\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Clinical outcomes of conventional HDR intracavitary brachytherapy
combined with complementary applicator-guided intensity modulated
radiotherapy boost in patients with bulky cervical tumor}



\author[1]{Shun Lu}%
\author[2]{Shubin Wang}%
\author[3]{Robert Y Kim}%
\author[4]{Jiayu Zhang}%
\author[5]{Xianliang Wang}%
\author[5]{ Weidong Wang}%
\author[5]{Guiquan Zhu}%
\author[5]{Jie  Zhou}%
\author[5]{Yan Tan}%
\author[5]{Mingyu Tan}%
\author[6]{Minglun Li}%
\author[5]{Gang Yin}%
\author[5]{Jie Li}%
\author[5]{Mei   Feng}%
\author[5]{Jinyi Lang}%
\affil[1]{Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China， Radiation Oncology Key Laboratory Of Sichuan Province}%
\affil[2]{University of Electronic Science and Technology of China School of Medicine}%
\affil[3]{University of Alabama at Birmingham, Birmingham, Alabama, U.S.A}%
\affil[4]{University of Electronic Science and Technology of China School of Medicine, School of Medicine No.2006, Xiyuan Avenue, High‑Tech Zone (West District),}%
\affil[5]{Sichuan Cancer Hospital \& Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China, 2Radiation Oncology Key Laboratory of Sichuan Province,}%
\affil[6]{ University Hospital, LMU Munich, Munich, Germany}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective To investigate the clinical outcomes and toxicity in patients
with locally advanced cervical cancer treated with supplementary
applicator guided-intensity modulated radiation therapy (IMRT) based on
conventional intracavitary brachytherapy (IC/IMRT). Population Large
high risk clinical target volume (HR-CTV) volume (\textgreater{}40cc) at
the time of brachytherapy cervical cancer patients were recruited.
Methods This study is a retrospective analysis of 76 patients with
locally advanced cervical cancer (FIGO IIB-IVA) treated with concurrent
chemo-radiotherapy followed by IC/IMRT between June 2010 and October
2016. External radiotherapy (45 Gy in 25 fractions) with cisplatin
chemotherapy treated before IC/IMRT. The prescription dose for HR-CTV
and IR-CTV were 6 Gy and 5 Gy per fraction for 5 fractions respectively.
Results: Mean HR-CTV was 65.8\selectlanguage{ngerman}±23.6 cc at the time of brachytherapy. D90
for HR-CTV and IR-CTV were 88.7±3.6 Gy and 78.1±2.5 Gy. D2cc for
bladder, rectum, sigmoid and small intestine were 71.8±3.8 Gy, 64.6±4.9
Gy, 63.9±5.3 Gy and 56.7±8.7 Gy respectively. Median follow-up was 85
months (47.9-124.2 months). Five-year local recurrence free survival
rate, metastasis recurrence free survival rate, disease free survival
rate and cancer special survival rate were 87.6\%, 82.4\%, 70.9\% and
76.3\%, respectively. The grade 1+2 gastrointestinal and urinary late
toxicities were 15.8\% and 21.1\%, while grade 3 late toxicities were
3.9\% and 5.2\%, respectively. Neither acute nor late grade 4
gastrointestinal or urinary toxicities were seen. Conclusions: The
combination of ICBT with an applicator-guided supplementary IMRT boost
achieved an excellent local control and overall survival with low
toxicity for bulky residual cervical tumor%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Clinical outcomes of conventional HDR intracavitary
brachytherapy combined with complementary applicator-guided intensity
modulated radiotherapy boost in patients with bulky cervical tumor}

S Lu\textsuperscript{a, b,*}, S-B Wang\textsuperscript{c,*}, RY.
Kim\textsuperscript{d}, J-Y Zhang\textsuperscript{c}, X-L
Wang\textsuperscript{a}, W-D Wang\textsuperscript{a,b}, Guiquan
Zhu\textsuperscript{a,b}, J Zhou\textsuperscript{a}, Y
Tan\textsuperscript{c}, M-Y Tan\textsuperscript{a}, M-L
Li\textsuperscript{e}, G Yin\textsuperscript{a,b}, J
Li\textsuperscript{a,b}, M Feng\textsuperscript{a,b}, J-Y
Lang\textsuperscript{a,b}

\textsuperscript{a} Department of radiation oncology, Sichuan Cancer
Hospital \& Institute, Sichuan Cancer Center, School of Medicine,
University of Electronic Science and Technology of China, Chengdu,
China\textsuperscript{b} Radiation Oncology Key Laboratory of Sichuan
Province, Chengdu, China \textsuperscript{c} School of Medicine,
University of Electronic Science and Technology of China, Chengdu,
China\textsuperscript{d} Department of Radiation Oncology, University of
Alabama at Birmingham, Birmingham, Alabama, U.S.A
\textsuperscript{e}Department of Radiation Oncology, University
Hospital, LMU Munich, Munich, Germany

Corresponding Author: J-Y Lang, Department of radiation oncology,
Sichuan Cancer Hospital \& Institute, Sichuan Cancer Center, School of
Medicine, University of Electronic Science and Technology of China,
Chengdu, China; Radiation Oncology Key Laboratory of Sichuan Province,
Chengdu, China. E-mail: langjy610@163.com

\textbf{* Co-first authors:} Shun Lu and Shu-Bin Wang contributed
equally to this work.\textbf{Abstract:}

\textbf{Objective} To investigate the clinical outcomes and toxicity in
patients with locally advanced cervical cancer treated with
supplementary applicator guided-intensity modulated radiation therapy
(IMRT) based on conventional intracavitary brachytherapy (IC/IMRT).

