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ABSTRACT
Year : 2013  |  Volume : 12  |  Issue : 4  |  Page : 186-220

Speakers Abstracts


Date of Web Publication18-Oct-2013

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How to cite this article:
. Speakers Abstracts. World J Nucl Med 2013;12, Suppl S2:186-220

How to cite this URL:
. Speakers Abstracts. World J Nucl Med [serial online] 2013 [cited 2019 Jun 25];12, Suppl S2:186-220. Available from: http://www.wjnm.org/text.asp?2013/12/4/186/119941

PC-01

Imaging in Non-Acute Chest Pain: Choosing the right test

Pushan Bharadwaj


Apollo Gleneagles Hospital, 58 Canal Circular Road, Kolkata, West Bengal, India

Stable angina is a common and disabling disorder. However, the diagnosis and management of stable coronary artery disease (CAD) have not been scrutinized as elaborately as those of acute coronary syndromes (ACS). The optimal strategy of investigation is difficult to define and the plethora of imaging options in the recent years has posed new challenges in the selection of the appropriate test. CAD can present differently in different individuals. At one end of the spectrum, there is stable CAD, where a gradually developing atherosclerotic plaque leads to progressive narrowing of the lumen of an epicardial coronary artery, causing anginal symptoms. At the other end of the spectrum, there are patients who do not demonstrate any flow limiting plaque burden but are prone to ACS, due to rupture of immature, vulnerable, and predominantly non-obstructive plaques. They may also turn up in non-acute chest pain clinics with recurrent resting pain. Clearly, the challenge in identifying these patients is steeper than those with stable angina. Both invasive and non-invasive anatomical imaging of the coronaries is now possible and there are various time tested methods of non-invasive functional testing with robust data supporting these methods. Although a non-imaging technique, an exercise ECG test continues to play an important role in the diagnosis of CAD, although its importance is being now questioned by several important guidelines. The application of a particular test should be strongly influenced by the pretest probability of disease and the clinical question involved. Atherosclerosis, stenosis, and ischemia are related but not identical terms and one particular or a combination of tests may best identify one or more of these phenomena. There is no role of any diagnostic test in extremes of clinical probabilities. In general, a test which has a high sensitivity like a multislice CT based angiogram is best applied to patients with low to intermediate probability of disease, primarily with a view to exclude it. Functional imaging using either myocardial perfusion scintigraphy or dobutamine stress echocardiography is best applied to patients with an intermediate probability of CAD. When the clinical probability is high, a catheter-based angiographic approach is the most cost effective method. It is equally important to identify patients with non-cardiac chest pain and avoid offering a diagnostic test as each and every individual test has its finite sensitivity and specificity and false positive studies in this group of patients may lead to waste of resources and increasing levels of uncertainty and anxiety among patients.

PC-02

The Challenge of Diagnosing Coronary Heart Diseases in Women: The Special Role of ECG-Gated SPECT Myocardial Scintigraphy

I. Garty


Department ofNuclear Medicine, Haemek Medical Center, Afula, Israel

Aim of the Study: Cardio vascular disease (CVD) is the number 1 health threat and the main cause of death in American women. According to the official publication of the American Heart Association, in women, heart disease is too often a "silent killer," and often is presented by non-specific symptoms. Furthermore, investigators from the University of Michigan found that women with heart disease tend to minimize their symptoms far more than men. Unfortunately, coronary angiography (CA) can look "normal" in female patients who actually have significant CHD. Based on the above mentioned facts and observations many authors consider the early diagnosis of CVD in women as a real challenge. The aim of this study is to try and improve the non-invasive imaging modalities for earlier and more accurate diagnosis of CVD in women, especially in patients with suspected false negative CA.

Materials and Methods
: During the last 10 years, (2003-2012) 4200 patients (1570 women and 2630 men) were admitted to our department for myocardial scintigraphy. All of them underwent ECG-gated SPECT study. A total of 2813 patients: 480 (17%) women and 2333 (83%) men achieved full stress ergometric study; prior to the injection of the radiopharmaceutical the rest (1387) patients (44% women and 35% men) underwent drug induced stress studies.

Results:
Comparison of the results of stress studies to the scintigraphic studies showed that among 480 females with full stress studies, 382 (79.5%) showed positive stress versus 1520 among 2333 males (65%). Among 382 female patients with positive stress study, 304 (79.5%) showed positive scintigraphic study. Among 1520 females with positive stress studies 1270 (83.5%) showed positive scintigraphic studies. Among 98 females with negative stress studies 42 (44%) showed positive scintigraphy versus 670 (82.5%) among the 813 males with negative stress study. A total of 1720 (75%) of 2286 patients with positive scintigraphy were sent for further evaluation by CA versus 220 (11.5%) patients with negative scintigraphic studies. The comparison of CA results to ECG stress and scintigraphic results in males and females are now in progress.

Conclusions:
(1) Fewer female patients are referred to stress scintigraphic studies compared to male patients. (2) More positive ECG stress studies in women probably due to the high percent of women that arrive too late for imaging evaluation. (3) More false positive scintigraphic results in women. (4) Due to the lower sensitivity of CA in women the combination of ECG exercise study results and myocardial scintigraphy results may considerably improve the diagnostic accuracy. (5) SPECT myocardial scintigraphy was proved to be an efficient non-invasive modality in women with suspected CHD and is much more sensitive than ECG study alone. (6) To women that are unable to achieve full ergo metric stress, drug induced myocardial scintigraphy is recommended. (7) Due to the difficulties in diagnosing CHD in diabetic women, myocardial scintigraphy should be the first choice in evaluating diabetic women with suspected CHD.

PC-03

Reporting of Gated MPI

Jerry M. Obaldo


Philippine Heart Center, Quezon City, Philippines

The scan report is the culmination of the imaging process, and is often the only communication between the attending physician and nuclear medicine. It is the sole and primary responsibility of the nuclear physician. It may be used during auditing and quality control, as well as reimbursement, and is a legal document. Standard terminology, consistent content, and structured format have been shown to improve the usefulness of scan reports. The scan report should show concordance between the indications - scan findings - interpretation of results. The concept of scintigraphic hierarchy of terms is useful for making reports clearer and for avoiding errors. Scan findings are the lowest in hierarchy and represent tracer localization (e.g., focal defect/area of photophenia); as such these should be in the scan description. The next higher level is the physiologic process involved (e.g. diminished flow), while tissue pathology is the highest level and should be reserved for the interpretation (e.g. infarct). There is a trend toward structured reporting, which may be carried out in various ways. The simplest method consists of transcribed manual checklists, while more elaborate ones are computer-driven, automated systems. The main advantages of structured reporting include ease of computerization and analysis. Many clinicians appreciate the standardized format inherent in structured reporting.

PC-04

Artifacts and Pitfalls in Myocardial Perfusion Imaging

Qaisar H. Siraj


Nuclear Medicine, Farwania Hospital, Kuwait

Myocardial perfusion imaging is a powerful tool in the diagnosis and prognosis of coronary artery disease. Nuclear cardiac imaging involves a succession of stages, procedures, and operations. This cascade of multidisciplinary processes is essential to the production of high-quality images. In order to consistently obtain optimum quality images, one should not only be cognizant of the idiosyncrasies of the equipment and software, but should constantly on the alert against various underlying causes of erroneous or inconsistent scan results, which may affect the quality and interpretation of individual images. The inherent complexity of myocardial imaging and the multiple steps involved in the process makes it vulnerable to a number of pitfalls that might originate from radiopharmaceutical preparation and patient administration to image acquisition, processing and display. Not surprisingly, a significant proportion (15-25%) of cardiac scans is associated with attendant artifacts. A knowledge and awareness of the multiple sources of artifacts, either patient-related or technical in nature, is therefore essential to enable the identification, timely correction and prevention of such artifacts. Prospectively, the technique and methodology should be optimized and tailored to the individual being investigated; retrospectively, knowledge of various sources of errors that impact on image quality is important for correct interpretation. Identification and correction of artifacts are essential to obtain high standard diagnostic studies.

PC-05

Role of Nuclear Cardiology in Cardiac Resynchronization Therapy

Felix Keng


Abstract is not available at the time of printing.

PC-06

Regional Myocardial Blood Flow Quantification Using Dynamic SPECT: A Clinical Study

U. Shrestha, Y. Seo, E. H. Botvinick, G. T. Gullberg


Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA

Aim of the Study: Myocardial perfusion imaging (MPI) using single photon emission computed tomography (SPECT) has remained a critical tool in diagnosis and risk stratification of the coronary artery disease (CAD). Although the conventional approach of visual assessment can be a powerful predicator, SPECT has not been tested, heretofore, for the kinetic parameter (tracer wash-in and wash-out rates) estimation, and quantifying the myocardial blood flow (MBF) and coronary flow reserve (CFR) due to limited spatial resolution and low photon signal-to-noise ratio. Measurement of regional MBF is a comprehensive approach for detecting CAD and related abnormalities. It can assess 1local tissue lesions and endothelial dysfunction, and will become a critical component of cost-saving initiative for screening CAD patients for medical intervention and/or referral to cardiac catheterization laboratories.

Materials and Methods
: A group of 4 patients (40 males and 7 females) with known or suspected CAD referred by clinician were recruited at the Imaging Center, University of California, San Francisco, (UCSF Medical Center, San Francisco, California, USA) to evaluate a new dynamic SPECT rest/pharmacologically-induced-stress MPI protocol. Seventeen patients also underwent clinical SPECT and 13N-NH3/82Rb PET MPI studies, while 31 patients were referred to cardiac-catheterization. A low/high-dose rest/pharmacologic-induced-stress (20 min/20 min) protocol was implemented in a single day visit using a SPECT/CT scanner (Infinia Hawkeye 4 SPECT/CT, GE Healthcare). The dynamic image acquisition began just prior to the dose infusion, with patient lying in supine position. Once the scanner heads began rotating, each patient manually received a continuous 10-20 s infusions of approximately 370 MBq (10 mCi) of 99m Tc-tetrofosmin (140 keV) (Myoview; GE Healthcare) for the rest study. For stress study, the patients were infused with a 0.4 mg bolus injection of a regadenoson (Lexiscan; Astellas Pharma, Inc.), and a dose of 937 MBq (25 mCi) of 99m Tc-tetrofosmin were injected approximately 1 min afterwards. The scanner detector heads equipped with low-energy high-resolution (LEHR) collimators were configured in H-mode (i.e., oriented 1800 to each other) for the dynamic acquisition. Two views with every second 30 rotation and a total of 120 projection images were acquired in each rotation. Projection data were binned into 128 × 128 detector pixels having bin area 4.4 × 4.4 mm 2 . The dynamic SPECT data for each patient were reconstructed using the standard 4-dimensional spatiotemporal image reconstruction software package developed by LBNL/UCSF research group. The quality of 4D images were compared and corroborated with that of the 3D images reconstructed by the standard MLEM algorithm before proceeding to image analysis and quantification. All filtered dynamic images were sampled uniformly with the interval of 5 s. The myocardium was oriented along the long-axis/short-axis view under standardized segmentation Nomenclature for tomographic imaging of heart using PMOD-PCARD software (PMOD technologies). The volume of interest (VOI) was drawn manually and the myocardium was divided into standard 17 segments from basal to mid-cavity and apical regions each of them corresponds to a coronary artery territory. The time activity curves for all segments plus total myocardium for each rest-stress pair were fitted with a two-tissue-compartment model, and corresponding uptake, washout rates and perfusion flow were estimated.

Results:
The regional myocardial blood flow measured from dynamic SPECT agreed quite well with that of dynamic positron emission tomography (PET) using tracer 13 N-NH 3 with segmental correlation 0.678. However, the territorial (LAD, LCX, and LCA) correlation was 0.895. The CFR values also showed statistically significant correlation between SPECT and PET studies. However, the average flow values in pharmacological stress study tended to be smaller than the conventional expected number implying a need for agent specific correction in the flow due to nonlinear behavior of the uptake of 99m Tc-tetrofosmin for higher flow values.

Conclusion:
Dynamic MPI in positron emission tomography (PET) using tracers such as 15 O-H 2 O, 13 N-NH 3 , and 82 Rb (1-3) yields semi-quantitative measurement of MBF and CFR. Significant technical developments in recent years have increased an awareness of the clinical use of MBF quantification. Although myocardial PET MBF measurement has shown to be better diagnostic/prognostic accuracy in clinical setting its use for MBF quantification to routine clinical use is questionable as they are not readily available in the market. PET is not easily accessible for routine clinical studies due to high cost of the scanner and radiopharmaceuticals. Tracers such as 13 N-ammonia and 15 O-water have very short half-lives (10 min and 2 min) that requires on-site cyclotron, a major hindrance for common use. In this work, we reported a clinical study for the measurement of MBF and CFR for a population comprised of 47 patients using a dynamic SPECT/CT rest/stress 99m Tc-tetrofosmin protocol, and the reproducibility of the regional MBF and CFR. Our results indicate a possibility of using dynamic SPECT/CT with 99m Tc-tetrofosmin for quantification of regional myocardial blood flow.

PC-07

Construction of a Respiratory Phantom to study SPECT MPI under the influence of respiratory motion

Y. Parpottas 1,2 , I. Chrysanthou 1 , A. Antoniou 1,3 , A. Lontos 1,3 , O. Demetriadou 4 , L. Livieratos 5,6 , I. Polycarpou 5 , S. Christofides 7 , C. Yiannakkaras 7 , D. Kaolis 7


1
Frederick Research Center, 2 General Department (Physics -Math), Frederick University, 3 Department of Mechanical Engineering, Frederick University, Nicosia, 4 Department of Nuclear Medicine, Limassol General Hospital, Limassol, Cyprus, 5 Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, Kings College of London, 6 Guy's and St. Thomas' Hopsitals NHS Foundation Trust, London, United Kingdom, 7 Department of Medical Physics, Nicosia General Hospital, Nicosia, Cyprus

Coronary artery disease (CAD) is the most common form of heart disease worldwide. Myocardial perfusion imaging (MPI) has been proven to be able to assess the functional significance of coronary artery stenosis. MPI is influenced not only by the cardiac motion. The effect of respiratory and diaphragmatic motion on MPI may lead to misinterpretation of images, especially for the left ventricular function. While analytic models and patient data are useful, a reproducible, compartmented, mechanical phantom is critical to optimize MPI studies, patient dose, and calibrate imaging systems. Thus, we developed a respiratory-diaphragmatic motion phantom, and implement it within the existing RSD fully tissue-equivalent anthropomorphic phantom (male, oversize man, oversize female), together with the existing pumping cardiac phantom, to study the influence the respiratory and diaphragmatic motion to MPI. The existing electrocardiography (ECG) gated pumping cardiac phantom with variable heart beats (30-120) and ejection fraction (30-65%), as well as with a capability of inserting various combination of defects that models the different cases of cardiac failure and coronary artery disease, was used to assessed the diagnostic sensitivity of various SPECT MPI procedures. [1] The newly elaborated respiratory system consists of highly-flexible silicon rubber human-sized lungs, a pumping system for inhalation and exhalation and a computerized heart/lung control unit. The lung moulds were designed using the AUTOCAD software package, taking into account the human lungs dimensions with CT slices, and they were manufactured from aluminum material on CNC machines. The type of silicone rubber used to produce the lungs was chosen after taking into account the hardness, elongation, density, and viscosity of the material. The lungs were filled with lung-equivalent material (same density as lungs) to simulate the lung cavity. Lung-shaped thermoplastics, of specific thickness, around the silicone lungs ensured the proper lung shape during the inhalation phase (human-like lung anterior and distal expansion). The existing cardiac phantom with the proper inclination and the elaborated lungs were positioned and stabilized within the anthropomorphic phantom. The human-like diaphragm, made of thermoplastic material, was properly positioned to follow the respiratory motion. The pumping system consists of two air flowing pumps and two vacuum pumps for inhalation and exhalation, two 2/2 solenoids valves to switch on/off the flow in the tubings, and two proportional valves to regulate the flow according to a sine-wave respiratory volume versus time equation-pattern.

