Unacceptable Toxicity in Phase I Trial Adding Pazopanib to Chemotherapy for Sarcoma: A Precautionary Tale

                                              https://www.austinpublishinggroup.com/sarcoma/

SoftTissue 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.

Althoughdoxorubicin-based 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 Vascular Endothelial Growth Factor (VEGF) is a potent tumor-produced 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 progression-free 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.