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Purpose It is plausible that patients with pancreatic cancer experience fear of tumor recurrence or progression (FOP). The aim of this study was to compare FOP in patients with pancreatic cancer treated with surgical resection, palliative systemic treatment, or best supportive care (BSC) and analyze the association between quality of life (QoL) and FOP and the effect of FOP on overall survival (OS). Methods This study included patients diagnosed with pancreatic cancer between 2015 and 2018, who participated in the Dutch Pancreatic Cancer Project (PACAP). The association between QoL and WOPS was assessed with logistic regression analyses. OS was evaluated using Kaplan-Meier curves with the log-rank tests and multivariable Cox proportional hazard analyses adjusted for clinical covariates and QoL. Results Of 315 included patients, 111 patients underwent surgical resection, 138 received palliative systemic treatment, and 66 received BSC. Patients who underwent surgical resection had significantly lower WOPS scores (i.e., less FOP) at initial diagnosis compared to patients who received palliative systemic treatment or BSC only (P < 0.001). Better QoL was independently associated with the probability of having a low FOP in the BSC (OR 0.95, 95% CI 0.91-0.98) but not in the surgical resection (OR 0.97, 95% CI 0.94-1.01) and palliative systemic treatment groups (OR 0.97, 95% CI 0.94-1.00). The baseline WOPS score was not independently associated with OS in any of the subgroups. Conclusion Given the distress that FOP evokes, FOP should be explicitly addressed by health care providers when guiding pancreatic cancer patients through their treatment trajectory, especially those receiving palliative treatment or BSC.

Background: Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective: To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods: European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (

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Interprofessional shared decision making (SDM), where medical oncologists, general practitioners, and nurses collaborate, is essential for allowing healthcare professionals (HCPs) and incurable cancer patients to choose treatment best fitting a patient’s end-of-life wishes. The aim of this dissertation was to effectively promote interprofessional SDM in palliative cancer care through communication skills training (CST) for HCPs. First, in two qualitative interview studies, the role of 1) GPs and 2) hospital nurses in SDM in palliative (cancer) care was explored. We found three strategies HCPs may deploy to support SDM: 1) checking the quality of a decision, 2) complementing SDM, and 3) enabling SDM. Second, the effects of CST in SDM were examined. A review of reviews on the current evidence for CST revealed that CST can probably improve HCPs’ communication skills, but that high-quality research is needed to increase the certainty of evidence on CST effects. Two one-group pre-posttest studies demonstrated 1) a large effect of a blended CST, i.e. e-learning and online training session, in SDM on medical oncologists’ skills and 2) a medium effect of a blended CST in SDM support on GPs’ and hospital nurses’ skills. An experimental study showed that, in contrast to these observations of professional assessors, cancer patients and survivors did not significantly differ in their assessments of trained and untrained HCPs in SDM support. In conclusion, CST seems helpful in promoting interprofessional SDM in palliative cancer care. Yet, research designs should be improved and the clinical relevance of CST established.

This thesis focuses on the role of religion in palliative settings involving Muslim doctors or religious professionals and Muslim patients and their relatives. It seeks to answer the question how religion shapes Muslim attitudes in medical decision-making in palliative care in the Netherlands. The thesis demonstrates that in classical Islamic discourse, medical treatment may be withheld or terminated in the case of incurable illness, while modern Islamic discourse tends to put great emphasis on prolonging life through maximum treatment. The results of the empirical part of the thesis suggest that the professional practice of Turkish imams and Muslim doctors regarding palliative decision making are embedded in the religious and medical institutions they represent and cater to the demands that are part of their jobs within these institutions. The thesis demonstrates that Muslim doctors take a comfort-oriented approach aimed at preventing suffering from pain, which for some of them conflicts with their personal religious beliefs. Turkish imams predominately advocate for maximum treatment in their advice regarding medical decision-making to their congregants, for the conviction that all Muslims involved will be held accountable by God for questioning His omnipotence. Together the results create the picture of a healthcare environment in which medical practice and religious beliefs are rather at odds.

