Neoadjuvant pazopanib with radiation therapy in patients with localized sarcoma: Experience from a sarcoma center.
Authors: Trybula Marcus , Mangla Ankit , Rothermel Luke Daniel , Jonard Brandon , Zuhour Raed , Nascimento Alessandra , Saab Shahrazad , Abboud Salim , Mansur David B. , Ammori John Brian , Wolf Monique , Sidiropoulos Jessica , Costello Taylor M. , Fu Pingfu , Schwartz Gary K. 
Published: June 2024

e23555

Background: Tissue oxygenation is critical to the success of radiation therapy (RT) in any tumor type. However, tumor vasculature is abnormally structured and dysfunctional. Anti-angiogenic molecules have been shown to stabilize the intratumoral vascular structures and improve tissue oxygenation, which may aid in the success of RT. Pazopanib (PAZO) is a multi-kinase inhibitor targeting the Vascular Endothelial Growth Factor Receptor. Here, we report the pathologic outcome and clinical correlates of concurrent use of neoadjuvant PAZO and RT in our cohort of patients with localized soft-tissue sarcoma (STS). Methods: This is a retrospective, single institution study of patients diagnosed with localized STS between January 2019 and October 2023. Patients who received concurrent PAZO and pre-operative external beam RT (50 Gy in 25 fractions) were included. Patients with metastatic disease, unplanned resections, and those requiring excisional biopsy/curettage for diagnosis were excluded. The primary endpoint was the rate of major pathologic response (mPR) defined by > 90% necrosis on surgical pathology specimen. The secondary endpoint was local relapse-free survival (RFS), distant metastasis-free survival (DMFS), and local and distant relapse rate (RR) at 6 months. All-grade toxicities from PAZO were recorded. Results: Ten patients with a median age of 51 years (Interquartile range (IQR): 34-76) were included. Undifferentiated pleomorphic sarcoma was the most common histologic subtype (50% patients). Median follow up was 24.2 months (IQR: 11-36). Six patients tolerated the maximum dose of PAZO until RT completion (800mg PO daily). The dose of PAZO was reduced in 4 patients due to grade 3 GI toxicity and HTN. Nine patients stayed on PAZO until RT completion. The median time to surgery after RT was 42 days (IQR: 37-77). The median largest tumor dimension prior to RT was 11.65 cm (IQR: 3.8 to 18), and 10.6 cm (IQR: 5.4 to 19.7) after RT completion. Nine of 10 patients had R0 resection, and 7 (70%) had mPR. Three of 7 (43%) patients had complete necrosis. All patients with R0 resection have no local recurrence after a median follow-up of 23 months (IQR: 11-36). Median local RFS was 20 months (IQR: 5-32), and DMFS was 6 months (IQR: 1-32). The local RR at 6 months was 10%, and the distant RR at 6 months was 30%. No correlation was observed between mPR and DMFS. Conclusions: Historically, neoadjuvant RT alone induces a mPR in ~30% of patients with localized STS. In our cohort, neoadjuvant PAZO with RT achieved an mPR in 70% of patients. Although dose reduction and grade 3 toxicity were noted in the majority of patients, these were reversible after stopping PAZO. There was no correlation between mPR and DMFS. However, a short course of PAZO with RT may help achieve R0 margins, which is the strongest predictor of better local RFS. A randomized trial is warranted to help understand the true impact of neoadjuvant PAZO with RT.