pet center of excellence

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1 President s Report By Eric M. Rohren, MD, PhD PCoE President Eric M. Rohren, MD, PhD Where Do We Go From Here? It appears that at long last, we may be making progress in our goal of advancing new radiotracers and new technologies into the clinical arena. It is amazing what has been accomplished with the current arsenal of clinical PET tracers: fluorodeoxyglucose, fluoride, ammonia, and rubidium. Yet gaps remain in our ability to diagnose and assess disease with these agents. The barrier to expanding our arsenal has not been innovation. There are literally thousands of labeled compounds which have been developed and analyzed, some showing significant promise. One of the major challenges, though, has been guiding these compounds through the regulatory processes to allow for their use in patients. The U.S. Food and Drug Administration (FDA) recently announced its approval of an amyloid imaging compound for the evaluation of patients with cognitive impairment, and other amyloid compounds are currently under review. Fluorinated cardiac perfusion compounds are also under development and seeking approval, with anticipation of FDA clearance soon. It is hoped that this will be the first in a new wave of diagnostic (and potentially therapeutic) molecular imaging compounds to enter the clinical arena. On the imaging side, there is a great deal of excitement about PET/MR and the improvements in the scanners and workflows. It remains to be seen what niche these scanners will carve out of the very robust PET/CT field, but there are logical areas of clinical need for which PET/MR seems ideally suited. Some of the task forces within the PET Center of Excellence are targeted toward these advancements. We are working along with the SNM Correlative Imaging Council to develop (Continued on page 6. See President.) Volume 9, Issue pet center of excellence newsletter Ga-68-DOTA TOCs, NOCs, and TATEs in Neuroendocrine Tumors Hossein Jadvar, MD, PhD, MPH, MBA, FACNM University of Southern California Note that portions of this article are adapted from Jadvar H. Hepatocellular Carcinoma and Gastroenteropancreatic Neuroendocrine Tumors: Potential Role of Other Positron Emission Tomography Radiotracers. Semin Nucl Med 2012 [In Press]. In this Issue Neuroendocrine tumors (NETs) are heterogeneous tumors that stem from the neural crest with the main localization in the gastroenteropancreatic (GEP) tract. The peptides produced by these neoplasms may cause symptoms (e.g. diarrhea, flushing). The liver is a major site for metastases. The typical treatment includes surgical resection for localized disease and chemotherapy, interferon, somatostatin analog therapy and peptide receptor radionuclide therapy (PPRT) for disseminated disease 1. Imaging evaluation of NETs with positron emission tomography (PET) is rapidly evolving 2. Although fludeoxyglucose (FDG) PET may demonstrate low sensitivity in terms of detection for well-differentiated tumors, it displays higher sensitivity for detection and localization of less differentiated and dedifferentiated tumors 3, 4. For example, Binderup and colleagues reported recently that the sensitivity of FDG PET is higher than those for In-111-octreotide and I-123-metaiodobenzylguanidine (MIBG) scintigraphy for detection of NETs with Ki-67 proliferation index above 15 percent 5. Other promising PET radiotracers have been developed and are being investigated for imaging NETs including those which bind to the somatostatin receptors using the chelator, 1,4,7,10-tetraazacyclododecane-N, N,N,N -tetraacetic acid (DOTA) 6. Current relevant tracers include the Ga-68-DOTApeptides (Ga-68-DOTA-d-Phe1-Tyr3-octreotide, abbreviated as Ga-68-DOTA-TOC; Ga- 68-DOTA-1-Nal3-octreotide, abbreviated as Ga-68-DOTA-NOC, and Ga-68-DOTA- DPhe1,Tyr3-octreotate, abbreviated as Ga- 68-DOTA-TATE) 7. Ga-68-DOTA-NOC uptake in GEP NET correlates strongly with the tumor-associated overexpression of somatostatin subtypes 2A and 5 receptors 8. In one study that compared Ga-68-DOTA-NOC PET/computed tomography (CT) with CT alone, the sensitivity and specificity for detection of osseous metastatic disease in 223 patients were 100 percent and 100 percent for PET/CT, respectively, and 80 percent and 98 percent for CT alone, respectively 9. In another single center study involving 109 patients with GEP NETs, PET/CT was more accurate than conventional imaging with sensitivity and specificity of 78.3 percent and 92.5 percent, respectively, for detection of primary tumor and 97.4 percent and 100 percent, respectively, for identification of metastases 10. The clinical impact of Ga-68-DOTA-NOC PET/CT has also been evaluated in patients with NET. In one investigation, Ga-68-DOTA- NOC PET/CT affected either stage or therapy in 55.5 percent of patients 11. A more recent investigation from India evaluated the role of (Continued on page 2. See Ga-68-DOTA.) View You Can Use 3 PET in the News 4 SNM Speaks Out on PET 5