A PLC (Programmable Logic Controller) is used to operate the lungs and heart function. VISIONLOGIC ladder programming language controls the lungs function. The respiratory system is calibrated with a flowmeter, water-tanks, and volumetric pipes to achieve up to 12 breathes/min and up to 550 ml tidal volume, using a sine-wave respiratory pattern. The current respiratory system has certainly higher capabilities. The cardiac phantom is also controlled by the same program.


   Acknowledgments Top


This project YΓEIA/ΔYΓEIA/0311(BIE)/27 is funded by the Cyprus Research Promotion Foundation and the European Regional Development Fund.

References

  1. Chrysanthou-Baustert I, Parpottas Y, Demetriadou O, Christofides S, Yiannakkaras C, Kaolis D, et al. Diagnostic sensitivity of SPECT myocardial perfusion imaging using a pumping cardiac phantom with inserted variable defects. J Nucl Cardiol 2003;20:609-15.
PC-08

SPECT MPI Mechanical Phantom with Cardiac and Respiratory Motion: FirstResults in Clinical Settings.

O. Demetriadou, I. Chrysanthou 1, L. Livieratos 2,3 , I. Polycarpou 2 , Y. Parpottas 1,4 , Chr. Panayidis 5 , S. Christofides 6 , C. Yiannakkaras 6 , D. Kaolis 6

Department of Nuclear Medicine, Limassol General Hospital, Limassol, 1 Frederick Research Center, Nicosia, Cyprus, 2 Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, Kings College of London, 3 Guy's and St. Thomas' Hospitals NHS Foundation Trust, London, United Kingdom, 4 General Department (Physics - Math), Frederick University, 5 Departments of Nuclear Medicine, 6 Medical Physics, Nicosia General Hospital, Nicosia, Cyprus

Aim of the Study: The diagnostic accuracy of MPI is influenced not only by the cardiac motion but also by various other parameters such as the respiratory motion and the attenuation caused by the diaphragm or the breast tissues. Using a developed mechanical respiratory motion phantom and a recently developed pumping cardiac phantom with defects inserted in the myocardial wall of the left ventricle, [1] both implemented within an anthropomorphic phantom, we study the influence of respiratory motion and attenuation on the myocardial perfusion images. This work investigates the diagnostic accuracy of non-attenuation corrected (NC), attenuation corrected (AC), and gated SPECT (GSPECT) techniques for small (1 × 1 cm 2 ) and large (2 × 2 cm 2 ) transmural defects in the three body-types of the anthropomorphic phantom with and without the respiratory motion (RM). Reference images of normal myocardial perfusion were as well obtained in all body-types.

Materials and Methods:
The abovementioned anthropomorphic phantom with cardiac and respiratory motion was scanned until now using Precedence Philips Gamma camera system and the JetStream processing workstation, located at the Guy's Hospital in London UK. We performed NC, AC, and GSPECT acquisitions using 26 MBq of 99m Tc introduced into the myocardial wall. The gated studies were performed at a heart rate of 50 beats per minute and at 10 breaths per min. Studies without respiratory motion but gated were as well acquired. Gated studies but without cardiac pumping and no respiratory motion were also performed to simulate "dead" patient. The processed images were visually and semi-quantitatively evaluated by one expert physician and one medical physicist.

Results:
Thin male patient without myocardial wall defects: The distribution of tracer, wall motion, and thickening were homogeneous with and without respiratory motion, with attenuation and no attenuation-correction, thus no significant influence of respiratory motion and attenuation correction on the distribution of tracer was observed. The ejection fraction was 53 ± 3% and the lungs tidal volume was 450 ± 10 ml. The EF on the simulated "dead patient" was calculated to be 5% and a "noise'' heart movement was observed on cine images. We believe that the 5% calculated EF is the minimum that can be measured using the commercially available soft-ware most likely due to noise. Fat lady without myocardial wall defects: Minor attenuation on the inferolateral wall, more intense in the expiration phase (no respiratory motion simulation). There is less attenuation on the images obtaining without respiratory motion, as in our setting the non-breathing images were acquired in expiration phase with the lungs pushing the water out of the anthropomorphic phantom, which mimics the soft-tissue, resulting in less soft tissue attenuation. All body types with small transmural myocardial wall defects 1 × 1 cm 2 in mid anteroseptal and mid inferolateral segments: The defects were not observed neither visually nor semi quantitatively in any of the acquisition and processing settings. All body types with large transmural myocardial wall defects, 2 × 2 cm 2 in mid anterior and mid inferior segments: defects visualized as a sub-segmental defect in extend and about 50% of uptake (moderate severity) in all acquisition settings. The attenuation corrected images brought out the basal segments, thus giving more sharp visualization of the defects (improving contrast), however did not change the degree of severity. They were visualized in two planes and in two to three consecutive slices.

Conclusion:
These first results are in agreement with the simulations of Yang et al.[2] Our results suggest that small transmural myocardial defects are underestimated in extend and severity, finding in agreement with the partial volume effect. More studies will be performed and with other gamma camera systems and more complicated respiratory motion correction algorithms will be applied. Finally, the images will be entered into the custom-build software PEONY and will be evaluated by more nuclear medicine doctors, and statistical data will be extracted. The work is expected to be finished by March 2014.


   Acknowledgments Top


This project YΓEIA/ΔYΓEIA/0311(BIE)/27 is funded by the Cyprus Research Promotion Foundation and the European Regional Development Fund.

References

  1. Chrysanthou-Baustert I, Parpottas Y, Demetriadou O, Christofides S, Yiannakkaras C, Kaolis D, et al. Diagnostic sensitivity of SPECT myocardial perfusion imaging using a pumping cardiac phantom with inserted variable defects. J Nucl Cardiol 2013;20:609-15.
  2. Yang YW, Chen JC, He X, Wang SJ, Tsui BM. Evaluation of Respiratory Motion Effect on Defect Detection inMyocardial Perfusion SPECT: A Simulation Study. IEEE Trans Nucl Sci 2009;56:671-6.
S-01

Present state of Nuclear Medicine Practice in Japan with the Special Emphasis on Radiopharmaceutical Therapy

Y. Sasaki


Clinical Research Center, Shonankamakura General Hospital, 1370-1 Okamoto, Kamakura, Japan

All radiopharmaceuticals used in hospitals have been purchased through Japan Radioisotope Association (JRIA) since its establishment in 1951. The trend of the use of radioisotopes in terms of their purchase in Japan is well known by the records of JRIA. In addition a scientific committee of JRIA has been performing the nationwide survey of nuclear medicine practices in Japan every 5 years since 1982. The present state of nuclear medicine practice and its trends will be reported in details based on the seven such surveys of which the latest was performed in 2012. The recent trends of radiopharmaceutical therapy will be reported including difficulties we are facing. A special situation in the aftermath of Fukushima Daiiichi nuclear power plant accident will be touched upon in relation to potential use of RI therapy units for the nuclear emergency medical response.

S-02

Updates in the Management of Graves' Disease

Wong Wai Yin


Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore

Graves' disease is the underlying cause of 60-80% of cases of hyperthyroidism. The highest risk of onset is between the ages of 40 and 60 years. The female-to-male ratio among patients with Graves' disease is between 5:1 and 10:1. Anti-thyroid drugs, radioiodine, and surgery are established therapies for Graves' hyperthyroidism. Despite the availability of these therapeutic choices for several decades, there remain several areas of uncertainty with large differences in opinion as to the preferred modality. This is reflected in variations in therapeutic choice among physicians. Radioiodine is used more frequently in the US compared to Europe and parts of Asia. Anti-thyroid drugs in the form of thioamides were introduced in 1943. Their main effect is to inhibit thyroid hormone synthesis by interfering with TPO mediated iodination of tyrosine residues in thyroglobulin. Improvement in symptoms generally occurs within 3 to 4 weeks after initiation of treatment. Patients are treated for 1 to 2 years, with the hope of achieving a remission. However, relapse eventually occurs in more than 50% of patients.

Radioiodine therapy may be used either as initial therapy or as definitive treatment in the event of relapse after a course of anti-thyroid drugs. The goal of radioiodine therapy is induced hypothyroidism. Therapy administered as calculated doses or fixed activities are equally efficacious in achieving this goal. One of the main concerns in using radioiodine is the risk of developing or worsening of ophthalmopathy. Thus, moderately severe eye disease may be a contraindication to use the radioiodine. Concurrent administration of glucocorticoids mitigates exacerbations, at least in patients with mild ophthalmopathy.

Thyroidectomy is the treatment that is least often used, but is effective in certain situations, e.g. patients with large goiters or suspicious thyroid nodules, patients with ophthalmopathy, and those who opt for rapid and definitive correction of hyperthyroidism. Total or near-total thyroidectomy is the preferred surgical technique. Graves' disease is an autoimmune disease characterized by the production of antibodies directed against the TSH receptor. Immune-modulatory agents which target the underlying pathogenesis of the disease such as rituximab and TSHR inverse agonists are being investigated.

S-03

Recent Advances in the Management of Thyroid Cancer

A. Nemencio, Jr. Nicodemus


Endocrinology, University of the Philippines, Manila, Philippines

The standard therapy for thyroid cancer has always included surgical removal of the gland with or without remnant ablation using radioiodine. This is often enough for "uncomplicated" differentiated thyroid carcinoma. Prognosis is good to excellent in most cases. Because differentiated thyroid cancers are very responsive to radioiodine therapy, chemotherapy has been relegated to the management of anaplastic or poorly differentiated thyroid carcinoma. Even then, chemotherapeutic agents present a challenge because of their toxicities. Among patients with differentiated thyroid carcinomas, there are those who continue to have persistent disease or even disease recurrence. For these advanced cases, repeated surgery, radioiodine therapy or even external beam radiation may not be sufficient.

Recent developments in the treatment of advanced thyroid carcinoma focus on targeted therapies. They are referred to as targeted therapies because they target specific oncogenic pathways in the differentiated thyroid cancer pathway. These groups of drugs were developed in order to extend life duration while assuring a good quality of life, in contrast to chemotherapy. These include tyrosine kinase inhibitors (e.g. sorafenib, vandetanib) and antibodies, which act as anti-angiogenesis agents (e.g. sunitinib). Another mechanism that is being utilized in creating new therapies is the based on the effect of the acylation of histones. These novel agents are still in their early years of development and application, particularly in thyroid carcinomas. However, they show promise and are welcome additions, especially among those with advanced disease.

S-04

Radioiodine Therapy Protocols Revisited: Patient Preparation and Medications during Therapy

Ugrinska Ana


Institute of Pathophysiology and Nuclear Medicine, Medical Faculty, University "Ss Cyril and Methodius", Skopje, Republic of Macedonia

Almost 70 years ago radioiodine was introduced by Seidlin in the treatment of the carcinoma of the thyroid gland. Although during this period I-131 has proven to be very good theranostic for thyroid disorders, there are still many controversies in regard to the optimal protocol for the use of radioiodine in the treatment of malignant thyroid diseases. The appropriate dose, dosimetry, use of rTSH are among the issues that still yield controversial results. Also the patient preparation and drugs used prior and during the radioiodine therapy (RAIT) might influence the success of RAIT and potential early and late sequelae of the RAIT. The low iodine diet has been adopted by many nuclear medicine centers as part of their protocol for RAIT for thyroid malignancies. The rationale behind this is that the total body iodine content may interfere with the radioiodine uptake in the thyroid remnants or metastases. Some centers also include measurement of 24 hours urinary iodine excretion (UIE) before the RAIT. According to the EANM guidelines levels of UIE above 150-200 μg/L are considered as iodine excess that can influence RAIT. Levels of UIE bellow this arbitrary cut-off value are easily achieved in some regions of the world with mild iodine deficiency, while in iodine rich areas more strict diet is required. Recently several studies have shown that the success of remnant ablation is not dependent on the UIE. Therefore, the stringent low-iodine diets do not seem to be justified. Instead advices that include avoidance of high iodine foods and drugs seem to be sufficient in most of the world regions.

The use of proton pump inhibitors and H2 blockers has been proposed in patients with gastritis, or in patients that will develop gastritis as early RAIT sequel. This group of medications induces increased gastric mucosal radioiodine uptake. Only one study till now has addressed this issue. Castro et al. have reported significantly increased uptake in the gastric mucosa of the patients that received omeprazole during the RAIT. Avoidance of these drugs during RAIT is recommended. However, in clinical practice there are patients that will need these drugs to address the issue of gastritis. Further studies are needed to establish the optimal protocol for the use of these medications.

Diuretics have been used in the past to accelerate the radioiodine excretion and to minimize the radiation burden. Recent guidelines emphasize proper hydration and frequent urination as method that successfully decreases the radiation burden. Recent study of Matovic et al. has shown that furosemide can induce decreased renal excretion of radioiodine and increased blood concentration during RAIT. Therefore, diuretics should be administered during RAIT with great caution. The salivary gland protectors are emerging as a new possibility for the reduction of salivary gland damage after RAIT. The recommendations in various protocols for RAIT are to stimulate the salivary flow with sour candies or vitamin C in order to decrease the radiation burden. However several recent studies have shown that the stimulation of salivary secretion during the first 24 h does not reduce the absorbed dose in the salivary glands. Medications like vitamin E and Amifostine have been proposed as possible salivary gland protectors. Unfortunately there are few studies that are investigating this issue and the results can't offer a clear recommendation for their use. So, what to do with a patient that is scheduled for second dose of radioiodine takes furosemide for heart insufficiency, Omeprazole for gastritis, and complains about xerostomia?

S-05

Thyroid Remnant Ablation using 1,110 MBq of I-131 for Outpatients with Thyroid Cancer in Japan

Naoyuki Watanabe


Professor, Department of Radiological Sciences, Gunma Prefectural College of Human Health, Maebashi, Department of Radiotherapy, Gunma Prefectural Cancer Centre, Ota, Japan

Iodine-131 ( 131 I) ablation after total thyroidectomy for differentiated thyroid cancer is undergone in order to reduce the recurrence rate of thyroid cancer and also the death rate from metastasis. The patients after radioactive iodine treatment can be released from hospital in Japan in the two conditions of (i) residual radioactivity in the patient body is less than 500 MBq and (ii) residual radioactivity in the patient body is measured less than 30 μSv per hour at 1 m from the surface of the patient body. They may allow that (i) maximally exposed individual not being likely to exceed an effective dose equivalent of 5 mSv and that (ii) public in general not being likely to exceed an effective dose equivalent for 1 mSv.

The medical capacity for radioactive iodine treatment is not so large in Japan because of severe medical economy as well as strict regulation of medical use of radioisotopes. Patients for radioactive iodine treatment should therefore wait for the treatment in hospitals more than 180 days after referral from surgeons. Right now, it is reported that the waiting time for radioactive iodine treatment is up to 10 months, 4.4 months on average. To overcome such difficult situation, a clinical study was conducted to determine the optimum conditions for outpatient based remnant thyroid ablation with 131 I 1,110 MBq through measuring the radiation exposure of the patients' family members (caregivers and others) during therapy. Here, the details on thyroid remnant ablation using 1,110 MBq of 131 I for outpatients with thyroid cancer will be reviewed.

