Radiation therapy is an essential treatment component for the local control of many primary tumors including breast cancer, rectal cancer, head/neck cancer, and soft tissue sarcoma. Local recurrence for primary soft tissue sarcomas after surgery alone can be as high as 33% for extremity tumors and 37-82% for retroperitoneal tumors. The addition of radiation therapy has been prospectively demonstrated to decrease the risk of local recurrence.  Despite aggressive surgery and radiation, large high-grade soft tissue sarcomas still have a significant risk of local or distant recurrence. Oxygen is the most important modifier of the biologic effect of radiation, and significantly higher doses of radiation are required to kill cancer cells in low oxygen environments. Vascular endothelial growth factor (VEGF) is over-expressed by the vast majority of human cancers including soft tissue sarcomas, and excess VEGF causes tumors to have highly irregular, porous tumor blood vessels with areas of hypoxia. Inhibition of VEGF leads to “normalization” of tumor blood vessels and improvement in tumor oxygenation. Numerous pre-clinical studies have demonstrated improvement in the tumoricidal effect of radiation therapy when radiation therapy is combined with anti-VEGF agents, but there is limited data in humans. Bevacizumab (Avastin) is a humanized anti-VEGF monoclonal antibody that binds VEGF and potently inhibits its activity (10). Bevacizumab has been used in over 30 phase I, II, and III trials, but no published clinical trial has yet examined the use of bevacizumab combined with radiation therapy (and in the absence of chemotherapy) in the adjuvant setting. 
           
In addition to VEGF overexpression, soft tissue sarcomas often overexpress platelet-derived growth factor (PDGF), c-KIT, and FLT3.  SU11248 (Sutent) is an oral, multi-targeted tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor (PDGFR), c-KIT, and FLT3 receptor tyrosine kinases. SU11248 can thus produce both anti-angiogenic and anti-tumor effects in sarcomas. Preclinical studies have demonstrated that SU11248 improves the efficacy of radiation therapy in mouse tumor models. In recent clinical trials, SU11248 showed clinical efficacy as single agent therapy for patients with metastatic renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors, and clinical trials are currently underway evaluating the effectiveness of SU11248 alone or in combination with other agents for several tumor types.

We are currently examining the hypothesis that the anti-angiogenic and anti-tumor effects of bevacizumab and SU11248 can increase the efficacy of radiation therapy in patients with soft tissue sarcomas through clinical trials with correlative science studies.

We have analyzed over 100 blood samples from soft tissue sarcomas patients for circulating angiogenic factors and found elevations in several angiogenic factors including VEGF. We have also examined expression of angiogenesis-related genes in 38 sarcoma specimens and 14 normal tissues using genechip microarrays and found increased expression in sarcomas of all three VEGF receptors, PDGFRa and b, c-KIT, and FLT3. We have assembled a team with significant expertise in the conduct and analysis of this proposed study, and this team includes Thomas DeLaney, MD (Department of Radiation Oncology, Massachusetts General Hospital), David Harmon, MD (Division of Hematology and Medical Oncology, Massachusetts General Hospital), Dushyant Sahani, MD (Department of Radiology, Massachusetts General Hospital), Peter Park, PhD (Biostatistician, Harvard-Partners Center for Genetics and Genomics), and Andrew Rosenberg, M.D. (Department of Pathology, Massachusetts General Hospital).

The bevacizumab/radiation protocol is already IRB approved, and the SU11248/radiation protocol is being submitted for IRB review. These studies will examine the use of neoadjuvant bevacizumab or SU11248 and radiation therapy for patients with high-grade, > 5 cm soft tissue sarcomas who are at moderate or high risk of recurrence. Patients (28 for each study) will be treated for two weeks with bevacizumab or SU11248 followed by six weeks of bevacizumab or SU11248 combined with radiation therapy. Surgical resection will be performed 5-6 weeks following completion of neoadjuvant therapy. Serial blood samples will be drawn and analyzed for plasma levels of VEGF, PDGFAA, and PDGFBB. Tumor tissue will be obtained by core needle biopsy prior to treatment, after two weeks of bevacizumab or SU11248, and at the time of surgery, and analyzed by immunohistochemistry for microvessel density and expression of VEGFR-1, VEGFR-2, PDGFRa, PDGRFb, c-KIT, and FLT3.  RNA will be isolated from tumor tissue and analyzed on Affymetrix microarrays for gene expression.  Perfusion CT scans and dynamic contrast-enhanced MRI will be obtained prior to treatment, after two weeks of bevacizumab or SU11248, and at the end of neoadjuvant treatment, and used to assess macroscopic tumor blood flow, and vascular permeability.

The proposed trials will determine if bevacizumab or SU11248 can improve the efficacy of radiation in patients with soft tissue sarcomas and will incorporate several correlative science studies to elucidate the mechanisms by which these agents act.  Results from this study may alter the way in which radiation is delivered to patients with soft tissue sarcomas and other solid tumors.

Sam S. Yoon, MD
2006