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\begin{document}

\title{BLADDER FUNCTION AFTER CONSERVATIVE SURGERY AND HIGH-DOSE-RATE
BRACHYTHERAPY FOR BLADDER-PROSTATE RHABDOMYOSARCOMA.}



\author[1]{Sara Lobo}%
\author[2]{Mark Gaze}%
\author[3]{Olga Slater}%
\author[2]{Peter Hoskin}%
\author[2]{Gordon Sands}%
\author[2]{Tracy Sullivan}%
\author[1]{Alexander Cho}%
\author[2]{Gemma Eminowicz}%
\author[1]{Naima Smeulders}%
\affil[1]{Great Ormond Street Hospital For Children NHS Foundation Trust}%
\affil[2]{University College London Hospitals NHS Foundation Trust}%
\affil[3]{Great Ormond Street Hospital For Children NHS Trust}%


\vspace{-1em}



  
  \date{June 07, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Conservative-surgery (CS) brachytherapy (BT) techniques for
local therapy in bladder-prostate rhabdomyosarcoma (BP-RMS) seeks to
retain organ function. We report bladder function after high-dose-rate
(HDR) BT combined with targeted CS for any vesical component of BP-RMS.
Procedure: Prospective cohort of all BP-RMS patients between 2014-19
receiving HDR-BT (Iridium-192, 27.5Gy in 5 fractions) with/without
percutaneous endoscopic-polypectomy (PEP) or partial cystectomy (PC).
Functional assessment included frequency-volume-chart, voided volumes,
post-void residual, flow studies, continence status and ultrasound
scanning; abnormalities triggered video-urodynamics. Results: Thirteen
patients (10 male), aged 9 months to 4 years (median 23 months),
presented with localised fusion-negative embryonal BP-RMS measuring
23-140mm (median 43mm) in cranio-caudal extent. After induction
chemotherapy, local treatment consisted of PC+BT in three, PEP+BT in
four and BT alone in six. At a median 3\selectlanguage{ngerman}½ years (range 1¾-7 years) follow
up, all were alive without relapse. At a median age of 6 years (4-9
years), the median bladder capacity was 86\% (47\%-144\%) of that
expected for age, including 75\% (74-114\%) after PC. There was no
relation to radiation dose to the bladder. Complications occurred in
two: one urethral stricture and one vesical decompensation in a patient
with pre-existing high-grade VUR. The remaining patients are dry by day;
five with anticholinergic medication for urinary urgency. Three patients
are enuretic. Conclusions: Day-time dryness at a median 3½ years after
CS-HDR-BT was achieved in 92\%, with 85\% voiding urethrally, and 62\%
attaining day-and-night continence aged 4-9 years. We report reduced
open surgery, with minimally-invasive percutaneous surgery with HDR-BT
or brachytherapy alone being suitable for many.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction}

With over 80\% long-term survival after bladder-prostate
rhabdomyosarcoma (BP-RMS), attention has turned to reducing the
long-term consequences of treatment while maintaining outcomes.
Management has moved away from upfront radical surgery in the 1970s to
initial biopsy, systemic chemotherapy and surgical resection and/or
radiation therapy for local control. The goal of simple organ
preservation has also progressed to functional maintenance. In the
1990s, the impact of external beam radiotherapy (EBR) on bladder
function was exposed. Yeung et al observed normal bladder dynamics only
in those managed without EBR for pelvic RMS. Raney et al and Hays et al
documented bladder dysfunction in 30\% and 47\% of those receiving EBR
compared to 11\% treated without radiation for BP-RMS. Newer approaches,
such as brachytherapy (BT), seek to reduce the long-term impact of
radiotherapy on the surrounding normal organs, while still delivering
high doses of radiation to the target volume. Today, conservative
surgery-brachytherapy (CS-BT) is the preferred local therapy for
BP-RMS{[}6,7,8,9{]}, where suitable. A deliberate incomplete surgical
resection is combined with brachytherapy to sterilise the remaining
tumour cells, but preserve organ function.

Different BT regimens have evolved. The total dose of radiation may be
delivered in one treatment or as two or more fractions depending upon
dose rate. Low-dose-rate (LDR-BT) delivers the radiation dose
continuously over several days{[}6{]}, but for children compliance and
parental radiation exposure are challenging. Pulsed-dose-rate (PDR-BT)
exposes the source in hourly pulses{[}11{]} and has similar challenges
to LDR-BT in the paediatric population. High-dose-rate (HDR-BT) involves
briefly passing a radioactive source via flexible cannulae into the
tumour to deliver the radiation dose over just a few minutes{[}10{]}.
Because the rate of delivery is rapid it is potentially more damaging to
surrounding normal tissues and therefore has to be delivered in several
exposures (fractions) to allow normal tissue repair between fractions.

