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\begin{document}

\title{Long-term result of 125 I seed brachytherapy for pediatric desmoid tumor
in the head and neck}



\author[1]{Yi-Wei Zhong}%
\author[1]{Xiao-Ming Lyu}%
\author[1]{Yan Shi}%
\author[1]{Chuan-Bin Guo}%
\author[1]{Jian-Guo Zhang}%
\author[1]{Lei Zheng}%
\affil[1]{Peking University Hospital of Stomatology}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background: Desmoid tumor (DT) is rare and challenging, often affects
head neck (HN) region in children, and its appropriate treatments are
under discussed. This study aimed to retrospectively evaluate long-term
effectiveness and safety of \textsuperscript{125}I seed brachytherapy
for pediatric DT in HN. Procedure: Seven pediatric patients with median
age of 3 years old suffered from DT in HN treated with
\textsuperscript{125}I brachytherapy from January 2008 to June 2018 were
included. Among which, 5 underwent sole brachytherapy and the others
combined with surgery under a prescription doses ranging from 10 000 cGy
to 12 000 cGy. The rate of local control (LC), complete response (CR)
and partial response (PR) were calculated after evaluation by
radiological and pathological means. The radiation-associated toxicities
were also evaluated Results: The LC rate was 7/7 during the follow-up
time ranging from 43 to 135 months and with a mean of 57 months. No
recurrent lesion was found in the patients receiving surgery combined
with brachytherapy. In patients treated with sole brachytherapy, the
radiological PR rate and CR rate were 4/5 and 1/5, respectively. In
those reaching radiological PR, 3/4 were pathological CR. Slight acute
radiation-associated toxicities were observed in all patients, and no
late or severe acute toxicity was observed. Conclusion:
\textsuperscript{125}I brachytherapy is effective and safe in the
management of pediatric DT in HN as sole modality or combined with
surgery in long term.%
\end{abstract}%



\sloppy


\textbf{1 Introduction}

Desmoid tumor (DT), also known as aggressive fibromatosis, is a rare
intermediate fibroblastic neoplasm derived from mesenchymal tissues with
an annual incidence of approximately 2 to 4 per million per year, and
two peaks of age 6-15 years and age 40 years\textsuperscript{1}. Locally
infiltrative growth is the nature of DT, and a threat to the vital
structure around the tumor. Especially for cranial nerve s (e.g., the
facial nerve), critical vessel (e.g., internal carotid artery and
internal jugular vein) and organ (e.g., salivary gland and maxillofacial
bone) in the head neck (HN) region, which accounts for 7-15\% of all the
DT, and higher in the pediatric population (26-33\%) than the adult
(7-9\%)\textsuperscript{2-4}, DT would cause severe morbidity.

Observation was advocated as the first treatment for DT by the guideline
of National Comprehensive Cancer Network (NCCN)\textsuperscript{5} and
the Desmoid Tumor Working Group \textsuperscript{6} under the
consideration of the spontaneous regression. However, interventions are
unavoidable for the relatively low spontaneous regression
rate\textsuperscript{7,8}and potential risk for further adjacent vital
tissue destruction and affecting growth by progression.

Complete resection is often the primary intervention for most DT other
than those in HN of pediatric patients for the difficulty to get
negative margin, and the demand of aesthetic and
function\textsuperscript{9}. Chemotherapy, radiotherapy or medical
therapy can be performed as supplementary treatment with positive margin
after surgery, or sole therapy, in the HN
region\textsuperscript{6,9,10}. Among which, the use of radiotherapy is
limited in children due to the long-term complication and toxic effects
caused by external beam radiation therapy such as secondary cancers and
growth retardation of craniofacial bone\textsuperscript{9,10}.

However, brachytherapy, the minimally invasive radiation method with
strength of minimizing the growth retardation or second primary cancer
in children\textsuperscript{11}, has the potential to offer selection of
either supplementary or definitive method for pediatric DT in HN, while
long term follow-up outcome is requested.

Therefore, this study attempted to retrospectively evaluate the
long-term effectiveness and safety of \textsuperscript{125}I seed
brachytherapy for pediatric DT in HN.

