Colorectal cancer Colorectal cancer is the third most common malignant tumor worldwide. Globally, more than 600.000 people die from colorectal cancer every year, mainly from metastatic disease. Before the era of chemotherapy, patients with mCRC had a median overall survival of 9 months. With the introduction chemotherapeutic agents and targeted agents against VEGF and the EGF receptor, overall survival has improved to over 30 months. Originally, when patients presented with metastases, the disease was viewed as always being widespread and patients have typically been treated with systemic therapy. However, local treatment of metastases is technically feasible in an increasing number of patients with mCRC by either resection, radiofrequency ablation or stereotactic radiotherapy. Preliminary and retrospective evidence suggests that patients with extensive multi-organ mCRC may benefit from local treatment of metastases. This results in a growing debate in multidisciplinary teams on whether local treatment of metastases should be performed in these patients. Part One: Debulking in metastatic colorectal cancer In Chapter 2, the rationale of debulking therapy for patients with multi-organ mCRC is reviewed. The ORCHESTRA trial is the first multicenter randomized clinical trial in which is evaluated if multidisciplinary local treatment in addition to first line palliative systemic treatment (NCT01792934) results in survival benefit for patients with extensive mCRC. A preplanned safety and feasibility evaluation was performed aftercompletion of study treatment of the first 100 patients enrolled in the trial and reported in Chapter 3. A translational study program was embedded in the ORCHESTRA trial protocol and blood and tissue samples were collected from all patients enrolled. Part Two: Predicting response to systemic therapy MicroRNA MicroRNAs (miRNAs) are small non-coding RNAs that have an impact on many important biological processes by regulation of protein expression levels. Previous studies have shown significant correlations between circulating miRNAs and tumor stage and between paired tissue and serum miRNA expression levels. These circulating miRNAs could function as a minimally invasive predictive biomarker and as biomarker for disease monitoring. We aimed to prospectively validate the predictive value of a previously identified miRNA signature in the patients enrolled in the ORCHESTRA trial, which is reported in Chapter 4. Circulating Endothelial Cells (CECs) Circulating endothelial cells (CECs) are cells detached from both damaged normal vasculature as well as tumor vasculature. Previously, it has been shown that in patients with metastatic cancer, CEC numbers at baseline and changes in CEC numbers during systemic therapy are associated with prognosis. Consequently, enumeration of CEC is considered a promising biomarker in oncology. In Chapter 5 the results of (CD276+)CECs measurements from patients enrolled in the ORCHESTRA trial are reported. The primary objective of the study was to establish the prevalence of CD276+CECs in patients with mCRC and evaluating the dynamics of CD276+CECs during systemic therapy. Zr89-labeled PET Imaging In Chapter 6 Zr89-labeled PET Imaging is used to acquire more insight in the body distribution of cetuximab, a monoclonal antibody targeting the EGF receptor. We hypothesized that response to treatment is dependent on uptake of cetuximab in tumor lesions. We performed 89Zr-cetuximab PET imaging in patients with wt K-RAS mCRC with an indication for anti- EGFR mAb monotherapy to investigate biodistribution and tumor uptake as well as to establish the optimal scanning time point to visualize tumor targeting. Most importantly, we evaluated whether uptake on 89Zr-cetuximab PET imaging can discriminate between patients responding to treatment with cetuximab versus non-responding patients. In Chapter 7 the main findings presented in this thesis are summarized and discussed.
|Qualification||Doctor of Philosophy|
|Award date||11 May 2021|
|Place of Publication||s.l.|
|Publication status||Published - 11 May 2021|