Neuroendocrine Neoplasia: Tailoring Treatment and Prognosis

Abstract

Neuroendocrine neoplasms are cancers that arise from various parts of the body. They can be divided in relatively indolent neuroendocrine tumours (NET) and relatively aggressive neuroendocrine carcinoma (NEC). The first part of this thesis focusses in tailoring prognosis in neuroendocrine tumours. The first chapters describe tumours of the small intestine. These are tumours that have the ability to cause fibrotic complications in the abdomen and in the heart. We found that a previously established nomogram to predict survival was unable to accurately predict survival but was able to differentiate between risk groups. Further, since NET of the small intestine may cause serious fibrotic complications in the gut, we investigated whether removing the primary tumour in stage IV disease was associated with survival. We saw that removing the primary tumour when metastatic disease was already present provided survival benefit and possibly less complications of fibrosis in the gut. Another fibrotic complication of small intestinal NET may be fibrosis of the heart, namely carcinoid heart disease. We identified a biomarker that was useful in the prediction and detection of this cardiac complications, and described a very large cohort of patients with this complication. In this latter chapter we found that in more recent years the survival of patients with carcinoid heart disease improved significantly, possibly partly due to more cardiac surgery. The final chapter of the first part of this thesis describes NET that arise from the pulmonary tract, namely bronchopulmonary NET. These tumours may arise in three different contexts. They arise in aa sporadic context or in the context of specific syndromes, namely the multiple endocrine neoplasia type 1 (MEN-1) syndrome and the diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We investigated whether bronchopulmonary NET were associated with different survival outcomes, depending on the context they arise in. In this chapter we found that the sporadic kind has a worse survival than the other two. The second part of this thesis focusses on tailoring treatment in neuroendocrine carcinoma. The first two chapters investigated patients with Merkel cell carcinoma, an aggressive neuroendocrine carcinoma of the skin. We identified that postoperative radiotherapy does not always provide survival benefit in patients with stage I-III MCC. This is explained by the fact that the population with MCC is often elder and frail, causing adjuvant treatment strategies to be omitted, thereby deviating from current guidelines. We hence proposed that guidelines should include life expectancy as a factor that aids in treatment decision. Further, we investigated whether a relatively new treatment strategy for MCC, immunotherapy, would show similar outcomes in a real-world setting as it did in clinical trials. We found that indeed immunotherapy for MCC showed favourable responses and survival, similar to results from clinical trials. Lastly, we performed a study in NEC that arise outside of the pulmonary tract, that investigated the effect of a new treatment combination, and found that it had similar survival results as conventional therapy, without the serious side effect of alopecia.