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Zaknun J.J.,International Atomic Energy Agency | Zaknun J.J.,Center for Molecular Radiotherapy and Molecular Imaging | Bodei L.,Italian National Cancer Institute | Mueller-Brand J.,University of Basel | And 6 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

Peptide receptor radionuclide therapy (PRRNT) is a molecularly targeted radiation therapy involving the systemic administration of a radiolabelled peptide designed to target with high affinity and specificity receptors overexpressed on tumours. PRRNT employing the radiotagged somatostatin receptor agonists 90Y-DOTATOC ([90Y-DOTA0,Tyr 3]-octreotide) or 177Lu-DOTATATE ([177Lu- DOTA0,Tyr3,Thr8]-octreotide or [ 177Lu-DOTA0,Tyr3]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine tumours expressing the somatostatin receptor subtype 2. Accumulated evidence from clinical experience indicates that these tumours can be subjected to a high absorbed dose which leads to partial or complete objective responses in up to 30 % of treated patients. Survival analyses indicate that patients presenting with high tumour receptor expression at study entry and receiving 177Lu-DOTATATE or 90Y-DOTATOC treatment show significantly higher objective responses, leading to longer survival and improved quality of life. Side effects of PRRNT are typically seen in the kidneys and bone marrow. These, however, are usually mild provided adequate protective measures are undertaken. Despite the large body of evidence regarding efficacy and clinical safety, PRRNT is still considered an investigational treatment and its implementation must comply with national legislation, and ethical guidelines concerning human therapeutic investigations. This guidance was formulated based on recent literature and leading experts' opinions. It covers the rationale, indications and contraindications for PRRNT, assessment of treatment response and patient follow-up. This document is aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRNT and to deliver the treatment in a safe and effective manner. This document is largely based on the book published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic Energy Agency. © 2013 Springer-Verlag Berlin Heidelberg.


Bodei L.,Italian National Cancer Institute | Bodei L.,Yale University | Kidd M.,Yale University | Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging | Modlin I.M.,Yale University
Journal of Nuclear Medicine | Year: 2014

Peptide receptor radionuclide therapy is a treatment for inoperable or metastatic neuroendocrine tumors. A key issue is the need to standardize the treatment and develop randomized controlled trials. Standardization would help define the characteristics of response, including progressionfree survival; provide homogeneous phase II and III studies; delineate the position of peptide receptor radionuclide therapy in the therapeutic algorithm for neuroendocrine tumors; and establish the basis for approval by the regulatory authorities. Standardization of treatments is the starting point to redefine the treatment paradigm from a one-size-fits-all to a personalized treatment. To delineate the treatment paradigm, treatments should be optimized for efficacy and minimization of long-term toxicity, through dosimetry, and adapted to each individual, including relevant patient characteristics. Although differences in therapy outcomes may be explained by the specific absorbed dose (or biologically effective dose), they may also be related to discrete tumor- and patient-specific features. In this respect, a particular area of investigation is the assessment of genetic elements regulating tumor cell proliferation, especially those involved in the response to cytotoxic therapies. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.


PubMed | University of Minnesota, Center for Molecular Radiotherapy and Molecular Imaging, Mochtar Riady Comprehensive Cancer Center Siloam Hospitals and Bombay Hospital and MRC
Type: Journal Article | Journal: Seminars in nuclear medicine | Year: 2016

As therapeutic options in advanced medullary and non-iodine avid differentiated (nonmedullary) thyroid cancers are limited and associated with significant toxicity, targeting of somatostatin receptors (SSTRs) for internal radiation therapy provides a promising option. Theranostics (therapy and diagnosis) using radiolabeled somatostatin analogues has proved to be a milestone in the management of SSTR-expressing tumors. Peptide receptor radionuclide therapy using (177)Lu-labeled or (90)Y-labeled somatostatin analogues may have a significant role in the management of medullary and nonmedullary thyroid cancers in those patients where PET/CT with (68)Ga-labeled somatostatin analogues demonstrates significant SSTR expression.


Kulkarni H.R.,Center for Molecular Radiotherapy and Molecular Imaging | Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging
PET Clinics | Year: 2014

Neuroendocrine tumors are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated neuroendocrine tumors overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy using the same peptide. The use of the same DOTA-peptide for SSTR PET/CT using 68Ga and for peptide receptor radionuclide therapy using therapeutic radionuclides like 177Lu and 90Y offers a unique theranostic advantage. © 2014 Elsevier Inc.


Kulkarni H.R.,Center for Molecular Radiotherapy and Molecular Imaging | Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging
PET Clinics | Year: 2014

Peptide receptor radionuclide therapy involves selective targeting of neuroendocrine tumors through the somatostatin receptors, the aim being to increase radiation dose to the tumors and spare the normal tissue. The advantage of this internal radiation therapy is the ability to selectively target multiple metastases throughout the body. Early and accurate assessment of therapy response helps not only to identify the poor responders but also to personalize the treatment regimes with the aim of achieving maximum treatment benefit. This is the basis of theranostics. © 2014 Elsevier Inc.


Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging | Kulkarni H.R.,Center for Molecular Radiotherapy and Molecular Imaging | Carreras C.,Center for Molecular Radiotherapy and Molecular Imaging
Seminars in Nuclear Medicine | Year: 2012

Theranostics of neuroendocrine neoplasms (NENs) based on molecular imaging using receptor positron emission tomography/computed tomography (PET/CT) with 68Ga-labeled somatostatin (SMS) analogs and molecular radiotherapy applying peptide receptor radionuclide therapy (PRRNT) with 90Y- and/or 177Lu-labeled peptides has paved the way to personalized medicine. SMS receptor PET/CT enables very accurate detection of NENs and their metastases with high diagnostic sensitivity and specificity and provides quantitative, reproducible data that can be used for selecting patients for PRRNT and evaluation of therapy response. Among other advantages are the fast imaging protocol (total study time, 60-90 minutes), low radiation burden (10-12 mSv), flexibility in daily use, and lower cost than octreotide scintigraphy. As we move toward personalized medicine, the diagnostic information obtained from PET/CT must be improved, that is, by fast routine quantification of lesions. PRRNT is highly effective for the treatment of NENs, even in very advanced cases, and lends a benefit in overall survival of several years. In addition, significant improvement in clinical symptoms and excellent palliation can be achieved. In patients with progressive NENs, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period (Bad Berka Concept) results in good therapeutic responses. By this concept, severe hematologic and/or renal toxicity can be reduced or completely avoided, and the quality of life can be improved. Sequential (DUO-PRRNT) and concurrent (TANDEM-PRRNT) administrations of radiopeptides are more effective in progressive NEN than using either radionuclide alone. PRRNT should only be performed at specialized centers, as NEN patients need highly individualized interdisciplinary treatment and long-term care. © 2012 Elsevier Inc. All rights reserved.


Puranik A.D.,Center for Molecular Radiotherapy and Molecular Imaging | Kulkarni H.R.,Center for Molecular Radiotherapy and Molecular Imaging | Singh A.,Center for Molecular Radiotherapy and Molecular Imaging | Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2015

Purpose: Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. Methods: Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using 90Y/177Lu-labelled peptides after positive confirmation of SSTR expression on 68Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with 68Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. Results: Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUVmax, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUVmax. The three asymptomatic patients showed no new lesions or symptomatic worsening. Conclusion: PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these are preliminary results, PRRT shows promise as a good treatment option for HNPGL, and hence study in a larger patient cohort is essential to establish its place in the management algorithm. © 2015, Springer-Verlag Berlin Heidelberg.


Kulkarni H.R.,Center for Molecular Radiotherapy and Molecular Imaging | Singh A.,Center for Molecular Radiotherapy and Molecular Imaging | Baum R.P.,Center for Molecular Radiotherapy and Molecular Imaging
Seminars in Nuclear Medicine | Year: 2016

Somatostatin receptor PET/CT using 68Ga-labeled somatostatin analogs, is a mainstay for the evaluation of the somatostatin receptor status in neuroendocrine neoplasms. In addition, the assessment of glucose metabolism by 18F-FDG PET/CT at diagnosis can overcome probable shortcomings of histopathologic grading. This offers a systematic theranostic approach for the management of neuroendocrine neoplasms, that is, patient selection for the appropriate treatment—surgery, somatostatin analogs, peptide receptor radionuclide therapy, targeted therapies like everolimus and sunitinib, or chemotherapy—and also for therapy response monitoring. Novel targets, for example, the chemokine receptor CXCR4 in higher-grade tumors and glucagon like peptide-1 receptor in insulinomas, appear promising for imaging. Scandium-44 and Copper-64, especially on account of their longer half-life (for pretherapeutic dosimetry) and cyclotron production (which favors mass production), might be the potential alternatives to 68Ga for PET/CT imaging. The future of molecular imaging lies in Radiomics, that is, qualitative and quantitative characterization of tumor phenotypes in correlation with tumor genomics and proteomics, for a personalized cancer management. © 2016 Elsevier Inc.


PubMed | Center for Molecular Radiotherapy and Molecular Imaging
Type: Journal Article | Journal: Seminars in nuclear medicine | Year: 2016

Somatostatin receptor PET/CT using (68)Ga-labeled somatostatin analogs, is a mainstay for the evaluation of the somatostatin receptor status in neuroendocrine neoplasms. In addition, the assessment of glucose metabolism by (18)F-FDG PET/CT at diagnosis can overcome probable shortcomings of histopathologic grading. This offers a systematic theranostic approach for the management of neuroendocrine neoplasms, that is, patient selection for the appropriate treatment-surgery, somatostatin analogs, peptide receptor radionuclide therapy, targeted therapies like everolimus and sunitinib, or chemotherapy-and also for therapy response monitoring. Novel targets, for example, the chemokine receptor CXCR4 in higher-grade tumors and glucagon like peptide-1 receptor in insulinomas, appear promising for imaging. Scandium-44 and Copper-64, especially on account of their longer half-life (for pretherapeutic dosimetry) and cyclotron production (which favors mass production), might be the potential alternatives to (68)Ga for PET/CT imaging. The future of molecular imaging lies in Radiomics, that is, qualitative and quantitative characterization of tumor phenotypes in correlation with tumor genomics and proteomics, for a personalized cancer management.


PubMed | Center for Molecular Radiotherapy and Molecular Imaging
Type: Clinical Study | Journal: European journal of nuclear medicine and molecular imaging | Year: 2015

Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT.Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using (90)Y/(177)Lu-labelled peptides after positive confirmation of SSTR expression on (68)Ga-DOTATOC PET/CT. All patients received two to fourcourses of PRRT. Subsequent serial imaging with (68)Ga-DOTATOC PET/CT was carried out every 6months to assess response to treatment. Clinical (symptomatic) response was also assessed.Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUVmax, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUVmax. The three asymptomatic patients showed no new lesions or symptomatic worsening.PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these are preliminary results, PRRT shows promise as a good treatment option for HNPGL, and hence study in a larger patient cohort is essential to establish its place in the management algorithm.

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