Following conservative surgery and LDR-BT or PDR-BT, day- and night-time
dryness is reported in 72\% of those aged more than 6 years, who did not
require cystectomy for vesical failure after completing treatment for
BP-RMS{[}7{]}. The aim of this study is to report the medium-term
bladder function after CS-BT in a prospective cohort of children treated
for BP-RMS using fractionated HDR-BT.

\textbf{Methods}

With institutional approval, all BP-RMS patients treated by interstitial
HDR-BT from 2014 to 2019 were included. Case records were prospectively
collected. Patients were treated on the EpSSG RMS 2005 protocol{[}12{]}:
after 3 cycles of chemotherapy (iFosfamide, Vincristine, Actinomycin D
with or without Doxorubicin), the response to chemotherapy is appraised
and local therapy options are considered on a case by case basis.

\textbf{Selection criteria}

Patients' suitability for a conservative approach was determined by a
combination of imaging, digital and cysto-urethroscopic examination
under anaesthesia and histology. An initial MDT reviewed the pathology,
diagnostic and re-assessment imaging for tumour size, location and
extent, histological subtype/fusion status and lymph node involvement.
Likely candidates underwent examination under anaesthesia jointly by the
surgeons and oncologists. The vesical extent of the tumour was
specifically assessed histologically by endoscopic biopsies mapped to
different sites in the bladder, using a cysto-urethroscopic or
percutaneous approach (described below). All patients were discussed at
National Advisory Panel. Involvement of more than a third of the bladder
above the trigone or tumour size greater than 5 cm following induction
chemotherapy and surgery (if required), lymph node or distant metastases
were contra-indications for a conservative procedure. There were three
forms of CS-BT: partial cystectomy of the vesical component and
brachytherapy (PC+BT), percutaneous endoscopic polypectomy and
brachytherapy (PEP+BT) or interstitial HDR-BT alone.

\textbf{Partial cystectomy}

For tumours involving the bladder cranial to the trigone, partial
cystectomy was required for this portion of the tumour as it is not
consistently covered by the interstitial HDR-BT system described below.
Through a Pfannenstiel incision the bladder was opened. While surgery
sought to achieve a microscopically tumour-free (``R0'') margin
cranially, a deliberate macroscopically incomplete (``R2'') resection
was intended at the trigone/bladder neck. Surgery avoided dissection to
the level of the prostate, in the knowledge that this area could be
reliably treated by HDR-BT and in order to prevent the genitourinary
sequelae of radical surgery at the bladder neck. Ureteric reimplantation
was not required. Regional lymph nodes were sampled as part of the
procedure.

\textbf{Percutaneous Endoscopic Polypectomy}

For patients with BP-RMS confined to the prostate and baldder neck up to
the level of the trigone, open surgery was not required. However, those
with large exophytic tumour polyps, which risk obstructing voiding, were
offered percutaneous endoscopic laser polypectomy. Under cystoscopic
vision (9.5Fr cystoscope, Storz\selectlanguage{ngerman}®), a suprapubic needle puncture into the
bladder above the tumour allowed placement of a 0.035Fr Sensor
PTFE-Nitinol guidewire (Boston Scientific®). The tract was dilated by
7Fr rigid dilator (Cook®) followed by a Nephromax balloon (Boston
Scientific®). Via a 18Fr or 30Fr Amplatz sheath (Boston Scientific®), a
15Fr or 20.8Fr R.Wolf® nephroscope allowed any tumour polyps to be
assessed in terms of their potential to create a ball-valve effect over
the bladder neck and posterior urethra. Holmium:YAG laser (Cook®) at
0.5-1J and 5-15Hz long-setting allowed the stalk of the polyp to be
coagulated and divided. The polyp was extracted via the Amplatz sheath
preventing contamination of the tract. This suprapubic access was also
used to obtain bladder ``mapping'' biopsies for patients whose urethra
was too narrow to accept the biopsy cystoscope.

\textbf{High-rate-dose brachytherapy}

For brachytherapy alone or after conservative surgery, cannulae were
inserted percutaneously through the perineum under general anesthesia
with ultrasound guidance. Post-implantation computed tomography
(sometimes supplemented by fusion with pre-procedural magnetic resonance
imaging (MRI)) was used for 3-dimensional treatment planning with
accurate delineation of the clinical target volume (CTV) and the organs
at risk (OAR). Following optimisation of treatment plans and quality
control, 27.5Gy in 5 fractions were administered over three days using
HDR Iridium-192 afterloading via the temporary cannulae{[}13,14,15{]}.

