Low dose angiostatic treatment counteracts radiotherapy-induced tumor perfusion and enhances the anti-tumor effect

Abstract

The extent of tumor oxygenation is an important factor contributing to the efficacy of radiation therapy (RTx). Interestingly, several preclinical studies have shown benefit of combining RTx with drugs that inhibit tumor blood vessel growth, i.e. angiostatic therapy. Recent findings show that proper scheduling of both treatment modalities allows dose reduction of angiostatic drugs without affecting therapeutic efficacy. We found that whilst low dose sunitinib (20 mg/kg/day) did not affect the growth of xenograft HT29 colon carcinoma tumors in nude mice, the combination with either single dose RTx (1x 5Gy) or fractionated RTx (5x 2Gy/week, up to 3 weeks) substantially hampered tumor growth compared to either RTx treatment alone. To better understand the interaction between RTx and low dose angiostatic therapy, we explored the effects of RTx on tumor angiogenesis and tissue perfusion. DCE-MRI analyses revealed that fractionated RTx resulted in enhanced perfusion after two weeks of treatment. This mainly occurred in the center of the tumor and was accompanied by increased tissue viability and decreased hypoxia. These effects were accompanied by increased expression of the pro-angiogenic growth factors VEGF and PlGF. DCE-MRI and contrast enhanced ultrasonography showed that the increase in perfusion and tissue viability was counteracted by low-dose sunitinib. Overall, these data give insight in the dynamics of tumor perfusion during conventional 2 Gy fractionated RTx and provide a rationale to combine low dose angiostatic drugs with RTx both in the palliative as well as in the curative setting.

The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future

“…Thus, improved tumor perfusion might represent an additional mechanism of radiotherapy-induced tumor oxygenation, next to previously described mechanisms like decreased oxygen consumption, increased inflammation and reduced tumor volume [55]. While the improved perfusion and oxygenation might increase the efficacy of subsequent irradiations, our recent findings confirm that the tumor areas with increased perfusion also contained more viable tumor tissue [28]. Apparently, the improved tumor vascularization and oxygenation can also contribute to tumor cell survival or to tumor regrowth following fractionated radiotherapy.…”

“…Despite this apparent conflict, several preclinical studies have shown that angiostatic treatment can enhance tumor oxygenation, thereby increasing the efficacy of radiation treatment [13, 22, 26–28]. The mechanisms by which angiostatic drugs improve tumor oxygenation are still not fully understood.…”

Combining Radiotherapy With Anti-angiogenic Therapy and Immunotherapy; A Therapeutic Triad for Cancer?

“…Using dynamic contrast-enhanced MRI and contrast-enhanced ultrasonography, we recently also observed increased tumor perfusion following two weeks of fractionated irradiation in a xenograft mouse tumor model. This was accompanied by reduced intratumoral hypoxia and increased tumor viability (35). Of note, increased tumor oxygenation during radiotherapy has been linked to different mechanisms, such as decreased oxygen consumption and vasorelaxation via increased inflammation (36).…”

Radiotherapy and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors in Renal Cancer

“…Other data [12, 15] suggest that giving RT before sunitinib allowed a dose reduction in sunitinib, while maintaining a comparable antitumor effect.…”