2 (Ga-68-DOTA. Continued from page 1.) Ga-68-DOTA-NOC PET/CT for localization of the primary tumor in 20 patients with occult neuroendocrine primary tumor 12. Not only did Ga-68-DOTA-NOC PET/CT localize the primary tumor in 60 percent of patients, but also it prompted surgery in 15 percent of these patients. Nevertheless, it has been noted there can be significant overlap between physiologic and pathologic pancreatic uptake of Ga-68-DO- TA-NOC, and therefore correlation with other clinical, laboratory and imaging studies are advised for the most accurate assessment 13. Similar observation with physiologic pancreatic uncinate process uptake of Ga-68-DOTA-TOC mimicking malignancy has recently been reported 14. Investigators from India compared Ga-68-DOTA-TOC PET/CT with FDG PET/CT and contrast-enhanced CT to assess 20 patients with clinically suspected or known pancreatic NET 15. The primary tumor was localized in all 20 patients with Ga-68-DOTA-TOC PET/ CT, in 15 patients with CT, and only two patients with FDG PET/ CT. In another investigation, Ga-68-DOTA-TOC PET was compared to CT or MRI using Response Evaluation Criteria in Solid Tumors (RECIST) in the evaluation treatment response to radionuclide therapy (Y-90-DOTA-TOC or Lu-177-DOTA-octreotate) 16. The authors reported 30 percent discrepancy between anatomic and physiologic imaging assessments. In one investigation from the United Kingdom, FDG PET/CT and Ga-68-DOTA-TATE PET/CT were compared in 38 patients with primary recurrent NET 17. The sensitivity for tumor detection was 66 percent for FDG PET/CT, 82 percent for Ga-68-DOTA-TATE PET/CT and 92 percent when findings of both PET/CT scans were combined. This study suggested that FDG and Ga-68-DOTA-TATE are complementary. Another study showed that tumor sequestration of Ga-68-DOTA-TATE may lead to a sink effect by reducing the bioavailability of the radiotracer to the healthy tissues that may allow PET/CT-guided individualized adjustment in a subsequent PPRT dosing regimen 18. A potential confounding factor for PET tracer avidity to the somatostatin receptor may be the competition and receptor occupation with the therapeutic unlabeled somatostatin analogs. In an investigation by Haug et al, Ga-68-DOTA-TATE uptake in disease sites was compared in two groups of patients with one group pretreated with long-acting octreotide 19. This study suggested that withdrawal of somatostatin analogs may not be necessary before imaging evaluation with Ga-68-DOTA-TATE PET/CT. Interestingly; the study showed that pretreatment with unlabeled octreotide may improve the lesion target-to-background uptake ratio. This may be due to higher concentration of the radiolabel at disease sites after cold agent saturation of nonspecific sites. Schreiter et al from Germany compared the total costs (i.e., direct costs such as equipment, variable costs such as material and labor, and consequential costs such as additional CT and/or magnetic resonance imaging examinations) of Ga-68-DOTA-TOC PET/CT performed in 29 patients with the total costs of In-111-DTPA-octreotide whole body planar and low-dose single photon emission computed tomography/ct performed in 22 patients with NET20. The investigators reported that Ga-68-DOTA-TOC PET/CT was not only less costly than In-111-DTPA-octrotide scintigraphy (548 Euros vs. 827 Euros, respectively) but also it resulted in less need for additional 2 PET Center of Excellence Newsletter/ imaging examinations (7 percent vs. 82 percent, respectively). In summary, the experience with Ga-68-DOTA-peptides in NET is expanding rapidly. It is hoped that in the near future, these novel PET tracers become available and reimbursed for the imaging evaluation of patients with NET. References: 1. Öberg, K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011; 30: Basu S, Kumar R, Rubello D, et al. PET imaging in neuroendocrine tumors: current status and future prospects. Minerva Endocrinol 2008; 33: Adams S, Baum R, Rink T, et al. Limited value of fluorine-18 fluorodeoxyglucose positron emission tomography for the imaging of neuroendocrine tumors. Eur J Nucl Med 1998; 25: Giammarile F, Billotey C, Lombard-Bohas C, et al. 18F-FLT and 18F- FDG positron emission tomography for the imaging of advanced welldifferentiated gastro-entero-pancreatic endocrine tumors. Nucl Med Commun 2011; 32: Binderup T, Knigge U, Loft A, et al. