Hepatic Radioembolization in Neuroendocrine Neoplasms

Abstract

Neuroendocrine Neoplasms (NEN) is a generic term for a class of rare tumours, consisting of an array of many different tumor types. Similar to the trends noticed internationally, in the Dutch population the incidence of gastro-intestinal pancreatic NEN has increased from 298 per 100.000 per year in 2000 to 828 per 100.000 per year in 2016, according to the Dutch Cancer Registry. On the one hand, the disease has gotten more attention in the last decades and on the other hand more and more accurate diagnostic modalities have become available to detect the disease. Unfortunately at time of diagnosis, 21% of grade 1 NET, 30% of grade 2 NET and 50% of grade 3 NET or NEC show disseminated disease, of which the liver is the most common affected site. Once a NEN patient is diagnosed with liver metastasis, only about 20-30% are eligible for surgical resection with curative intent. Ineligibility for surgery is mainly caused by bilobar involvement of the liver. Additionally, patients with liver metastases of functioning (hormone-producing) NEN suffer of debilitating complaints, like frequent diarrhea and flushing, with a direct impact on quality of life. This emphasizes the clinical need for new therapeutic approaches of NEN liver disease. Radioembolization is a well-established liver-directed treatment for patients suffering from hepatic malignancies. The thesis ‘Hepatic Radioembolization in Neuroendocrine Neoplasms’ will discuss current status and future directions of the treatment in patients suffering for neuroendocrine liver metastases. Besides the promising body of clinical data, the other side of the radioembolization procedure needs to be emphasized, namely its many rapid technical developments in nuclear medicine imaging and the interventional radiology, e.g. angiography suite. Compared to other malignancies, NEN are relatively rare, thus literature on radioembolization in NEN is sparse. The conducted meta-analysis on all available literature reported very promising results on objective response rates and median overall survival. However proper data on patient characteristics and its correlations to treatment outcome were lacking. An additional retrospective study was performed, in an attempt to addresses these gaps in available literature. As most NEN patients suffer from both intra- and extrahepatic disease, it was hypothesized that combining a systemic treatment with an liver directed treatment might be beneficial. The protocol of first prospective trial (HEPAR PLUS) on the combination of PRRT with 177Lu-DOTATATE with 166Ho radioembolization and its preliminary results are discussed. The thesis elaborates on new indications for radioembolization in an upfront, curative setting, instead of the common salvage setting where it currently resides. Based on available literature, radioembolization could have several benefits in pre-operative, pre-ablative or pre-transplantation patients. Furthermore, the thesis reports on several important technical developments in the field of radioembolization; The safety of a small amount of 166Ho microspheres as a treatment simulation prior to the actual radioembolization procedure, as an improved alternative to the current standard, and, aspects and challenges of SPECT/CT imaging with both 166Ho and 99mTc (a.k.a. dual isotope imaging) for future semi-automated patient individualized dosimetry.