Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction

Abstract

The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting.

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

“…The temporary character of improved oxygenation suggests only a limited effect of vascular normalization which would not benefit patients receiving conventional 2 Gy fractionated RTx (RTx FR ) for several weeks. In addition, our previous preclinical observations and several clinical case reports by others show that maintenance angiostatic therapy during and after RTx is also beneficial [15-17]. This demonstrates that there are other feasible treatment schedules of the combination therapy.…”

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.…”

“…Sunitinib potentiated the inhibitory effect of irradiation on angiogenesis; in addition, RT and sunitinib inhibited tumor growth [12]. In a xenograft mouse model of renal cancer [13] and squamous cell carcinoma [14], dynamic contrast-enhanced MRI revealed an improvement in tumor perfusion after 3 days of sunitinib, and a tumor growth delay when irradiation was applied on day 4.…”

Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy

“…Combined drug therapy can increase the efficacy of radiotherapy by targeting both cancer cells and the microenvironment, including tumor vessels. Anti-angiogenic therapy targets endothelial cells, disrupting the pre-existing tumor vasculature and inhibiting angiogenic vessel formation [1,3]. Sunitinib (Su11248, Sutent) is a multi-target tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR1/2/3), platelet-derived growth factor receptor (PDGFRa/b), c-kit, FLT3 and ret.…”

“…Combination treatment using anti-VEGF therapy, such as sunitinib, and radiotherapy is limited in dose, treatment schedule, and tumor size [3,9]. In vivo, tumor size at therapy onset plays a key role in the efficacy of radiation and anti-VEGF therapy [10].…”