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET. J Nucl Med 2010; 51: Al-Nahhas A, Win Z, Szyszko T, et al. Gallium-68: a new frontier in receptor cancer imaging. Anticancer Res 2007; 27: Breeman WA, de Blois E, Sze Chan H, et al. (68)Ga-labeled DOTApeptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives. Semin Nucl Med 2011; 41: Kaemmerer D, Peter L, Lupp A, et al. Molecular imaging with Ga- 68-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2011; 38: Ambrosini V, Nanni C, Zompatori M, et al. Ga-68-DOTA-NOC PET/CT in comparison with CT for the detection of bone metastasis in patients with neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2010; 37: Naswa N, Sharma P, Kumar A, et al. Gallium-68-DOTA-NOC PET/CT of patients with gastroeneteropancreatic neuroendocrine tumors: a prospective single-center study. Am J Roentgenol AJR 2011; 197: Ambrosini V, Campana D, Bodel L, et al. Ga-68-DOTANOC PET/CT clinical impact in patients with neuroendocrine tumors. J Nucl Med 2010; 51: Naswa N, Sharma P, Kumar A, et al. Ga-68-DOTONOC PET/CT in patients with carcinoma of unknown primary of neuroendocrine origin. Clin Nucl Med 2012; 37: Krausz Y, Rubinstein R, Appelbaum L, et al. Ga-68 DOTA-NOC uptake in the pancreas: pathological and physiological patterns. Clin Nucl Med 2012; 37: Jacobsson H, Larsson P, Johnson C, et al. Normal uptake of Ga- 68-DOTA-TOC by the pancreas uncinate process mimicking malignancy at somatostatin receptor PET. Clin Nucl Med 2012; 37: Kumar R, Sharma P, Gang P, et al. Role of (68)Ga-DOTATOC PET-CT in the diagnosis and staging of pancreatic neuroendocrine tumors. Eur Radiol 2011; 21: Gabriel M, Oberauer A, Dobrozemsky G, et al. Ga-68-DOTA-Tyr3- octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med 2009; 50: Kayani I, Bomanji J, Groves A, et al. Functional imaging of neuroendocrine tumors with combined PET/CT using Ga-68-DOTATATE (DOTA- (Continued on page 4. See Ga-68-DOTA.)

3 Views You Can Use Fig. 1 Fig. 2 This 57 year-old woman had initially presented with an abdominal soft tissue mass. A PET/CT scan performed at that time showed that the mass had low, patchy tracer uptake with a maximum SUV of 6.0 (Fig. 1). A diagnosis of follicular lymphoma, grade I-II, was subsequently made. She was treated with chemotherapy and radioimmunotherapy. A PET/CT scan performed for restaging at 18 months showed much more intense and extensive FDG uptake, with a maximum SUV of 35. A repeat biopsy showed transformation to diffuse large B-cell lymphoma (Fig. 2). PET/CT and Follicular Lymphoma Therapy for follicular lymphoma is generally not curative, and almost all patients develop a recurrence or transformation to a higher grade lymphoma. Recent studies have shown that PET/CT performed at the completion of induction immunochemotherapy is a strong predictor of the patient s subsequent course and that a significant increase in SUV on follow-up scans as compared to pretreatment studies are highly suggestive of transformation to a more aggressive histology 1,2. (1) J Clin Oncol Aug 10;29(23): (2) Ann Oncol Mar;20(3): About Views You Can Use Advanced Radiology at Medical Arts PET/CT Gabriel Soudry, M.D., Medical Director

4 PET in the News The international literature on PET and PET/CT continues to grow at a pace that challenges both researchers and clinicians. The media has recognized the value of PET and PET/CT and regularly features advances in research and technology in the news. In each issue, the PET CoE Newsletter presents a tomographic slice of the breadth of PET media coverage that appears in publications around the world. Additional news articles can be found online at under MI: Making a Difference. CT perfusion plus PET/CT aids lung cancer diagnosis Aunt Minnie dis&itemid=98443 F-18-DOPA PET/CT changes management plan for brain tumor patients Molecular Imaging articles&view=article&id=32414 JNM: PET/CT predicts survival after radioembolization of breast cancer Molecular Imaging articles&article=32586 FDG-PET/CT Effective in Head and Neck Carcinoma Diagnosis Medscape Half of MCI Patients With Amyloid on PET Convert to AD Medscape Friendly to a fault, yet tense: Personality traits traced in brain National