This thesis focuses on the use of population-based data to provide more insight into the outcomes of patients with esophagogastric cancer treated in daily clinical practice. A large part of this thesis is based on data from the nationwide Netherlands Cancer Registry that covers the total Dutch population. Part I of this thesis focuses on patients in the curative setting and includes two studies that provide information on communication of life expectancy by providing conditional relative survival results and survival according to multiple scenarios of patients with non-metastatic esophagogastric cancer. In addition, a study is included that provides real-world outcomes of patients with esophageal- or gastroesophageal junctional cancer selected on the inclusion criteria of CheckMate 577. Part II of this thesis focuses on patients in the palliative setting and begins with a study that provides information on survival according to multiple scenarios of patients with metastatic disease. Additionally, an overview of treatment patterns and outcomes is provided for patients with esophageal squamous cell carcinoma as well as a comparison of adenocarcinoma by primary tumor location of the esophagus, gastroesophageal junction and stomach. Lastly, two studies provide insights on treatment and outcome after previous treatment with curative intent for non-metastatic disease, that is disease recurrence after esophageal or gastroesophageal junction cancer and a comparison of synchronous versus metachronous metastatic esophagogastric cancer.

This dissertation focused on the application of visual methods, literature, and art to support patients with cancer. Having cancer impacts people in many ways, from physical discomfort to the loss of life goals. Therefore, it can be described as an experience of contingency. Contingency means that everything could have been different in life, that what happened was not impossible, but also not necessary. When an experience of contingency arises, patients need to make meaning of their life with cancer and integrate the diagnosis and prognosis in their life story. In other words, they need to adjust their life story. To be able to support patients with cancer with such adjustments, insight into their experiences is needed first. However, talking about what it means to have cancer can be difficult. For this reason, the present dissertation had two objectives. First, we explored the potential of using visual tools to gain insight into the story of patients with cancer. Second, we examined how patients may adapt their story using literature and art-based interventions. We adopted two visual tools to gain insight into the stories of patients with cancer: rich pictures (RPs) and photovoice. RPs are visual representations in the form of a drawing, that attempt to capture an individual’s perspective of a difficult or complex situation. In photovoice, participants are invited to make photographs to document meaningful aspects of their experience. We investigated two examples of interventions in which art is used to adapt the story of patients with cancer: art therapy and co-creative art-making.

Various treatments exist to remove tumours, alleviate symptoms and combat recurrence in oesophagogastric cancer patients. Survival often remains poor and treatments can come at the cost of health-related quality of life (HRQoL). Providing accurate information to patients and physicians about the outcomes of relevant treatments, such as survival and HRQoL, is crucial to determine which course of treatment is best and coincides with the patients’ preferences. However, these outcomes depend on many factors and accurately determining these outcomes beforehand is complex. The goal of this thesis is therefore to provide accurate and evidence-based information on treatment outcomes. We developed and validated prediction models to predict overall survival in individual patients based on readily available patient, tumour and treatment characteristics. These models were aimed at patients with both metastatic and potentially curable oesophagogastric cancer. The models had a fair discriminatory ability and demonstrated a close agreement between predicted and observed survival. Furthermore, meta-analyses were performed to determine the effect of treatment of HRQoL. In patients with metastatic disease, HRQoL was impaired prior to treatment and remained stable for most treatments. However, in potentially-curable patients short-term differences were found between treatments, favouring neoadjuvant treatment. A lasting impaired HRQoL was observed in patients that underwent oesophagectomy. Finally, a patient-friendly web-interface and training were created to inform patients with oesophagogastric cancer about treatment outcomes in an evidence-based, precise, personalised, and tailored manner. The resulting prediction models and analyses can provide complementary information and visualisations to facilitate shared decision making in clinical practice.