For this study, the doses are reported based on the day 1
post-implantation CT scan. CTV and OAR were contoured by the oncologist
and radiation doses calculated using the Nucletron Oncentra treatment
planning system (TG-43 dose calculation method{[}16{]}). The doses
reported were the D90 (the minimum dose to 90\% of the volume) for the
CTV, D2cm\textsuperscript{3} doses (the minimum dose received by the two
cubic cm of tissue that receives the highest dose) for the bladder, and
D0.1cm\textsuperscript{3} doses (the minimum dose received by 0.1 cubic
cm of tissue that receives the highest dose) for the urethra. All doses
were converted to EQD2 doses, taking 2.8Gy as the alpha beta ratio for
the CTV and 3Gy for OAR{[}15{]}.

If the likely proximity of radiation field justified, an oophoropexy was
offered to female patients before brachytherapy.

\textbf{Post-treatment Assessment}

On completing treatment, patients commenced surveillance imaging as per
RMS2005 protocol{[}12{]} for recurrence and complications. In addition,
a multidisciplinary clinic was established by the surgeons and
oncologists to jointly review BP-RMS patients. A full history,
examination and a systematic bladder function assessment were obtained
for all, including frequency-volume-chart, voided volumes,
post-void-residual (PVR) volume, flow studies, continence status and
ultrasound scanning of the upper tracts and bladder. If a problem was
identified, invasive video-urodynamics were performed. The expected
bladder capacity for age (EBCA) was calculated based on the formula 30ml
+ (30ml times age in years) for children above 2 years of age{[}17{]}
and 38ml + (2.5ml times age in months) for children less than 2
years{[}18{]}. Patients underwent serial bladder assessments as part of
their follow-up. Variations in the documented functional capacity were
oberved but only the most recent assessment reported.

\textbf{Statistical analysis}

Categorical data are presented as numbers and percentages, and
continuous variables presented by median and range. Patients after PC+BT
were compared to age-matched PEP+BT or BT alone.

Due to the small size of the study population, non parametric tests were
used: Kruskal-Wallis-test, Mann-Whitney test and Spearman test
(p\textless{}0.05 considered statistically significant), using IBM SPSS
24.0.

\textbf{Results}

During the study period, 13 patients (10 male), aged 9 months to 4 years
(median 23 months), with BP-RMS were deemed suitable for CS-BT. Relevant
clinical background was present in 2 patients: neurofibromatosis type 1
and high-grade vesico-ureteric reflux (VUR). All presented with
localised fusion-negative embryonal BP-RMS (2 botyroid subtype),
measuring a median 43mm (23-140mm) in cranio-caudal axis on MRI at
diagnosis.

Local control was by PC+BT in three, PEP+BT in four and BT alone in six
patients. One patient underwent oophoropexy before brachytherapy. For
PC+BT, one third of the bladder was excised in one and one fifth of the
bladder in two. The lymph nodes sampled confirmed N0 status.

Follow-up was available for all to a median 3½ years (range 1¾-7 years)
from diagnosis. No recurrence or relapse occurred. At a median age of 6
years (range 4-9 years), the median (range) bladder capacity was 86\%
(47\%-144\%) of that expected for age, including 75\% (74-114\%) after
PC compared to 97\% (47\%-144\%) for other CS-BT patients (p=0.700).
Maximum flow rates (Qmax) were 8 to 26ml/sec. There was no significant
PVR in all but the VUR-patient with volumes after micturition of 20\%
the total voided volume.

Invasive video-urodynamic studies were performed in 2 patients who
developed complications after treatment. In the patient with
pre-existing VUR, this recorded a stable, compliant system with free
vesico-ureteric reflux and normal voiding pressures. On extended
clamping of the supra-pubic catheter, however, a decompensated picture
emerged and a refluxing ureterostomy was created to optimise the safety
of the upper tracts. The other patient developed a urethral stricture
with a stable compliant bladder but high voiding pressures and low flows
on urodynamics; a Mitrofanoff channel was formed for clean intermittent
catheterisation. He is dry by day on anticholinergic medication and on
free urinary drainage overnight.