\textbf{2 Materials and methods}

2.1 Patients

Under the guidance of the Ethics Committee of Peking University School
and Hospital of Stomatology, 7 pediatric patients with DT in HN treated
with \textsuperscript{125}I seed brachytherapy from January 2008 to June
2018 in the Peking University School of Stomatology were included in
this study. All the pediatric patients' guardians signed their informed
consents, which were well documented. Among the included patients, 4
were male and 3 were female. The median age was 3 years old, ranging
from 3 to 8 years old. The median of maximum diameter of the primary
tumor was 6.0 cm, ranging from 2.5 to 10.0 cm. The median follow-up time
was 57 months, ranging from 43 to 135 months. The site tumor involved
including 4 at the parapharyngeal region and 3 at the skull base region.
The detailed patients' characteristics were listed in Table 1. The R
stage was classified as R0 with microscopically negative margin
according to pathological examination, R1 with macroscopically negative
margin according to the surgeon but microscopically positive margin, and
R2 with macroscopically positive margin.

2.2 Treatment

After evaluation by an experienced medical group, 4 to 6 weeks before
brachytherapy, 2 patients underwent surgery with R2 margin for vital
organ preservation, and 1 to 2 weeks before brachytherapy, biopsies were
performed on the other five patients with tumors invading the critical
structures in HN, such as skull base, facial nerves and any other vital
nerves or vessels. The pathological specimens were examined and
diagnosed by two centers with expert pathologists in consensus. Then the
computed tomography (CT) scanning of the HN with a slice thickness of
0.75 mm, tube voltage of 120 kV, and tube current of 225--300 mA was
performed on all patients using a GE Optima CT680 scanner. Then all the
Digital Imaging and Communications in Medicine (DICOM) data were
transferred into a brachytherapy treatment planning system (BTPS,
Beijing Atom and High Technique Industries). Referring to the tumor
boundary based on the magnetic resonance imaging (MRI), the planning
target volume (PTV) were contoured by extending the gross tumor volume
(GTV) with a distance of 0.5 to 1.0 cm in the BTPS based on CT imaging.
The prescription doses were set from 10 000 cGy to 12 000 cGy according
to the size, subsite and the tolerance doses of the adjacent vital
structures, with a median of 12 000 cGy, in the BTPS, using the
\textsuperscript{125}I seeds with a surface radioactivity of 18.5 MBq
per seed (type 6711, t1/2, 59.4 days, Beijing Atom and High Technique
Industries, Beijing, China).

Three-dimensional printed individual templates\textsuperscript{12} along
with intraoperative CT or a far-infrared navigation guidance system
(iPlan 3.0, Brainlab, Feldkirchen, Germany) were used to assist the
\textsuperscript{125}I seeds distribution. Then the
\textsuperscript{125}I brachytherapy were performed under general
anesthesia according to the previous design. Finally, the post-implant
dosimetry parameters were calculated based on the post-implant CT by
BTPS (Figure 1).

2.3 Follow-up

Patients received physical examination, CT and (or) MR every two months
in the first half year, and every three or six months thereafter, and
core-needle biopsy when confirmation for tumor response was needed. The
safety were evaluated with radiation-relevant toxicities according to
the Radiation Therapy Oncology Group (RTOG) grading
system\textsuperscript{13}. The effectiveness was evaluated with local
control (LC) rate. And LC were defined as the absence of tumor after
surgery combined with brachytherapy, or complete response (CR) and
partial response (PR) according to the Response Evaluation Criteria in
Solid Tumors (RECIST), version 1.1\textsuperscript{14} after sole
brachytherapy.

\textbf{3 Results}

3.1 Post-implant dosimetry

The mean \selectlanguage{ngerman}± standard deviation of post-implant D\textsubscript{90} (the
doses delivered to 90\% of the target volume) of the patients was 115.1
± 19.9 Gy, and higher than the prescribed dose for each patient. The
V\textsubscript{100} (the percentage of target volume that receives at
least 100\% of the prescribed dose) was more than 85\% for every patient
with a median of 94.5\% ranging from 87.7 to 96.1, and the mean ±
standard deviation of V\textsubscript{150} (the percentage of target
volume that receives at least 150\% of the prescribed dose) was 50.2\% ±
11.7\%.

