Peptide receptor radionuclide therapy using radiol

Authors: Sander M Bison Mark W Konijnenberg Marleen Melis Stefan E Pool Monique R Bernsen Jaap J M Teunissen Dik J Kwekkeboom Marion de Jong

Publish Date: 2014/03/05

Volume: 2, Issue: 1, Pages: 55-66

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Abstract

Peptide receptor radionuclide therapy PRRT has been shown to be an effective treatment for neuroendocrine tumors NETs if curative surgery is not an option A majority of NETs abundantly express somatostatin receptors Consequently following administration of somatostatin SST analogs labeled with γemitting radionuclides these tumors can be imaged for diagnosis staging or followup purposes Furthermore when βemitting radionuclides are used radiolabeled peptides radiopeptides can also be used for the treatment for NET patients Even though excellent results have been achieved with PRRT complete responses are still rare which means that there is room for improvement In this review we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal Although randomized clinical trials are still lacking early studies have shown that tumor response might be improved by application of other radionuclides such as αemitters or radionuclide combinations or by adjustment of radiopeptide administration routes Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles resulting in more personalized treatment schedules Other options include the application of novel radiolabeled SST analogs with improved tumor uptake and radionuclide retention time or a combination of PRRT with other systemic therapies such as chemotherapy or treatment with radio sensitizers Though promising directions appear to bring improvements of PRRT within reach additional research including randomized clinical trials is needed to achieve such improvementsNeuroendocrine tumors NETs are welldifferentiated tumors derived from diffuse neuroendocrine cells in the lung gut or pancreas NETs are rare having an incidence of 2–5 per 100000 inhabitants 1 2 3 their prevalence however is much higher on account of the relatively slow progression rate of the disease 3 In general NETs are diagnosed at a relatively late stage with metastatic spread present at the time of diagnosis in the majority of patients 3 Often therefore curative surgery is no longer an option Since chemotherapy and external beam therapy are incapable of treating distant metastases in most cases these therapeutic options are of limited value 4 Peptide receptor radionuclide therapy PRRT using radiolabeled somatostatin SST analogs has proven to be an effective therapeutic option for NET patients with metastasized disease as it allows targeted delivery of therapeutic radionuclides to tumor cells 5 6 Despite the fact that high tumor response rates have been reported after treatment with177LuDOTATyr3octreotate DOTA = 14710tetraazacyclododecane14710tetraacidic acid 177LuDOTATATE 7 and 90YDOTATyr3octreotide 90YDOTATOC 8 complete responses are still rare indicating that there is room for improvement of PRRT The aim of this review is to describe directions that may lead to improvement of imaging and especially treatment of NETs with radiolabeled SST analogsSST is a biologically active neuropeptide secreted by the hypothalamus It acts by binding to Gproteincoupled somatostatin receptors SSTRs expressed in different organs in the body such as the gastrointestinal tract and the pancreas 9 SST inhibits the secretion of a wide range of hormones Besides this normal organ expression SSTRs are overexpressed by certain malignant tissues in particular most NETs 10 SSTRs consist of five Gproteincoupled receptors subtypes SSTR1–SSTR5 11 of which SSTR2 in particular is overexpressed by NETs 12 The abundant expression of SSTRs by the majority of NETs enables their visualization in patients This is achieved using nuclear imaging techniques by receptor targeting with radiolabeled SST peptide analogs such as octreotide DPhecCysPheDTrpLysThrCysThrol or Tyr3octreotate DPhecCysTyrDTrpLysThrCysThr 13 14 These stabilized eightamino acid compounds are derived from native SSTs which consist of 14 or 28 amino acids 15 Unlabeled SST analogs like longacting release octreotide octreotide LAR are currently applied as initial treatment for patients with metastatic midgut NETs 16 Octreotide LAR has been shown to have a positive influence on clinical symptoms as well as some tumorstabilizing effects leading to a lengthening of time to progression compared with placebo 16Functional imaging using SPECT or PET imaging with the radiolabeled SST analogs 111IndiumDTPA diethylenetriaminepentaacetic acid octreotide 111Inoctreotide or Octreoscan® Mallinckrodt Petten the Netherlands 13 68GaDOTATyr3octreotide 68GaDOTATOC 68Ga DOTA 1Nal3octreotide 68Ga DOTANOC 68GaDOTATyr3octreotate 68GaDOTATATE 17 99mTcEDDA/HYNICoctreotate 18 or 99mTcEDDA/HYNICoctreotide 19 is being widely applied in clinical practice for diagnosis staging and monitoring of NETs111Inoctreotide is currently the only registered imaging tracer 20 Over the last few years however SST analogs radiolabeled with the positron emitter 68Ga have been increasingly used for PET imaging Compared with SPECT using 111Inlabeled analogs PET using 68Galabeled analogs resulted in a higher spatial resolution better tissue contrast and a higher sensitivity for detection of metastases Several studies have shown PET with 68Galabeled SST analogs to be superior to SPECT performed using 111Inlabeled STT analogs 21 22 In addition as 68Ga is generator produced 23 it allows for inhouse labeling and applications of 68Ga in nuclear medicine departments which do not have access to a cyclotronFollowing the successful applications of 111Inoctreotide for imaging of NETs the next logical step was to apply this radionuclide not only emitting γ radiation but also therapeutic Auger and conversion electrons at high activities for PRRT of metastasized disease as well 24 25 Although treatment with 111Inoctreotide often resulted in symptom relief in patients with metastasized NETs objective tumor responses were rare especially in patients with advanced disease and in those with large tumors 8 24 25 Application of 177LuDOTATATE and 90YDOTATOC on the other hand resulted in impressive therapeutic effects 8 26 27 28 29 Since 177Lu also emits γ rays 177Lulabeled peptides can be used for treatment as well as for dosimetry and monitoring of tumor response The first clinical phase III study to evaluate safety and tolerability of 177LuDOTATATE and compare therapeutic responses after 177LuDOTATATE with those after treatment with a high dose of the unlabeled SST analog octreotide LAR is currently running in several countries http//clinicaltrialsgov/ct2/show/NCT01578239term=NCT01578239rank=1Recently developed STT analogs acting as receptor antagonists seem to be a highly promising alternative to the receptor agonists currently applied in clinical practice as several newly developed SSTR antagonists have shown increased tumor uptake compared to STTR agonists 32 33 34 leading to higher tumor radiation doses We report on recently achieved results in different tumor models and discuss the possible mechanisms behind these results and the translation of preclinical studies into the clinic

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