Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience

Abstract

BACKGROUND: The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed standard chemotherapy. METHODS: All patients with metastatic bone sarcomas treated with pazopanib between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed. RESULTS: Nineteen patients were identified. The median age was 38 years (range 18–62). Most of the patients (50%) were diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4 months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of pazopanib was reduced because of toxicity. CONCLUSION: Off-label use of pazopanib is effective in the treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with chemotherapy or other targeted therapies are needed.

Molecular Biology of Osteosarcoma

“…Longhi et al [181] reported a 60% disease control rate (DCR) with 1 partial response among 15 patients with relapsed osteosarcoma treated with pazopanib. Similar outcomes were reported by Aggerholm-Pedersen et al [182] in 19 patients with bone tumors, including eight osteosarcoma patients, treated with pazopanib. Four patients with osteosarcoma had a partial response to the treatment.…”

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…These very promising results paved the way for further exploration of this type of targeted therapy. In this context, pazopanib, a MKI inhibiting VEGR1-3, PDGFRα/β, and c-KIT, showed objective responses in metastatic or relapsed patients [160,161]. Preclinical and in vitro data reinforced the relevance of MKI in OS.…”

“…If the first clinical trial including the anti-VEGF antibody bevacizumab was disappointing [127], encouraging results emerged from initial clinical trials using the MKI sorafenib, which targets intracellular kinase activity of VEGFRs [125,126]. Since then, several MKIs like regorafenib [158,159], pazopanib [160,161], and more recently cabozantinib, have been reported to have beneficial effects in advanced OS and Ewing sarcoma bone tumors [162]. Accordingly, these agents had promising therapeutic results in selected patients, probably through the combined action on both angiogenic vascular compartment and OS cells in which they inhibit multiple growth factor pathways with potential oncogenic activity (c-MET, c-KIT).…”

A Pharmacological Analysis of the Activity and Failure of the Medical Treatment of High-Grade Osteosarcoma

“…On this basis, various targeted agents were studied: Sunitinib (anti VEGFR 1, 2 and 3, ckit, FTL, CSF 1, RET) [ 46 ]; Bevacizumab (BRAF, ckit, FGFR, FLT-3, VEGFA) [ 47 ]; Pazopanib (VEGFR 1, VEGFR3, PDGFR) [ 48 ]; Sorafenib and Regorafenib provided some relevant benefits [ 47 , 48 ]. …”

“…The most common signs of toxicity of antiangiogenic agents are fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome, thyroid dysfunction, myelotoxicity, and hypertension [ 45 , 46 , 47 , 48 , 49 , 50 ].…”