4 Discussion
Desmoid tumor is a rare intermediate tumor characterized by infiltrative
growth and a tendency to local recurrence6, with an annual
incidence of approximately 2 to 4 per million per year, and two peaks of
age 6-15 years and age 40 years1. 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%)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 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 DT6. 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 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 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 study16. While in the region
of HN, the local control rate declined to between 24 and 70%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 acceptable18, at price of
excessive long-term functional or cosmetic sequelae was not recommended
in tumors located at HN of pediatric population9. Therefore, sole
surgery have been abandoned as a choice for most DT in the HN5. 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 articles19. 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 DT20-22. 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 dead23.
Medical therapy including anti-hormonal therapies, non-steroidal
anti-inflammatory drugs (NSAIDs), chemotherapy and tyrosine kinase
inhibitors (TKIs) was another way the clinicians turned to6. Anti-hormonal agents
such as tamoxifen or toremifene, along with or without NSAIDs were
reported retrospectively
effective24. However, a
phase II study in pediatric population using tamoxifen25 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 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 26. Therefore,
chemotherapy and Tyrosine kinase inhibitors were advocated as active
treatments5,6.
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 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 tissues28. 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 radiotherapy11. Previous studies in
our department had reported the application of brachytherapy on
pediatric population in HN, and showed good effectiveness and safety29-31. Besides, the
study on pediatric survivors with parotid gland carcinoma after
brachytherapy showed mild affection on the mandible growth32. The use of
brachytherapy on DT in adult had also been reported with well local
control33,34.
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 effect6. 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 Group6 and NCCN guideline5, the125I seeds would affect the observation on the tumor
outline on CT with radiological artifact. As an alternative, clinicians
will measure the cluster volume of 125I seeds and a
general volumetric shrinkage tendency indirectly showed the shrinkage of
tumor volume 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 the125I 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 content6,36.
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.