Institute of Mental Health php Stopping gout in its tracks Research and Development Magazine Investigational Psoriasis Drug Reduces Vessel Inflammation Skin & Allergy News single-article/investigational-psoriasis-drug-reduces-vesselinflammation/69d2d219aa.html New Scanning Technology Might Help Guide Prostate Cancer Care Doctor s Lounge (Ga-68-DOTA. Continued from page 2.) DPhe1, Tyr3-octreotate) and 18F-FDG. Cancer 2008; 112: Beauregard J-M, Hofman MS, Kong G, et al. The tumor sink effect on the biodistribution of Ga-68-DOTA-octreotate: implications for peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging 2012; 39: Haug AR, Rominger A, Mustafa M, et al. Treatment with octreotide does not reduce tumor uptake of Ga-68-DOTATATE as measured by PET/CT in patients with neuroendocrine tumors. J Nucl Med 2011; 52: Schreiter NF, Brenner W, Nogami M, et al. Cost comparison of 111In- DTPA-octreotide scintigraphy and Ga-68-DOTATOC PET/CT for staging enteropancreatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2012; 39: Vote on Proposed SNM Name Change The vote on the proposed SNM name change to the Society of Nuclear Medicine and Molecular Imaging will take place on Monday, June 11, at the SNM Business Meeting, held between 8:00 am and 10:00 am, during the Annual Meeting in Miami, FL. We strongly encourage all voting members to attend the meeting in order to actively participate in this historic and very important vote. If you are unsure whether you are a voting member, please contact memberservices@snm.org. For more information, please visit 4 PET Center of Excellence Newsletter/

5 Speaks Out on PET Molecular Imaging Links Systemic Inflammation with Depression New data open door to potential diagnostic and treatment options New research published in the April issue of The Journal of Nuclear Medicine reveals that systemic inflammation causes an increase in depressive symptoms and metabolic changes in the parts of the brain responsible for mood and motivation. With this finding, researchers can begin to test potential treatments for depression for patients that experience symptoms that are related to inflammation in the body or within the brain. Multiple studies in rodents have shown that inflammation in the body has effects on the brain. This has also been shown in a few human studies both through measurements of behavioral changes and brain imaging when subjects were engaged in various computer tasks. The study Glucose Metabolism in the Insula and Cingulate Is Affected by Systemic Inflammation in Humans, however, for the first time measured brain activity when subjects were at rest. In the study we used F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), which can accurately measure glucose metabolism in the brain, to determine which brain regions responded to systemic inflammation. Since the subjects were at rest, the changes we observed in the brain can only be attributed to systemic inflammation, noted Jonas Hannestad, MD, PhD, lead author of the article. In the study, nine healthy individuals received a double-blind endotoxin (which elicits systemic inflammation and mild depressive symptoms such as fatigue and reduced social interest) and placebo on different days. After administration, F-18 FDG PET was used to measure the differences in the cerebral metabolic rate of glucose in the insula, cingulate and amygdala regions of the brain. Behavior changes were also primarily assessed on the Montgomery-Asberg Depression Rating Scale (MADRS). A statistical analysis of the results showed that endotoxin administration was associated with a higher normalized glucose metabolism (NMG) in the insula and lower NMG in the cingulate compared to the placebo; there was no significant difference in the NMG in the amygdala. Seven of nine subjects had an increase in NMG in the insula and a decrease in NMG in the cingulate, and all nine subjects had a decrease in NMG in the right anterior cingulate, suggesting that systemic inflammation induces fundamental physiologic changes in regional brain glucose metabolism. In addition, the MADRS increased for each subject after endotoxin administration, whereas no significant change was noted with the placebo. Most researchers agree that depression is not a homogeneous disease, but rather that there are multiple mechanisms that can lead to similar symptoms. If we can show that a subtype of depression is caused in part by inflammation, said Hannestad, we can test the ability of treatments that reduce inflammation in only patients in