\textbf{Design} A retrospective cohort study.

\textbf{Setting} Sichuan Cancer Hospital \& Institute, Sichuan Cancer
Center, China.

\textbf{Population} Large high risk clinical target volume (HR-CTV)
volume (\textgreater{}40cc) at the time of brachytherapy cervical cancer
patients were recruited.

\textbf{Methods} This study is a retrospective analysis of 76 patients
with locally advanced cervical cancer (FIGO IIB-IVA) treated with
concurrent chemo-radiotherapy followed by IC/IMRT between June 2010 and
October 2016. External radiotherapy (45 Gy in 25 fractions) with
cisplatin chemotherapy treated before IC/IMRT. The prescription dose for
HR-CTV and IR-CTV were 6 Gy and 5 Gy per fraction for 5 fractions
respectively.

\textbf{Results:} Mean HR-CTV was 65.8\selectlanguage{ngerman}±23.6 cc at the time of
brachytherapy. D90 for HR-CTV and IR-CTV were 88.7±3.6 Gy and 78.1±2.5
Gy. D2cc for bladder, rectum, sigmoid and small intestine were 71.8±3.8
Gy, 64.6±4.9 Gy, 63.9±5.3 Gy and 56.7±8.7 Gy respectively. Median
follow-up was 85 months (47.9-124.2 months). Five-year local recurrence
free survival rate, metastasis recurrence free survival rate, disease
free survival rate and cancer special survival rate were 87.6\%, 82.4\%,
70.9\% and 76.3\%, respectively. The grade 1+2 gastrointestinal and
urinary late toxicities were 15.8\% and 21.1\%, while grade 3 late
toxicities were 3.9\% and 5.2\%, respectively. Neither acute nor late
grade 4 gastrointestinal or urinary toxicities were seen.

\textbf{Conclusions:} The combination of ICBT with an applicator-guided
supplementary IMRT boost achieved an excellent local control and overall
survival with low toxicity for bulky residual cervical tumor.

\textbf{Key words} : Cervical cancer; applicator-guided IMRT boost;
intracavitary brachytherapy; survival; toxicity

\textbf{Tweetable abstract} Applicator guided-intensity modulated
radiation therapy (IMRT) based on conventional intracavitary
brachytherapy (IC/IMRT) technologies showed the excellent local control
and low morbidities in locally advanced cervical cancer that
cannot~be~satisfied by intracavitary brachytherapy.

\textbf{Introduction}

The standard of care for treatment of advanced cervical cancer is the
combination of concurrent chemotherapy with external beam radiation
therapy (EBRT) followed by an intracavitary brachytherapy (ICBT)
boost\textsuperscript{1-4}. This comprehensive treatment achieves a
favorable outcome for cervical cancer patients\textsuperscript{5-7}, but
for patients with bulky irregular shaped tumors, the local recurrence
rate remainedl relatively high \textsuperscript{8-10}.

ICBT plays a crucial role in the radiotherapy for cervical cancer. It
has been shown in large patient series that omission of brachytherapy
results in a dramatic reduction of the curative
chance\textsuperscript{11-14}. Conventional ICBT is typically prescribed
to a defined point based on the Manchester system \textsuperscript{15},
in which the individual tumor size or shape is not taken into account.
Several studies have demonstrated that the dose distribution of
conventional ICBT often fails to cover the entire target volume,
especially in patients with large irregular tumors\textsuperscript{16,
17}, which result in a relatively high relapse rate
\textsuperscript{18}.

3D image-guided brachytherapy has been demonstrated to improve outcomes
in comparison to conventional BT-planning, and the combination of IC/IS
applicators can be incorporated into planning for bulky
tumors\textsuperscript{19, 20}. In locally advanced cervical cancer,
tumors tend to spread laterally along the cardinal ligament. Therefore,
in order to improve the dose coverage of the entire target volume,
previous investigators have made many efforts to develop novel
brachytherapy techniques such as trans-perineal interstitial BT (ISBT)
and trans-cervical interstitial BT with ICBT
(IC/ISBT)\textsuperscript{21, 22}. Previously, the concept of
supplementary IMRT based on conventional ICBT (IC/IMRT) has been
introduced \textsuperscript{23}. Furthermore, proof of principle with
IC/IMRT demonstrated that IC/IMRT is able to supplement radiation dose
to the parametrial tumor extension where ICBT optimized based on image
guidance is unable to cover the target volume \textsuperscript{24 25}.

To date, clinical outcomes with IC/IMRT have not been reported. In the
present study, we retrospectively analyzed the local control (LC),
survival rates and side effects of 76 patients treated with IC/IMRT in
order to further clarify the present and future clinical impact of this
technique.

\textbf{Materials and Methods}

\textbf{Patient Selection}

Between June 2010 and October 2016, a total of 76 patients with primary
cervical carcinomas were treated at Sichuan Cancer Hospital with IMRT
boast based on ICBT after concurrent chemoradiotherapy. All patients had
a large high risk clinical target volume (HR-CTV) volume
(\textgreater{}40cc) at the time of brachytherapy, excluding patient
with adequate coverage of HR- CTV by optimized ICBT. excluding patient
with adequate coverage of HR- CTV by optimized ICBT.

