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Summarizing discussion and future perspectives1096This final chapter summarizes the findings and main conclusions of the reported studies in this thesis followed by an interpretation and discussion.Part one: Pancreatic cancerChemoradiation and systemic therapyIn part 1 we focus on two clinical studies to improve the treatment of pancreatic cancer. As described in the introduction of this thesis only a minority of patients present with resectable disease. Resection alone typically results in a 5-year overall survival (OS) rate of approximately 10%. However, the prognosis for patients with resected pancreatic ductal adenocarcinoma (PDAC) is notably enhanced with the addition of adjuvant chemotherapy. Adjuvant chemotherapy with 5-fluorouracil (5-FU), folinic acid, irinotecan and oxaliplatin (modified FOLFIRINOX) vs gemcitabine improved median OS (53.5 vs 35.5 months) after 5 years follow up (1). The optimal neoadjuvant treatment with chemotherapy or chemotherapy in combination with radiotherapy (CRT) for patients with resectable and borderline resectable tumours is not clear and preferably given in a clinical trial. Neoadjuvant CRT with gemcitabine, followed by resection and 4 courses of adjuvant gemcitabine resulted in an 15% 5-year OS improvement versus immediate surgery and 6 courses of adjuvant gemcitabine in the PREOPANC study (patients with resectable or borderline resectable tumors) (2). The PREOPANC-2 trial compared FOLFIRINOX versus CRT with gemcitabine and adjuvant gemcitabine in the same neoadjuvant setting. Interestingly neoadjuvant FOLFIRINOX did not improve OS or resection rates compared to neoadjuvant gemcitabine based CRT (OS 21.9 vs. 21.3 months; HR 0.87; 95% CI 0.68-1.12, p=0.28; resection rates 77% vs. 75%, p=0.69)(3).Around 35% of patients present with unresectable locally advanced pancreatic cancer (LAPC). Treatment with CRT in combination with gemcitabine has been extensively studied for LAPC and did not consistently show survival benefit compared to chemotherapy alone (4, 5). Human pancreatic cancer cells overexpress the epidermal growth factor receptor (EGFR) compared to normal pancreatic cells (6). Clinical data have shown a modest survival benefit by the addition of the EGFR inhibitor erlotinib to gemcitabine alone for patients with advanced PDAC (7). Therefore the combination of EGFR inhibitors cetuximab or erlotinib with gemcitabine based CRT was investigated in a pancreatic cancer model (8). In this