Versican and vascular endothelial growth factor expression levels in peritoneal metastases from colorectal cancer are associated with survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can increase survival of colorectal cancer (CRC) patients with peritoneal metastases (PM). This treatment is associated with high morbidity and mortality rates. Therefore, improvement of patient selection is necessary. Assuming that the clinical phenotype is dictated by biological mechanisms, biomarkers could play a crucial role in this process. Since it is unknown whether and to what extent angiogenesis influences the course of disease in patients with PM, we investigated the expression of two angiogenesis-related markers and their relation to overall survival (OS) in CRC patients after CRS and HIPEC. Clinicopathological data and tissue samples were collected from 65 CRC patients with isolated metastases to the peritoneum that underwent CRS and HIPEC. Whole tissue specimens from PM were evaluated for versican (VCAN) expression, VEGF expression and microvessel density (MVD) by immunohistochemistry. The relation between these markers and OS was assessed using univariate and multivariate analysis. Associations between VEGF expression, VCAN expression, MVD and clinicopathological data were tested. High stromal VCAN expression was associated with high MVD (p = 0.001), better resection outcome (p = 0.003) and high T-stage (p = 0.027). High epithelial VCAN expression was associated with MVD (p = 0.007) and a more complete resection (p < 0.001). In multivariate analysis, simplified peritoneal cancer index (p = 0.001), VEGF expression levels (p = 0.012), age (p = 0.030), epithelial VCAN expression levels (p = 0.042) and lymph node status (p = 0.053) were associated with OS. Concluding, VCAN and VEGF were associated with survival in CRC patients with PM after CRS and HIPEC. Independent validation in a well-defined patient cohort is required to confirm the putative prognostic role of these candidate biomarkers.

Angiogenesis-Related Markers and Prognosis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Metastatic Colorectal Cancer.

BACKGROUND: Patients presenting with peritoneal metastases (PM) of colorectal cancer (CRC) can be curatively treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Angiogenesis is under control of multiple molecules of which HIF1a, SDF1, CXCR4, and VEGF are key players. We investigated these angiogenesis-related markers and their prognostic value in patients with PM arising from CRC treated with CRS and HIPEC. PATIENTS AND METHODS: Clinicopathological data and tissue specimens were collected in 2 tertiary referral centers from 52 patients who underwent treatment for isolated PM of CRC. Whole tissue specimens were subsequently analyzed for protein expression of HIF1a, SDF1, CXCR4, and VEGF by immunohistochemistry. Microvessel density (MVD) was analyzed by CD31 immunohistochemistry. The relationship between overall survival (OS) and protein expression as well as other clinicopathological characteristics was analyzed. RESULTS: Univariate analysis showed that high peritoneal cancer index (PCI), resection with residual disease and high expression of VEGF were negatively correlated with OS after treatment with CRS and HIPEC (P < 0.01, P < 0.01, and P = 0.02, respectively). However, no association was found between the other markers and OS (P > 0.05). Multivariate analysis showed an independent association between OS and PCI, resection outcome and VEGF expression (multivariate HR: 6.1, 7.8 and 3.8, respectively, P ≤ 0.05). CONCLUSIONS: An independent association was found between high VEGF expression levels and worse OS after CRS and HIPEC. The addition of VEGF expression to the routine clinicopathological workup could help to identify patients at risk for early treatment failure. Furthermore, VEGF may be a potential target for adjuvant treatment in these patients.

Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival.

BACKGROUND: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity. METHODS: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20). RESULTS: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04). CONCLUSIONS: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.