This thesis sheds light on several topics within pancreatic and periampullary cancer and outcomes after pancreatic surgery. In 2013, the Dutch Pancreatic Cancer Project (PACAP) was launched, which comprises several registries and patient reported outcomes measures. Based on these data, part I demonstrates that practice variation was present. The PACAP-1 trial aimed to decrease this variation and improve care by enhanced implementation of best practices, regarding chemotherapy, biliary stenting, and exocrine insufficiency. The results of this trial are awaited in July 2021. Part II enhances quality of life and clinical outcomes after pancreatic surgery. For total pancreatectomy, short-term postoperative outcomes are still relatively concerning and require further research, but might be improved by increased centralization. Long-term consequences will improve due to new treatment modalities for endocrine insufficiency and more attention and guidance for pancreatic enzyme supplementation. Part III focuses on survival and predictors for survival in patients with pancreatic and periampullary cancer. A nomogram which predicts personalized conditional survival probabilities based on patient and tumor characteristics with the possibility to adjust for the period already survived after resection was developed. It is also demonstrated that overall happiness, a quality of life summary score, and several functioning and symptom scale item scores were predictive of survival. The collaboration within the Dutch Pancreatic Cancer Group (DPCG) and further development of the PACAP will be cornerstones to reach future improvements in daily clinical practice and to decrease current practice variation to ultimately increase life expectancy of pancreatic cancer patients.

The aim of this thesis was to explore novel systemic treatment approaches in esophagogastric cancer that could improve treatment outcome. For this purpose we investigated the addition of dual HER2 blockade through trastuzumab and pertuzumab to neoadjuvant chemoradiotherapy for resectable HER2+ esophageal adenocarcinoma and concluded that this treatment is both feasible and promising. The hybrid LC-MS/MS method we developed for quantifying co-administered trastuzumab and pertuzumab can be used in further studies where these two (or other) mAbs are administered and can reduce the required sampling volume. Furthermore, since currently patients do not receive further treatment after surgery, adjuvant therapy could improve survival. However, we showed that, unfortunately, six cycles of SOX after neoadjuvant chemoradiation and esophagectomy in esophageal adenocarcinoma patients is not feasible and appears to lack efficacy in unselected patients. In the curative treatment of esophageal cancer, research should be directed towards optimization of neoadjuvant treatment. Since a substantial number of patients present with synchronous metastases, and unfortunately most curatively treated patients eventually develop disease recurrence, more effective palliative treatment is urgently needed. Despite our finding that the addition of nab-paclitaxel to first-line palliative treatment with CapOx caused more toxicity and apparent improvement of survival was modest, this study did provide valuable information on the potential prognostic serum biomarker ADAM12. Other prognostic factors we identified in our systematic review can be used for future trial design, and aid in the development of survival nomograms. The identified predictive factors can be used to increasingly personalize treatment decisions.

This thesis includes studies that focus on the palliative treatment of patients with advanced esophageal and gastric cancer in daily clinical practice. Rather than curation, palliative treatment aims to prolong survival, optimize quality of life and reduce symptom burden. Most results regard palliative systemic treatment, which consists of either chemotherapy, targeted therapy or both. This thesis provides insights into the management of patients with advanced esophagogastric cancer in The Netherlands using data of the nationwide Netherlands Cancer Registry, supplemented with patient-reported outcomes of the Prospective Observational Cohort Study of Oesophageal-gastric Cancer Patients (POCOP). It sheds light on several factors that are associated with the allocation of palliative systemic treatment, e.g. gender, but also factors that are not patient or tumor-related, e.g. the number of patients diagnosed in a hospital annually. Practice variation in first-line and second-line palliative systemic treatment administration as well as in biomarker testing is described. Moreover, aspects that are associated with treatment outcomes, such as skeletal muscle mass and cachexia, are discussed. The real-world results provide an overview of the contemporary situation of palliative systemic treatment administration in esophagogastric cancer in clinical practice, and enabled to reveal differences between treatment effectiveness in clinical practice and treatment efficacy described in clinical trials.