The analysis of the data was performed in October 2020 with a median
patient follow up of 85 months (range 47.9-124.2) and a median patient
age of 48.9±8.3 years. The initial loco-regional staging included
clinical examination under local anesthesia, chest and abdominopelvic
computed tomography (CT) and pelvic magnetic resonance imaging (MRI).
Positron Emission Tomograpy/Computed Tomography (PET/CT) was not done.
The disease was staged according to the 2009 International Federation of
Gynecology and Obstetrics (FIGO) classification. Patients with distant
metastases (except para-aortic lymph nodes) were excluded from this
treatment. All included patients were treated with curative intent. The
clinic-pathological features of the patients are given in Table 1.

\textbf{External beam radiotherapy}

Prior to BT, seventy two patients (94.7\%) were treated with 45 Gy (25
fractions of 1.8 Gy) EBRT using an IMRT technique with 10 MV photons.
Four (5.3\%) patients with advanced bulky disease received 50.4 Gy (28
fractions of 1.8 Gy).

\textbf{Concurrent chemotherapy}

During radiotherapy, cisplatin-based chemotherapy every three weeks (75
mg/ m2) was administered to patients.

\textbf{ICBT combined with IMRT boost (IC/IMRT)}

After whole pelvic EBRT, five fractions of brachytherapy with an IMRT
boost were performed based on the MRI and pelvic examination findings.
The prescription dose for HR-CTV was 6 Gy per fraction. CT and MRI scans
were acquired while the Fletcher CT/MRI compatible applicator (Elekta
AB, Stockholm, Sweden) was in the patient. The applicator was
subsequently fixed to a board, which can slide between the mobile bed,
treatment couch, and computed tomography (CT) couch. According to
GEC-ESTRO recommendations, gross tumor volume (GTV), HR-CTV, and
intermediate risk CTV (IR-CTV) were identified from the fusion of CT and
MRI images. OARs include bladder, rectum, sigmoid colon and small
intestine \textsuperscript{26, 27}. To achieve an ideal combination\selectlanguage{english},the
interval~between~brachytherapy and IMRT boost was to be completed within
6\textasciitilde{}10 minutes. The total cumulative dose of EBRT and
brachytherapy boost were evaluated in terms of equivalent dose in 2 Gy
per fraction (EQD2), using \selectlanguage{greek}α/β \selectlanguage{english}= 3 Gy for OAR and \selectlanguage{greek}α/β \selectlanguage{english}= 10 Gy for
targets. The treatment planning aimed to achieve D90 \textgreater{} 86
Gy for HR-CTV and D90 \textgreater{} 75 Gy for IR- CTV from combined
EBRT and IC/IMRT boost. Dose volume constraints for cumulative dose to
the OAR were mean D2cc \textless{} 90 Gy for the bladder, and mean D2cc
\textless{} 75 Gy EQD2 for rectum and sigmoid.

The IMRT plan was optimized using the ICBT plan base dose plan by an
inverse dose optimization tool which allows the use of DVH constraints
on the total dose of ICBT. A seven-field gantry angle IMRT plan was
devised in order to avoid hotspots when optimizing the boost plan. The
IC/IMRT plan was evaluated three dimensionally to determine the coverage
of the target and the sparing of OARs. HDR brachytherapy treatment was
delivered immediately after the approval of the plan. Its execution
varied between a few minutes to ten minutes according to the source
activity (Figure 1). When HDR brachytherapy treatment finished, the
patient was transferred to the linac (Elekta Synergy) with the
applicator still in patient. The IMRT boost was guided by the applicator
position on Cone Beam CT (CBCT). Therefore, this procedure ensured that
the IMRT plan dose gradients were aligned with the ICBT dose gradients.
The applicator was not removed until the IMRT boost ended in order to
minimize any tissue movement and deformation. This procedure was
repeated two times a week.

\textbf{Analysis of treatment outcome}

Patients were followed for disease related parameters and adverse side
effects every 3 months in the first 2 years, in 6 month intervals for
the next 3 years and then annually. MRI was done every 6 months in the
first 5 years. Complete response (CR) was defined as total resolution of
clinically visible and/or palpable tumor of the cervix and vagina.
Treatment failures were classified according to the site(s) of first
tumor relapse and were defined as primary (cervix, uterine corpus,
vagina, parametrium), pelvic node, or distant metastases. Time intervals
for disease free survival (DFS), local recurrence free survival (LRFS),
metastasis recurrence-free survival (MRFS) and cancer specific survival
(CSS) rates were calculated from the date of diagnosis to the date of
event or last follow-up appointment. Acute toxicities were defined as
those occurring within 90 days after the last treatment date, and late
toxicities were defined as those that occurred more than 90 days after
the last treatment date.

Late toxicity was graded according to site and severity using the
National Cancer Institute CTCAE v4.03 (Common Terminology Criteria for
Adverse Events version 4.03) guidelines. Cox regression models were used
to analyze the association between predictors and time-to-event
outcomes. The Kaplan--Meier test was used to calculate survival curves.
All analyses were performed using SPSS software, version 21 of the SPSS
System for Windows.

\textbf{Result}

\textbf{Targets coverage and OARs doses}

The average D90(EQD\textsubscript{2})of GTV, HR-CTV and IR-CTV was
103.2Gy, 88.7Gy, and 78.1Gy (\selectlanguage{greek}α/β\selectlanguage{english}=10) respectively. V100 of the
prescription dose corresponding to HR-CTV and IR-CTV was 94.1\% and
92.3\%. The mean D\textsubscript{2CC} of the bladder, rectum, sigmoid
colon and small intestine were 71.8Gy, 64.6Gy, 63.9Gy and 56.7Gy,
respectively (Table 2).

