Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy

Imaging of neuroendocrine tumours (NET) poses significant challenges because of the heterogeneous biology of the tumours that are represented by this class of neoplasia. NET can range from benign lesions to highly aggressive cancers. Structural imaging techniques have suboptimal sensitivity in most published series and diagnosis is often delayed until metastatic disease is present. Current guidelines emphasise the importance of functional imaging for evaluating the extent of NET. The mainstay of this type of imaging has been somatostatin receptor scintigraphy (SRS) with [(111)In]diethylenetriaminepentaacetic acid-octreotide (Octreoscan™). Routine use of single-photon emission computed tomography (SPECT) and particularly of hybrid SPECT/computed tomography (CT) has significantly improved localisation of tumour sites and evaluation of somatostatin receptor (SSTR) expression, which is important for predicting the likelihood of response to somatostatin analogues (SSA). Positron emission tomography (PET) can also now be used for evaluating SSTR expression. There are a number of peptides that have been evaluated but [(68)Ga]tetraazocyclodecanetetraacetic acid (DOTA)-octreotate (GaTate) PET/CT, which has been shown to be significantly more sensitive for detecting small lesions than Octreoscan™, is now probably the preferred agent because high uptake in known sites of disease provides a diagnostic pair for assessing suitability of patients for [(177)Lu]DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT). A range of other radiolabelled SSA has also been used for PRRT. Lesions without SSTR expression require alternative imaging and therapeutic strategies. Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the diagnostic sensitivity of FDG PET/CT. High FDG avidity is associated with a poorer prognosis but increases the likelihood of response to chemotherapy. Functioning tumours also require substrates for their secreted products. This can be exploited for NET imaging with amine precursor uptake being imaged using [(18)F]3,4-dihydrophenylalanine and serotonin-secreting tumours being sensitively detected using [(11)C]5-hydroxytryptamine. Both these agents are suitable for imaging with PET. [(123)I]meta-Iodo-benzyl-guanidine (MIBG) SPECT/CT may also be useful as a staging technique, particularly for NET of the sympathetic neuronal chain, and can identify patients who may be suitable for [(131)I]MIBG therapy. In the future, paradigms guided by clinical and biopsy features should allow personalized imaging paradigms aligned to therapeutic options.