S-06

Sensitivity of Preparation with rhTSH or Thyroid Hormone Withdrawal Using 131 I Whole Body Scans to Identify Metastases of Differentiated Thyroid Cancer

K. Liepe, M. Vereb


GH Kassel, Department of Nuclear Medicine, Mönchebergstr. 41, 34125 Kassel, Germany

Aim of the Study: Van Nostrand et al., reported a higher sensitivity for thyroid hormone withdrawal (THW) in detection of metastases of differentiated thyroid cancer (DTC) compared to recombinant human thyroid-stimulating hormone (rhTSH). This study aims to confirm the reported differences in the sensitivity using 131-I whole body scans (WBS).

Materials and Methods: Forty three patients with evidence or suspicion to have metastases of DTC (evaluated thyroglobulin, abnormal findings in previous WBS) underwent WBS using 370 MBq 131-I. The WBS was interpreted by two independent experienced observers by categorizing the findings into a positive or negative group.



Results: Of the evaluated patients, 14 patients were prepared with rhTSH and 29 with THW. No statistical differences were documented between the two groups for any of the evaluated parameters evaluated [Table 1]. In this study no differences in the sensitivity of WBS of patients prepared with rhTSH or THW were found: 11 of 14 patients (78%) were positive after rhTSH and 19 of 29 patients (65%) after THW.

Conclusion:
In contrast to van Nostrand et al., this study could not found any differences in the sensitivity of rhTSH or THW for the preparation of DTC patients.

S-07

An Overview of our Specially-Developed Online Remote Radiation Monitoring System For Patients With Differentiated Thyroid Carcinoma Treated with Radioiodine

M. Matović, M. Jeremić, V. Urošević, M. Ravlić, M. Vlajković


Department of Nuclear Medicine, Clinical Center Kra gujevac and Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia

Following the application of the ablative dose of radioiodine in differentiated thyroid carcinoma (DTC) treatment, the patient must remain hospitalized for a certain amount of time in special restricted access premises until radiation in their body drops below a certain level. This period usually lasts 2-5 days, and its duration depends on several factors. The most important two are certainly the radiation dose applied and the size of the remaining post-operative thyroid tissue, but other factors are of importance as well, e.g. those affecting individual biokinetics and biodistribution of radioiodine, such as kidney function, the use of various medications, etc., Having in mind the costs of medical treatment on the one hand, and the spatial limitations of the hospital premises for radionuclide therapy on the other, it is of vital importance to estimate as early as possible, when the radiation in a patient's body is expected to drop below the set limit. We have developed our own online remote radiation monitoring system, which measures the exposition dose by means of a pancake probe (LND, model 7312). This detector is connected to a PTZ (PanTiltZoom) device, which enables precise positioning of the detector on the given patient's body part. The positioning of the detector is visually controlled by a high sensitivity micro camera, placed at the centre of detector's field of view. A digital video recorder (DVR) and the appropriate software enable us to control the position of the detector and have a video control of its position at the same time. Furthermore, there are four laser pointers placed around the detector, which can also be controlled by the DVR and which at all times precisely mark the area which detector is ''seeing.'' The acquisition of the measured data from the detector to PC is performed using hardware/software developed by Theremino R Italian group. The entire system enables a most precise positiong of the detector during the measurement, as well as the initiation of the measurement through either an Intranet or the Internet. It also enables the WEB based online remote monitoring of radiation levels from diffrent body parts of the patient. The mesurements are performed at three reference points in the body: the neck, the chest and the stomach, at a 1 m distance. Thus, we can choose the referential zone of highest radiation in accordance with which we can monitor changes in the radiation levels (0, 1, 3, 6, 9 and 12 h after the application of the radioiodine therapy) and be able to predict, based on those results, when it would drop below the set limit. To process this data, we used our own developed software, which fits the measured data by means of the exponential function. The obtained data can help predict when the radiation levels would reach the set limit. In other words, we can predict when the patient would be released from hospital. By using this system, we can decrease the overall expenses of health insurance for hospitalizing patients in the special, restricted area. Moreover, we can optimize the use of limited hospital space allotted to radioiodine therapy.

S-08

Recent Advances in the Imaging and Therapy of Active Atheromatous Disease Using Theragnostic High-Let Electron Emitters

Suresh C. Srivastava


Department of Collider-Accelerator,Brookhaven National Laboratory, Upton, New York, USA

Therapeutic particle emissions consist of Auger electrons, alpha emission, beta particles, and conversion electrons. Except for the beta particles, all of these are classified as high-LET (linear energy transfer) electron emitters. Conversion electrons, which are generally monoenergetic, have a discrete range in tissue, as opposed to beta electrons that may have a range of energies, and thus a maximum and an average energy value. Auger electrons are very effective in cell kill but proximity to cellular DNA is often a necessary requirement. Alpha emitters are generally effective over several cell diameters (~4-10), whereas conversion electron emitters (depending upon energy) are effective over 1-50 cell diameters. Targeted high LET electron therapy is very promising as a potent treatment of inflammatory conditions including certain cancers, and for active atheromatous disease in carotid and coronary arteries. However, a major problem that remains to be resolved is the lack of availability, in sufficient quantities and at reasonable cost, of a majority of the best candidate theragnostic high LET radionuclides in a no-carrier-added (NCA) form. At BNL, in collaboration with Clear Vascular, Inc., we have recently addressed this issue for Sn-117m, and have initiated a research program to increase the supply of Ac-225, parent of the theragnostic daughter Bi-235, a high LET alpha emitter. Because of the short range of these particles in the tissue and their high-LET nature, the radiation damage is mainly confined to the targeted cells, and the radiation burden to the surrounding healthy tissues is much lower when compared with beta emitters.

Tin-117m (T 1/2 14.0 d; γ 159 keV, 86%), is a very promising radionuclide for the development of theragnostic radiopharmaceuticals. [1] In contrast to most other theragnostic beta emitters, Sn-117m decays via isomeric transition with the emission of monoenergetic conversion electrons (127, 129, and 152 keV; abundance 65, 12, and 26% respectively). These emissions have short discrete ranges of between 0.22 mm (127 keV) and 0.29 mm (152 keV) in water. Therefore, Sn-117m, which has a very strong anti-inflammatory effect, should be effective for therapy of metastatic disease and for other inflammatory conditions (e.g. atherosclerotic disease) causing much reduced myelosuppression and greatly reduced dose to normal organs. Moreover, having the 159 keV γ-photon, tin-117m is perfect for pre-therapy imaging in the same patient.

Cardiovascular diseases represent a leading cause of death and, specifically, a ruptured vulnerable plaque (VP) accounts for about 70% of fatal acute myocardial infarctions and/or sudden death. Despite this, there are no available methods to both image (monitor) and treat this problem. Recently, Sn-117m labeled annexin has found successful application in pre-clinical and clinical studies for this purpose. [2] Biological labeling demands high specific activity (>1000 Ci/g) that can only be produced with accelerators. We employed the Cd-116(α,3n) Sn-117m reaction and a novel chemical separation/purification method to produce the radioisotope. [2] The targeting molecule developed for vulnerable plaque (VP) imaging and therapy is [tin-117m]-DOTA-annexin (TA). Annexin V, found on the inner cell membrane, specifically binds to phosphatidylserine (PS). When cells undergo apoptosis, the PS is exposed for binding. Tin-117m was first attached to a bifunctional chelating agent (aminobenzyl-DOTA) using a microwave reactor at elevated temperatures and then purified using HPLC. Conjugation of the chelate to annexin V-128 was accomplished by preparing the isothiocyanate version of the chelate and then reacting it with lysine residues on the annexin for 90 min at 37°C [Figure 1].



Several analytical methods (cell binding, electrophoresis, gel permeation chromatography) were used to evaluate the cGMP [Sn-117m]-DOTA-annexin (TA) that was produced. PAGE determined that the product was > 95% monomer; cell binding results were typically pK = 20-24. Overall chelation yields were ~ 95% and ~ 40% for conjugation to the annexin. This product was injected in ApoE mice and a therapeutic effect observed at very low doses (~1.7 μCi - equivalent to 3-5 mCi in humans). Statistically significant data were obtained showing that apoptotic bodies and macrophages decreased while smooth muscle cells and collagen increased in the cardiac brachiocephalic arteries and the sinotubular junction where VP was observed to occur. The dose dependent results obtained are indicative of plaque stabilization, inflammatory reduction and a positive therapeutic outcome. [2],[3]

Early human studies [4] have also indicated that imaging with as low as ~ 5 mCi TA may be possible. All studied patients had carotid artery stenosis (CAS), and were candidates for carotid endarterectomy. The first phase of the trial involved 6 patients and the second part 9 patients. For the first part of the study a dose of 500 μCi cGMP to determine dosimetry and biodistribution was used. The second phase was performed with an imaging dose (3 mCi of TA) based on organ toxicity results from phase1. All patients were followed with scintigraphic images up to 14 d post-injection. Blood and urine samples were collected to establish blood clearance and urinary excretion. Complete hematological, renal, biochemical and liver parameters were measured in blood weekly until 4 week post injection. All patients underwent endarterectomy and both groups had optical, autoradiography, and histology data comparison from excised carotid plaque tissue. The TA activity in blood cleared after 24 h. Urine TA excretion at 7 day was less than 5% of total urinary activity. Scintigraphic images showed mild bone marrow uptake, moderate spleen uptake and high uptake in liver and kidneys. Kidney activity decreased after 7 day and disappeared at 2 weeks. There was no change in uptake pattern in bone marrow, liver and spleen during the 2-wk period of observation. No significant clinical changes or blood test abnormalities were detected. Imaging of atherosclerotic plaques was not achieved in these patients, although tissue analysis confirmed the presence of TA on all inflammatory plaques. TA uptake was visualized in one patient with an abdominal aortic aneurism and other with a previous surgery at the lumbar spine. [4]

In conclusion, these preliminary studies demonstrated that this novel inflammatory tracer (Tin-117m-DOTA-Annexin) specifically targeted vulnerable atherosclerotic plaques. Biological safety, imaging capability, as well as therapeutic response, were demonstrated in animal models. Preliminary results in humans showed selective uptake of TA in cardiovascular and carotid VP and other inflammation sites.

The work at BNL was supported by the U.S. Department of Energy (NNSA NA-24 IPP Program, and the NP Office of National Isotope Programs), under Contract # DE-AC02-98CH10886. Additional research grant support by Clear Vascular Inc., including a Cooperative Research and Development Agreement (CRADA) with BNL, is gratefully acknowledged trials.

References

  1. Srivastava SC. Paving the way to personalized medicine: Production of some promising theragnostic radionuclides at Brookhaven National Laboratory. Semin Nucl Med 2012;42:151-63.
  2. Stevenson NS, et al. Presented at the 20 th ISRS Symposium, Jeju, Korea: ICC JEJU; 2013.
  3. Gonzales G, et al. World J Nucl Med 2012;11:152.
  4. Orellana P, et al. Presented at the 6 th WMIC, Savannah, GA, September 18-21, 2013.
S-09

To Ablate or Not to Ablate: An Evidence-Based Approach

Savvas Frangos


Thyroid Cancer Unit, Bank of Cyprus Oncology Center, Nicosia, Cyprus

The first radioiodine therapy was published by Seidlin, Marinelli and Oshry 1946. [1] On August 4, 1949, the newspaper Courier Mail published an article about the use of an "atomic cocktail" as cancer cure. The same year, the Life magazine published that: "radioactive chemicals bring about history-making recovery of patient dying from thyroid tumors." What is evidence-based medicine? According to Sackett et al: [2] "Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients." Trisha Greenhalgh [3] defines evidence-based medicine as: "the use of mathematical estimates of the risk of benefit and harm, derived from high-quality research on population samples, to inform clinical decision-making in the diagnosis, investigation or management of individual patients." Can we apply Evidence Based Medicine for ablation Therapy? For this, a randomized Trial is needed. E. Mazzaferri [4] thinks that a Randomized Trial of Remnant Ablation seems an Impossible Dream. Most agree that a randomized trial of remnant ablation using thyroid cancer mortality as an endpoint may never be performed, because of the low number of events. One would require at least 1000 patients followed over 25 years, to detect a desirable significant reduction of 20% in disease mortality, and 4000 patients would be required to detect a more realistic reduction of 10%. There are a lot of guidelines regarding Thyroid cancer management especially regarding Iodine-131 therapy. For this presentation, we check the following: American Thyroid Association (ATA), European Thyroid Association (ETA), National Comprehensive Cancer Network (NCCN), Society of Nuclear Medicine and Molecular Imaging (SNMMI), European Association of Nuclear Medicine (EANM).

The goal of the first dose of Iodine-131 is the remnant ablation (to facilitate the detection of recurrent disease and initial staging), adjuvant therapy (to decrease risk of recurrence and disease specific mortality by destroying suspected, but unproven metastatic disease), or therapy (to treat known persistent disease). Between the associations there is almost agreement for the indication to ablate: ETA [5] suggests the ablation for distant metastases or incomplete tumor resection or complete tumor resection but high risk for recurrence or mortality, as well as for tumour extension beyond the thyroid capsule (T3 or T4) or lymph node involvement. ATA [6] includes patients for ablation who have T3 > 4 cm in all patients, T4 with any size gross extra thyroidal extension and M1 with distant metastasis present The NCCN [6] mentions the gross extra thyroidal extension, primary tumour >4cm, known or suspected distant metastasis. SNMMI [8] considers tumour diameter greater than 1.0 cm or with a maximum tumour diameter less than 1.0 cm but with the presence of high-risk features, lymphatic or vascular invasion, lymph node or distant metastases, multifocal disease, capsular invasion or penetration, perithyroidal soft-tissue involvement elevated antithyroglobulin antibody level. The authors of EANM [9] guidelines think that radioiodine ablation after total or near-total thyroidectomy is a standard procedure. The only exception is patients with unifocal papillary thyroid carcinoma ≤1 cm in diameter without: Evidence of metastasis, thyroid capsule invasion, history of radiation exposure, unfavourable histology such as tall cell, columnar, insular, solid variants, poorly differentiated thyroid cancer, the presence of intrathyroidal vascular invasion and gross or microscopic multifocal disease.

What is the reason for not using the "atom cocktail" in all cases, as it was used to treat cancer back in 1949? One of the reasons is the increase in the incidence of Well Differentiate Thyroid Cancer (WDTC), from 3.5 per 100,000 in 1973 to 11.4 per 100,000 in 2007. In 1983, low-risk WDTC (intrathyroid T1N0M0 tumours <2 cm) accounted for 28.6% of all WDTC. Since 1983 the incidence of low-risk WDTC has increased from 1.2 to 5.2 per 100 000. This accounts for the majority (55.6%) of the increased incidence of WDTC overall. Among patients aged <45 years with low-risk tumors, RAI increased from 3.3% in 1973 to 38.1% in 2006.