\textbf{Local Control and survival}

The median follow-up for all investigated patients was 85 months (range
47.9-124.2). A total of 23 failures were observed. Recurrence in the
primary tumor site occurred in 10 patients. In addition, 2 patients had
recurrence in the pelvic lymph nodes, 13 patients had distant metastases
alone.

For all investigated patients, the local recurrence free survival rate
at 5 years was 87.6\%, metastasis recurrence-free survival at 5 years
was 82.4\%, respectively. The estimated overall actuarial cancer
specific survival rate at 5 years was 76.3\%, respectively. Moreover, 5
years disease free survival rate was 70.9\%, respectively. Analysis of
survival according to FIGO stage is shown in Figure 2 and table S1-4.

\textbf{Side effects and toxicity}

Acute GI symptoms were observed in 48(63.2\%) patients (nausea,
vomiting, loss of appetite, diarrhea) during the period of treatment: 26
(34.2\%) cases of grade 1, 14 (18.4\%) cases of grade 2, 8 (10.5\%)
cases of grade 3. There were 17 (22.3\%) cases of patients with acute
urinary symptoms: 9(11.8\%) cases of grade 1, 6 (7.9\%)cases of grade 2,
2 (2.6\%)cases of grade 3. No grade 4 toxicity was observed. The most
common hematological toxicity was neutropenia in 27(35.5\%) followed by
anemia in 10(13.2\%) and thrombocytopenia in 4(5.2\%).

A total of 15 (19.7\%) patients have gastrointestinal late side effects:
7(9.2\%) cases of grade 1, 5(6.6\%) of grade 2, and 3 (3.9\%) of grade
3. Additionally, a total of 20(26.3\%) cases had urinary late toxicity,
of which 11(14.5\%) cases of grade 1, 5(6.6\%) cases of grade 2,
4(5.2\%) cases in grade 3. No grade 4 chronic toxicity was observed.
Late side effects were mainly radiation cystitis 7(9.2\%), radiation
proctitis 5(6.6\%), hydronephrosis 3(3.9\%), intestinal obstruction
2(2.6\%), and lower extremity edema 3(3.9\%). Actuarial rate for G3 + G4
morbidity was 2.6\%/3.9\% for the GI, 3.9\%/5.2\% for the GU at 3/5
years, respectively.

\textbf{Discussion}

Brachytherapy is an essential part of cervical cancer treatment. It is
able to provide the maximal dose to the target area while minimizing the
dose to OARs. Previous studies demonstrated that ICBT is a safe,
effective modality for cervical cancer\textsuperscript{28}. However,
tumors with large residual disease after EBRT present a therapeutic
challenge. Attempts have been made to improve tumor dose coverage by
ICBT. Optimization of pear shaped isodose configuration is an easy and
simple method but it is limited because of the limited number of source
position. Other dosimetric studies have investigated the possibility
replacing ICBT with IMRT or stereotactic body radiotherapy
(SBRT)\textsuperscript{29-31}. One must also consider the uncertainty of
interfraction and intrafraction motion of the target due to bladder and
rectal filling\textsuperscript{30-32}. Hybrid IC/ISBT is a relatively
new technique using intra-cervical interstitial brachytherapy to improve
the target volume coverage\textsuperscript{8}. Multi-institutional
clinical studies, retroEMBRACE and EMBRACE-I, have investigated a large
number of patients and confirmed favorable clinical outcome and
acceptable toxicity \textsuperscript{20, 33}. EMBRACE-II was launched as
a prospective study based on the outcome results of retroEMBRACE and
EMBRACE-I with IC/ISBT\textsuperscript{34}.

In 2008, Duan et al \textsuperscript{23}and Assenholt et al
\textsuperscript{35}reported that a combination of ICBT with IMRT boost
maintained the dose distribution and characteristics of ICBT while
adequate tumor dose coverage was achieved by supplementary IMRT
(IC/IMRT). Comparative dosimetric studies between conventional ICBT,
optimized 3-D ICBT and IC/IMRT confirmed that IC/IMRT has better target
volume coverage for large tumors while maintaining low dose to
OARs\textsuperscript{35-37}. One unique feature of IC/IMRT is this
treatment is carried out with the applicator in situ to provide spatial
registration and immobilization of the gynecologic organs. After
treatment of the ICBT, the supplementary IMRT plan is executed
immediately at the same position to ensure the accuracy of target
irradiation during the entire treatment process.

Our study included only patients with unfavorable large residual tumor
at the time of ICBT. Therefore, Mean HR-CTV volume was a much larger
volume (65.8 \selectlanguage{ngerman}± 23.6cc) than other studies. The mean HR-CTV volume was 34
± 17cc in Kirisits et al study\textsuperscript{38}, 38 ± 20cc in
Tanderup et al study\textsuperscript{39}, and 55 ± 38cc in
Jurgenliemk-Schulz et al study\textsuperscript{40}.\emph{Ken Yoshida} et
al \textsuperscript{41}demonstrated that classical conventional ICBT is
suitable for the treatment of most HR-CTV size of 36cc or smaller
tumors. For bulky tumors patients who poorly responding to EBRT may
increase the need for more sophisticated brachytherapy, such as
comprehensive interstitial techniques, due to unfavourable geometry at
the time of brachytherapy implant. Therefore, it would seem reasonable
that IC/IMRT is an alternative to the IC/ISBT or ISBT modality to
deliver the boost of dose to the bulky tumors.

