Phase II Study of Neoadjuvant Bevacizumab and Radiotherapy for Resectable Soft Tissue Sarcomas

Abstract

Purpose Numerous preclinical studies demonstrate that angiogenesis inhibitors can increase the efficacy of radiation therapy (RT). We sought to examine safety and efficacy of bevacizumab (BV) and RT in soft tissue sarcomas (STS) and explore biomarkers for treatment response. Methods and Materials Patients (pts) with ≥5 cm, intermediate- or high-grade STS at significant risk of local recurrence (LR) received neoadjuvant BV alone followed by BV plus RT prior to surgical resection. Correlative science studies included analysis of serial blood and tumor samples as well as serial perfusion CT scans. Results The 20 pts had a median tumor size of 8.25 cm, with 13 extremity, 1 trunk, and 6 retroperitoneal/pelvis tumors. Neoadjuvant treatment was well tolerated with only 4 pts having grade 3 toxicities (hypertension, LFT elevation). BV plus RT resulted in ≥80% pathologic necrosis in 9 of 20 tumors (45%), which is over double the historical rate seen with RT alone. 3 pts had a complete pathologic response. Median microvessel density (MVD) decreased 53% after BV alone (p<0.05), and following combination therapy, median tumor cell proliferation decreased by 73%, apoptosis increased 10.4 fold, and blood flow, blood volume, and permeability surface area decreased by 62–72% (p<0.05). Analysis of gene expression microarrays of untreated tumors identified a 24-gene signature for treatment response. MVD and circulating progenitor cells at baseline and reduction in MVD and plasma soluble c-KIT with BV also correlated with good pathologic response (p<0.05). After a median follow-up of 20 months, only 1 patient had a LR. Conclusions This exploratory study indicates that BV increases the efficacy of RT against STS and may reduce LR, and thus this regimen warrants further investigation. Gene expression profiles and other tissue and circulating biomarkers show promising correlations with treatment response.

Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

“…Consistent with multiple prior studies of anti-VEGF/VEGFR agents, including bevacizumab in sarcoma, rectal, breast, and ovarian cancer, we found that anti-VEGF therapy led to a sustained increase in PlGF, suggesting that this may be a pharmacodynamic marker of activity (21)(22)(23)(24)(25)(26)(27)(28). We also found that, although pretreatment plasma VEGF does not associate with outcome, higher levels of sVEGFR1 before combination therapy were associated with worse survival.…”

The Benefit of Adjuvant Radiotherapy in High-grade Nonmetastatic Retroperitoneal Soft Tissue Sarcoma

“…A small study of neoadjuvant bevacizumab and RT in patients with STS (30% of which were retroperitoneal) suggested bevacizumab might increase the sensitivity of such tumors to radiation without significant adverse events. 50 On multivariate analysis, this series of patients also suggested that age above 65 years and male sex were associated with a worse prognosis regarding high-grade RPS after surgical resection. These are both in agreement with current literature.…”

A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities

“…Nevertheless, the targeted agents sorafenib [16], bevacizumab [17], and pazopanib exert their anti-tumor activity by targeting the tumor vasculature, and are or have been studied in combination with RT. sunitinib combined with RT is currently under investigation [18] and further discussed below.…”