In recent years it has become evident that the tumor microenvironment is a key player in the development, resistance and progression of solid tumors. Esophageal adenocarcinoma and pancreatic ductal adenocarcinoma are both tumors of the upper gastrointestinal tract with a very high mortality. Moreover, they are characterized by an abundance in cells and proteins surrounding the tumor cells, the so-called tumor microenvironment. In this thesis, we have aimed to unravel the role of the tumor microenvironment in tumors of the upper gastrointestinal tract. We revealed that it can serve as a biomarker for prognosis as well as a target for tailored treatment, and identified ways to improve multimodality treatment directed against both tumor cells and the tumor microenvironment. Importantly, we obtained new insights into the extensive cross-talk between the intratumoral compartments (i.e. tumor cells, extracellular matrix, (myo)fibroblasts and blood vessels). It shows that when changes are made to one compartment of the tumor, this effect can be impaired or fortified by other compartments depending on patient-specific characteristics. This complex interaction is decisive for tumor development and therapy response. The results presented in this thesis provide a deeper understanding of the role of the tumor microenvironment in tumors of the upper gastrointestinal tract. For future purposes, a balance should be sought for the targeting of each compartment in these tumor types where maximum therapy efficacy is achieved.

There is compelling evidence that the gut microbiota are key regulators of many physiological processes, including eating behavior, mental well-being, immune response and metabolism. Although this influence seems a promising target for novel therapeutics, the underlying mechanisms through which these microbiota exert their influence are far from apprehended. In this thesis, we aimed to further elucidate the microbial influence in the regulation of body composition, insulin sensitivity (IS) and anti-tumor efficacy. Based on the research questions stated in the thesis, we conclude the following: 1. Modulation of the gut microbiota through FMT can – partially – affect body composition and effectiveness of anticancer therapies. 2. New microbial-metabolite pathways involved in insulin resistance and anticancer efficacy, could not be identified, emphasizing the intricate relation between microbes, metabolites and host health. 3. Visiting in-laws during Christmas disturbs the gut microbiota composition and might consequently affect both physical and mental health. These findings provide important insights in the role of the gut microbiota in host metabolism, cancer therapy and mental wellbeing. However, many more questions remain to be answered before we can move towards microbiota-based therapies to treat metabolic diseases and enhance anti-tumor efficacy and toxicity.

Om uitkomsten van patiënten met pancreas- en periampullaire tumoren te verbeteren is de Dutch Pancreatic Cancer Group (DPCG) opgezet; dit is een landelijke samenwerking van artsen, onderzoekers, verpleegkundigen en patiëntenorganisaties. Een van de grootste projecten van de DPCG is het Dutch Pancreatic Cancer Project (PACAP). Binnen PACAP worden klinische data, biomaterialen en kwaliteit van leven gegevens verzameld. Onderdeel van het PACAP project is het ontwikkelen van gepersonaliseerde behandeling. In deze thesis worden de verschillende bestaande methoden om uitkomsten voor individuele patiënten te voorspellen geëvalueerd. In het eerste deel beschrijven we de huidige prognostische factoren voor het pancreascarcinoom en distaal cholangiocarcinoom. We bekeken welke voorspellingsmodellen voor overleving na een resectie vanwege een pancreascarcinoom beschikbaar zijn in de literatuur en valideerden een van de meest belovende. Ook analyseerden we de huidige uitkomsten van het distaal cholangiocarcinoom in Nederland, welke factoren de uitkomsten voorspellen en of de uitkomsten van distaal cholangiocarcinoom anders zijn dan die van andere anatomische subtypes van cholangiocarcinomen. In het tweede deel rapporteren we vernieuwende methoden om uitkomsten te voorspellen, zoals biomarkers en genetische mutaties. Eerst beschrijven we de opzet van de PancreasParel (Dutch Pancreas Biobank). Binnen dit project wordt oa bloed, DNA en tumorweefsel verzameld in 13 ziekenhuizen. Ook onderzoeken we de prognostische en predictieve waarde (voor voordeel van adjuvante therapie) van de serum stroma marker ADAM12 in patiënten die een resectie ondergingen vanwege een pancreas- of periampullaire tumor. Als laatste kijken naar circulerend tumor DNA, en de relatie met 3D tumor volume in gemetastaseerd pancreascarcinoom.