The DVH parameters of cervical cancer radiotherapy are related to the
local control rate and side effects. Dimopoulos et
al\textsuperscript{42} retrospectively analyzed 141 cervical cancer
patients with 51 months median follow-up and demonstrated that the
HR-CTV D90 \textgreater{} 87Gy resulted in a LC rate of 96\% compared to
80\% for HR-CTV D90 \textless{} 87Gy. Pötter et al \textsuperscript{8}
reported that the average D90 dose of HR-CTV in 156 patients treated
with HDR-ICBT was 93 Gy, resulting in a 3-year LC rate of 95\%.
Lindegaard et al\textsuperscript{43} reported that patients treated by
HDR-ICBT with the average HR-CTV D90 doses of 91 Gy had an actuarial
3-year pelvic control rate of 85\%. The retroEMBRACE
study\textsuperscript{44} showed that with the systemic usage of IC/IS
the D90 of HR-CTV increased 9Gy from 83 ± 14Gy to 92 ± 13Gy and 3-year
local control rate in patients having a HR-CTV \selectlanguage{english}[?] 30cm\textsuperscript{3}
was 10\% higher in IC/IS group.

In our study, the average D90 doses of HR-CTV and IR-CTV in 76 cases
were 88.7 Gy and 78.1 Gy, respectively. The V100 of HR-CTV was more than
90\%. Estimated Local recurrence free survival rate at 5 years was
87.6\% for all investigated patients, respectively. Estimated metastasis
recurrence free survival rate at 5 years was 82.4\%. The estimated
overall actuarial cancer specific survival at 5 years was 76.3\%, the
disease free survival at 5 years was 70.9\%, respectively.

The side effects of image-guided brachytherapy have been relatively low.
The EMBRACE studies showed that a D2cc~\selectlanguage{english}[?] 75 Gy was associated with
12.5\% risk of fistula and 2.7\% with low dose at 3 years.~A D2cc
\textless{} 65 Gy was associated with a two times lower risk of
proctitis than \selectlanguage{english}[?] 65 Gy in 960 patients\textsuperscript{45}.~ Grade 3 to
4 urinary morbidity was 5.3\% in 1176 patients\textsuperscript{46}.~
French STIC prospective study \textsuperscript{19}showed that 3-D
imaging based plan reduced Grade 3 to 4 toxicities than 2-D plan, 2.6\%
and 22.7\% respectively in 117 patients. Our study showed that the crude
grade 3 late toxicities were 3.9\% gastrointestinal and 5.2\% urinary
system. Neither crude grade 4 acute nor late toxicities were found in
gastrointestinal and urinary systems. Actuarial rate for G3 + G4
morbidity was 2.6\%/3.9\% for the GI, 3.9\%/5.2\% for the GU at 3/5
years, respectively. Our mean D2cc for OARs was comparable with other
studies (bladder 71.8, rectum 64.6, sigmoid colon 63.9 and intestine
56.7 Gy).

Several limitations in our study should be acknowledged. This is a
retrospective and single institutional study. Also, due to time
limitation, an IMRT-QA check was not done before the IMRT treatment was
delivered.

Based on our experience, we would like to emphasize the following
points. The IC/IMRT technique can be logistically challenging if the
procedure is not orchestrated in proper order. First, the time between
ICBT and IMRT should be as short as possible to maintain applicator
stability and patient comfort. Second, complementary IMRT was designed
to compensate the dose of ICBT due to the lack of dose coverage from
ICBT alone, thus the ICBT always contributed the majority of the dosage
in this technique, which is important to reduce the dose for OARs.
Finally, patient selected criteria needs to be defined for using IC/IMRT
in the future. IC/IMRT is potentially less invasive, and a more
applicable treatment than IC/ISBT and ISBT. IC/IMRT is another
alternative technique when IC/ISBT or ISBT is not feasible.

\textbf{Conclusion}

This is the first clinical report of IC/IMRT. Our results showed the
excellent local control and low morbidities in locally advanced cervical
cancer. To validate our finding and compare to other currently wide used
techniques, further well designed prospective clinical trials are
needed.

\textbf{Disclosure of intersets}

The authors have declared that they have no conflict of interest
regarding the present study.

\textbf{Contribution to Authorship:} J-Y Lang and S Lu designed the
study. S Lu is the study project manager. S-B Wang, J-Y Zhang, X-L Wang,
J Zhou , S-Y Deng and M-Y Tan wrote the manuscript and researched data.
W-D Wang, Guiquan Zhu researched data and contributed to discussion. RY.
Kim, M-L Li, M Feng reviewed/edited the manuscript. All authors reviewed
and contributed to the manuscript.

\textbf{Details of ethical approval}

All procedures performed in studies involving human participants were in
accordance with Sichuan Cancer Center the ethical standards of the
institutional research committee and with the 1964 Helsinki declaration
and its later amendments or comparable ethical standards.

\textbf{Funding}

This work was supported by National Key Research and Development Program
of China (grant number, 2017YFC0113100), and Key Research Project of
Science and Technology Department of Sichuan Province (grant number,
2017SZ0013)

\textbf{Acknowledgements}

none

\textbf{Data availability}

Data available on request from the authors.

\textbf{Transparency}

The lead author affirms that the manuscript is an honest, accurate, and
transparent account of the study being reported; that no important
aspects of the study have been omitted; and that any discrepancies from
the study as planned (and, if relevant, registered) have been explained.