The remaining eleven patients are dry by day (Table 1); five with
continuous or intermittent assistance of anticholinergic medication for
urinary urgency. At night, three patients are enuretic at ages 5, 5 and
9 years; all received BT alone and bladder capacity was assessed at
56\%, 120\% and 75\% of EBCA at last review. Urinary ultrasound scans
showed no hydronephrosis in all except one (BT alone) with unilateral
mild hydronephrosis (antero-postero-pelvic diameter 12 mm).

No relationship was observed between the radiation dose to the bladder
(2cm\textsuperscript{3} EQD\textsubscript{2}) and the assessed bladder
capacity (Figure 1), p=0.535. 2cm\textsuperscript{3}EQD\textsubscript{2}
radiation doses (Table 2) to the bladder were similar for those
prescribed anticholinergic medication for urinary urgency (median
191.79Gy, range 61.65-406.17Gy) as compared to those without urgency
(median 152.84Gy, range 36.56-217.98Gy), p=0.107. Likewise, no
difference in 2cm\textsuperscript{3} EQD\textsubscript{2}to the bladder
was observed between those enuretic (median 154.38Gy, range
61.65-217.98Gy) and those dry at night (median 156.56Gy, range
36.56-406.17Gy), p=1.000. Nor was a patterns observed in the
0.1cm\textsuperscript{3} EQD\textsubscript{2} to the urethra for urgency
(median 64.79Gy vs 72.14Gy, ranges 54.59-82.78Gy vs 60.52-222.15Gy),
p=0.143; or enuresis (median 64.65Gy vs 71.65Gy, ranges 68.51-72.14Gy vs
54.59-222.15Gy), p=0.540.

\textbf{Discussion}

The clinical management of BP-RMS has changed dramatically over the last
decades and improvements in chemotherapy, treatment algorithms including
delayed surgery and radiation therapy have made organ preservation
feasible for many patients. Published oncological outcomes after CS-BT
are good with 84\% 5yr EFS and 91\% OS survival reported by Chargari et
al{[}7{]}. Unlike our cohort, their series included 12\% with metastatic
disease, 4\% treated for local relapse and 3\% with alveolar histology.
At a median follow up 3½ years, all our patients were alive without
relapse.

For decades, a radical cystectomy with either an incontinent (ileal
conduit) or a continent urinary diversion (ileocecal pouch and
catheterizable urinary stoma) was standard treatment. In contrast, our
CS-BT approach maintained urethral voiding for 85\% of patients. This
compares to 75\% of those treated by CS and HDR-BT for BP-RMS by Fuchs
et al{[}8{]}.

Fuchs et al{[}8{]} also used a HDR-BT technique delivering 30-36 Gy via
4 to 7 cannulae in 12 fractions (3Gy per fraction). However, their
surgical approach is much more radical aiming for a ``R0'' or ``R1''
resection. While surgery was limited to a partial cystectomy in five of
the eight BP-RMS patients in their series, three underwent a partial
prostatectomy as well as a partial cystectomy. Only one of the latter
group enjoys normal voiding; the others having required urinary
diversion surgery. Of those with a partial cystecomy, 60\% received
anticholinergic medication at 4 to 27 months follow up. In our series, 5
(38\%) patients were prescribed anticholinergic medication for urgency
with variable uptake.

Of note, Rodeberg et al found the amount of radiotherapy administered
for BP-RMS impacted on the functional sequelae for the bladder with 17\%
of patients receiving \textless{}40Gy having dysfunction versus 61\%
receiving \textgreater{}40Gy. Correcting for differences in
fractionation and dose-rate between Chagari et al{[}7{]}, Fuchs et
al{[}8{]} and this study, the EQD2 doses used for BT are in fact very
similar and lie above the 40Gy threshold identified by Rodeberg et
al{[}19{]}. We specifically examined the radiation burden on the bladder
and urethra as organs at risk, but could not find a relation between the
radiation exposure of the bladder or urethra and urinary urgency,
enuresis or bladder capacity. Schmidt et al{[}20{]} compared the urinary
tract function between patients receiving CS with HDR-BT and after
bladder-preserving surgery without BT. At 3-111months follow up, no
difference in normal voiding behaviour (61\% (14/23) vs 60\% (6/10)) was
observed, based on parental reports, voiding frequency charts, uroflow
examination with sonographic bladder emptying, but with improved EFS for
those managed with HDR-BT.