Second reason is the second primary malignancies. Significantly, elevated risk because of radioactive iodine (RAI) can be seen in salivary gland malignancies and leukemia. The increased risk of second primary malignancies in patients with low-risk (T1N0) WDTC, along with a lack of data demonstrating improved survival outcomes with adjuvant RAI, provides a compelling argument in favour of rationing the use of RAI in this patient population. [10] In a systematic analysis of the peer-reviewed literature from 1966 to April 2008, [11] it was found that the majority of studies did not find a statistically significant improvement in mortality or disease specific survival in those low-risk patients treated with RAI. However, improved survival was confirmed for high risk (AJCC stages III and IV) patients. Evidence for RAI decreasing recurrence was mixed. Half of the studies showed a significant relationship and half showed no relationship

Size of tumour is important for the decision to ablate or not to ablate. EANM guidelines [9] say that radioiodine ablation after total or near-total thyroidectomy is a standard procedure in patients with WDTC. The only exception is patients with unifocal papillary thyroid carcinoma ≤ 1 cm in diameter. ATA [4] does not recommend ablation for patients with unifocal cancer < 1 cm without other higher risk, and for patients with multifocal cancer when all foci are < 1 cm in the absence other higher risk features. If size is important, what is the definition of one cm? The measurement is till now based on the histopathology, but studies show a discrepancy between the size in histopathology and ultrasound. [12,13] In one study [12] in the diagnostic group, the size of the nodules targeted by US imaging for FNA averaged 2.1 cm (range, 0.8-5.0 cm). On resection, the average PTC size in the diagnostic group was found to be 1.7 cm. The absolute difference between the US size and the resection size was 0.41 cm, a difference that was statistically significant (P = 0.0005). In the other study [13] a total of 263 thyroid specimens with a solitary nodule were identified. Of these, 68 were found to harbor WDTC. A median underestimation by pathology of 0.54 cm was present in WDTC, averaging 20% of the nodule size by pathology. This trend was consistent with subgroup analysis for size, pathology, and nodularity. An underestimation by pathology of 0.4 cm was present for papillary carcinoma under 1 cm.

One very important aspect is the surgeons' experience. According to the New York's Columbia-Presbyterian, one of USA's top thyroid surgery centers, surgeons are rated in terms of total number of thyroid/parathyroid surgeries performed. Less than 200 surgeries: Inexperienced. 200 to 500 surgeries: Intermediate. More than 500 surgeries: Experienced. More than 1000 surgeries: Expert. The EANM guidelines [9] suggest that, when thyroid surgery is performed by highly expert hands at selected tertiary referral centres, the positive influence of radioiodine ablation may not be apparent. Another study [14] shows that recurrences did not differ between patients with unifocal and multifocal disease overall. However, among patients who received less than a near-total thyroidectomy (NTT), those with multifocal disease had more recurrences than those with unifocal disease (18 vs. 4%, P0 = 0.01).

Another one parameter that should be taken into account is the level of thyroglobulin. According to the NCCN guidelines, [7] inappropriate thyroglobulin level in the absence of thyroglobulin antibodies should be considered for performing ablation therapy. Based on a study of our own patients, [15] out of 110 patients, only 18 of them satisfied the criteria of NCCN to have TG < 1 ng/ml in absence of Anti-Tg. A total of 43 patients had TG from 2 to 119.3 ng/ml.

Appropriate surgery is important in the staging of patients. Nx in the staging characterizes if regional (nearby) lymph nodes cannot be assessed. The risk of patient with Differentiated Thyroid Carcinoma according to the European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium [5] is high at any T3 and T4 or any T, N1 or any M1. That means that if the lymph nodes are not assessed, the patients are not necessarily in stage N0, which means low risk but it could be N1 which means high risk, hence it needs ablation.

It is obvious that there are studies showing no benefit from ablation therapy in small thyroid cancer. The increasing number of low risk Thyroid cancer cases, should rationalize the use of Iodine-131 as ablation Therapy. There is the possibility of Second Primary Cancer, even if is not yet proven. There are still a lot of questions to be answered in order to determine whether a patient does or does not need ablation therapy. The simplification to size (i.e. less than 1 cm) does not need ablation therapy, could be wrong for many reasons. A series of questions should be answer before making the decision to perform ablation therapy, like: What is the surgeon's experience? Is the evaluation of lymph nodes appropriate? How big is the residual thyroid volume? What is exactly the histopathology? What is the level of thyroglobulin? Are thyroglobulin antibodies present? Unfortunately, a prospective randomised trial does not exist and is possibly not feasible. The recommendations and guidelines should be adapted according to the local situation, considering especially the presence of experienced surgeons. More facts should be taken into account, other than the size, in order to ablate or not ablate.

References

  1. Seidlin SM, Marinelli LD, Oshry E. Radioactive iodine therapy: Effect on functioning metastases of adenocarcinoma of the thyroid. JAMA 1946;132:838-47.
  2. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: What it is and what it isn't. BMJ 1996;312:71-2
  3. Greenhalgh T. How to read a paper: Papers that summarise other papers (systematic reviews and meta-analyses). BMJ 1997;315:672-5.
  4. Mazzaferri E. A randomized trial of remnant ablation--in search of an impossible dream? J Clin Endocrinol Metab 2004;89:3662-4.
  5. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154:787-803.
  6. Revised american thyroid association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-1214.
  7. NCCN guidelines thyroid carcinoma version 1.2013.
  8. The SNM Practice Guideline for Therapy of Thyroid Disease with 131I. J Nucl Med 2012;53:1633-51.
  9. Luster M, et al. Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging 2008;35:1941-59.
  10. Iyer NG, Morris LG, Tuttle RM, Shaha AR, Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer 2011;117:4439-46.
  11. Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: A systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid 2010;20:1235-45.
  12. Siddiqui MA, Griffith KA, Michael CW, Pu RT. Nodule heterogeneity as shown by size differences between the targeted nodule and the tumor in thyroidectomy specimen: A cause for a false-negative diagnosis of papillary thyroid carcinoma on fine-needle aspiration. Cancer 2008;114:27-33.
  13. Sowerby L, Franklin JH, Chin CJ, Turner B, Fung K, Zaleski W, et al. Discrepancy between ultrasound and final pathologic measurements in thyroid cancer. J Otolaryngol Head Neck Surg 2011;40:453-7.
  14. Ross DS, Litofsky D, Ain KB, Bigos T, Brierley JD, Cooper DS, et al. Recurrence after treatment of micropapillary thyroid cancer. Thyroid 2009;19:1043-8.
  15. Frangos S, Patsali L, Vanezi A. Level of thyroglobulin in patients with papillary thyroid carcinoma received radioiodine ablation therapy (abstract).
S-10

Radioiodine for Thyroid Cancer: Less is More Findings from a Multicenter, Randomized Non-Inferiority Trial And Its Applicability In Practice

B. K. Yap


The Christie NHS Trust Wilmslow Road, Manchester, United Kingdom, England

The recent publications of the British HiLo and French ESTIMABL randomized trials showing low-dose radioiodine (LDA) was as effective as high-dose radioiodine ablation in patients with differentiated thyroid tumors, and recombinant human thyrotropin (Thyrogen™) was as effective as thyroid hormone withdrawal. There are increasing longer term data to support the use of LDA. However, LDA has resulted in the re-visiting of the issues regarding 'ablation paradox' where question is being asked whether radioiodine ablation is necessary in low risk thyroid cancer. Where do we go from here?

S-11

The Ups and Downs of MIBG: A Historical Perspective

Cornelis A. Hoefnagel


Amsterdam, The Netherlands

The development and subsequent clinical uses of radioiodinated meta-iodobenzylguanidine (MIBG) represent a good example of truly molecular targeting "avant la lettre" (before the word was coined). The credit goes to Prof. William Beierwaltes, whose group at the University of Michigan in Ann Arbor already in the 1960's studied and developed tracers for the adrenal cortex and medulla and the heart. After working with 14 C-epinephrine for neuroblastoma (1967) and 14 C-dopamine for pheochromocytoma (1973) initially, they switched to radioiodinated bretylium analogs and quaternary ammonium derivatives for imaging. It was Don Wieland who synthesized and compared 125 I-labelled ortho-, para-, and meta-isomers of iodobenzylguanidine and was the first to describe the imaging of the dog's adrenal medulla by 131 I-para-iodobenzylguanidine (1980) and in 1981 Sisson et al. reported imaging of pheochromocytoma in man by 131 I-meta-iodobenzylguanidine. The downside was that 131 I-MIBG was a poor tracer for cardiac imaging and that initial attempts of imaging other neuroendocrine tumors showed false negative results.

The subsequent "up" development occurred in Europe, where 131 I-MIBG with low and high specific activity (for imaging and therapy, respectively) became commercially available and where, from 1984 on, several groups reported its successful use for scintigraphy and therapy of pheochromocytoma, paraganglioma, neuroblastoma, carcinoid tumors, and medullary thyroid carcinoma. In 1987 123 I-labeled MIBG became available, which had better imaging properties allowing SPECT and proved to be a good cardiac agent after all, as a specific tracer for sympathetic innervation of the myocardium. In 1991 the therapeutic results in 534 patients from 14 centers were gathered and demonstrated an objective response rate of around 50% in malignant pheochromocytoma, paraganglioma, as well as in children with neuroblastoma, refractory to other forms of treatment. In contrast, in carcinoid tumors and medullary thyroid carcinoma objective responses were far fewer or even absent, although stabilization of disease, metabolic effects and palliation (in 60% of the patients) were associated with significantly prolonged survival.

The decline in use of 131 I-MIBG for therapy of neuroendocrine tumors occurred with the development of radiolabeled peptide for diagnosis and therapy. Although in the individual patient combined imaging of neuroendocrine tumors using MIBG and octreotide is the key to select the therapy with best dosimetric characteristics, in clinical practice, literature and at congresses we see that the use of radiolabeled peptides for therapy is far more prominent. Although the indications for both therapies do not overlap completely, also in radiolabeled peptide therapy the objective response rates are relative low (up to 30%) and the metabolic and palliative effects are more pronounced, the latter also having bearing on the survival of patients, as was also observed in 131 I-MIBG therapy of carcinoid tumors.

Then why is therapy using radiolabeled peptides more popular? Certainly the availability of a good pair of a PET tracer and a therapeutic agent is an important factor, as high quality PET/CT imaging using 68 Ga-DOTATOC or -octreotate, clearly showing the tumor targeting and biodistribution, is indicative and promotional, convincing clinicians to refer their patients for treatment with 177 Lu-octreotate, which also has good properties for post-therapy imaging.

It is concluded that a new "up" in MIBG therapy may be foreseen. The similar use of a high quality pair of a diagnostic tracer for PET/CT and/or PET/MR (e.g. 18 F-DOPA and 124 I-MIBG) and an therapeutic radiopharmaceutical may bring this way of molecular tumor targeting to the clinical attention and lead to a "reinvention" of MIBG therapy, not in competition with, but parallel to peptide therapy.

S-12

SPECT-CT in Post Therapy Imaging

John Buscombe


Nuclear Medicine and PET, Addenbrooke's Hospital, Cambridge, UK

Post therapy imaging remains essential when possible to determine the biodistribution of a therapeutic isotope after administration. This can be performed for different clinical reasons. Firstly it is important to check that the product has been taken up by the target tissue. Also as the therapy activity is often much greater than the diagnostic study, a higher count rate may be obtained and it may be possible to see smaller structures. Therefore unsuspected metastases can be identified. The third use of imaging is to identify if there is any unsuspected or unwanted distribution of the therapeutic agent which could cause an adverse event. An example of this would be high renal uptake of PRRT would increase the risk of renal toxicity and extra-hepatic Y-90 SIRT in the stomach could lead to gastric ulceration. The fourth and most underused reason for post therapy imaging is to allow a calculation of organ by organ residence of the therapeutic radioisotope. From this dosimetry can be calculated. Many of the organs of interest overly each over especially in the upper abdomen. Therefore to allow for separation of these structures SPECT is of great use. However, looking at SPECT images can look like a series of "blobs". For example does a site of intra-abdominal I-131 represent a peritoneal metastases or normal gut physiological activity. All this depends on the radionuclide emitting a suitable gamma or similarly detectable radiation. Therefore the use of hybrid SPECT-CT imaging after use of a therapeutic radionuclide is ideal in identifying the structure in which activity is localized. For example is there uptake in sites of known tumor? This can be used to specifically pinpoint the site of any post therapeutic input. It is also useful in dosimetry as the CT component can be used to attenuate correct the images, which will lead to more accurate dosimetry. None of the commonly radionuclides used in therapy have a high yield of positrons so gamma imaging remains the main method by which these patients are assessed post therapy. SPECT-CT allows that to be an accurate process.

S-13

Imaging of Drug Resistant TB Decoded

Mike Sathekge


South Africa

Abstract is not available at the time of printing.

S-14

The Role of PET in Radiotherapy Planning

Sze-Ting Lee


Austin Hospital, Melbourne, Australia

Molecular imaging with PET/CT in radiotherapy allows better tumor staging, modification of treatment fields, localized symptom control and therapy response evaluation. There is a clear dose − response relationship between radiation dose and biochemical tumor control rates. The basics of radiotherapy relevant to nuclear medicine will be outlined with a focus on intensity modulated radiotherapy planning, which is a strategy that has been proposed to enable the delivery of high radiotherapy doses without giving an unacceptably high risk of toxicity. There will be a review of the current literature and the emerging role of PET in radiotherapy planning, including the role of various non-FDG radiopharmaceuticals in this arena.

S-15

Choline PET/CT in Staging and Restaging of Biochemical Recurrence of Prostate Cancer: A Systematic Review and Meta-analysis in >6000 Patients

Finn Edler von Eyben 1 , Kalevi Kairemo 2


1
Center of Tobacco Control Research, Odense M, Denmark, 2 Department of Molecular Radiotherapy and Nuclear Medicine, Docrates Cancer Center, Helsinki, Finland

Aim of the Study: PET and PET/CT add information to the staging of patients with prostate cancer. The systematic review aimed to evaluate the clinical impact of PET/CT scans.

Materials and Methods:
We undertook a search in PUBMED and EMBASE databases, and a manual search for primary studies. Titles and abstracts were screened by one reviewer, and clinical information was extracted.

Results:
115 articles were selected. Overall, 3849 of 6630 (58%) patients had positive PET/CT scans. Of these patients, 1513 (23%) had lesions in the prostatic bed, 999 (15%) had lesions in pelvic lymph nodes, 861 (13%) had lesions in distant organs, and 476 (7%) had lesions in two or more regions. 18 F-choline PET/CT scans more often gave positive findings than 11 C-choline PET/CT scans (58% versus 48%, P < 0.001, chi 2 test). Patients more often had cancer lesions in the prostate bed at staging and at restaging for biochemical recurrence after external beam radiation therapy than at restaging for biochemical recurrence after radical prostatectomy (35% and 50% versus 20%, P < 0.001, chi 2 test). A third of the patients with prostate cancer had a change in therapy after the PET/CT scans. Incorporation of PET/CT gave promising results.

Conclusion:
Our review supports a wide use of PET/CT scans for patients with prostate cancer.

S-16

A Perspective on Positron Emission Mammography

Enrique Estrada


Mexico

Abstract is not available at the time of printing.

S-17

Alpha Therapy and SPECT/CT Imaging of Metastatic Bone Disease

Homer Macapinlac


USA

Abstract is not available at the time of printing.

S-18

Molecular Imaging of Neuroendocrine Tumors

G. Kaminski, S. Piszczek


Military Institute of Medicine, Warsaw, Poland

Since genetic engineering has given us tools to discover biological processes in a micro-scale - fortunately - the medical world has been equipped with devices to observe them. Oncology became the arena of spectacular development of molecular imaging. SPECT and PET techniques allow to visualize small particles like peptides and receptors. These novel applications let us observe the primary lesion, metastatic processes and immune cells reactions. Potentially, each particle triggered with radioisotope which is involved in a cell structure and/or its metabolism can be useful in molecular imaging. The first group of molecules used in radioisotope molecular imaging is peptide receptors agonists and antagonists. Somatostatin receptors (mostly SSTR-2) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP/NET). Therefore somatostatin analogues triggered with radioisotopes are used in either imaging (Technetium, Indium) or treatment (Yttrium, Lutetium) of these malignancies. Implementation of chelator DOPA allowed to create radiopharmaceuticals conjugated with either SPECT or PET isotopes. Beside GEP-NET, the overexpression of SSTR was found in lung cancer, intestinal adenocarcinoma, pheochromocytoma, paraganglioma, neuroblastoma and the pituitary adenoma. Recent studies with radiolabeled SSTR antagonists indicate that they may be superior to agonists in diagnosis and treatment of neuroendocrine tumors because of better tumor-to-background, tumor-to-kidney ratio and longer tumor radiopharmaceutical retention time.