\textbf{Supporting Information}

Additional supporting information may be found online in the Supporting
Information section at the end of article.

Appendix \textbf{S1.} Local recurrence free survival of all investigated
patients.

Appendix \textbf{S2.} Metastasis recurrence free survival of all
investigated patients.

Appendix \textbf{S3.} Disease free survival of all investigated
patients.

Appendix \textbf{S4.} Cancer special survival of all investigated
patients.

References

1. Chemoradiotherapy for Cervical Cancer Meta-analysis C. Reducing
uncertainties about the effects of chemoradiotherapy for cervical
cancer: individual patient data meta-analysis. The Cochrane database of
systematic reviews. 2010 Jan 20(1):CD008285.

2. Green J, Kirwan J, Tierney J, Vale C, Symonds P, Fresco L, et al.
Concomitant chemotherapy and radiation therapy for cancer of the uterine
cervix. The Cochrane database of systematic reviews. 2005 Jul
20(3):CD002225.

3. Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M,
et al. Survival and recurrence after concomitant chemotherapy and
radiotherapy for cancer of the uterine cervix: a systematic review and
meta-analysis. Lancet. 2001 Sep 8;358(9284):781-6.

4. Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al.
Concurrent cisplatin-based radiotherapy and chemotherapy for locally
advanced cervical cancer. The New England journal of medicine. 1999 Apr
15;340(15):1144-53.

5. Nakano T, Kato S, Ohno T, Tsujii H, Sato S, Fukuhisa K, et al.
Long-term results of high-dose rate intracavitary brachytherapy for
squamous cell carcinoma of the uterine cervix. Cancer. 2005 Jan
1;103(1):92-101.

6. Nag S, Cardenes H, Chang S, Das IJ, Erickson B, Ibbott GS, et al.
Proposed guidelines for image-based intracavitary brachytherapy for
cervical carcinoma: report from Image-Guided Brachytherapy Working
Group. International journal of radiation oncology, biology, physics.
2004 Nov 15;60(4):1160-72.

7. Potter R, Tanderup K, Schmid MP, Jurgenliemk-Schulz I, Haie-Meder C,
Fokdal LU, et al. MRI-guided adaptive brachytherapy in locally advanced
cervical cancer (EMBRACE-I): a multicentre prospective cohort study.
Lancet Oncol. 2021 Apr;22(4):538-47.

8. Potter R, Georg P, Dimopoulos JC, Grimm M, Berger D, Nesvacil N, et
al. Clinical outcome of protocol based image (MRI) guided adaptive
brachytherapy combined with 3D conformal radiotherapy with or without
chemotherapy in patients with locally advanced cervical cancer.
Radiother Oncol. 2011 Jul;100(1):116-23.

9. Fallon J, Park SJ, Yang L, Veruttipong D, Zhang M, Van T, et al. Long
term results from a prospective database on high dose rate (HDR)
interstitial brachytherapy for primary cervical carcinoma. Gynecol
Oncol. 2016 Oct 29.

10. Tan LT, Potter R, Sturdza A, Fokdal L, Haie-Meder C, Schmid M, et
al. Change in Patterns of Failure After Image-Guided Brachytherapy for
Cervical Cancer: Analysis From the RetroEMBRACE Study. International
journal of radiation oncology, biology, physics. 2019 Jul
15;104(4):895-902.

11. Han K, Milosevic M, Fyles A, Pintilie M, Viswanathan AN. Trends in
the utilization of brachytherapy in cervical cancer in the United
States. International journal of radiation oncology, biology, physics.
2013 Sep 1;87(1):111-9.

12. Gill BS, Lin JF, Krivak TC, Sukumvanich P, Laskey RA, Ross MS, et
al. National Cancer Data Base analysis of radiation therapy
consolidation modality for cervical cancer: the impact of new
technological advancements. International journal of radiation oncology,
biology, physics. 2014 Dec 1;90(5):1083-90.

13. Hanks GE, Herring DF, Kramer S. Patterns of care outcome studies.
Results of the national practice in cancer of the cervix. Cancer. 1983
Mar 1;51(5):959-67.

14. Coia L, Won M, Lanciano R, Marcial VA, Martz K, Hanks G. The
Patterns of Care Outcome Study for cancer of the uterine cervix. Results
of the Second National Practice Survey. Cancer. 1990 Dec
15;66(12):2451-6.

15. Tod M, Meredith WJ. Treatment of cancer of the cervix uteri, a
revised Manchester method. The British journal of radiology. 1953
May;26(305):252-7.

16. Kim RY, Pareek P. Radiography-based treatment planning compared with
computed tomography (CT)-based treatment planning for intracavitary
brachytherapy in cancer of the cervix: analysis of dose-volume
histograms. Brachytherapy. 2003;2(4):200-6.

17. Fellner C, Potter R, Knocke TH, Wambersie A. Comparison of
radiography- and computed tomography-based treatment planning in cervix
cancer in brachytherapy with specific attention to some quality
assurance aspects. Radiotherapy and oncology : journal of the European
Society for Therapeutic Radiology and Oncology. 2001 Jan;58(1):53-62.

18. Murakami N, Kasamatsu T, Wakita A, Nakamura S, Okamoto H, Inaba K,
et al. CT based three dimensional dose-volume evaluations for high-dose
rate intracavitary brachytherapy for cervical cancer. BMC cancer. 2014
Jun 17;14:447.

