fibroids is being re-evaluated. Methods: RCTs, Prospective or
Retrospective non-randomized, and cross-over studies that considered
clinically symptomatic uterine fibroid treatment were included. The
author has searched the data in Cochrane Library, PubMed/MEDLINE,
SCOPUS, EMBASE databases. Meta-Analysis was performed using NCSS
software, and data were analyzed at a 95\% confidence level with a level
of precision at 0.05. The NPV\%, tSSS change\%, and QoL were computed.
Meta-Regression was done to evaluate the association between the
different parameters. Results: The overall effect of NPV\% was 70.24,
where the 95\% confidence interval ranged from 61.9\% to 78.16\%. The
overall impact of tSSS\% change is near 50\% after the follow-up of 3
months, 6 months, and 12 months in the included studies. There was a
significant improvement in the health-related quality of life (Hr-QoL).
Conclusion: The efficacy of MR-HIFU therapy was improved as treatment
protocols aimed for total ablation. On the other hand, regulated studies
are required to determine the function of MR-HIFU in the treatment of
uterine fibroids.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Women, mostly in their reproductive age, suffer from uterine leiomyomas,
also called uterine fibroids or uterine myomas. These are benign tumors
of uterine muscle and are clinically detectable with prolonged heavy
bleeding during the menstrual period, sacral pain, secondary
dysmenorrhea, constipation, increased frequency of UTIs, and
pregnancy-associated problems\textsuperscript{1}. About 25\% of women
are clinically symptomatic\textsuperscript{2}. Fibroids may affect
fertility, thereby negatively influencing a woman who desires pregnancy.
These uterine fibroids also impact the usual activities, leads to
diminished quality of life and increasing healthcare
costs\textsuperscript{3}. Although surgeries like hysterectomy are the
gold standard for most women\textsuperscript{4}, this approach is not
the prime choice for women who want to conceive. Enucleation via
laparoscopy is a uterine-conserving treatment. Medical treatment options
are also available and applied, but their aftermath is sizeable as it
results in the recurrence of leiomyomas. Non-invasive procedures are
making ground in recent years because of fewer complications, patient
compliance, short hospital stay, and cost-effectiveness. They include
uterine artery embolization (UAE) and Magnetic Resonance-High Intensity
Focused Ultrasound (MR-HIFU)\textsuperscript{5-6}.

In place of uterine conserving treatment and fertility, however, UAE
leads to a potential reduction of the ovarian reserve. Even though it is
an attractive efficacious treatment choice, its implication is confined
only to pre-or post-menopausal women.

MR-HIFU is a non-invasive ablative novel therapy. The process of MR-HIFU
involves coagulative necrosis of the fibroid by thermal effect and no
disruption to the adjacent structures. There are no bleeding or drug
side effects after this treatment modality\textsuperscript{7}. Usually,
tissue necrosis occurs when subjected to 43\selectlanguage{ngerman}°C or more for at least an
hour; however, the necrosis can occur within a second if subjected to
56°C or more \textsuperscript{8,9}. Two real times guided HIFU
treatments are available; ultrasound-guided and MRI-guided. The
ultrasonography-guided HIFU has a low resolution and limited precision
for targeting and visualizing the adjacent structure's details.
Simultaneously, MRI-guided HIFU has a high resolution allowing detection
of even a tiny thermal increase outside the target points before any
tissue damage\textsuperscript{10-11}. Various studies have also shown
that MR-HIFU effectively eradicates multiple uterine fibroids and leads
to a reduction in the non-perfused volume (NPV) of fibroids with no side
effects\textsuperscript{12}.

Even after the effective therapy of MRI guided HIFU, all patients are
not eligible for this treatment modality. Funaki type 3 fibroids are
challenging to treat because of high T2 signal intensity and high BMI of
women are the significant reasons for excluding this treatment option
for uterine fibroid \textsuperscript{13}.

\emph{Rationale:} Several studies on the efficacy of MRHIFU therapy for
uterine fibroids have been released to date. Overall, they found that
MRHIFU successfully reduces symptoms, but there was a high rate of
re-intervention\textsuperscript{14--17}. However, trials that used
restrictive treatment methods that are no longer in use in clinical
practice influenced the findings of these analyses.

