Soft Tissue Sarcomas
(STS) represent a very heterogeneous family of tumors derived from mesenchymal
cells. Despite a variety of cells of origin, most STS are treated with the same
chemotherapy regimens, although there are some exceptions. For example alveolar,
soft part sarcoma is now treated with tyrosine kinase inhibitor in first line.
Treatment of sarcomas is multidisciplinary, but the approach to the management
of high risk primary STS remains controversial. While the combination of
surgery and radiotherapy prevents local recurrence, the role of adjuvant or
neoadjuvant chemotherapy to reduce the risk of metastatic disease or to reduce
tumor size to facilitate an R0 resection is not established. Over 50% of
patients with very high risk STS will eventually develop metastatic disease.
Additional curative options must be identified in appropriate patients. The
definition of high risk STS is also somewhat controversial. For the purpose of
this clinical trial, we considered any high grade STS greater than 5cm in the
greatest dimension, for which chemotherapy could be indicated in the first line
setting. Although doxorubicinbased regimens are favored in first line for
metastatic disease, the new combination of docetaxel and gemcitabine might have
greater activity in some STS subtypes with less long term toxicity especially when administered on an every two-week schedule.
VascularEndothelial Growth Factor (VEGF) is a potent tumorproduced angiogenic factor
whose overexpression is usually associated with an adverse outcome in most STS. Median pretreatment serum VEGF levels are significantly raised in patients
with grade 2 and grade 3 sarcomas compared with concentrations in patients with
benign lesions. Serum VEGF expression correlates with grade in soft tissue
sarcoma and reflects response to treatment. The tyrosine kinase inhibitor,
pazopanib, is now approved for recurrent or metastatic STS, with good clinical
benefit. Health-related quality of life does not improve with pazopanib,
but the improvement in progressionfree survival without impairment of quality
of life was considered meaningful. When administered as a single agent, side
effects are manageable and include hypertension, diarrhea, nausea, liver
inflammation, mild myelosuppression, and hair de-pigmentation. In
combination with chemotherapy, however, there is a synergistic effect on the
toxicity profile and combination with multi-agent chemotherapy is not tolerable
(Table 1). This study proposes to combine the least toxic chemotherapy
regimen with intermittent pazopanib administration to avoid
pharmacokinetics synergy, to be tested in the neoadjuvant setting for patients
with high risk STS.
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