3.2 Local control

During the follow-up, the local control rate was 7/7. No recurrent
lesion was found in the patients undergoing surgery combined with
brachytherapy. In patients treated with sole brachytherapy, 4/5 were
radiological partial response and 1/5 was radiological complete
response. In those reaching radiological partial response, 3/4 were
pathological complete response. Among all 5 patients undergoing sole
brachytherapy, local control condition was also described as the changes
of tumor maximum diameter, MR signal evaluation and pathological
examination by core-needle aspiration as follow.

3.2.1 Tumor maximum diameter

There was only one lesion in every patient. And the tumor maximum
diameter at first visit, 2 months' follow-up, 6 months' follow-up and
last follow-up were demonstrated in Figure 2. All the lesions were
stable at the first follow-up, and reached partial regression or
complete regression at 6 months' follow-up (Figure 3).

3.2.2 MR signal evaluation

Of the patients treated with sole brachytherapy, 3/5 underwent MR
examination before and after the brachytherapy. The MR were performed no
more than 1 month before the pre-operative or post-operative biopsy. All
lesions presented hyper-intense compared with muscle in the
pre-operative T2 weighted images, and 2 lesions turned to hypo-intense
and 1 lesion turned to isointense compared with muscle in the
post-operative T2 weighted images (Figure 4).

3.2.3 Core-needle aspiration

Pathological examination by core-needle aspiration was performed on 3/4
of the lesion reaching partial regression, and specimens from at least
five spots in the radiological tumor volume were taken under the
guidance of the far-infrared navigation guidance system mentioned
before. No tumor cell was found in all the specimens (Figure 5). Thus,
all the patients receiving core-needle aspiration were regarded as
pathological complete regression.

3.3 Side effects or toxicity

No operative complication such as cerebrospinal fluid leakage, hematoma
or infection was observed. Radiation related acute toxicity, including
dry desquamation, edema and erythema on skin were observed in all the
patients, while 6/7 were classified as RTOG grade 1 and 1/7 was
classified as RTOG grade 2, and no RTOG grade 3 or 4 toxicity were
observed. None experienced late toxicity. Notably, no radiation related
growth retardation and secondary cancer were observed.

\textbf{4 Discussion}

Desmoid tumor is a rare intermediate tumor characterized by infiltrative
growth and a tendency to local recurrence\textsuperscript{6}, with an
annual incidence of approximately 2 to 4 per million per year, and two
peaks of age 6-15 years and age 40 years\textsuperscript{1}.
Infiltrative growth is a threat to the vital structure around the tumor,
especially in the HN, which accounts for 7-15\% of all the DT, and
higher in the pediatric population (26-33\%) than the adult
(7-9\%)\textsuperscript{2-4}. The treatment was challenging in the
pediatric DT in HN, for the stronger demand of organ and tissue
preservation than those of adults and limit of treatment modality
\textsuperscript{9}. Although the treatment varied, in recent years, the
strategy of the treatment changed in the trend from surgery and
radiotherapy to conservative methods, with the development of targeted
therapy and knowledge to the nature of DT\textsuperscript{6}. But for DT
in HN of pediatric population, the treatment modalities used now are not
satisfactory.

Observation, also described as ``wait and see'' approach, was proved
reasonable for the indolent nature of DT, with evidence of stabilization
and even regression in the absence of therapy \textsuperscript{15}.
Since 2020, observation had been listed as first-line management, while
both NCCN guideline and Desmoid Tumor Working Group stressed that
initial observation was only recommended for cases not causing morbid
even if progressed \textsuperscript{5-7}. With the threat to functional
or cosmetic preservation from progression, observation was only suitable
for small DT in HN, which would often be managed by surgeons with
complete resection at first. The condition for choosing observation is
strict in HN, as all cases in this study underwent intervention and none
took observation for organ preservation.