\emph{Objectives:} The aim was to re-evaluate the efficacy of MR-HIFU in
reducing fibroid-related symptoms using treatment protocols that focused
solely on total ablation. We also looked at care failures and technical
performance as assessed by the post-treatment NPV percent. We also
looked at the disease-specific quality of life, re-intervention rates,
stability, fertility, costs, and fibroid shrinkage.

\textbf{Methods}

We followed the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) normative recommendations in this study with the
registration number WU \# RC/IRB/2020/1040.

\emph{Eligibility Criteria:}

For inclusion, studies on MR-HIFU treatment of women with clinically
symptomatic uterine fibroids were reviewed. Treatment procedures that
did not target complete ablation (except for a five-mm protection margin
from the serosal surface) or ultrasound-guided HIFU systems were ruled
out.

The RCTs, prospective or Retrospective non-randomized, and cross-over
studies that considered the treatment of clinically symptomatic uterine
fibroids were included. The studies that did not have treatment
protocols regarded as complete removal of fibroid or used
ultrasound-guided HIFU were excluded. Also, animal studies, case
reports, and studies not reporting NPV were excluded.

\emph{Data Search:}

The studies were searched in Cochrane Library, PubMed/MEDLINE, SCOPUS,
EMBASE databases. Six hundred eighty-four articles were searched, out of
which 230 were excluded because they were either duplicated or book
chapters. The full article found in the database was 82, out of which
the authors removed 73 articles. The reasons for eliminating these
articles are mentioned in Table 1. The articles included in
meta-synthesis were 11. Articles of the past five years were considered,
that is, from 2014 to 2019.

\emph{Data Extraction:}

Data were derived separately from all qualifying studies by the same two
scientists. A description of findings table was developed, which
included (a) research characteristics such as authors, year of
publication, study style, MRHIFU method, sample size, and follow-up
time; (b) Treatment parameters: NPV percent, patient eligibility
percentage, number of technological errors, use of bowel-interference
reduction methods, and sonication duration are all metrics to consider.
(c) primary outcome: reduction of fibroid-related symptoms, preferably
as measured by the validated disease-specific Uterine Fibroid Symptom
and Quality of Life Questionnaire (UFS-QoL); (d) secondary outcomes:
Health-Related Quality of Life (HRQL), as measured by the UFS-QoL
questionnaire, fibroid shrinkage as measured by follow-up MR imaging,
and the occurrence of any (serious) adverse events.

The outcomes analyzed were NPV\%, defined by the formula: (non-perfused
volume/fibroid volume)*100\textsuperscript{25-27}. Fibroid shrinkage is
defined as the reduction in the size of the uterine fibroids after
MR-HIFU. A higher transformed Symptom Severity Score (ISS) indicates
more significant symptom severity\textsuperscript{28}. Health-related
quality of life concerning uterine fibroid comprises questions asked on
a five-point Likert scale, and the score is transformed in numeric from
0 to 100\textsuperscript{29}. The patient who had to undergo a second
intervention after MRI-HIFU treatment for uterine fibroid related
problems was considered in reintervention percentage.

Skin burns, menstrual bleeding or unexplained discharge, cystitis,
urinary obstruction, constitutional complications, nerve injury, or
discomfort for more than seven days were all considered minor adverse
events. Patients that needed a second injection due to fibroid-related
symptoms were included in the re-intervention percentage (second
MR-HIFU, hysterectomy, myomectomy, or UAE).

Disagreements are settled by dialogue or consultation with a third
author. Several reports of a single clinical trial were available, the
most recent publication was used as the guide, and additional
information was gleaned from secondary journals. We tried to reach the
relevant authors by submitting an e-mail with a submission for
supplementary data if results were unavailable. A second e-mail was sent
if there was no response after seven days.

\emph{Proof quality and the possibility of bias}

Two reviewers separately measured the level of proof in all publications
using the Oxford Centre for Evidence-based Medicine (OCEBM)
recommendations. A Delphi methodology was used to build an 18-criterion
method to determine the consistency of the case series. A score of 14 or
higher showed high efficiency. Dissension was used to identify and
address discrepancies. When the two authors could not agree, a third
author was contacted.

