Ezgi Ilan: Theranostics in Neuroendocrine Tumors: Somatostatin Receptor Imaging and Therapy

Abstract

Neuroendocrine tumors (NETs) are characterized by cellular overexpression of somatostatin receptors (SSTR), which allows for the use of radiolabeled somatostatin analogs (SSA) for both imaging and therapy. Because NETs often are diagnosed at a metastatic stage, curative surgery is not possible. Monthly long-acting SSA preparation constitutes first-line therapy for low-grade small-intestinal NETs and pancreatic NETs. Peptide receptor radionuclide therapy (PRRT), with radiolabeled SSAs such as 177Lu-DOTATATE, has been shown to be an effective therapeutic alternative for NETs, improving symptoms and quality of life. The gold-standard method for SSTR imaging and diagnosis of NETs is positron emission tomography (PET) using Gallium-68 (68Ga)-labeled SSAs, such as 68Ga-DOTATOC and 68Ga-DOTATATE. The tumor standardized uptake value (SUV) has been proposed both as a marker of SSTR tumor density and a tool for evaluating therapy response. Changes of tumor SUV on 68Ga-DOTATOC- and DOTATATE-PET have, however, not been shown to correlate with the patient outcome.

This thesis is based on five original papers, evaluating the relation between tumor-absorbed dose and tumor shrinkage and developing novel theranostic methods in which quantitative PET imaging with 68Ga-DOTATATE and 68Ga-DOTATOC is used to optimize PRRT with 177Lu-DOTATATE in NET patients.

A high and significant positive correlation was found between tumor-absorbed dose and tumor shrinkage in pancreatic NETs treated with 177Lu-DOTATATE. Furthermore, it was found that tumor SUV in 68Ga-DOTATATE and 68Ga-DOTATOC failed to correlate linearly with the net influx rate (Ki), assumed to reflect the SSTR density, due to low tracer availability in blood for high Ki values. SUV blood was significantly higher in tumors with high Ki (>0.2) than in tumors with low Ki, and it was found that the tumor-to-blood ratio (TBR) correlates linearly with Ki. Thus, both Ki and TBR may be used as tools to monitor NET therapy response rather than SUV. It was also found that parametric Ki images, illustrating Ki at the voxel level, provide higher tumor-to-liver contrast than static whole-body PET images. Further, it was found that administration of a single dose of cold peptide pre-PRRT with 177Lu-DOTATATE gave rise to faster recycling of SSTRs in tumors than in normal organs. A linear relation was found for tumor SUV and early Ki, between 68Ga-DOTATATE-PET and 177Lu-DOTATE-SPECT; however, the kinetics for 68Ga-DOTATAE could not be used for predicting that of 177Lu-DOTATATE because of tumor clearance of 177Lu-DOTATATE at late time interval.

In conclusion, quantitative PET imaging with 68Ga-DOTATATE and 68Ga-DOTATOC shows great potential for both evaluating therapy response and optimizing PRRT with 177Lu-DOTATATE.