Synchronous Irresectable Liver metastases: Effects of Neo-adjuvant Therapy
Histological proven colorectal cancer without signs of bowel obstruction or bleeding
Synchronous liver metastases
WHO performance status 0-1
immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary
Difference in response of liver metastases to resection of the primary tumor between the experimental groups and the control group, as determined by histopathological scoring of vascular density, apoptotic and mitotic index and by measurement of the metabolic activity of liver metastases by FDG-PET and SUV measurements.
Toxicity of neo-adjuvant treatment
Complications of surgery
Dr. T.J.M. Ruers, Dept. of Surgery, NKI/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Prof.dr. C.J.A.Punt, Dept. of Medical Oncology, UMC St Radboud, Nijmegen, The Netherlands
Prof. dr. W.J.G. Oyen, Dept. of Nuclear Medicine, UMC St Radboud, Nijmegen, The Netherlands
Drs. M.G.W.Scheer, Dept of Surgery, UMC St Radboud, Nijmegen, The Netherlands
Trial Office IKO, Nijmegen, The Netherlands, Phone 024-3616837, Fax 024-3619080
In animal models primary tumor-mediated inhibition of metastatic vascularization and outgrowth is nowadays an established concept in tumor biology. In mice, O'Reilly et al. developed a specific Lewis lung carcinoma model in which surgical removal of the primary tumor was followed by explosive growth of previous dormant lung metastases. The primary tumor produced a potent anti-angiogenic factor, which prevented vascularization and thereby outgrowth of metastases. This inhibitor was shown to be a proteolytic fragment of plasminogen, and was designated angiostatin. In this Lewis lung carcinoma model outgrowth of metastases in the presence of the primary tumor was prevented by a delicate balance between pro-and antiangiogenic factors. Removal of the primary tumor resulted in loss of antiangiogenic factors resulting in a loss of its inhibitory effect on the outgrowth of the distant metastases.
In humans, rapid outgrowth of metastases after resection of the primary tumor is a phenomenon that is observed periodically within clinical practice for at least certain tumor types e.g. colorectal cancer. Recently, we demonstrated in patients with colorectal cancer and synchronous liver metastases an increase in the intra- and peritumoral vessel density of the liver metastasis after resection of the primary colorectal tumor. Furthermore, a increase in the percentage proliferating cells and a decrease in the percentage apoptotic cells was observed. In addition, we demonstrated by FDG-PET a significant increase in metabolic activity of the liver metastases after resection of the primary colorectal tumor. These preliminary data strongly suggest an inhibitory effect of the primary colorectal tumor on the outgrowth of its liver metastases. Resection of the primary tumor seems to result in abrogation of this inhibitory effect and subsequent enhanced tumor growth of the liver metastases. This may have direct implications for the timing of systemic therapy. In primary colorectal cancer adjuvant chemotherapy is generally applied after resection of the primary tumor. However, administration of systemic therapy before resection of the primary tumor (neo-adjuvant) may improve results of chemotherapy, since it may affect accelerated growth of (micro)metastases as observed after resection of the primary tumor. In this study we aim to demonstrate that outgrowth of metastatic disease in colorectal cancer, as observed after resection of the primary tumor, can be inhibited by preoperative treatment with the antiangiogenic agent bevacizumab and/or chemotherapy before resection of the primary colorectal tumor.