To facilitate research and to ultimately improve outcomes on a nationwide level, the Dutch Pancreatic Cancer Project (PACAP) was launched in 2013. PACAP was an initiative of the national multidisciplinary Dutch Pancreatic Cancer Group (DPCG). PACAP includes several registries; the Netherlands Cancer Registry (NCR), Patient Reported Outcome Measures (PROMs), the surgical Dutch Pancreatic Cancer Audit (DPCA), the Dutch Pancreas Biobank (PancreasParel), and an online expert panel. This thesis describes several projects all aimed to improve outcomes for all patients with pancreatic cancer in the Netherlands by identifying differences in outcomes and points of improvement in care. First, it was investigated whether nationwide compliance to the Dutch pancreatic cancer guideline changed in the six years since its introduction. This provided a backbone for more extensive research through the different PACAP registries in Part I through the NCR and PROMs, and in Part II through the DPCA. It was demonstrated that nationwide guideline non-compliance and practice variation exist regarding cancer treatment as well as supportive care for patients with pancreatic cancer. This resulted in differences in patient outcomes, such as procedural complications, survival, and quality of life. Subsequently, a nationwide ‘best-practices’ implementation trial (PACAP-1) was developed and performed. Part III depicts the details on nationwide improvement of outcomes with the study protocol of the PACAP-1 trial and through collaboration within the DPCG.

Patient with pancreatic and esophageal cancer have a dismal prognosis and treatment response varies greatly between them. In the clinical work-up of pancreatic and esophageal cancer patients there is therefore a great demand for non-invasive makers that can stratify patients and predict treatment response. Potentially, such markers could be extracted using non-invasive, quantitative, imaging methods. Such quantitative imaging biomarkers can inform on biological processes involved in the development and treatment of cancer. The general aim of this thesis is to characterize the tumor microenvironment of pancreatic and esophagogastric cancer by quantitative imaging and to investigate if these methods enable to monitor treatment and predict patient outcome in these cancers. We develop, validate and apply multiple imaging techniques and processing methods on multiple imaging modalities in both a clinical and pre-clinical setting to investigate the potential of imaging biomarkers in the clinical work-up of pancreatic and esophagogastric cancer. The methods and results described in this thesis demonstrate the potential impact of quantitative imaging biomarkers in clinical practice. However, implementation of such methods in a clinical work-up and routine is still lacking.

The Dutch Pancreatic Cancer Project (PACAP) has one goal: to improve the outcomes and quality of life of pancreatic cancer patients. PACAP is one of the largest national collaborations for the collection of clinical outcomes and biomaterials. It is estimated that by 2030, pancreatic cancer will be the second most common cause of cancer-related death in Europe. Without treatment, median survival of pancreatic cancer patients is only several months. The Dutch Pancreatic Cancer Group (DPCG, www.dpcg.nl) is the national multidisciplinary tumor working group for pancreatic cancer patients. Members include gastro-intestinal surgeons, gastroenterologists, medical oncologists, radiologists, pathologists, radiotherapists, dieticians, nurses and patient representatives. Within the DPCG, PACAP also functions as a platform to discuss all data, initiate translational research, initiate improvements, and develop strategies to test these improvements in clinical trials. All this is realized in a nationwide, multidisciplinary approach with strong patients’ involvement. In the Dutch Pancreatic Cancer Audit (DPCA) each patient undergoing pancreatic operation for pancreatic cancer is registered. The DPCA has been expanded with a registration for patients who cannot undergo surgery. All patients with pancreatic cancer are invited for a three-monthly, online questionnaire of patient-reported outcomes (‘quality of life’). The thesis also describes the first international collaborations of PACAP, and investigates several ‘hot topics’ within pancreatic cancer which may find their implementation within PACAP. PACAP provides the need for nationwide information on pancreatic cancer patients. The combination of a registration of treatment, quality of life and biomaterials on a nationwide scale provides information which will benefit many researchers, patients and other organizations in future.