19. Charra-Brunaud C, Harter V, Delannes M, Haie-Meder C, Quetin P, Kerr
C, et al. Impact of 3D image-based PDR brachytherapy on outcome of
patients treated for cervix carcinoma in France: results of the French
STIC prospective study. Radiotherapy and oncology : journal of the
European Society for Therapeutic Radiology and Oncology. 2012
Jun;103(3):305-13.

20. Fokdal L, Sturdza A, Mazeron R, Haie-Meder C, Tan LT, Gillham C, et
al. Image guided adaptive brachytherapy with combined intracavitary and
interstitial technique improves the therapeutic ratio in locally
advanced cervical cancer: Analysis from the retroEMBRACE study.
Radiother Oncol. 2016 Sep;120(3):434-40.

21. Nomden CN, de Leeuw AA, Moerland MA, Roesink JM, Tersteeg RJ,
Jurgenliemk-Schulz IM. Clinical use of the Utrecht applicator for
combined intracavitary/interstitial brachytherapy treatment in locally
advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2012 Mar
15;82(4):1424-30.

22. Beriwal S, Rwigema JC, Higgins E, Kim H, Houser C, Sukumvanich P, et
al. Three-dimensional image-based high-dose-rate interstitial
brachytherapy for vaginal cancer. Brachytherapy. 2012
May-Jun;11(3):176-80.

23. Duan J, Kim RY, Elassal S, Lin HY, Shen S. Conventional
high-dose-rate brachytherapy with concomitant complementary IMRT boost:
a novel approach for improving cervical tumor dose coverage. Int J
Radiat Oncol Biol Phys. 2008 Jul 1;71(3):765-71.

24. Assenholt MS, Vestergaard A, Kallehauge JF, Mohamed S, Nielsen SK,
Petersen JB, et al. Proof of principle: Applicator-guided stereotactic
IMRT boost in combination with 3D MRI-based brachytherapy in locally
advanced cervical cancer. Brachytherapy. 2014 Jul-Aug;13(4):361-8.

25. Klepczyk L, Shen S, Duan J, Kim RY. Image-Based Intracavitary
Brachytherapy with Concurrent Applicator-Guided IMRT Boost for Cervical
Cancer. Brachytherapy. 2013;12(Suppl 1):S56-S7.

26. Haie-Meder C, Potter R, Van Limbergen E, Briot E, De Brabandere M,
Dimopoulos J, et al. Recommendations from Gynaecological (GYN) GEC-ESTRO
Working Group (I): concepts and terms in 3D image based 3D treatment
planning in cervix cancer brachytherapy with emphasis on MRI assessment
of GTV and CTV. Radiotherapy and oncology : journal of the European
Society for Therapeutic Radiology and Oncology. 2005 Mar;74(3):235-45.

27. Potter R, Haie-Meder C, Van Limbergen E, Barillot I, De Brabandere
M, Dimopoulos J, et al. Recommendations from gynaecological (GYN) GEC
ESTRO working group (II): concepts and terms in 3D image-based treatment
planning in cervix cancer brachytherapy-3D dose volume parameters and
aspects of 3D image-based anatomy, radiation physics, radiobiology.
Radiotherapy and oncology : journal of the European Society for
Therapeutic Radiology and Oncology. 2006 Jan;78(1):67-77.

28. Vordermark D. Radiotherapy of Cervical Cancer. Oncol Res Treat.
2016;39(9):516-20.

29. Albuquerque K TV, Lea J, Ahn C, Richardson D, Miller D, Timmerman R.
A Phase II Trial of Stereotactic Ablative Radiation Therapy as a Boost
for Locally Advanced Cervical Cancer. Int J Radiat Oncol Biol Phys.
2020;106((3)):464-71. .

30. Alektiar KM. Can intensity-modulated radiation therapy replace
brachytherapy in the management of cervical cancer? Point.
Brachytherapy. 2002;1(4):191-2.

31. Dobelbower MC, Shen S, Popple R, Kim RY. Dosimetric comparison of
IMRT to HDR intracavitary brachytherapy for cervical cancer.
Brachytherapy. 2007;6(2).

32. Kilic S, Cracchiolo B, Mahmoud O. Non-brachytherapy alternative in
cervical cancer radiotherapy: Why not? Applied radiation Oncology.
2015;4:11-7.

33.\emph{www.embracestudy.dk}

34. Potter R, Tanderup K, Kirisits C, de Leeuw A, Kirchheiner K, Nout R,
et al. The EMBRACE II study: The outcome and prospect of two decades of
evolution within the GEC-ESTRO GYN working group and the EMBRACE
studies. Clin Transl Radiat Oncol. 2018 Feb;9:48-60.

35. Assenholt MS, Petersen JB, Nielsen SK, Lindegaard JC, Tanderup K. A
dose planning study on applicator guided stereotactic IMRT boost in
combination with 3D MRI based brachytherapy in locally advanced cervical
cancer. Acta Oncol. 2008;47(7):1337-43.

36. Yin G, Wang P, Lang J, Tian Y, Luo Y, Fan Z, et al. Dosimetric study
for cervix carcinoma treatment using intensity modulated radiation
therapy (IMRT) compensation based on 3D intracavitary brachytherapy
technique. Journal of contemporary brachytherapy. 2016 Jun;8(3):221-32.

37. Wang X, Li J, Wang P, Yuan K, Yin G, Wan B. Image guided radiation
therapy boost in combination with high-dose-rate intracavitary
brachytherapy for the treatment of cervical cancer. J Contemp
Brachytherapy. 2016 Apr;8(2):122-7.