Bombesin receptors analogues are the other group of peptides, which gives us new hopes in oncological diagnosis and treatment. Four subtypes of bombesin-like peptides (Gastrin Releasi- ing Protein - GRP) receptors are known up till now. Three of them (subtypes 1-3) were found in humans. The subtype 1 with high affinity to GRP has been found in various neoplasms such as: breast, prostate, pancreatic, ovarian cancers, small cell lung cancer and gastrointestinal stromal tumors. Subtypes 2 and 3 are found mostly in GEP/NETs. Only a few clinical studies concerning bombesin receptors were conducted in humans. The SPECT/CT imaging with radiolabeled bombesin analogue 99m Tc-RP527 in breast and prostate cancer showed specific uptake in some of this lesions. Furthermore Tamoxifen-resistant breast cancers did not show the uptake of this tracer. In another study, the multi-receptor analogue - with affinity to three bombesin receptor subtypes - was applied in 17 patients treated with Imatinib because of gastro-intestinal stromal tumors. Seven of 17 patients showed this bombesin multi-receptor tracer uptake in comparison to 14 of 17 patients in whom the 18 F-FDG PET/CT scans were positive. Also, the studies with bombesin antagonists in SPECT/CT and PET/CT imaging are promising. In preclinical study, such a bombesin antogonist RM2 labelled with 111 In and 68 Ga showed good quality images of prostate cancer cells with high tumor-to-background and tumor-to-kidney ratio. In the clinical study with 64 Cu labeled bombesin antagonist, tracer uptake in prostate cancer was observed in 3 of 4 patients in PET/CT scans. The first clinical trials with bombesin analogues in oncological treatment have been started.

The expression of glucagon-like peptide-1 (GLP-1) receptors was depicted in normal tissues of pancreas, stomach, blood vessels and parafollicular C cells. It can also be observed in well differentiated (benign) neuroendocrine tumors. In the study concerning 10 patients with insulinoma (8 patients with benign, 2 with malignant insulinoma), the SPECT/CT imaging with 99m Tc labeled GLP-1 analogue showed increased tracer uptake in all patients with benign tumor but no uptake in malignant insulinomas. Vasoactive intestinal peptide (VIP), neuropeptide acting through the VPAC1 and VPAC2 receptors can stimulate cancer cells proliferation. Overexpression of VIP receptors is found in many neoplasms: neuroendocrine tumors, brain tumors, adenocarcinomas of the pancreas, prostate, breast, colon, stomach and liver. 99m Tc and 123 I labeled VIP analogues can be useful in visualization of these tumors. Molecular imaging is fast developing part of medicine. Finding new and new radiolabelled carriers, we are closer to the possibility of choosing the most corresponding to the biology of neoplasm radiopharmaceutic and hence we are closer to personal patient diagnosis and treatment.

Suggested Reading

1. Pepe G, Moncayo R, Bombardieri E, Chiti A. Somatostatin receptor SPECT. Eur J Nucl Med Mol Imaging 2012;39 (Suppl 1):S41-51.

2. Wild D, Fani M, Behe M, Brink I, Rivier JE, Reubi JC, et al. First clinical evidence that imaging with somatostatin receptor antagonists is feasible. J Nucl Med 2011;52:1412-7.

3. Wang X, Fani M, Schulz S, Rivier J, Reubi JC, Maecke HR. Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy. Eur J Nucl Med Mol Imaging 2012;39:1876-85.

4. Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR. Radiopeptide Imaging and Therapy in Europe. J Nucl Med 2011;12:42S-55S.

5. Fani M, Maecke HR, Okarvi SM. Radiolabeled peptides: Valuable tools for the detection and treatment of cancer. Theranostics 2012;2:481-501.

6. Sowa-Staszczak A, Pach D, Mikołajczak R, Mäcke H, Jabrocka-Hybel A, Stefańska A, et al. Glucagon-like peptide-1 receptor imaging with [Lys 40 (Ahx-HYNIC- 99m Tc/EDDA) NH 2 ]-exendin-4 for the detection of insulinoma. Eur J Nucl Med Mol Imaging 2013;40:524-31.

7. Eder M, Eisenhut M, Babich J, Haberkorn U. PSMA as a target for radiolabelled small molecules. Eur J Nucl Med Mol Imaging 2013;40:819-23.

S-19

Theragnostic Hybrid Molecular Imaging

Juan Pablo Gambini


The future of Nuclear Medicine is intimately associated to therapy with open sources and the concept of personalized diagnosis and treatment, theranosis. This concept is clearly illustrated by 68 Ga DOTA TATE and 177 Lu DOTA TATE in the treatment of neuroendocrine tumors (NETs). As our knowledge and comprehension of pathology advances we will be able to develop different tracers to perform personalized medicine as the standard of care. To make it possible we should aim to have a multimodality approach to theranosis. In this way we should start thinking of incorporating optical imaging; in particular, optical imaging using near infrared (NIR) fluorescent light (700-900 nm). NIR light exhibits high tissue penetration (mm to cm deep) and low autoflorescence, which provides good contrast. To be able to detect NIR light it is necessary to use a NIR camera, because we do not have photoreceptors sensitive to NIR light. Indocyanine green (ICG) is excited by NIR light and emits fluorescence that can be detected with a NIR camera. ICG was developed in the 1950s by Kodak Research Laboratories and has been approved by FDA for several clinical applications being retinal angiography one of the most common indications for ICG. Recently, a hybrid tracer for sentinel node imaging was developed by the combination of two available and approved products such as 99m Tc nanocolloid and ICG. These hybrid probes are used for preoperative scintigraphic or SPECT/CT imaging and transcutaneous evaluation with a NIR camera of the sentinel node. This information is useful to plan surgery. During surgery these probes allow identification of the sentinel node using real time imaging with both modalities through an intraoperative gamma camera or probe and a NIR camera. An intraoperative NIR camera would have a complementary role to the one provided by the gamma camera and also aid the gamma probe. Although there are several available NIR cameras for surgical settings, availability and costs have dictated that we construct our own camera taking into account the properties of ICG and its detection. Our results are encouraging and we plan to continue to apply this hybrid approach in sentinel node procedures and look forward to other oncological applications of it. ICG is considered a standard of NIR imaging, and can be compared to what 18 FDG is to PET. 99m Tc nanocolloid ICG has opened the path for clinical hybrid probes and has shown us the proof of concept, but new hybrid specific probes must be developed. Maybe we can imagine a nice synergy between 68 Ga DOTA TATE and a somatostatin analogue NIR probe to be used during surgery of NETs. We would be performing diagnosis with 68 Ga DOTA TATE and afterwards therapy during surgery looking at the somatostatin analogue NIR probe to remove the tumor. In this way we would be taking a theranostic approach for the treatment of NETs using Nuclear Medicine and Optical Imaging. We can even think about the possibility of an hybrid probe, a NIR and positron emitting somatostatin analogue probe. This strategy could also be applied not only to cancer but also to other pathologies that could benefit from this hybrid approach for diagnosis and treatment. Hybrid probes can have an important role to play not only in the diagnosis but also in providing ways for safer and successful surgeries or biopsies being part of theranosis. WARMTH worldwide can work through Standard Operating Procedures and make this hybrid tracer approach to therapy a reality. We need an interdisciplinary team that can be able to address this challenge. The 8 th WARMTH International Conference on Radiopharmaceutical Therapy could be a nice opportunity to exchange ideas, broaden the field of theranostic Nuclear Medicine and Molecular Imaging incorporating theranostic hybrid alternatives and embrace optical imaging.

S-20

Yttrium-90 Microspheres in the Management of Liver Tumours -

A Decade of Experience

Adil AL-Nahhas


Imperial College, London, UK

Primary and secondary liver tumours are common malignancies characterised by unsatisfactory treatment and unfavourable prognosis. Surgical resection is ideal if tumours are limited and amenable to such procedures but this is not the case in a large proportion of cases. Other modalities such as radiotherapy and chemotherapy are not ideal and further approaches such as laser therapy, radiofrequency ablation, TACE, and cryotherapy have been used in particular situations with limited success. Selective internal radiation therapy (SIRT) has been has been increasingly used for treatment of liver tumours since it is selectively attracted to the tumours with minimal radiation effect on normal liver tissue. This discussion will focus on our experience in treating more than 200 patients since early 2004 in terms of patients' data technique and survival.

S-21

PRRT of Neuroendocrine Neoplasms - The Bad Berka Experience after more than 4,000 Treatment Cycles in NEN Patients

Richard P. Baum


THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, ENETS Center of Excellence, Zentralklinik Bad Berka, Germany

The strong expression of SSTR2 by neuroendocrine tumors (NENs) enables peptide receptor radionuclide therapy (PRRT), the molecular internal radiation therapy of NENs. The most important points to consider for PRRT are:

  • Patient selection
  • Appropriate choice of peptide and radionuclide
  • Kidney protection
  • Tumor and organ dosimetry (post-treatment scans) and
  • Monitoring of toxicity (follow-up).
In our hospital, which was certified as ENENS Center of Excellence in March 2011, a dedicated multidisciplinary team of experienced NEN specialists is responsible for the management of NEN patients (over 1,000 patient visits per year). Patient selection for PRRT is based on the Bad Berka Score (BBS) which takes into account clinical aspects and molecular features. The therapy plan for each patient is individualized. Frequent therapy cycles (4-6 and up to 8), applying low or intermediate doses of radioactivity are suitable for these relatively slow-growing tumors ("long term low dose, not short term high dose concept"). For kidney protection, patients are well hydrated and receive an amino acid infusion containing lysine and arginine given intravenously for 4 hours beginning 30 minutes before PRRT. Renal function is serially determined by Tc-99m MAG3 scan/TER and by Tc-99m DTPA (GFR) measurements. Before each new treatment cycle, restaging is performed by morphologic (CT/MRI) and molecular imaging (Ga-68 SSTR PET/CT, in selected cases F-18 FDG or F-18 fluoride PET/CT studies are additionally performed), blood chemistry and tumor markers. All data are entered in a prospective structured database. Another very important aspect is dosimetry. Estimation of tumor and normal organ doses performed after PRRT (using Lu-177 labeled somatostatin analogs DOTATATE or DOTATOC) is important to ensure that maximum dose is delivered to the tumors and therefore optimizing an individualized treatment protocol. 20

Treatment Results in Neuroendocrine Neoplasms

A German multi-institutional registry study with prospective follow up in 450 patients indicates that PRRT is an effective therapy for patients with G1-2 neuroendocrine tumors, irrespective of previous therapies, with a survival advantage of several years compared to other therapies and only minor side effects. Median overall survival (OS) of all patients from the start of treatment was 59 months. Median progression-free survival (PFS) measured from last cycle of therapy accounted to 41 mo. Median PFS of pancreatic NEP was 39 mo. Similar results were obtained for NEP of unknown primary (median PFS: 38 mo) whereas NEP of small bowel had a median PFS of 51 months. Side effects like grade 3-4 nephro- or hematotoxicity were observed in only 0.2% and 2% of patients respectively. It can be concluded that PRRT is highly effective in the management of NEN, even in advanced cases.

At Zentralklinik Bad Berka over 1200 patients (more than 4,000 treatment sessions) have been treated since 1999. In patients with progressive neuroendocrine tumors, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period of time (Bad Berka Concept using sequential PRRT) results in excellent therapeutic responses. Objective tumor responses (including improvement of clinical symptoms) were seen in 93% of the patients. Significant hematological toxicity (mainly erythrocytopenia, rarely neutropenia, and thrombocytopenia) occurred in less than 15% of all patients. Myelodysplastic syndrome (MDS) developed in seven patients (most of them received also chemotherapy before).

The analysis of 416 patients (all NEN sub-types) treated at the BBNENC showed a median overall survival from the time of first diagnosis of 210 months (Rotterdam data 128 months) and a median survival after 1 st PRRT of 59 months (Rotterdam data 46 months). Our experience confirms a previous report from the Rotterdam group that - compared with historical controls - there is a benefit in overall survival from time of diagnosis of several years. In progressive NENs, sequential (DUO) or concurrent (TANDEM) PRRT with Lu-177 and Y-90 has been found to be most effective (highest CR/PR/SD rate).

End stage renal insufficiency was not observed in any of the patients with normal kidney function before PRRT. In most patients receiving Lu-177 DOTATATE alone (>2200 cycles), kidney function did not change significantly. Therefore, the probability and magnitude of renal toxicity can be significantly reduced (or completely avoided) when PRRT is administered in fractionated doses in patients without any pre-existing risk factors and under appropriate nephroprotection. Chemotherapy, diabetes mellitus, hypertension, Hedinger's syndrome, and cachexia were identified as the risk factors for nephrotoxicity after PRRT.

We also have treated patients with progressive metastases of NENs and with a single functional kidney (24 patients) using Lu-177 DOTATATE. None of these patients showed grade 3 or 4 nephrotoxicity. PRRT resulted in partial remission in 36% and stable disease in 36% of the patients, 28% had PD. In 2009, we have given fractionated low dose PRRT to 2 patients on hemodialysis (to the best of our knowledge, this was the first ever worldwide experience).

The Bad Berka Neuroendocrine Tumor Center was first to use Y-90 DOTATATE, and in a large patient group, Lu-177 DOTATOC in progressive NENs, non-responsive to octreotide/interferon treatment or chemotherapy.

An important influence on the decision of the choice of radionuclide is the size of tumors. More commonly, patients present with tumors of various sizes and in-homogeneous distribution of somatostatin receptors. The use of a combination of radionuclides Lu-177 and Y-90 takes this heterogeneity into account. Sequential administration of Y-90 and Lu-177 labeled analogues also is similarly helpful for the treatment of larger tumors, followed by treatment of smaller metastases respectively in further treatment cycles. The BBNENC group pioneered the systematic use of Y-90 and Lu-177 DOTATATE (DUO-PRRT) in sequence and concurrently, as well as the intra-arterial use of Y-90 DOTATATE and DOTATOC.

Lu-177 DOTATATE or Lu-177 DOTATOC is predominantly used for small metastases or in patients with impaired renal or hematological function. Long term follow-up of up to 9 years after DUO PRRT showed no significant grade 3 or grade 4 nephrotoxicity attributed to concurrent or sequential DUO PRRT. The median fall in tubular extraction rate (TER) was lesser in patients undergoing DUO PRRT than in those undergoing PRRT with Lu-177 or Y-90 alone. The results of a study by Kunikowska et al. also indicated that tandem PRRT (with Y-90/Lu-177 DOTATATE) provided longer overall survival than with a single radioisotope (Y-90 DOTATATE) and the safety of both methods was comparable.

Thus, in patients with progressive NENs, fractionated, personalized PRRT with lower doses of radioactivity given over a longer period of time (Bad Berka Protocol) is effective even in advanced cases and results in excellent therapeutic responses. Up to 9 cycles of PRRT, given over several years were tolerated very well by most patients. Severe hematological and/or renal toxicity can be avoided or reduced. Quality of life can be significantly improved. Though cure is rarely possible, excellent palliation with significant improvement of symptoms can be achieved by PRRT. In addition, neoadjuvant PRRT could be administered in cases of inoperable NEN so as to render the tumor operable by inducing radiation induced necrosis.