While an impact on bladder capacity after partial cystectomy would be
expected{[}6{]}, we found no difference in bladder capacity after
resection of one third to one fifth of the bladder compared to those
having no resection or minimally-invasive polypectomy alone. Longer
follow-up will be required to understand whether this will hold true
into adulthood. The median percentage of bladder capacity as expected
for age across the study population was 86\%, which should be adequate
for daytime continence. Indeed, 92\% of all our patients were dry by day
and 62\% dry by night. Day- and night-time continence seems lower than
the 72\% reported by Chargari et al{[}7{]}. However, only children, who
had not required cystectomy for bladder failure after completing
treatment for BP-RMS, for whom data was available and who were aged over
6 years, were included in their continence analysis.

Not only do techniques of conservative surgery and brachytherapy vary
between centres, but the selection criteria also differ. Martelli et
alconsider tumour extent \textgreater{}1 cm above the trigone on the
posterior bladder wall as unsuitable. In contrast, we consider only
localised disease, with a tumour diameter less than 5 cm and/or
involvement upto a maximum 1/3 of the bladder after a minimum three
cycles of chemotherapy as candiates for CS-BT. In our experience,
placement of multiple percutanous brachytherapy cannulae affords
reliable coverage of the prostate and bladder neck, meaning that only
the bladder above the level of the trigone as well as polyps that remain
partially mobile in the bladder are at risk of falling outside the
radiation field. Unlike Chargari et al{[}7{]} and Fuchs et al{[}8{]},
resection of the prostate is not needed, and almost half the patients
required no surgerical resection.

One patient suffered a urethral stricture and another suffered
decompensation on a background of high-grade VUR on clamping the
suprapubic catheter. Despite this, and contrary to others'
experience{[}7,8{]}, none of our patients have developed a
poorly-compliant small capacity bladder, so far. Whether this is a
matter of time or the result of less surgery at the bladder neck remains
to be seen. We whole-heartedly agree with previous authors that in- and
out-of theatre collaboration by the multi-disciplinary team is essential
for optimal tailoring of surgery and brachytherapy to each patient.

Systematic bladder function assessment in children with BP-RMS at a
median 3½ years after CS-HDR-BT revealed day-time dryness in 92\%, with
85\% voiding urethrally, and 62\% achieving day-and-night continence at
age 4 to 9 years. Bladder capacity remained adequate despite resection
of up to one third of the bladder. In comparison to other CS-BT
approaches, we report reduced open surgery, with minimally-invasive
percutaneous surgery and HDR-BT or brachytherapy alone being suitable
for many. So far, all are alive without relapse.

\textbf{Conflict of Interest statement}

The authors have no conflict of interest to declare.

\textbf{Acknowledgements}

MNG is supported by the National Institute for Health Research
{[}NIHR{]}, University College London Hospitals, Biomedical Research
Centre {[}BRC{]} and the Radiation Research Unit at the Cancer Research
UK City of London Centre Award (C7893/A28990).

PH is supported by the National Institute for Health Research
{[}NIHR{]}, Manchester Biomedical Research Centre.

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\textbf{Data available on request due to privacy/ethical restrictions.}

\textbf{Legends}

\textbf{Table 1.} Continence status at last follow-up.

\textbf{Table 2.} Conservative surgery and HDR brachytherapy treatment,
including radiation dose and continence outcome.

Radiation dose is presented in Gy to target volume as the D90
EQD\textsubscript{2}, the bladder as the
2cm\textsuperscript{3}EQD\textsubscript{2} and the urethra using the
0.1cm\textsuperscript{3}EQD\textsubscript{2..} Male (M), Female (F); DD-
dry day, DN- dry night, WN - wet night, CIC -- clean intermittent
catheterisation. See methods for further details.

\textbf{Figure 1.} Bladder 2cm\textsuperscript{3}
EQD\textsubscript{2}radiation dose and observed bladder capacity as a
percentage of that expected for age.

\textbf{Hosted file}

\verb`Table 1 CS-HDR-BT.docx`  available at \url{https://authorea.com/users/423099/articles/528656-bladder-function-after-conservative-surgery-and-high-dose-rate-brachytherapy-for-bladder-prostate-rhabdomyosarcoma}

\textbf{Hosted file}

\verb`Table 2 CS-HDR-BT.docx`  available at \url{https://authorea.com/users/423099/articles/528656-bladder-function-after-conservative-surgery-and-high-dose-rate-brachytherapy-for-bladder-prostate-rhabdomyosarcoma}

\textbf{Hosted file}

\verb`Figure 1 CS-HDR-BT.docx`  available at \url{https://authorea.com/users/423099/articles/528656-bladder-function-after-conservative-surgery-and-high-dose-rate-brachytherapy-for-bladder-prostate-rhabdomyosarcoma}

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