Complete resection with clear margin used to be regarded as mainstay
treatment before 2000, and the 5-years local control rate were up to
80\% according to several retrospective study\textsuperscript{16}. While
in the region of HN, the local control rate declined to between 24 and
70\%\textsuperscript{17}. And for pediatric patient involved HN, a
systematic review demonstrated a 27.2\% recurrence rate of 125 patients
treated with surgery in reports from 1982 to 2015. However, the pursue
of complete resection or at least R1 margin, which was regarded
acceptable\textsuperscript{18}, at price of excessive long-term
functional or cosmetic sequelae was not recommended in tumors located at
HN of pediatric population\textsuperscript{9}. Therefore, sole surgery
have been abandoned as a choice for most DT in the
HN\textsuperscript{5}. And in this study, patient with R2 margin after
surgery were treated supplementarily with brachytherapy for local
control.

External beam radiotherapy was considered to be either sole modality for
inoperative cases of DT or complementary therapy for resectable ones,
and the latter was regarded as better solution than sole surgery by a
review of 22 articles\textsuperscript{19}. However, while considering on
pediatric population, the long-term sequelae and adverse effects of
external beam radiation exposure in children, such as secondary
malignancy and inhibition of the cranial-facial bone, caused the limited
use of radiotherapy on pediatric DT\textsuperscript{20-22}. Besides,
efficacy of radiotherapy on pediatric DT was uncertain according to a
study reporting 10 out of 13 children recurrent and 3 out of 13
dead\textsuperscript{23}.

Medical therapy including anti-hormonal therapies, non-steroidal
anti-inflammatory drugs (NSAIDs), chemotherapy and tyrosine kinase
inhibitors (TKIs) was another way the clinicians turned
to\textsuperscript{6}. Anti-hormonal agents such as tamoxifen or
toremifene, along with or without NSAIDs were reported retrospectively
effective\textsuperscript{24}. However, a phase II study in pediatric
population using tamoxifen\textsuperscript{25} showed limit activity for
an progression free rate of 36\%, and notable safety problem with 40\%
females developing ovarian cysts. Chemotherapy including a ``low-dose''
regimen with methotrexate plus vinblastine or vinorelbine, was evaluated
and proved well efficacy and acceptable toxicity \textsuperscript{6}.
Tyrosine kinase inhibitors seemed hopeful with progression-free survival
ranging from 59\% to 89\% and low toxicity according to several phase II
and III studies \textsuperscript{26}. Therefore, chemotherapy and
Tyrosine kinase inhibitors were advocated as active
treatments\textsuperscript{5,6}. But meanwhile, there was still a need
for a back-up therapy since the effectiveness of tyrosine kinase
inhibitors might related to certain genome type \textsuperscript{27},
and also a solution for relapse from medical therapy.

Brachytherapy is a minimally invasive radiotherapy modality with high
local dose while sparing surrounding normal tissues\textsuperscript{28}.
Late radiation induced toxicity complications like growth retardation
and second primary malignancies, with a strong relation to a dose-volume
effect, can be kept to a minimum by the brachytherapy for its smaller
target volume than external beam radiotherapy\textsuperscript{11}.
Previous studies in our department had reported the application of
brachytherapy on pediatric population in HN, and showed good
effectiveness and safety\textsuperscript{29-31}. Besides, the study on
pediatric survivors with parotid gland carcinoma after brachytherapy
showed mild affection on the mandible growth\textsuperscript{32}. The
use of brachytherapy on DT in adult had also been reported with well
local control\textsuperscript{33,34}. However, the application of
brachytherapy on pediatric DT in HN remained unclear, with long term
effectiveness and safety needing to be reported.

In this study, during the long-term follow-up time, it was inspiring
that no recurrence was observed. In spite of the limit of the amount of
cases, we could still concluded that brachytherapy as an effective
method for pediatric DT in HN for many other evidence we collected.
There were several methods the Desmoid Tumor Working Group recommended
for assessment of treatment effect\textsuperscript{6}. And we adopted
the dimensional criteria, MR signal, and the gold standard, core-needle
aspiration.

