In this study of patients with ≥5 cm, intermediate- or high-grade STS, the addition of neoadjuvant BV to RT led to no grade IV toxicities and grade III toxicities in only 4 patients. Neoadjuvant BV and RT resulted in ≥80% necrosis in 45% of tumors, which is over double the historical rate with RT alone. Thus this treatment regimen appears be safe and to increase the degree of pathologic necrosis compared to RT alone.
Despite numerous preclinical studies demonstrating that VEGF inhibitors augment the efficacy of RT, this is the first clinical trial combining BV with RT for STS. Very few clinical trials have evaluated a specific anti-angiogenic agent combined with RT and no chemotherapy. One study treated patients with a variety of solid tumors with angiostatin at increasing doses and RT for a minimum of 25 fractions (22
). There were 17 evaluable patients, no added toxicity was observed in normal tissue within the RT field, and tumor response was noted in 90% of patients. In another study, 25 patients with recurrent gliomas were treated with BV and RT with an overall response rate of 50% and median overall survival of 12.5 months (23
). In addition to the rectal cancer studies described earlier (12
), Koukourakis et al.
found that BV combined with amifostine, capecitabine, and conformal hypofractionated RT caused a complete response in 13 of 19 (69%) of evaluable patients with locally advance inoperable colorectal cancer (13
). Crane et al.
examined BV combined with capecitabine and RT in a phase I trial for locally advanced pancreatic cancer. (25
). Twenty percent of patients had a partial response, and median survival was 11.6 months. These studies illustrate the broad variations in response that solid tumors may have to the combination of BV and RT, with or without chemotherapy.
All untreated tumors were analyzed using gene expression microarrays. Unsupervised hierarchical clustering of STS has found clustering of histologic subtypes in some studies (26
) but not in others (27
). Gene signatures have been developed that are associated with extent of disease, metastasis, and response to treatment (26
). We previously demonstrated that histological subtypes of STS often share expression of angiogenesis-related genes, and these expression patterns are distinct from normal tissues (7
). In this study, gene expression analysis of STS samples prior to treatment revealed that good responders and poor responders had global gene expression patterns that were significantly different. Thus global gene expression patterns or a more limited gene expression profile may be accurate means of discriminating tumors which will respond well to this therapy.
Our correlative science studies were designed to examine the effects of BV alone and BV with RT on tumors and tumor vasculature. Given the wide heterogeneity that is inherent in STS, we found significant variations in STS in terms of tumor proliferation, apoptosis, microvessel density, circulating proteins and cells, and perfusion CT parameters. BV alone significantly decreased tumor microvessel density by about 50% without decreasing blood flow rate, suggesting that the function of remaining tumor vasculature was not impaired but rather improved by BV, consistent with vascular normalization (10
). Moreover, combination therapy significantly decreased tumor proliferation and increased apoptosis. As seen in studies of anti-angiogenic agents in other tumors, we show that VEGF blockade with BV increased plasma VEGF and PlGF concentration in STS patients (28
). Moreover, we found that BV treatment decreased plasma concentration of sVEGFR3 (a receptor for VEGF-C and -D but not for VEGF or PlGF) suggesting a previously unrecognized indirect effect of VEGF blockade on this pathway in cancer patients. No validated biological markers currently exist for appropriately selecting cancer patients for anti-angiogenic therapy, although several biomarkers have been identified from examination of host factors, blood, tumor tissue, and radiological studies (28
). The promising but preliminary associations found in this trial should be further explored in larger studies.
In summary, the results of this single arm, phase II study of neoadjuvant BV and RT for STS show encouraging activity and safety, and support the further evaluation of this regimen. Local recurrence occurred in only one patient. Using a large battery of correlative science studies, we found that BV alone can decrease microvessel density in tumors, and that combining BV with RT increased the degree of tumor necrosis and tumor cell apoptosis, and reduced tumor cell proliferation, blood flow, blood volume, and permeability. Several potential biomarkers for response to therapy, including gene expression profiles, were identified. These mechanistic insights and the potential response biomarkers identified in this study require further validation.