Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally advanced rectal cancer (XELOXART).

Neo-adjuvant chemo-radiotherapy (CT-RT) has been shown to decrease local recurrence rate in locally advanced rectal cancer. This multicenter phase II trial was conducted to evaluate the feasibility, safety and effectiveness of a combination of pre-operative radiotherapy and concurrent Capecitabine plus Oxaliplatin (XELOXART Trial). From October 2008 to May 2011, fifty consecutive patients affected with T3/T4 and/or N+ rectal cancer were enrolled. Treatment protocol consisted of 50.4 Gy in 28 fractions, Oxaliplatin 60 mg/m(2) once a week for 6 weeks and oral Capecitabine 825 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35. Surgery was planned 6-8 weeks after. Main endpoints were pathological complete response rate (pCR) and the type of surgery performed compared to the planned one at diagnosis. 50 patients were included; pCR (ypT0N0M0) was achieved in 6 patients (12 %). Tumour downstaging was observed in 27 patients (54 %), and nodal downstaging in 32 patients (64 %). A total of 32 patients had lower rectal cancer, with 24 candidate for abdominal-perineal resection. At the end of CT-RT, a total of 12/24 (50 %) underwent conservative surgery. Grade 3 toxicity (fatigue and diarrhoea) occurred in 4 % of patients; grade 4 sensory neuropathy occurred in 2 % of patients. Perioperative complications of any grade occurred in 10 % of patients. Pre-operative CT-RT with Capecitabine-Oxaliplatin was well tolerated and resulted in an encouraging sphincter preservation and tumour downstaging rate. No improvements in terms of pathological complete response rate were shown.

Hyperthermia inhibits angiogenesis by a plasminogen activator inhibitor 1-dependent mechanism.

Hyperthermia (HT) associated with radiotherapy or chemotherapy is a promising method for cancer treatment, although the molecular mechanisms of this process are not well understood. HT exhibits various antitumor effects, including damage of tumor vasculature. Here, we investigate the effect of HT on in vitro and in vivo angiogenesis. We show that heat treatment of endothelial cells (ECs) affect their differentiation into capillary-like structures in two models of in vitro angiogenesis. Furthermore, the formation of new vessels promoted by angiogenic inducers in the chick embryo chorioallantoic membrane assay is impaired after heat treatment. These effects cannot be explained by direct cytotoxicity but are dependent on modulation of angiogenesis-involved genes. Gene expression profile of ECs subjected to heat shock demonstrates that plasminogen activator inhibitor 1 (PAI-1), a protein involved in the control of extracellular matrix degradation, is specifically up-regulated. The use of anti-PAI-1-neutralizing antibodies reverts the effect of HT on the in vitro EC morphogenesis and in vivo vessel formation. Moreover, microvessel outgrowth from PAI-1(-/-) aortic rings was not affected by HT compared with aortic rings from PAI-1(+/+) mice. Heat treatment of murine mammary adenocarcinomas results in inhibition of tumor growth, associated with a reduction of microvessel number and an increase of PAI-1 expression. These results indicate that heat-mediated PAI-1 induction is an important pathway by which HT exerts its antitumor activity and may represent a rationale for a combined cancer therapy based on HT associated with antiangiogenic molecules.