The articles that were considered had applied similar inclusion
criteria: patients of more than 18 years of age or at pre-or
peri-menopausal state. These studies have excluded patients in whom MRI
with gadolinium is contraindicated or pregnant women. Chen et
al\textsuperscript{. 15}, Tung S L et al\textsuperscript{. 16}, Jeong J,
H et al\textsuperscript{. 17} and Tan N et
al.\textsuperscript{20}excluded uterine fibroids larger than 10 to 12
cm. Funaki Type 3 fibroid was also excluded in Chen et
al\textsuperscript{. 15}, Tung S L et al\textsuperscript{. 16}, Jeong J
H et al\textsuperscript{. 17} and Park M J et al.\textsuperscript{22}.
Besides, Jeong J H et al\textsuperscript{. 17} also included the
effectiveness of MR-HIFU in patients with concomitant adenomyosis. The
characteristics of these studies are tabulated in Table 2.

Meta-analysis was performed using NCSS software. The data were analyzed
at a 95\% confidence level with a level of precision at 0.05. The NPV\%,
tSSS change\%, and QoL were computed. Meta-Regression was done to
evaluate the association between the different parameters.

\textbf{Results}

\emph{Literature search}

Six hundred eighty-four articles were searched, out of which 230 were
excluded because they were either duplicated or book chapters. The full
article found in the database was 82, out of which the authors removed
73 articles. The reasons for eliminating these articles are mentioned in
Table 1. The articles included in meta-synthesis were 11. Articles of
the past five years were considered, that is, from 2014 to 2019.

\emph{Characteristics of the study and data extraction}

The articles that were considered had applied similar inclusion
criteria: patients of more than 18 years of age or at pre-or
peri-menopausal state. These studies have excluded patients in whom MRI
with gadolinium is contraindicated or pregnant women. Chen et
al\textsuperscript{. 15}, Tung S L et al\textsuperscript{. 16}, Jeong J,
H et al\textsuperscript{. 17} and Tan N et
al.\textsuperscript{20}excluded uterine fibroids larger than 10 to 12
cm. Funaki Type 3 fibroid was also excluded in Chen et
al\textsuperscript{. 15}, Tung S L et al\textsuperscript{. 16}, Jeong J
H et al\textsuperscript{17} and Park M J et al.\textsuperscript{22}.
Besides, Jeong J H et al\textsuperscript{. 17} also included the
effectiveness of MR-HIFU in patients with concomitant adenomyosis. The
characteristics of these studies are tabulated in Table 2.

\emph{Evidence Quality}

Except for one cross-over study, where only the first step was included
in our review, all included trials were case series. According to the
OCEBM standards of data, all of the included experiments had a degree of
proof of IV. Using the 18-criteria tool, the consistency of the proof
varied from 9 to 16 points, suggesting significant variations in quality
between the included tests. The articles included in meta-synthesis were
11. Furthermore, the included studies did not adequately disclose the
various statistical parameters, necessitating the estimation of standard
deviations. However, where experiments with imputed standard deviations
for all result parameters were excluded, predictions for standard
deviation imputation were found to be sufficiently robust.

\emph{Technical Parameters}

\emph{Bowel-interference mitigation strategies}

The overall effect of NPV\% was 70.24, where the 95\% confidence
interval ranged from 61.9\% to 78.16\%. The p-value after
meta-regression was less than 0.05 (0.023), indicating that the use of
bowel interference mitigation strategy results in higher NPV\% ``(Fig
1)''.

\emph{Time spent in treatment}

11 studies recorded a mean sonication time of 146.2 minutes. The
sonication time that took the least amount of time was the method used
by Chongqing\textsuperscript{18}. The latest findings have shown that
extended patient cohorts have shorter waiting periods and that the total
treatment period has declined\textsuperscript{19-22}.

\emph{NPV percentage:}

The included studies show that the overall effect of tSSS\% change is
nearly 50\% after a follow-up of 3 months, 6 months, and 12 months in
the included studies. The meta-regression showed no association between
NPV\%, fibroid shrinkage, and tSSS\% change ``(Fig 2)''.

\emph{Health-Related Quality of Life (HRQL)}

There were only three studies that evaluated the health-related quality
of life. The quality of life improved after the follow-up, and the
combined effect revealed a better quality of life ``(Fig 3)''.

\emph{Fibroid shrinkage}

The fibroid shrinkage was also significant in the studies included for
review \textsuperscript{15, 27,39}. After MR-HIFU therapy, all studies
demonstrated average fibroid shrinkage. Only minor variations were seen
when stratified by follow-up type. Three researches, however, found a
significant impact of time on fibroid shrinkage percentage. NPV percent
was not statistically correlated with fibroid shrinkage (p=0.012) in an
exploratory meta-regression study. At the 6-month follow-up, there was a
slight difference/trend, indicating a favorable relationship.

