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Mortality in colorectal cancer is associated with the development of liver metastases. Surgical removal of these tumors is the only hope for cure, but recurrence is common. During liver surgery, ischemia/reperfusion (I/R) often occurs as a result of hemorrhage or vascular clamping. Although the adverse effects of I/R on postoperative liver function are well documented, the influence of I/R on the outgrowth of residual micrometastases is unknown. We used a highly standardized mouse model of partial hepatic I/R to study the effects of I/R on the outgrowth of preestablished colorectal micrometastases. Five days following intrasplenic injection of C26 colon carcinoma cells, the vascular structures of the left lobe were clamped for 45 minutes under hemodynamically stable conditions. Tissue glutathione, plasma liver enzymes, hepatocellular necrosis, and tumor growth were assessed over time. I/R caused oxidative stress and early liver tissue damage. The outgrowth of micrometastases in occluded liver lobes was accelerated five-to sixfold compared with nonoccluded lobes and was associated with areas of necrotic liver tissue surrounded by inflammatory cells and apoptotic hepatocytes. Accelerated tumor growth and tissue necrosis were completely prevented by occluding blood flow intermittently. In contrast, ischemic preconditioning or treatment with the antioxidants ␣-tocopherol or ascorbic acid failed to protect against late tissue necrosis and tumor growth, although early hepatocellular damage was largely prevented by these methods. In conclusion, I/R is a strong stimulus of recurrent intrahepatic tumor growth. Measures to prevent I/R-induced late tissue necrosis cross-protect against this phenomenon. (HEPATOLOGY 2005;42:165-175.)

We conclude that RFA stimulates the outgrowth of tumor cells at the lesion periphery. Angiogenesis is not the driving force behind RFA-stimulated tumor growth, but other hypoxia/HIF-activated pathways are likely to be important.

BackgroundThe peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate.These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay.Methods/DesignThe aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA.DiscussionAdjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival.Trial registration numberNCT02231086 (Clinicaltrials.gov)