2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

evaluation, because desmoid tumor is a largely localized
disease, treatment approaches have historically focused on
focal therapies, such as surgery or external beam ionizing
radiation.
Most would agree that surgical resection represents the
best therapy for children in whom the tumor can be completely
removed without substantial functional or cosmetic
consequences. The ability to obtain a complete surgical
resection is generally believed to be an important factor that
influences tumor control. However, other factors, such as
whether the disease is primary or recurrent 10 and the
presence of certain CTNNB1 mutations, 7 also seem to be
important. Numerous issues regarding ongoing physical and
emotional development in children add to the complexity
regarding long-term surgical outcomes in children with
desmoid tumor; and this has not been well studied in this
patient population.
Ionizing radiation therapy has been shown to be effective
in many studies of adult patients. In particular, when
applied in conjunction with surgery, ionizing radiation
therapy improves local disease control. 11 The high radiation
dose needed makes its use more complicated if the
radiation port includes growing bones or joints. Furthermore,
radiation therapy may be less effective in children
than adults. This concern led to a retrospective review,
which concluded that the role of radiation in the initial
treatment of children with desmoid tumors should be reconsidered.
12 In this series, five of 13 children received radiation
therapy immediately after diagnosis, whereas the
remaining eight patients received radiation therapy after
recurrence. The median dose of radiation used was 50 Gy.
Tumor recurred after radiation therapy in 11 of the 13
patients, and three patients died of their disease. In those
surviving, substantial morbidity associated with the radia-
KEY POINTS
● Desmoid-type fibromatosis (desmoid tumor) represents
a locally aggressive soft tissue neoplasm that
has a propensity for locally aggressive growth and
recurrence after attempted surgical resection.
● Desmoid tumor is associated with loss of function
mutations in the adenomatous polyposis coli tumor
suppressor and gain of function mutations in
�-catenin.
● Surgical resection with or without radiation therapy
has represented the historical standard for treating
this disease.
● A variety of cytotoxic and noncytotoxic chemotherapies
have demonstrated the capacity to control desmoid
tumor when surgery or radiation are not
effective; however, most of this literature is in the
form of case reports or retrospective studies, often
including children and adults.
● Two multicenter, prospective clinical trials conducted
through the Pediatric Oncology Group and Children’s
Oncology Group have demonstrated the feasibility of
this approach and the added value stemming from
systematic, prospective study.
594
POUNDS AND SKAPEK
Table 1. Event-Free Survival for Children Enrolled in POG 9650
or COG ARST0321 and Treated With Vinblastine/Methotrexate or
Tamoxifen/Sulindac, Respectively
Chemotherapy Event-Free Survival at 1 Year (Range)
Vinblastine/methotrexate 0.58 (0.29–0.57)
Tamoxifen/sulindac 0.44
Abbreviations: COG, Children’s Oncology Group; POG, Pediatric Oncology
Group.
tion therapy was noted. A more recent study, though,
supports the role that radiation therapy can play in this
disease in children. 13
Like surgery, radiation therapy holds the potential for
consequences that can be particularly troubling in a growing
child. Reported adverse effects include bone fractures, skeletal
and soft tissue growth retardation, tissue fibrosis, and
lymphedema. 12 Jabbari and colleagues 13 also reported substantial
morbidity in the form of peripheral neuropathy,
pain, bowel obstruction, and the development of papillary
cancer.
Chemotherapy for Children with Desmoid Tumor
For many children with desmoid tumor, surgery or radiation
has proven ineffective or is believed to be associated
with unacceptable consequences, which has led to the use of
chemotherapeutic agents that are believed to act by cytotoxic
or noncytotoxic mechanisms. Regrettably, most of the
reports stemming from their use represent retrospective,
single-institution analyses of small groups of patients,
thereby limiting the conclusions that one can draw.
Cytotoxic regimens demonstrated to have some activity in
retrospective analyses include liposomal doxorubicin 14 ;
doxorubicin with dacarbazine 15 ; vincristine, dactinomycin,
and cyclophosphamide 16 ; hydroxyurea 17 ; and vinblastine
and methotrexate. 18 Perhaps the most striking report centered
on the use of doxorubicin and dacarbazine by 96-hour
infusion and followed by the nonsteroidal anti-inflammatory
drug (NSAID) meloxicam. 19 The authors reported complete
and partial responses in three and four, respectively, of 11
adult patients, with a mean progression-free survival of
approximately 6 years. Beyond the biases inherent in retrospective
analyses, the complex nature of desmoid tumor,
which has been reported to undergo prolonged stabilization
and even spontaneous regression, 20 limits the conclusions
one can draw on the relative efficacy of any of these regimens.
The same is true of reports of noncytotoxic regimens, most
of which include NSAIDs, such as sulindac and meloxicam,
and estrogen antagonists, such as tamoxifen. In some cases,
tamoxifen 21 or NSAIDs 22 are used alone. In most, though,
tamoxifen is combined with an NSAID, such as sulindac. 23
In one series, 10 of 13 adults with FAP-associated disease
had either a partial or complete response. 23 Although the
initial rationale for using NSAIDs may have been based on
incomplete understanding of the disease biology, more recent
laboratory studies provide a potential mechanism: the
transcription factor PPAR� is deregulated in the setting of
APC mutations, but NSAIDs can block PPAR� activity. 24
Receptor tyrosine kinase inhibitors, particularly imatinib
mesylate, also have shown the capacity to stabilize desmoid
tumor and foster regression in a smaller subset. 25 Its activity
may be based on expression of platelet-derived growth
factor receptor �. 25