\emph{Costs}

The writers did not mention any cost-related results. As a result,
assumptions about cost-effectiveness cannot be drawn based on the
studies used.

\emph{Adverse Events}

Just one of the researches included in this review did not use AE as an
endpoint parameter\textsuperscript{13}. 124 of 1360 patients (9.1\%) had
an adverse reaction to one of the 1360 therapies studied. During the
follow-up period, 120 AEs were minor and self-limiting. Just two
patients (0.3\%) had a severe adverse effect (SAE), one of which was a
deep venous thrombosis (DVT), and the other was a third-degree skin
burn. Two of the most recent studies listed these SAEs (patient
enrollment between 2005 and 2009)\textsuperscript{24,39}. Sonalleve and
ExAblate had a significant gap of (S) AE stratification, 18.4 percent,
and 6.7 percent, respectively. Meta-regression verified that the
difference between Sonalleve and ExAblate was statistically significant
(p \textless{}0.05). None of the other covariates studied (NPV percent,
sonication time) was linked to adverse outcomes. However, not many
serious adverse events were reported in the study.

However, a follow-up MRI is expensive and not required. Similarly,
re-interventions were found in two studies that showed reintervention
needed in 18-24\% of patients.

\textbf{Discussion}

This meta-analysis aimed to evaluate the effectiveness of MRI-HIFU on
patients with uterine fibroids. The results showed that there was an
overall decrease in NPV\% and tSSS\% change. The health-related quality
of life among patients with uterine fibroids also improved with
follow-up; however, this was seen only in three studies and needs to be
assessed further. Studies involved in the meta-analysis have also
proclaimed improved reproductive outcomes. It has come to light that
reintervention was needed in 18-24\% of patients. This meta-analysis has
included studies that have focussed on complete ablation for looking at
the overall effect of MR-HIFU.

The overall level of data, which was low to moderate, affected all of
the outcome criteria examined in this study. For inclusion, only
non-randomized, non-comparative trials were available. The sources of a
high risk of prejudice are linked to the sample designs themselves:
insufficient documentation of loss of follow-up and the possibility of
selection bias.

Increased expertise improves care effectiveness by reducing technical
errors and treatment time in extended patient cohorts. Xu et al.
registered the shortest sonication duration, suggesting that the
Chongqing method could increase treatment effectiveness. The pooled NPV
percent immediately after MR-HIFU was 70.24 percent, which is higher
than other reviews\textsuperscript{14,18}, owing to the lack of
stringent treatment protocols. The distribution of dispersed points into
two classes showed a remarkable asymmetry in our findings.
Unfortunately, we were unable to provide a complete explanation. Through
bowel-interference avoidance methods, only a minor disparity was
discovered, meaning that this may lead to a higher NPV percent.

The pooled tSSS declined on average and continued to increase during
follow-up. There was no data available for more than a year. MR-HIFU was
not linked to other therapeutic choices in any of the trials included.
At a 3-months follow-up, Jacoby et al. compared MRgFUS to
placebo\textsuperscript{21} and found that the MRgFUS community had a
more significant tSSS decline, -31 vs. -13 points. We looked for other
uterine fibroid studies that used the UFS-QoL questionnaire to equate
the tSSS of MR-HIFU to other treatment alternatives (UAE, hysterectomy,
and myomectomy). Similarly, studies by Spies JB\textsuperscript{30} and
Manyonda IT\textsuperscript{31} have also reported a decrease in tSSS\%
change in myomectomy and hysterectomy, and the present meta-analysis has
indicated an overall tSSS\% change of 49.27, which is comparable to
hysterectomy and myomectomy. Few studies reported health-related quality
of life, but the enrolled studies have improved uterine fibroid-related
quality of life.

Fibroid shrinkage was shown in all the studies, and the percentage of
shrinkage ranged over time, indicating that fibroids will continue to
shrink in volume for at least a year. The relationship between fibroid
shrinkage and NPV percent was marginally significant, implying that a
higher NPV percent could lead to more fibroid shrinkage. Please keep in
mind that a follow-up MRI exam is costly and mostly needless.