However, PRRT should only be performed at specialized centers as NEN patients need highly individualized interdisciplinary treatment and long term care. Use of intra-arterial PRRT (>150 treatments already performed up to now) is more effective for selectively targeting liver metastases and large, inoperable primary tumors. PRRT can be effectively combined with transarterial chemoembolization (TACE), radiofrequency ablation (RFA), chemotherapy (e.g. using Capecitabine, Temazolomide or Doxorubicin), kinase inhibitors (e.g. Everolimus, Sunitinib or Sorafenib).

Acknowledgement

I want to thank my co-workers (especially Harshad R. Kulkarni and Carolin Zachert) and our radiopharmacy at Zentralklinik Bad Berka for support over many years as well as many collaborators from other centers worldwide. This lecture is dedicated to all patients who have received benefit from PRRT over the last 16 years.

References

  1. Baum RP, Kulkarni HR, Carreras C. Peptides and receptors in image-guided therapy: Theranostics for neuroendocrine neoplasms. Semin Nucl Med 2012;42:190-207.
  2. Baum RP. Kulkarni HR. THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience. Theranostics 2012;2:437-47.
  3. Zaknun JJ, Bodei L, Mueller-Brand J, Pavel ME, Baum RP, Hörsch D, et al. The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2013;40:800-16.
  4. Schmidt MC, Uhrhan K, Markiefka B, Hasselbring L, Schlaak M, Cremer B, et al. 68 Ga-DotaTATE PET-CT followed by Peptide Receptor Radiotherapy in combination with capecitabine in two patients with Merkel Cell Carcinoma. Int J Clin Exp Med 2012;5:363-6.
  5. Hörsch D, Bert T, Schrader J, Hommann M, Kaemmerer D, Petrovitch A, et al. Pancreatic neuroendocrine neoplasms. Minerva Gastroenterol Dietol 2012;58:401-26.
  6. Kulkarni HR, Prasad V, Schuchardt C, Baum RP. Is there a correlation between Peptide receptor radionuclide therapy-associated hematological toxicity and spleen dose? Recent Results Cancer Res 2012;194:561-6.
  7. Kulkarni HR, Schuchardt C, Baum RP. Peptide Receptor Radionuclide Therapy with (177) Lu Labeled Somatostatin Analogs DOTATATE and DOTATOC: Contrasting Renal Dosimetry in the Same Patient. Recent Results Cancer Res 2012;194:551-9.
  8. Schuchardt C, Kulkarni HR, Prasad V, Zachert C, Müller D, Baum RP. The Bad Berka Dose Protocol: Comparative Results of Dosimetry in Peptide Receptor Radionuclide Therapy Using (177) Lu-DOTATATE, (177) Lu-DOTANOC, and (177) Lu-DOTATOC. Recent Results Cancer Res 2012;194:519-36.
  9. Hörsch D, Ezziddin S, Haug A, Gratz KF, Dunkelmann S, Krause BJ, et al. Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors in Germany: First Results of a Multi-institutional Cancer Registry. Recent Results Cancer Res 2012;194:457-65.
  10. Baum RP, Roesch F. First World Congress on Ga-68 and Peptide Receptor Radionuclide Therapy (PRRT), June 23-26, 2011, Zentralklinik Bad Berka, Germany. World J Nucl Med 2011;10:1-2.
  11. Roesch F, Baum RP. Generator-based PET radiopharmaceuticals for molecular imaging of tumours: On the way to THERANOSTICS. Dalton Trans 2011;40:6104-11.
  12. Baum RP, Prasad V. PET and PET/CT Imaging of Neuroendocrine Tumors. In: Wahl RL, (Editor), Principles and Practice of PET and PET/CT, 2 nd ed., Wolters Kluwer/Lippincott Williams and Wilkins 2008. p. 411-37.
  13. Baum RP, Prasad V, Hommann M, Hörsch D. Receptor PET/CT imaging of neuroendocrine tumors. Recent Results Cancer Res 2008;170:225-42.
  14. Kaemmerer D, Peter L, Lupp A, Schulz S, Sänger J, Prasad V, et al. Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2011;38:1659-68.
  15. Wehrmann C, Senftleben S, Zachert C, Müller D, Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177 Lu DOTA-TATE and 177 Lu DOTA-NOC. Cancer Biother Radiopharm 2007;22:406-16.
  16. Oh S, Prasad V, Lee DS, Baum RP. Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT. Int J Mol Imaging 2011;2011:524130.
  17. Salavati A, Prasad V, Schneider CP, Herbst R, Baum RP. Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177 lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: A potential novel treatment based on molecular pathology. Ann Nucl Med 2012;26:365-9.
S-22

Design of an International Multicentre Randomised Controlled Phase II Clinical Trial of 177 Lu-Octreotate/Capecitabine/Temozolomide, Radiopeptide Chemotherapy of Gastro-Entero-Pancreatic Neuroendocrine Tumours: The CONTROL - NET Study

J. Harvey Turner, Nick Pavlakis, Katrin Sjoquist, John Zalcberg, for AGITG


Neuroendocrine tumours (NETs) are a heterogeneous group of malignancies that can arise at any site in the gastrointestinal tract. These rare tumours are rising in incidence and due to relatively long survival have much higher prevalence, second behind colorectal cancers. Modern randomised controlled trials (RCTS) have confirmed efficacy with several expensive targeted therapies. Peptide receptor radionuclide therapy (PRRT) and combination chemotherapy with Capecitabine (C) and Temozolomide (TMZ) have shown promising activity in initial trials "Claringbold PG, Price RA, Turner JH. Phase I-II study of Radiopeptide 177 Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biotherapy and Radiopharmaceuticals 2012;27:561-560." However a prospective RCT is urgently needed to determine the role of these therapies in clinical practice. The aim of this study is to determine the optimal treatment regimen for the treatment of metastatic gastroenteropancreatic neuroendocrine tumours (GEPNETs) to further investigate in a comparative phase III randomized controlled trial.

The primary endpoint is to determine the progression-free survival at 12 months in each treatment arm. Secondary endpoints will include objective tumour response rate and overall survival, safety, quality of life and resource utilisation. The design is a 3-arm open label RCT with 1:1:1 allocation and stratification by lines of prior systemic therapy, site of primary tumour and tumour grade. Eligibile patient must have low or intermediate grade (ki67 < 20%) with < 1 prior systemic therapy (not including long acting somatostatin receptor analogues).

Treatment: A) PRRT alone: 177 Lu-octreotate given intravenously every 8 weeks, for 4 cycles. B) CTMZ alone: oral chemotherapy with Capecitabine and TMZ on a 28 day cycle, max 8. C) PRRT + CTMZ: the same 4 cycles PRRT as arm A plus a total of 4 cycles oral chemotherapy with CTMZ every 8 weeks. CT 68 Gallium PET and serum biomarkers will be undertaken at baseline, then every 4 months until radiologic progression by RECIST. A total sample size of 180 will be recruited from 7 centres over 24 months, with a further 12 months follow up period.

S-23

Targeting Tumor Heterogeneity to Improve Outcomes of Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Michael S. Hofman


Molecular Imaging, Centre for Cancer Imaging and Neuroendocrine Tumour Service, Peter MacCallum Cancer Centre; Department of Medicine, University of Melbourne, Melbourne, Australia

Peptide receptor radionuclide therapy (PRRT) has high response rates and low toxicity for treatment of metastatic or locally advanced inoperable gastroenteropancreatic and other neuroendocrine tumors (NETs). PRRT works by targeting the somatostatin receptor (SSTR) which is ubiquitous on the cell surface of these tumors. Whilst most NETs express this target, more poorly differentiated and aggressive sites of disease may lose this receptor rendering them non-responsive to PRRT. Optimal staging is critical to identify patients where all sites of metastatic disease can be effective targeted. Molecular imaging is changing diagnostic and treatment paradigms through its ability to non-invasively characterize disease, supplementing the traditional role of using imaging for localizing and measuring disease. Positron emission tomography (PET) is now able to characterize the spectrum of well- and poorly-differentiated disease through its ability to quantify SSTR expression and glycolytic metabolism with 68 Ga-SSTR and 18 F-fluorodeoxyglucose (FDG) PET. This is providing new insights such as identifying tumor heterogeneity with different phenotypes of disease at different sites within an individual, highlighting the limitations of histopathology obtained from a single site. Using this information enables better selection of patients for PRRT, and optimal integration of other therapeutic approaches including surgery, liver-directed therapies, chemotherapy and targeted therapeutics.

S-24

Quality of Life in Oncological Patients and Radionuclide Therapy

William Claxton


Carcinoid and Neuroendocrine Tumor Society, Singapore

Neuroendocrine tumors - what we now describe as NET cancer - is a relatively rare disease which is poorly understood and is often misdiagnosed. As recently as 25 years ago, there was no medication and no treatment available other than surgery. But this has changed dramatically with the discovery that neuroendocrine tumors frequently express a high density of receptors which bind somatostatin and various synthetic peptides. This has led swiftly to the evolution of precise imaging techniques and therapy using targeted radiation. From the patients perspective, a diagnosis of NET cancer is no longer a terminal illness. Today one can view NET cancer as a chronic disease if it is well-managed using a combination of surgical debulking, regular monitoring with receptor-based imaging techniques and properly-staged peptide receptor radiotherapy. The patient journey is ideally one in which they work collaboratively with their specialist physicians to diagnose and treat the disease. The guidance which patients need as they embark on this journey is to seek coordinated multidisciplinary care, ideally from a centre of excellence, and ensure that their treatment follows concensus guidelines. Such patients can live long and with productive lives.

S-25

Nuclear Medicine: A Patient's Viewpoint - Understanding Patient Education/Advocacy

Josh Mailman


NorCal CarciNET, Oakland, California, USA

Aim of the Study: With access to the internet becoming more and more ubiquitous, patients from around the globe are becoming are better educating themselves as to their treatment options. At the same time molecular diagnostic and treatment choices have expanding. In 2010 sensing a need for patient involvement with molecular imaging and therapies, the Society of Nuclear Medicine established a patient advocate advisory board (PAAB) and a patient focused website DiscoverMI.org. Shortly thereafter PRRTinfo.org was launched in 2011 focusing exclusively on PRRT. Visitors from around the world have made the website a destination for patient centered information on PRRT treatment and Ga68 imaging.

Materials and Methods:
Both discovermi.org and prrtinfo.org collect de-identified on data on external and internal search and by studying the search patterns along with article requests, a map of phrase and interests can help better understand what patients are interested in learning about.

Results:
Over 24,000 visits and 5,000 search will be analyzed to better understand what type of information patients are looking for when consider PRRT. The results will be analyzed by search term and type of article (educational versus informational).

Conclusion:
With over 1,500 unique visitors a month to both sites it is clear that patient, caregivers and other medical professionals are interested in understanding molecular imaging and therapies at a lay person level. Medical societies and Centers offering this type of treatment should look to engage the patient and patient advocates to provide relevant education material to the patient population.

S-26

Long Term Efficacy of i.v. and i.a. PRRT using 90 Y or 177 Lu in Patients with NET/NEN

Jarosław B. Ćwikła


Department of Radiology, Faculty of Medical Science, University of Varmia and Masuria, Olsztyn, Poland

Peptide receptor radionuclide therapy (PRRT) consists in the systemic administration of a synthetic peptide, labeled with a suitable beta-emitting radionuclide, able to irradiate tumors cells primary and secondaries as well via direct binding into specific receptor, often overexpressed on the cell membrane. In case of neuroendocrine tumors most common somatostatin receptors (SSTR) family. PRRT with 90 Y or 177Lu-labelled peptides is generally well tolerated, as previous many reports mention. Acute side effects (Adverse events) are usually mild, some of which are related to the co-administration of amino acids (AA), such as nausea and vomiting. Others are related to the radioisotopes conjugated with peptide, such as fatigue or the exacerbation of an endocrine syndrome, which is very rarely occurs, especially in functioning tumors. Chronic and permanent effects on target organs, particularly the kidneys and the bone marrow, are generally mild if the necessary precautions are taken. Currently, the potential risk to kidney and red marrow limits the amount of radioactivity that may be administered; all should be carefully noted using CTC-AE-NCI v. 4.03. 90 Y-octreotide (DOTATOC) has been the most widely used radiopeptide in the first 8-10 years of experience, others like 90 Y DOTALAN or 90 Y DOTATAE are less common used in clinical practice. Unfortunately, all of the published results derive from different and inhomogeneous phase I/II studies. Hence, a direct comparison is virtually impossible to date. Nevertheless, even with these limitations, objective responses are registered in 10-34% of patients. The optimal timing of 90 Y-DOTATOC in the management of somatostatin receptor (SSTR)-positive tumors and the way in which it should be integrated with other treatments have yet to be defined, and prospective phase II/III trials comparing the efficacy and toxicity of different schemes of 90 Y-DOTATOC administration are needed. 177 Lu is a medium-energy β-emitter with a maximum energy of 0.5 MeV and a maximal tissue penetration of 2 mm. Its half-life is 6.7 days. 177 Lu also emits low-energy γ-rays at 208 and 113 keV with 10 and 6% abundance, respectively, which allows scintigraphy and subsequent internal dosimetry with the same therapeutic compound. The shorter β-range of 177 Lu provides better irradiation of small tumors, in contrast to the longer β-range of 90 Y which allows more uniform irradiation in large tumors that may show heterogeneous uptake. Currently the 2 most widely used radiopharmaceuticals are 90 Y-DOTA-Tyr 3 ?octreotide (-octreotide ( 90 Y-DOTATOC or 90 Y-octreotide) and, more recently, 177 Lu-DOTA-Tyr 3 -octreotate (or 177 Lu-DOTATATE or 177 Lu-octreotate). In general PRRT consists of the systemic administration of a synthetic peptide, labeled with a suitable beta-emitting radionuclide. SST analogues represent to date the prototype and the most successful paradigm of radiopeptide therapy, due to the fortunate discovery of a successful class of synthetic peptides, such as octreotide and its variants, like octreotate and to the inhibiting properties of somatostatin and its analogues, which induce few and limited side effects. Over 15 years PRRT with 90 Y-octreotide and over 10 years with 177 Lu -DOTATATE proved to be efficient, with tumor responses, symptom relief and improvement in quality of life, based on standard EORTC QoLQ, biomarker reduction and, ultimately, an impact on survival.