Locally unresectable or metastasized upper gastrointestinal cancer, in example esophageal, gastric and pancreatic cancer, is a multifactorial disease with a poor prognosis. The current approach to upper gastrointestinal cancer has evolved in the past decade, but is still suboptimal. Chemotherapy and other forms of systemic therapy can prolong survival but are associated with toxicity. In this PhD-thesis, we made extensive use of multiple types of data that can be derived from clinical studies conducted in the past 20 years using systematic review and (network) meta-analysis, in order to facilitate the optimal clinical approach. In the first part, we aimed to established the optimal first-line chemotherapy regimen for advanced esophagogastric cancer, as a globally accepted regimen is still lacking. In the second part, we aimed to answer important clinical questions concerning second- or later-line treatment of advanced esophagogastric cancer. In the third part, we constructed a new graphical method to present toxicity of palliative systemic therapy to patients with advanced esophagogastric cancer in clinical practice. Moreover, we assessed the current state of reporting on quality-of-life outcomes in randomized-controlled-trials and we assessed the influence from palliative systemic therapy on the quality-of-life of patients with advanced esophagogastric cancer. In the fourth and final part, we identified baseline characteristics with prognostic and predictive value for treatment efficacy in patients with advanced esophagogastric cancer. Furthermore, we established an international guideline using both literature evidence and expert opinion to state which baseline and prognostic characteristics should be included in future clinical trials on advanced pancreatic cancer.

Hedgehog-dependent cancers make up a large fraction of all cancers diagnosed worldwide. Aberrant activation of the Hedgehog (Hh) signaling pathway occurs in malignancies of the breast, lungs, stomach, skin and pancreas. Around 340.000 new cases of pancreatic cancer (PDAC) are diagnosed yearly, almost none of which are cured. Basal cell carcinoma (BCC) occurs at much higher incidences, but this disease is rarely fatal. The causes of Hh pathway activation mechanisms differ between BCC and PDAC, and both diseases were studied in this thesis to unravel the underlying mechanisms. The focus of this thesis was mostly on PDAC. Besides providing an in-depth analysis of Hh pathway regulation, we have also identified proteins that are regulated by the Hh pathway and are important for tumor growth in PDAC. Furthermore, we have identified clinically relevant molecular subgroups in PDAC, of which the therapeutic vulnerabilities were revealed. Additionally we have established the clonal dynamics that underlie tumor growth in our in vivo models for PDAC.

In dit proefschrift staan klinische onderzoeksvragen centraal die betrekking hebben op slokdarmkanker. Op het moment van diagnose is bij 40% van de patiënten sprake van lokaal gevorderde ziekte (d.w.z. uitbreiding van de tumor door de slokdarmwand en / of uitzaaiingen in omliggende lymfeklieren). De focus van dit proefschrift ligt op deze groep patiënten, die momenteel een combinatiebehandeling van bestraling, chemotherapie en chirurgie wordt aangeboden. Deel I belicht onderwerpen die verband houden met de fase tussen vaststelling van de slokdarmtumor en de uiteindelijke chirurgische behandeling. In deze fase zijn diagnostiek en voorbehandeling cruciale thema’s. Zo wordt geconcludeerd dat een PET-CT scan onmisbaar is om na de voorbehandeling (bestraling en chemotherapie) uit te sluiten dat patiënten uitzaaiingen in andere organen hebben, hetgeen een reden is om van de uiteindelijke slokdarmoperatie af te zien. Daarnaast wordt op basis van een vergelijkende studie gesteld dat een combinatie van bestraling en chemotherapie de voorkeur verdient boven alleen chemotherapie in de voorbehandeling van slokdarmkanker, omdat laatstgenoemde behandeling meer bijwerkingen kent. Een geïntensiveerde versie van deze combinatiebehandeling kan ook tumoren met ingroei in vitale structuren (zoals de luchtpijp of de grote lichaamsslagader) geschikt maken voor chirurgische verwijdering. In deel II van het proefschrift worden nieuwe chirurgische technieken beschreven en worden suggesties gedaan om de nauwkeurigheid te vergroten van de voorspellingen die na de slokdarmoperatie worden gedaan ten aanzien van (ziektevrije) overlevingskansen. De voornaamste conclusie in dit verband is dat niet alleen het aantal lymfeklieruitzaaiingen, maar vooral ook de locatie van deze uitzaaiingen belangrijke voorspellende waarde bevat.