whom we believe inflammation plays a role. In the future, I expect that researchers in this field will be able to develop more Axial multislice images from SPM showing differences in glucose metabolism in right anterior insula (A), right ventrolateral thalamus (A), right posterior insula (B), and right anterior cingulate (C and D). Colors correspond to T values at voxel level. Increased metabolism (endotoxin minus placebo) is displayed in yellow-red, whereas decreased metabolism (placebo minus endotoxin) is displayed in blue precise PET measures that can be used to distinguish between, for instance, a person with inflammatory depression and a person with another kind of depression. PET could then be used as diagnostic biomarker to separate subtypes of depression and as a therapeutic biomarker to detect the response to treatment. Nearly 17 percent of adults experience depression at some point over their lifetime, with 30.4 percent of cases classified as severe, according to the U.S. National Institute of Mental Health. Fiftyseven percent of adults with depression report receiving treatment in the past 12 months, although 37.8 percent receive minimally adequate treatment. Authors of the article Glucose Metabolism in the Insula and Cingulate Is Affected by Systemic Inflammation in Humans include: Jonas Hannestad, Kalyani Subramanyam, Nicole DellaGioia and Brian Pittman, Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut; and Beata Planeta-Wilson, David Weinzimmer and Richard E. Carson, Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut. 5

6 (President. Continued from page 1.) educational programs and materials directed toward the clinical use of PET/ MR, in particular the use of MR sequences in the arena of hybrid imaging. We are also collaborating with other centers and councils within SNM to develop educational tracks at the society s Annual and Mid-Winter Meetings on the topic of new tracer technologies. Despite the optimism which is naturally generated from these recent successes, significant barriers remain. In this current issue of the PCoE newsletter is an article by Hossein Jadvar, MD, PhD, MPH, MBA, FACNM, on Ga- 68-based peptide imaging of neuroendocrine malignancies. We clearly have a need for better imaging compounds in the field of neuroendocrine malignancies, particularly when these same compounds can be modified into a therapeutic form with an exchange of radioisotope. There is growing evidence out of Europe and other parts of the world that these agents are safe and effective, yet this data has not yet been accepted by the regulatory bodies here in the United States. SNM, through outreach and governmental relations, continues to work toward making these types of agents available to our patients and referring clinicians. So in answer to the question of Where do we go from here? the answer, I think, is upwards and onwards, recognizing that the path may be somewhat slow and winding at times. Recent successes should give us cause for optimism. pet center of excellence newsletter The PET Center of Excellence Newsletter is a quarterly member information service published under the direction of the PET CoE leadership and SNM. PCoE Newsletter Editorial Board François Bénard, MD fbenard@bccrc.ca Hossein Jadvar, MD, PhD, MPH, MBA, FACNM, Editor jadvar@usc.edu Gabriel Soudry, MD gabriel.soudry@medstar.net Jian (Michael) Yu, MD michael.yu@fccc.edu PCoE Board of Directors Eric M. Rohren, MD, PhD President Hossein Jadvar, MD, PhD, MPH, MBA, FACNM PET Center of Excellence Working Groups The PCoE strives to further the clinical practice of PET/CT in the and near-clinical realm. As we enter a new cycle of PCoE board of directors membership, following working groups have been developed to lead specific projects to meet the needs of our members. PET/MR Roadmap Task Force Chair: Heiko Schoder, MD New Tracers Task Force Chair: Hossein Jadvar, MD, PhD, MPH, MBA, FACNM Quality and Reporting Task Force Chair: Ryan Niederkohr, MD Appropriateness Criteria Task Force Chair: Eric Rohren, MD, PhD PET PROS Technologists Working Group Chair: Ruth Tesar, CNMT, RT(N) Vice President Heiko Schoder, MD Secretary/Treasurer George M. Segall, MD Immediate Past President Ryan Niederkohr, MD Lalitha Ramanna, MD, FACNM Bennett Greenspan, MD John O. Prior, PhD MD Ruth Tesar, CNMT, RT(N) Frederic H. Fahey, DSc Gary Dillehay, MD, FACNM, FACR SNM Chief Executive Officer Virginia Pappas, CAE Managing Editor Susan Martonik Graphic Designer Laura Mahoney 6 PET Center of Excellence Newsletter/