Tumor response on 90 Y DOTA PRRT

90 Y-octreotide has been the most widely used radiopeptide in the first 8-10 years of experience. Alas, all of the published results derive from different phase I/II studies, inhomogeneous as to inclusion criteria and treatment schemes. Hence, a direct comparison is virtually impossible to date. Nevertheless, even with these limitations, objective responses have been registered in 10-34% of patients. Currently, the therapy administration protocols rely mostly on empirical criteria. Many of them schedule the injection of standard activities, as derived from escalation studies and clinical experience or for historical reasons, with huge differences among protocols as to activities, fixed or related to body weight or surface, number of cycles and time intervals between cycles. Protocols combining 177 Lu- and 90 Y-labelled peptides have been recently contemplated, in order to benefit from the different physical properties of the radionuclides, although 177 Lu and 90 Y activities have been designed empirically and not based on dosimetric values. The first studies with 90 Y-octreotide were carried out in relatively advanced phases of disease, while further trials demonstrated a higher efficacy of PRRT in earlier phases of disease. Previous studies have indicated that the tumor load, especially in the liver, and the performance status (PS WHO or ECOG) would influence the outcome of PRRT. Therefore, early treatment rather than a "wait and watch" approach could be advantageous. In addition, the type of disease has to be taken into account, as e.g. pancreatic NETs tend to show higher tumor reductions. In an initial study of, 39 patients with NETs, mostly of gastroenteropancreatic (GEP-NET) origin, were treated with 4 cycles of 90 Y-octreotide, with a cumulative activity of 7.4 GBq. Objective responses, according to WHO criteria, were described in 23%, with a complete remission in 2 patients, partial in 7 and disease stabilization in 27. Pancreatic NETs (13 patients) showed a better objective response (38% partial + complete) than the other classes did. In another multicentre phase I study, carried out at some centers, including 60 patients affected by GEP NETs were treated with 4 cycles of 0.9, 1.8, 2.8, 3.7, 4.6 and 5.5 GBq/m 2 administered 6-9 weeks apart. In an initial evaluation of the results published in 2002 in 32 evaluable patients, objective responses, according to Southwest Oncology Group (SWOG) criteria, consisted in about 9% of partial responses and 9% of minor responses. In a later analysis of the same population published in 2006 on 58 assessable patients who were treated with cumulative activities of 1.7-32.8 GBq, a 57% clinical benefit, including stabilization and minor responses, was observed, according to SWOG criteria. A true objective response was described in 5% of the patients. The most relevant finding of the study was the observed overall survival (OS), with a median 37 months and a median progression-free survival (PFS) of about 29 months. The results of two phase I/II studies and a retrospective evaluation in 141 patients were published by the Milan group in 2004. Patients were affected mainly by NETs and were treated with a cumulative activity of 7.4-26.4 GBq of 90 Y-octreotide, divided into 2-16 cycles, administered 4-6 weeks apart. The objective response rate was 26%, including partial and complete responses, according to SWOG criteria. DS was observed in 55% of the patients and DP in 18%. The mean duration of response ranged between 2 and 59 M (median 18). The study showed that, by dividing the objective response according to the basal status, stable patients at baseline had better outcome (PR and CR in 32%) than did progressive ones (PR and CR in 24%). Recently, a multicentre study aimed at studying the role of 90 Y-octreotide in 90 patients with symptomatic, metastatic "carcinoids," namely NETs originating from the small intestines, was published. This study showed that PRRT with 90 Y-octreotide was able to induce stabilization or tumor response, according to SWOG criteria, in 74% of patients as well as a significant clinical response including most the symptoms related to the tumor mass and the hypersecretion of bioactive agent. More recently, the Basel group published the results of their open-label phase II trial in 1,109 patients treated with 90 Y-octreotide, divided into multiple cycles of 3.7 GBq/m 2 each. Objective morphological responses, according to RECIST criteria, were observed in 378 (34.1%), biochemical response in 172 (15.5%) and symptomatic response in 329 (29.7%). Longer survival was correlated with tumor and symptomatic response. The best predictor of survival was the tumor uptake at baseline. A number of phase II studies, mostly retrospective, oriented at defining the objective response in specific classes of diseases, were published in the past few years. There is few reports about use of 90 Y-DOTATATE in one of them group of 60 patients with histologically proven GEP NETs were treated with 4.1-16.2 GBq per patient (mean 3.7 GBq per therapy) in 1-3 cycles. Six months after PRRT completion, partial response was registered in 13 patients (23%), while the remaining patients showed stable disease (77%). Median progression-free survival was 17 months, while the median overall survival was 22 months. Hematological toxicity WHO grade 3 and 4 was noted during therapy in 10% of patients and persisted in 5%. After 24 months of follow-up, renal toxicity grade 2 was seen in seven patients, and the authors pointed out the need for careful renal monitoring.

Tumor response on 177 Lu DOTA PRRT

Kwekkeboom et al. analyzed responses to 177 Lu-DOTATATE treatment according to tumor type at 3 months after the last therapy cycle in 310 patients. Patients were treated up to an intended cumulative activity of 22.2-29.6 GBq (600-800 mCi). The overall objective tumor response rate including complete remission (CR), PR and minor response (MR) was 46%. Prognostic factors for predicting tumor remission (CR, PR or MR) as the treatment outcome were high uptake on diagnostic Somatostatin Receptor Scintigraphy (Octreoscan) (P < 0.01) and a Karnofsky performance score of > 70 (P < 0.05). A small percentage of patients who had either stable disease (SD) or MR at their first two evaluations after therapy, i.e. 6 and 12 weeks after the last treatment cycle, had a further improvement in categorized tumor response at 6 months and 12 months, occurring in 4% of patients and 5% of patients, respectively. In a small group of 21 patients treated with 177 Lu-DOTATATE by Garkavij et al. 12 were evaluated for objective response using RECIST criteria. PR was found in two patients, MR in three and SD in five. In the last study reported by Bodei et al. One patient had CR, 14 had PR, 14 had MR, 14 had SD, and 9 had progressive disease (PD). Others reports indicated high effective treatment using 177 Lu DOTATATE. Some new algorithms are used like sequential use of 90 Y and 177 Lu DOTATATE (duo) Baum et al. and mix of both radioisotopes (tandem) Kunikowska et al. This study indicated that tandem PRRNT (with 90 Y/ 177 Lu DOTATATE) provided longer overall survival than with a single radioisotope ( 90 Y DOTATATE). Another option for more efficient therapy using PRRT is combination of radioisotopes and chemotherapy, which is currently used by Australian team. In their initial study 177 Lu DOTATATE (7.8 GBq) was used together with Capecitabine in case of progressive disseminated neuroendocrine tumors. The results of this approach were as follows: Objective response rates (ORR) were 24% partial response (PR), 70% stable disease (SD) and 6% progressive disease. Median progression-free survival and median overall survival had not been reached at a median follow-up of 16 months (range 5-33 months). Survival at 1 and 2 years was 91% (95% CI 75-98%) and 88% (95% CI 71-96%). Next study of the same team shows even better results using combination of standard activity and protocol including mean four times administration of 177 Lu DOTATATE (7.8 GBq each dose) and chemotherapy using Capecitabine and Temozolomide in treating advanced low-grade neuroendocrine tumors (NETs). Overall, complete response (CR) was achieved in 15% (95% CI 3-27); partial response (PR), in 38% (95% CI 22-55); stable disease (SD), in 38% (95% CI 22-55); and 3 patients failed to respond to treatment. Median progression free survival (PFS) was 31 months (95% CI 21-33), and median overall survival (OS) has not been reached with 90% surviving at 24 months follow-up (range 21-30). Overall objective response rate (ORR) in patients with gastroenteropancreatic NETs showed CR 16% (95% CI 3-28), PR 41% (95% CI 24-58), SD 37% (95% CI 21-54), and PD 6% (95% CI 0-15). Response rates were higher in patients with gastropancreatic NETs than in those with bowel primaries (enteric-NETs); CR 18% vs 13%, PR 64% vs 13%, SD 12% vs 67%.

Conclusion of PRRT using 90 Y or 177 Lu DOTA PRRT

Using 90 Y or 177 Lu DOTATOC/TATE PRRT seems to be an effective palliative method of treatment for patients with progressive, extensive SSTR - positive NEN/NET, with clinical and biochemical response in most of the cases;

Clinical evidence of OS and PFS improvement but not documented in Randomized Control Trails (RCTs);

PRRT induce improvement of the quality of life (QoL), and reduce symptoms related to hormone oversecretion;

The objective radiological response and clinical response is variable dependent on study group, protocol and radioisotopes.

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68 Ga-DOTATOC PET/CT in Patients with Carcinoma of Unknown Primary of Neuroendocrine Origin: Impact on Patient Management

O. Alonso, M. Rodríguez, L. Servente, A. Quagliata, V. Gigirey, G. Lago, M. García Fontes, J. Gaudiano, H. Engler


Uruguayan Center of Molecular Imaging (CUDIM), Uruguay

Aim of the Study: There is little evidence regarding the role of 68 Ga-DOTATATE PET/CT for the identification of primary tumors in patients with metastatic neuroendocrine carcinoma of unknown primary. Thus, the objective of this study was to assess the value of this technique in the mentioned clinical scenario.

Materials and Methods:
We studied twenty-nine patients (mean age: 59.5 ± 10.6 years; female: 17) with pathologically proven differentiated neuroendocrine metastases. In all cases conventional imaging was negative for primary tumor identification. 68 Ga-DOTATATE PET/CT was performed with a mean dose of 104.2 ± 18.8 MBq, using a 64-slice PET-CT with time-of-flight correction. A team of an experienced radiologist and a nuclear medicine physician evaluated images. The maximum SUV (SUVm) was measured in all abnormal foci. Histopathology (when available) and/or clinical follow up with correlative imaging were considered as reference standard.

Results:
68 Ga-DOTATATE PET/CT identified the primary tumor in 17/29 (59%) patients in the following locations: pancreas (n = 7), duodenum (n = 1), ileum (n = 7), colon (n = 1) and stomach (n = 1). In this population a significant correlation was found between SUVm of primary tumor and metastases (r = 0.815, P < 0.0001). Furthermore, additional sites of unsuspected metastases were demonstrated in eight patients of this group and in six patients in whom no primary tumor was localized, mainly in lymph nodes and mesentery. Pathology confirmation was obtained in seven patients who underwent surgery, whereas in the remaining ten patients, correlative imaging and follow-up confirmed primary tumor localization. Referring physicians from patients with positive PET findings (n = 23) considered the study as clinically relevant with impact in therapy planning.

Conclusion:
We conclude that 68 Ga-DOTATATE PET/CT is a clinically useful imaging technique for the localization of primary tumors in patients with neuroendocrine metastatic carcinoma of unknown origin with the potential of having a significant impact in patient management and therapy planning.

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89 Sr bremsstrahlung SPECT imaging using SPECT/CT system in bone metastases for theranostics strategy.

H. Toyama


Department of Radiology, Fujita Health University, Toyoake, Japan

89 Sr has been used for therapy of patients in bone metastases. Detecting the uptakes of 89 Sr in abnormal lesions of bone scan would be significant for theranostics strategy. We have reported the significance of 89 Sr bremsstrahlung SPECT imaging as compared with planar imaging in detecting the hot spots for bone metastases. Recently, the number of SPECT/CT system has been increasing in Japan such as other countries. SPECT/CT system has two advantages as follows: (1) accurate attenuation correction using CT data, (2) accurate detection of abnormal uptakes based on the anatomical information of CT images. 89 Sr bremsstrahlung whole body SPECT images were acquired by using two detectors type SPECT/CT system (Symbia T6 and T16, SIEMENS). We have reconstructed SPECT images with and without CT attenuation correction. Several cancer patients with bone metastases were compared with and without attenuation correction images. We could easily identify the anatomical regions of hot spots with 89 Sr bremsstrahlung whole body SPECT/CT images. In addition, SPECT/CT images with CT attenuation correction showed much higher contrast and sharpness than those images without attenuation correction. 89 Sr bremsstrahlung SPECT imaging using SPECT/CT system would be useful for detecting the more detailed whole body 89 Sr distribution than SPECT system imaging for theranostics strategy.

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Alpha-therapy: Which Radionuclide, which Carrier Molecule, which Clinical Indication?

Jean-François Chatal 1 , Ferid Haddad 1 , François Davodeau 2 , Michel Chérel 2 Jacques Barbet 1,2


1
GIP Arronax, Nantes, 2 Nantes-Angers Cancer Research Center CRCNA, France

For the last decade the use of alpha particle-emitting radionuclides has been growing in a lot of preclinical studies but a limited number of clinical studies. Some encouraging results have been obtained after both intravenous and intracavitary injections of peptides and antibodies labeled with bismuth-213 and astatine-211. Surprisingly toxicity and particularly hematologic toxicity was not limiting as it could have been expected. The choice of a radionuclide should include a suitable half-life, favorable chemical properties for labeling and (quasi-) stable daughter products. If the daughter is a long-lived alpha-emitting radionuclide, it will be released because of the strong recoil associated with the emission of alpha particle, which may cause unwanted collateral damage. This is the case of actinium-225, thorium-227, or uranium-230. So the current preferred radionuclides are bismuth-212/213 and astatine-211. Bismuth-213 has a very short half-life (46 minutes) but can be eluted from actinium-225 generators (T 1/2: 10 days) and easily coupled to vectors. Bismuth-212 has also a very short half-life (61 minutes) and is the daughter of lead-212 (T 1/2: 10.6 hours), which may be eluted from radium-224 or thorium-228 generators. Astatine-211 has a more favorable half-life (7.2 hours) but radiochemical R and D is still necessary to optimize labeling yields and in-vivo stability. This radionuclide is produced by irradiation of bismuth-209 targets with 28-29 MeV alpha beams. A limited number of cyclotrons are able to accelerate positive ions including Arronax cyclotron in Nantes, France. Astatine-211 could also be obtained through a radon-211/bismuth-211 generator. Radon-211 (half-life: 14.6 hours) can be obtained by irradiation of bismuth-209 targets with lithium-7 beam. The choice of the vector should fit the half-life of the chosen radionuclide. Due to the short half-lives of bismuth-213, lead-212 and astatine-211, small carrier molecules such as antibody fragments or peptides with fast pharmacokinetics should be preferred to large antibody molecules which have been clinically used up to now. Finally the choice of the clinical indication is crucial for an optimal efficacy. As the range of alpha particles roughly fits the cancer cell diameter and a few alpha particles are sufficient to kill a radioresistant cancer cell due to their high linear energy transfer, the best clinical situation should correspond to micro-metastases of various cancer types or adjuvant treatment in patients with minimal residual disease. In Nantes we plan to implement a phase I alpha-immunotherapy using an antibody fragment of anti-PSMA antibody labeled with astatine-211 produced by Arronax cyclotron for treatment of patients with minimal residual disease from prostate cancer.

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First-Line Outpatient Radioimmunotherapy of Follicular Non-Hodgkin Lymphoma With 131 I-Rituximab in Patients Followed Up to 5 Years

J. Harvey Turner


The University of Western Australia, Department of Nuclear Medicine, Fremantle Hospital, Fremantle WA 6160, Australia

Aim of the Study: The efficacy and safety of first-line radioimmunotherapy of advanced symptomatic follicular non-Hodgkin lymphoma (NHL) was investigated prospectively over 6 years, in sixty two patients.

Materials and Methods:
Each patient received a therapy activity of 131 I-rituximab predicated upon a prescribed whole body radiation dose of 0.75 Gy. The clinical response endpoint comprised Fluorine-18-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET/CT) at 3 months compared with baseline 18 F-FDG PET/CT at study entry. Durability of response was defined by time to next treatment (TTNT) and clinical follow-up of median duration 34 months.

Results:
The overall response rate (ORR) was 98%. Complete remission (CR) was achieved in 82% of patients with a partial response (PR) in 16%. Median progression-free survival (PFS) was not reached. Only 3 patients achieving a CR required further treatment. Toxicity was limited to grade 4 neutropenia in 8% of patients and thrombocytopenia in 6%. There was no episode of bleeding. No grade III/IV infections were encountered. Subclinical hypothyroidism occurred in 9 patients (15%).

Conclusion:
First-line radioimmunotherapy of follicular NHL with 131 I-rituximab is safe and efficacious and should be considered as a less toxic alternative to chemotherapy-based rituximab regimens. Durable response is achieved in most patients with advanced symptomatic follicular NHL with potential for repeat 131 I-rituximab radioimmunotherapy on relapse.

