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Introduction and outline of this thesis131Patients with LAPC were historically treated with gemcitabine monotherapy (17). CRT was extensively studied in patients with LAPC with conflicting results and did not consistently show survival benefit compared to chemotherapy alone (18, 19). At the time of the study outlined in chapter two, CRT was considered a standard treatment approach for LAPC. This was because FOLFIRINOX had not yet been widely adopted in clinical practice. In an effort to increase the sensitivity of CRT, we conducted a phase I trial that incorporated treatment with an epithelial growth factor receptor (EGFR) inhibitor based on the following considerations. In human pancreatic cancer cells overexpression of EGFR is correlated with rapidly progressive disease (20, 21) and inhibition of the EGFR pathway using erlotinib was associated with a modest survival benefit in metastatic PDAC when combined with gemcitabine (22). PDAC is known for its high (>90%) oncogenic KRAS mutation phenotype (23, 24), and while in colorectal cancer the clinical efficacy of antibodies against EGFR is restricted to patients without an activating KRAS or BRAF V600E mutation (25, 26), several preclinical studies showed that EGFR pathway inhibition can improve the radiosensitivity of pancreatic tumour cells independent of KRAS mutation status. Indeed, inhibiting the EGFR-PI3K-AKT pathway as well as the HRAS signaling pathway are potential mechanisms through which blocking of EGFR signaling can reduce cell repair capacity following radiotherapy regardless of downstream activating KRAS mutations (27, 28). These data together with preclinical studies demonstrating that the radiosensitizing activity of gemcitabine may be further enhanced by EGFR pathway inhibition, provided the rationale to explore the addition of EGFR inhibition to CRT with gemcitabine (29). Panitumumab, an EGFR specific monoclonal antibody, approved for the treatment of metastatic colorectal cancer, is generally well tolerated although skin toxicity, hypomagnesemia, and diarrhea are commonly observed (30). In order to improve the prognosis of patients with LAPC and based on the above described preclinical data we studied the addition of panitumumab to gemcitabine based CRT. The results of this dose finding and feasibility phase I trial are described in chapter 2.FOLFIRINOX is the preferred multi-agent cytotoxic regimen for the initial treatment of patients with metastatic PDAC and LAPC who are in good overall condition. In the landmark study of Conroy et al. in 2011 the median number of treatment cycles of first-line FOLFIRINOX administered was 10 (range, 1 to 47)(11). In clinical practice the maximal number of cycles in patients with stable disease or response is commonly limited to 12 cycles to reduce toxicity. In daily practice, reintroduction