38. Kirisits C, Potter R, Lang S, Dimopoulos J, Wachter-Gerstner N,
Georg D. Dose and volume parameters for MRI-based treatment planning in
intracavitary brachytherapy for cervical cancer. Int J Radiat Oncol Biol
Phys. 2005 Jul 1;62(3):901-11.

39. Tanderup K, Potter R, Lindegaard JC, Berger D, Wambersie A, Kirisits
C. PTV margins should not be used to compensate for uncertainties in 3D
image guided intracavitary brachytherapy. Radiother Oncol. 2010
Dec;97(3):495-500.

40. Jurgenliemk-Schulz IM, Tersteeg RJ, Roesink JM, Bijmolt S, Nomden
CN, Moerland MA, et al. MRI-guided treatment-planning optimisation in
intracavitary or combined intracavitary/interstitial PDR brachytherapy
using tandem ovoid applicators in locally advanced cervical cancer.
Radiother Oncol. 2009 Nov;93(2):322-30.

41. Yoshida K, Yamazaki H, Kotsuma T, Takenaka T, Ueda MM, Miyake S, et
al. Simulation analysis of optimized brachytherapy for uterine cervical
cancer: Can we select the best brachytherapy modality depending on tumor
size? Brachytherapy. 2016 Jan-Feb;15(1):57-64.

42. Dimopoulos JC, Lang S, Kirisits C, Fidarova EF, Berger D, Georg P,
et al. Dose-volume histogram parameters and local tumor control in
magnetic resonance image-guided cervical cancer brachytherapy.
International journal of radiation oncology, biology, physics. 2009 Sep
1;75(1):56-63.

43. Lindegaard JC, Fokdal LU, Nielsen SK, Juul-Christensen J, Tanderup
K. MRI-guided adaptive radiotherapy in locally advanced cervical cancer
from a Nordic perspective. Acta Oncol. 2013 Oct;52(7):1510-9.

44. Potter R, Dimopoulos J, Georg P, Lang S, Waldhausl C,
Wachter-Gerstner N, et al. Clinical impact of MRI assisted dose volume
adaptation and dose escalation in brachytherapy of locally advanced
cervix cancer. Radiother Oncol. 2007 May;83(2):148-55.

45. Mazeron R, Fokdal LU, Kirchheiner K, Georg P, Jastaniyah N, Segedin
B, et al. Dose-volume effect relationships for late rectal morbidity in
patients treated with chemoradiation and MRI-guided adaptive
brachytherapy for locally advanced cervical cancer: Results from the
prospective multicenter EMBRACE study. Radiother Oncol. 2016
Sep;120(3):412-9.

46. Fokdal L, Potter R, Kirchheiner K, Lindegaard JC, Jensen NBK,
Kirisits C, et al. Physician assessed and patient reported urinary
morbidity after radio-chemotherapy and image guided adaptive
brachytherapy for locally advanced cervical cancer. Radiother Oncol.
2018 Jun;127(3):423-30.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Abbreviations: FIGO, International Federation of Gynecology and
Obstetrics 2009

HR-CTV, high risk clinical target volume

SD, standard deviation

\textsuperscript{a} maximum diameter of tumor measured by MRI at the
time of brachytherapy

\textsuperscript{b} HR-CTV Volume measured by MRI at the time of
brachytherapy\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Abbreviations: GTV, gross tumor volume; HR-CTV, high risk clinical
target volume; IR-CTV, intermediate risk CTV; SD, standard deviation;
D100, 100\% volume in contouring target receiving the prescription dose;
D90, 90\% volume in contouring target receiving the prescription dose;
V100, percentage volume of contouring target cover by 100Gy isodose
curve; \textbf{D\textsubscript{0.1CC,}} the maximum dose of 0.1 cc in
contouring target; \textbf{D\textsubscript{1CC,}} the maximum dose of 1
cc in contouring target; \textbf{D\textsubscript{2CC,}} the maximum dose
of 2 cc in contouring target;

\textsuperscript{a} EQD2\selectlanguage{greek}\textsubscript{α/β=10}\selectlanguage{english};
\textsuperscript{b}EQD2\selectlanguage{greek}\textsubscript{α/β=3}\selectlanguage{english}

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 1.} The HR CTV contouring with no filling on MRI (A), A
sample dose distribution from intracavitary brachytherapy (ICBT) (B),
IMRT supplement dose (C), B+C plan for one fraction in (D) cross
section, (E) sagittal and (F) coronal planes.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 2. Kaplan-Meier analysis of survival according to FIGO stage.

(A) Local recurrence-free survival (LRFS). (B) Metastasis
recurrence-free survival (MRFS)

(C) Disease free survival (DFS). (D) Cancer specific survival (CSS).

\textbf{Supporting Information}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

\textbf{Table S1.} Local recurrence free survival of all investigated
patients.

Abbreviations: N, Number of patients\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image6/image6}

\end{center}
\end{figure}

\textbf{Table S2.} Metastasis recurrence free survival of all
investigated patients.

Abbreviations: N, Number of patients\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image7/image7}

\end{center}
\end{figure}

\textbf{Table S3.} Disease free survival of all investigated patients.

Abbreviations: N, Number of patients\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image8/image8}

\end{center}
\end{figure}

\textbf{Table S4.} Cancer special survival of all investigated patients.

Abbreviations: N, Number of patients\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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

\end{center}
\end{figure}

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