The reintervention has seen in Tan et al.\textsuperscript{20}, Mindjuk
et al.\textsuperscript{19}, and Chen et al.\textsuperscript{16} was 9\%,
12.7\%, and 0.9\%, respectively, while other studies did not report the
need for reintervention on the follow-up period. This particular result
pointed at the efficacy of the procedure. The procedure of MR-HIFU is
non-invasive and does not indicate any effect on the reproductive
outcome of the patients after the treatment. None of the studies has
included the reproductive outcome and hence raised concern. However,
studies by Lee JS\textsuperscript{32} and Cheung
VY\textsuperscript{33}have shown no effect on the Anti-Mullerian
Hormone, indicating that women can try for pregnancy after treating
uterine fibroids.

Just two SAEs were identified in older studies\textsuperscript{24,39},
which may be clarified by a slight learning curve effect when MR-HIFU
was first used in clinical practice {[}13{]}. As AE was stratified by
method, trials using the Sonalleve system had slightly more AE than
trials using the ExAblate device \textsuperscript{14,15,17,22}. Two
Ex-Ablate reports, on the other hand, reported `no unforeseen or major
AE,' implying under-reporting\textsuperscript{16,27}. Furthermore, there
is no agreement about how to define AE in the context of MR-HIFU. For
example, although irregular vaginal discharge is often classified as AE,
fibroid expulsion was identified as a common finding in 21\% of ExAblate
patients \textsuperscript{19}. Surprisingly, a Sonalleve study
classified constitutional symptoms as AE, although none of the other
studies did \textsuperscript{22}. Although a reporting bias may clarify
the disparity in AE between Sonalleve and ExAblate, more research is
needed in the future.

These treatment modalities may have shown to be cost
effective\textsuperscript{34-38} but not included in this analysis.
MR-HIFU can be considered a cost-effective treatment for patients ready
to pay.

Methodological flaws were to blame for the meta-analysis's flaws.
Standard deviations were often estimated. There was a lack of follow-up
in some trials, and some sub-studies had different sample
sizes\textsuperscript{41}. As a consequence, the findings should be
viewed with caution. Furthermore, since the findings are based on
published means rather than actual patient records, the ecological
fallacy may have influenced the results. We questioned if we should
generalize our findings because of the significant and often mysterious
heterogeneity in each outcome parameter. However, since we used a
random-effects model for meta-analysis\textsuperscript{40}, this
approach is accurate.

Even though MR-HIFU has been used to treat uterine fibroids for 14
years, it is still not widely used or reimbursed worldwide. The gold
standard for obtaining reimbursement is a randomized clinical
experiment, and one is currently underway to compare UAE and
MR-HIFU\textsuperscript{42}. However, they had difficulty selecting
volunteers, and some patients refused to be randomly assigned. As a
result, randomized experiments are challenging to perform and face
statistical difficulties. More extensive retrospective randomized cohort
trials with longer follow-up are needed to establish the role of MR-HIFU
in the management of symptomatic uterine fibroids before it can be used
in routine clinical care.

\textbf{Conclusion}

The present meta-analysis has shown that it is an entirely effective
non-invasive treatment for uterine fibroids; this is evident by reducing
the overall NPV, tSSS\% change, and decrease in the fibroid size. The
studies focussing on the impact of HrQoL are needed in this aspect. The
trials focusing on the reproductive outcomes should focus on the
recommendation of this therapy for uterine fibroids.

Acknowledgment: None Declared.

Statement of Ethics: All procedures performed in the study were in
accordance with the institutional and/or national research committee's
standards and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards.

Conflict of Interest Statement: The authors declare that they have no
competing interests.

Funding Sources: No Funding was received.

Author Contributions: SZ and YR: Concept and designed the study, HZ and
XZ: analyzed data and drafting of the manuscript; XL and YW: Collected
the data and helped in data analysis; MZ: Proofreading and final editing
along with guarantor of the manuscript.

``All authors read and approved the final version of the manuscript''.

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\textbf{Figure Legends}

Figure 1: Forest Plot of studies included for NPV\%.

Figure 2: Forest Plot of studies included for tSSS change\%.

Figure 3: Forest Plot of studies included for Disease-specific quality
of life.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1-1/Figure-1-1}

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-1/Figure-2-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3-1/Figure-3-1}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Tables New.docx`  available at \url{https://authorea.com/users/730196/articles/710059-magnetic-resonance-high-intensity-focused-ultrasound-mr-hifu-in-uterine-fibroids-management-an-updated-meta-analysis}

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