Targeted therapies in upper gastrointestinal cancer

Upper gastrointestinal (GI) cancers, as esophageal, gastric and pancreatic cancer, are still highly lethal diseases, in spite of advances in surgery, radiotherapy, chemotherapy and specific targeted therapy. Especially when patients are diagnosed with locally advanced or metastasized disease, upper GI cancer patients have a dismal prognosis, with a median survival of less than a year, despite extensive chemotherapy treatments. However, even when surgery is still an option and patients are treated with curative intentions, median survival rates are 49 and 24 months in esophageal and pancreatic cancer, respectively.
Insights into the role of aberrant functioning signalling pathways in malignant transformation and cancer progression resulted in the identification of crucial oncogenic molecules, as the epidermal growth factor receptor (EGFR), and the development of drugs able to inhibit these molecules (targets). However most cancer cells are not addicted to one aberrant functioning pathway and crosstalk between pathways is an important escape mechanism for target directed therapy, resulting in primary or secondary (acquired) resistance. To improve anti-cancer activity of targeted therapy, combined inhibition of multiple targets in one or more oncogenic pathways is an attractive strategy that has to be explored in clinical trials.
The main aim of this thesis is to investigate the clinical possibility and efficacy of combining conventional chemo(radio)therapy with targeted therapies inhibiting the EGFR- and other oncogenic pathways in upper GI cancer patients.