Peritoneal metastases of colorectal cancer: Insights from molecular and clinical perspectives

Colorectal cancer (CRC) patients with peritoneal metastases (PM) are currently treated with cytoreductive surgery (CRS) and HIPEC. This thesis primarily focuses on optimizing the preoperative work-up of CRC patients with PM. Part I Molecular insights The first part aims to provide insight in the molecular biology of colorectal PM. Chapter 2 outlines the process of peritoneal dissemination according to two phases, which could help us identify novel candidate biomarkers. Especially tumor cell adhesion to the peritoneum was considered crucial to form PM. Chapter 3 systematically reviews the functional importance of adhesion molecules and their clinical options. For patient selection, especially sLea and MUC16 were found to be of interest. α2β1 integrin antibodies, CD44 antibodies, hyaluronan-bound cytostatic agents, and EpCAM antibodies could target adhesion molecules and theoretically prevent formation of PM. Once a tumor cell has attached to the peritoneal surface, formation of PM depends on angiogenesis. In Chapter 4, we analyzed the expression of the angiogenesis-related markers VCAN, VEGF, and microvessel density in colorectal PM. The PCI, high VEGF expression, age, low epithelial VCAN expression, and lymph node metastases were associated with poor OS after CRS-HIPEC. The expression of the other angiogenesis markers HIF1α, SDF1, CXCR4, and VEGF is described in Chapter 5. The PCI, resection outcome, and VEGF expression had an independent association with OS after CRS-HIPEC. Both studies suggest that additional systemic administration of anti-VEGF agents could enhance survival. Chapter 6 provides a first step towards the clinical use of circulating tumor (ct)DNA analysis by setting out mutation-, copy number alteration- and hypermethylation markers in ctDNA to facilitate early diagnosis, prognostication, and monitoring of CRC patients. For CRC detection, copy number alterations and SEPT9 hypermethylation analysis could be promising. Regarding prognostication, mutation analysis of KRAS and APC could be of value. For monitoring, sequential ctDNA KRAS mutation analysis showed promise. Chapter 7 prospectively assesses ctDNA in CRC patients with PM. Preoperative ctDNA was found in 33% of patients using droplet digital PCR and was associated with a reduced DFS after CRS-HIPEC. In the follow-up, ctDNA was detected in 4/4 patients with a systemic- and 1/8 patients with a local relapse. Thus, sensitivity of single marker ctDNA is currently too low for detection of PM, but it could be used to guide therapy. Part II Insights from a clinical perspective Improved imaging is key to detect PM in an early stage and to optimize patient selection. Chapter 8 prospectively compares the advanced imaging techniques narrow-band imaging (NBI), near-infrared ICG, and spray-dye chromoendoscopy for detection of PM (n=28)15. NBI improved sensitivity for detection of PM from 80.0% to 96.0% (p=0.006), without loss of specificity. Prospective trials are warranted to investigate the clinical value of promising advanced imaging techniques regarding tumor detection, cost-effectiveness, and oncologic outcomes. Chapter 9 aimed to identify prognostic factors that could be assessed prior to surgery in a large prospective cohort of 175 CRC patients with PM treated with CRS-HIPEC. High PCI and peritoneal recurrence within 1 year following adjuvant chemotherapy were associated with worse DFS and OS and should be considered in patient selection prior to CRS-HIPEC. Also tumor subtype could be assessed preoperatively. Patients with PM of GGCs and MANECs might benefit of CRS-HIPEC. However, this is not standard part of care and guidelines. Chapter 10 presents a propensity-matched cohort together with a systematic review to compare outcomes between patients treated with CRS-HIPEC and patients treated with surgery without HIPEC. After matching, CRS-HIPEC was associated with improved median OS accompanied by acceptable morbidity rates, showing that GCC and MANEC patients with PM could benefit from this treatment offered by specialized HIPEC centers.