PET imaging of the somatostatin receptor and norepinephrine transporter in neuroendocrine and neural crest tumors for better radionuclide therapy selection

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that develop from cells of the diffuse (neuro)endocrine system. Many NETs show an overexpression of the somatostatin receptor (SSTR), which represents an ideal target for molecular imaging and radionuclide therapy with radiolabeled somatostatin analogues (SSAs). [68Ga]Ga-DOTA-SSA PET, the current gold standard for SSTR imaging, faces challenges such as high cost, limited availability and low throughput, inherent to the use of gallium-68, preventing its widespread implementation in clinical practice. These challenges could be largely overcome by a fluorine-18-labeled SSA alternative. The first part of this PhD project was dedicated to the evaluation of [18F]AlF-NOTA-octreotide ([18F]AlF-OC) as an SSTR imaging agent in NET patients for clinical practice. In a first prospective, monocenter study in six healthy volunteers and six NET patients, we found that [18F]AlF-OC was safe and well tolerated, and showed a favorable dosimetric profile, biodistribution pattern and tracer kinetics, and excellent tumor lesion targeting. Subsequently, in a prospective, multicenter follow-up study in 75 NET patients, we were able to demonstrate that the diagnostic performance of [18F]AlF-OC was non-inferior and even superior compared with [68Ga]Ga-DOTATATE/NOC PET in NET patients. Therefore, we were able to validate [18F]AlF-OC as an option for SSTR PET imaging for clinical practice.

Peptide receptor radionuclide therapy (PRRT) with radiolabeled SSAs, such as [177Lu]Lu-DOTATATE and [90Y]Y-DOTATOC, is an evidence-based treatment for patients with inoperable or disseminated well-differentiated NETs. Predictive tools to adequately stratify patients, prior or early into treatment, are becoming increasingly important, but reliable predictors are lacking. The second part of this research project focused on the role of baseline SSTR PET-derived imaging parameters in combination with an inflammatory biomarker, the inflammation-based-index (IBI; based on serum CRP and albumin levels), and interim SSTR PET early into treatment to help determine PRRT outcome. In a first retrospective study, we performed post-hoc analyses on data of 43 NET patients that were treated with [90Y]Y-DOTATOC in the setting of a prospective phase II trial. We found that normal baseline IBI and high [68Ga]Ga-DOTATOC tumor uptake (SUVmean > 13.7) were independently associated with better survival, whereas high [68Ga]Ga-DOTATOC-avid tumor volume (> 578 ml) was associated with worse survival in NET patients treated with [90Y]Y-DOTATOC. Early interim [68Ga]Ga-DOTATOC PET did not allow to identify patients with poorer prognosis that would justify a change in treatment strategy. In a second retrospective study in 83 NET patients treated with [177Lu]Lu-DOTATATE in a routine clinical setting we found that low baseline [68Ga]Ga-DOTATATE uptake (SUVmean <= 11.2), high [68Ga]Ga-DOTATATE-avid tumor volume (> 672 ml) and elevated IBI were independently associated with worse overall survival. Therefore, adding these parameters to the pre-therapeutic work-up may be helpful to guide treatment decisions, however none of these parameters should be used as the sole basis to deselect patients from PRRT.

Another molecular target expressed in NETs, and especially in neural crest tumors (neuroblastoma, pheochromocytoma and paraganglioma), is the human norepinephrine transporter (hNET). For several decades, [123I]MIBG scintigraphy has been the standard for hNET imaging, despite several limitations, such as the need for a two-day imaging protocol and thyroid blockade, and the fact that iodine-123 is a gamma-emitter and thus only allows for planar or SPECT imaging. Recently, [18F]MFBG has emerged as a promising PET alternative. The final part of this research project was dedicated to the evaluation of [18F]MFBG as an hNET imaging agent in neural crest tumor patients. In a small, prospective study in 6 neural crest tumor patients, we found that [18F]MFBG showed a favorable safety profile, biodistribution pattern and excellent tumor targeting. Notwithstanding our small patient cohort, the improved diagnostic performance, combined with the practical advantages over [123I]MIBG scintigraphy, suggest that [18F]MFBG PET is a promising alternative for hNET imaging for clinical practice.