All the lesions in this study reach partial regression six month visit
after brachytherapy, with dimensional change evaluated using CT or MR.
Although CT examination was advised for measurement on dimensional
change according to the Desmoid Tumor Working Group\textsuperscript{6}
and NCCN guideline\textsuperscript{5}, the\textsuperscript{125}I seeds
would affect the observation on the tumor outline on CT with
radiological artifact. As an alternative, clinicians will measure the
cluster volume of \textsuperscript{125}I seeds and a general volumetric
shrinkage tendency indirectly showed the shrinkage of tumor volume
\textsuperscript{35}. However, that was not a common parameter to use
for comparison with other studies. Another alternative was measurement
using MR, with artifact still but would not affect the measurement,
because the\textsuperscript{125}I seeds showed as small black area. But
as for children, the time consuming on MR examination was a problem for
their weak obedience ability and often needed sleeping pill. Therefore,
in this study, we still used CT as an assessment on tumor diameter
change, and accomplished with other methods.

Changes in T2 weighed intensity signal of MR image is useful for
evaluation on activity of DT, because low T2 weighed signal corresponds
to relatively lower cellularity and higher collagen
content\textsuperscript{6,36}. In this study, all cases with
preoperative and postoperative MR showed clearly reduction in T2 weighed
intensity signal. The change in T2 weighed signal can be evaluated even
though artifact existed after brachytherapy, and therefore can be added
as an ancillary criteria for treatment evaluation, following the
diameter change. However, the acquisition of MR from children still
remained difficult. And to ensure the treatment effect, some cases in
this study underwent core-needle aspiration for pathological
examination, and no tumor cell was found, which further confirmed the
result concluded from change of T2 weighed signal and diameters.

All children in this study experienced mild acute side effects after
brachytherapy (RTOG1-2), and no late or severe toxicity (RTOG 3--4) or
second primary cancer were observed. Besides, except for cases already
had massive bone defect before therapy, no growth retardation was
observed. Based on the long-term follow-up, the safety of brachytherapy
could be shown as only mild and short-term toxicity was observed and no
severe or late radiation induced toxicity complications occurred.

However, as discussed above, since the relatively indolent nature of DT,
more conservative method should be considered firstly, such as TKIs or
observation if suitable, and then aggressive method like surgery and
brachytherapy if needed and possible. Brachytherapy could be turned to
for unresectable lesion with looming unacceptable destruction, or as a
salvage after failure of the former treatments, or a combination with
them as an potential alternative for external-beam radiation in
pediatric DT in HN.

Even though DT is rare, the number of cases in this study is still
obviously limited, while more cases reported was expected. Besides, the
data of toxicity evaluation is limited also because of the small sample
size.

\textbf{5 Conclusion}

\textsuperscript{125}I Brachytherapy is effective and safe as sole
modality or combined with surgery, for pediatric desmoid tumor in the
head and neck region proven by multi-dimensional evaluation, and can be
adopted as an alternative therapy in certain situation.

\textbf{6 Conflict of Interest statement}

None.

\textbf{7 Acknowledgements}

None.

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Figure 5

\textbf{Legends}

Figure 1 The procedure of the brachytherapy. A,B) Brachytherapy was
performed with the help of far-infrared navigation guidance system and
three-dimensional printed individual templates, C) The post-implant
dosimetry parameters were then calculated.

Figure 2 Change from baseline in tumor size. Five cases with desmoid
tumor underwent sole brachytherapy and the number of cases with
radiological partial and complete response were 4 and 1.

Figure 3 The follow-up computed tomography image of case with partial
response. A) Baseline, B) 2 days after brachytherapy, C) 2 months
follow-up D) 6 months follow-up.

Figure 4 Change of the magnetic resonance intense signal. Magnetic
resonance images from 3 cases underwent sole brachytherapy showed
decline in the intense signal of lesion to muscle ratio.

Figure 5 The procedure of pathological examination. A,B) Core-needle
aspiration was performed with the help of far-infrared navigation
guidance system, C) No tumor cell was found in the specimen.

Table 1 Patients' characteristics.

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/495193/articles/577006-long-term-result-of-125-i-seed-brachytherapy-for-pediatric-desmoid-tumor-in-the-head-and-neck}

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