The incidence of esophageal adenocarcinoma (EAC) has increased six-fold during the last three decades, with approximately 2.500 newly diagnosed patients each year in the Netherlands. Depending on tumor stage, patients face a poor 5-year survival of 5-40% despite the benefits of recent multimodality treatment options. This is mainly due to the activation of efficient therapy resistance mechanisms and aggressive tumor behavior leading to early onset of metastatic disease. The results described in this thesis show that EAC cells are able to activate various mechanisms of resistance, following therapeutic pressure, making it challenging to treat EAC patients in a uniformly effective manner. Furthermore, limited treatment options are currently available for the treatment of EAC, which contributes to the poor overall survival of these patients. In this thesis we unraveled mechanisms of therapy resistance and identified biomarkers, hopefully enabling the development of more effective treatment options and may contribute to patient stratification. Especially the identification of therapy induced Epithelial-to-Mesenchymal Transition (EMT) is likely to open new avenues for treatment of EAC patients. The development of in vitro and in vivo EAC models, such as the patient-derived xenografts and novel primary organoid cultures described in this thesis provide excellent tools to further unravel mechanisms of drug resistance. Taken together, the new findings described in this thesis can guide the development of new anticancer treatment strategies directed against EAC and are -due to availability of FDA approved drugs for most of the targets identified- ready to be used in clinical trials.

Throughout their lives, people are confronted with unexpected life events, which can have a profound impact on their lives and can be difficult to incorporate into their life narratives. Such a confrontation can be called an experience of contingency. The aim of this thesis is to describe experiences of contingency in advanced cancer patients, qualitative as well as quantitative. Furthermore, this thesis provides practical guidelines for placing spiritual care in a multidisciplinary care setting.

Upper gastrointestinal (GI) cancers - esophageal, gastric and pancreatic cancer - have a dismal prognosis. Despite treatment with curative intent, randomized clinical trials report 5-year survival rates of only 47% in esophageal cancer, 36 % in gastric cancer and 21% in pancreatic cancer. In population-based series 5-year survival rates of patients treated with curative intent are even lower and range from in 19-25% in esophageal cancer, 20-31% in gastric cancer and 11-16% in pancreatic cancer. Besides the poor results of treatment, management of upper GI cancers is further complicated by the occurrence of side effects of oncological treatment. This is more prominent in upper GI cancer due to the extent of upper GI surgery, with potentially severe complications, as well as the use of multimodality treatment (radiation, chemotherapy), which cannot always spare vital organs. This may severely impact quality of life and functional outcome of these patients. The poor prognosis, the potentially severe toxicity of treatment and late presentation of the disease together with the relatively low incidence pose a great challenge to the optimization of outcomes of patients with upper GI cancer. The main aim of this thesis is to investigate toxicity and functional outcome of treatment of locally advanced esophageal cancer and to investigate treatment strategies for metastatic esophagogastric and pancreatic cancer, with a special focus on differences in management and survival between Dutch hospitals in daily practice.