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Selection for PRRT in neuroendocrine tumors: Which patients should we treat and which radionuclide should we use?

Shaunak Navalkissoor


Department of nuclear medicine, Royal Free London NHS Foundation Trust, Pond Street, London NW32QG, United Kingdom

Peptide receptor radionuclide therapy (PRRT) has now become and established therapeutic modality in the treatment of patients with metastatic neuroendocrine tumors (NETs). In the first part of my talk, I discuss patient selection for PRRT. There are several considerations to take into account when selecting patients for PRRT. Optimal selection should be facilitated through a multi-disciplinary team meeting. I discuss the pre-requisites and contra-indications for patient selection in this talk under the following headings: tumor histology, tumor primary, somatostatin receptor imaging, cross-sectional imaging, blood investigations, and functional status of the patient. The second part of the talk discussed the current evidence for PRRT, focusing on Y-90 and Lu-177 DOTA-peptides. The published response rates and significant toxicities for the two agents are discussed. In the last part of the talk I discuss the differences in physical properties of Y-90 and Lu-177 DOTA-peptides. I examine which PRRT agent may potentially be preferable in different situations as a result of differences in physical properties and toxicities of these 2 agents. Lastly, I also discuss the emerging evidence about using a combination of these two agents as compared to a single agent to improve outcomes.

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A Vision Beyond Mammography

Antonio C Garcia


Philippines

Breast cancer is the most common cancer among women world-wide. Molecular breast imaging (MBI) is a relatively new imaging modality in nuclear medicine. MBI utilizes a non-conventional gamma camera, in a mammographic configuration, similar to standard mammographic views, to reveal sub-centimeter breast lesions, otherwise, undetected in dense breasts. MBI has been shown to have comparable sensitivity to breast MRI. Its use of dual, opposing, semiconductor detectors, currently enhance sensitivity, by improved energy and spatial resolution, over single multicrystal detectors. MBI is a complementary functional diagnostic procedure to its anatomical diagnostic standards, such as, mammography, ultrasound and tomosynthesis.

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THERANOSTICS of Prostate Cancer - An Outstanding Opportunity for Nuclear Medicine

Richard P. Baum


THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, ENETS Center of Excellence, Zentralklinik Bad Berka, Germany

Collaborative groups: Pharmaceutical Radiochemistry, Faculties of Chemistry and Medicine, TU Munich, Germany (H.J. Wester) Institute for Nuclear Chemistry, University of Mainz, Germany (F. Roesch) Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", Athens, Greece (T. Maina, B. Nock, D. Charalambidis) Dept. of Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands (M. de Jong, H. Bergsma, E.P. Krenning); ImaginAb, Inc., Inglewood, USA (J. Keppler, D. Behrenbruch, A. Wu); TCMRMI Zentralklinik Bad Berka (D. Mueller, I. Klette, R. Wortmann, C. Schuchardt, S. Wiessalla, H.R. Kulkarni)

The acronym THERANOSTICS characterizes the emerging field of molecular targeting of vectors, e.g., peptides, antibodies or small molecules, which can be used - when modified accordingly - for both, therapy and diagnosis. When labeled with a positron or gamma emitter these radiopharmaceuticals can be used for diagnosis (using PET/CT or SPECT/CT), and when labeled with a beta or alpha emitter, may be applied for radionuclide therapy of a particular disease, targeted specifically by that radiopharmaceutical. The importance of THERANOSTICS is that molecular imaging and diagnosis of the disease can be effectively followed by personalized treatment utilizing the same molecular vector and that success (and risk) of therapy can be predicted as the tumor and organ uptake and retention of the tracer used for imaging may be predictive of tumor dose and possible adverse effects.

Prostate cancer (PCA) can be imaged with "unspecific" PET tracers such as 18 F-fluorodeoxyglucose [FDG] and 18 F-fluoroethylcholine [FEC]. Peptides directed against GRPR (gastrin releasing peptide receptor) have been synthesized, and an antagonist, DOTA Sarabesin 3 has been obtained, suitable for labeling with a variety of medically appealing radiometals, such as 68 Ga for receptor PET/CT imaging of PCA (and eventually for peptide receptor-mediated radionuclide therapy (PRRT) when labeled with 177 Lu). Biodistribution studies in SCID mice bearing human PC-3 × enografts at 1, 4 (with/without 40 nmol [Tyr 4 ]BBN for GRPR-blockade) and 24 h p.i displayed high and specific tumor uptake (40.0 ± 6.9%ID/g at 4 h) of 68 Ga Sarabesin. These encouraging results were followed by first clinical studies in 23 patients (8 with breast cancer, 9 with prostate cancer and 6 with other cancers) where we applied the 68 Ga-labeled GRP-R antagonist Sarabesin 3, and evaluated biodistribution, pharmacokinetics and tumor binding characteristics in patients with prostate and breast cancer. SUVmax mean values (and standard deviation) were: pancreas 43.8 ± 19.6, kidneys 5.4 ± 1.2, blood pool 2.6 ± 0.7 and liver 1.8 ± 0.5. Tumor SUVmax mean values (and range) were 3.6 (0.7-17.8). Four (50%) out of 8 patients with breast cancer and 5 (55%) out of 9 patients with prostate cancer had pathological uptake on 68 Ga Sarabesin 3 scan. Initial attempts, which were, however, not yet successful, were also made for PRRT of patients with very advanced PCA (exhibiting strong uptake on 68 Ga Sarabesin PET/CT) administering the 177 Lu labeled peptide.

Monoclonal antibodies and small molecules that recognize a specific protein on the prostate cell membrane, Prostate Specific Membrane Antigen [PSMA, a complex transmembrane protein with an intracellular and extra-cellular portion] have been labeled and used as imaging agents and for radioimmunoscintigraphy (RIS) and radioimmunotherapy (RIT). PSMA expression is significantly increased in prostate cancer, somewhat proportional to the degree of malignancy, i.e. less in very well-differentiated tumors and higher in advanced, undifferentiated (G3) PCA.

A PSMA minibody was produced by "phase appropriate" manufacturing process in a 10 L disposable bioreactor from an existing stable cell pool (CHO) using a generic fed batch protocol and supplemented with end-product biochemical characterization, functional validation, and safety testing. The PSMA minibody was reacted with 20-fold excess of DOTA-NHS for 30 minutes at room temperature and subsequently sterile filtered and aseptically vialed. Biochemical characterization was performed using SEC, SDS PAGE, Western Blot, Mass Spectometry and Isoelectric Focusing. Assays confirmed a purity of 98% and an average of 5.9 DOTA per minibody. The functionality of the anti PSMA minibody was confirmed using in vitro and in vivo assays: ELISA, Flow Cytometry, cell-based immunoreactivity (post radiolabeling), and small animal PET xenograft studies with isogenic cell lines (using release material) to confirm selective targeting.

The anti-PSMA minibody (a humanized version of the J591 antibody that recognizes the external epitope of PSMA) was labeled with 111 In-chloride (370-740 MBq) for pharmacokinetic and biodistribution studies in patients having castrate-resistant metastatic prostate cancer base on serum PSA elevation, doubling time and PET/CT imaging ( 18 F fluoride, 18 F FDG, and 68 Ga labeled GRP-R antagonists). Protein doses from 2 mg to 10 mg were explored.

Although the 111 In-J591 minibody imaging protocol was not designed to detect extent of disease, initial results were encouraging and support future immuno-PET studies using 89 Zirconium-J591 minibody.

A different approach has identified molecules that inhibit the enzymatic activity of PSMA with a high degree of specificity. These molecules, urea-based heterodimers [ie lysine-urea-lysine and glutamate-urea-lysine] have high affinity for PSMA and are essentially antagonists to the enzyme activity. They have been evaluated in PSMA + tumor cell suspensions as well as in animal models and show high affinity and specificity. Utilizing derivatives of the lysine moiety, analogues of these enzyme antagonists have been radiolabeled. Initially, a 123 I labeled agent became available for patient imaging. It was recognized, however, that although images were of sufficient quality to identify metastatic tumor, a 123 I labeled tracer was less desirable than a 99m Tc labeled agent that could be prepared from a kit. First studies have been reported applying the 124 I labeled tracer for PET/CT imaging (and the 131 I-labeled molecule for therapy). At the present time, we have studied more than 10 patients with the 68 Ga-PSMA enzyme ligand for identifying metastatic disease in both soft tissue and bone marrow, and for detection of intra-prostate tumor foci in patients prior to prostatectomy (for pre-operative staging and molecular radiation therapy planning (dose painting using IMRT). The results are stunning and will be presented in the lecture.

BPAMD (4-{[bis-(phosphonomethyl)] carbamoyl} methyl)-7, 10-bis (carboxymethyl)-1, 4, 7, 10- tetraazacyclododec-1-yl acetic acid) is a novel bisphosphonate and a highly potent bone-seeking ligand, which can be easily labeled with 68 Ga and 177 Lu, a beta emitting radionuclide (with gamma emission enabling also dosimetry). We present the first clinical experience of treating skeletal metastases in prostate cancer using 177 Lu-BPAMD. BPAMD was prepared and labeled with 177 Lu according as reported by Fellner et al. 177 Lu-BPAMD therapy was performed in 6 prostate cancer patients (age 69 ± 3 years) with widespread, painful skeletal metastases (SM), presenting with progressive disease and refractory to conventional treatment. Up to now, 10 therapy cycles were performed (administered activity of 3.5-6.2 GBq per cycle). 4 patients received 1 cycle, one received 2 cycles (cumulative activity 11.3 GBq) and one 4 cycles (totally 19.9 GBq). All patients underwent 18 F-fluoride PET/CT before/after therapy for assessment of SM. Tests for blood cell counts, creatinine/BUN were performed before therapy and serially in follow-up. 5 planar whole body images were acquired up to 120 hours post injection of 177 Lu-BPAMD and dosimetry was performed (MIRD/OLINDA) to estimate the dose to the whole body, normal organs and metastases. Blood samples were counted for radioactivity to estimate the dose to the red marrow.

SUVmax of skeletal metastases ranged from 11.7-66.3 and intense uptake was seen on post-therapy images with 177 Lu-BPAMD. Whole body dose was 0.08 ± 0.04 mGy/MBq, dose to the red marrow 0.07 ± 0.03 mGy/MBq and kidney dose was 0.21 ± 0.19 mGy/MBq. Due to the very long half-life of the radiopharmaceutical in the metastases (>80 hours), the tumour doses delivered were much higher, ranging from 2.4-209 mGy/MBq (wide range due to different size of the lesions). A significant reduction in osteoblastic activity of the bone metastases was seen on the follow up 18 F -PET/CT. The treatment was very well tolerated by all patients without any significant adverse effects. There were only mild changes in the blood cell counts (not needing any intervention), and no significant alterations of serum creatinine/BUN or other lab parameters were observed.

In conclusion, 177 Lu-BPAMD is a novel and very promising radiopharmaceutical for the effective treatment of osteoblastic metastases. Due to the high tumor-to background ratio in terms of the dose delivered, very high activities in multiple cycles can be administered without major significant hematological adverse effects or any other organ toxicity.

Further Readings

  1. Baum RP, Kulkarni HR, Carreras C. Peptides and receptors in image-guided therapy: Theranostics for neuroendocrine neoplasms. Semin Nucl Med 2012;42:190-207.
  2. Baum RP. Kulkarni HR. THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience. Theranostics 2012;2:437-47.
  3. Roesch F, Baum RP. Generator-based PET radiopharmaceuticals for molecular imaging of tumors: On the way to THERANOSTICS. Dalton Trans 2011;40:6104-11.
  4. Fellner M, Baum RP, Kubícek V, Hermann P, Lukes I, Prasad V, et al. PET/CT imaging of osteoblastic bone metastases with (68) Ga-bisphosphonates: First human study. Eur J Nucl Med Mol Imaging 2010;37:834.
  5. Bander NH, Milowsky MI, Nanus DM, Kostakoglu L, Vallabhajosula S, Goldsmith SJ. Phase I trial of 177 lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 2005;23:4591-601.
  6. Milowsky MI, Nanus DM, Kostakoglu L, Vallabhajosula S, Goldsmith SJ, Bander NH. Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 2004;22:2522-31.
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Radionuclide Therapy of Refractory Prostate and Breast Cancer Bone Metastases - Improved Survival

H. J. Biersack, H. Palmedo, S. Ezziddin,

H. Ahmadzadehfar


Department of Nuclear Medicine, University of Bonn, Bonn, Germany

Bone pain palliation with Re-188 HEDP is available at our institution since more than 20 years now. This radiopharmaceutical offers excellent dosimetry with regard to the half-life of 19 h. The isotope is the daughter of Tungsten-188. The generator has a shelf life of 4 months. Carrier added radiochemistry is necessary. A dose calculation study published in 2000 showed that the appropriate dose is 3.3 GBq (90 mCi). Only minor and reversible changes of the leucocytes and thrombocytes were observed, the values turning to normal after 8 weeks.

In 2003, we published another study on repeated bone targeted therapy for hormone refractory prostate carcinoma bone metastases in a randomized phase II trial with high energy Re-188 HEDP. For this purpose, we investigated 64 patients of whom 58 were evaluable. In 30 patients, 1 injection was applied, in 28 patients 2 injections of Re-188 HEDP with in interval of 8 weeks. This study included pain documentation (VAS), antitumor effect (PSA, scintigraphy) and toxicity (blood counts, creatinine, liver, electrolytes). Toxicity was mild, and a pain response could be achieved in 60% after 1 injection and 92% after 2 injections. Survival could be increased from 7 to 12.7 months, a PSA decrease was achieved in 39%.

In a consecutive study, published in 2011, we evaluated the therapeutic success after 3 and more Re-188 HEDP injections. The total number of patients was 60, 19 of whom had received a single injection, 19 patients had 2 injections and 22 patients had 3 or more successive injections. The overall survival was increased for 4.5 months (1 injection) to 9.98 months (2 injections) and 15.7 months (3 injections).

We also evaluated Rhenium therapy of refractory breast cancer bone metastases. This study included a total of 60 patients, 30 had 1 therapy, 12 2 therapies and 7 had 3 or more therapies. Median overall survival was 12 months (1 therapy) and 7.4 months (2 injections), compared to 66.3 months in patients who received 3 and more therapies. However, the number of patients receiving multiple therapies is too small to draw valid conclusions. An extended trial is under way.

In 2012/2013 data of Alpharadin (Radium-223) therapy have been published, and the median overall survival could be improved from 11.3 months to 14.9 months in this trial. However, we strongly feel that the results using the beta emitter Re-188 concerning survival are better than with Alpharadin. Ra-223 only reaches some cell layers of the metastases adjacent to the increased bone metabolism. However, beta emitters reach deeper parts of the metastases from the rim of increased bone metabolism. This makes evident, that a comparative trial is desirable.

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Present Status of Radioimmunotherapy of Castrate-Resistant Prostate Cancer with 177 Lu-J591 mAb (ATL101)

Jean-François Chatal, Bruno Giroux, Jean-Marc Le Doussal, Scott Tagawa 1 ,

Neil Bander 1

Atlab Pharma, Nantes, France, 1 Weill Cornell Medical College, New York, USA

Since October 2000, 150 patients have been enrolled in 4 clinical studies including 29 with J591 MAb labeled with yttrium-90 and 121 with the same MAb labeled with Lutetium-177. The latter was chosen for all subsequent trials. A phase I dose-escalation study performed in 35 patients allowed to establish the MTD at 70 mCi/m 2 and showed a manageable hematologic toxicity and some biologic activity with ≥50% PSA decline in 4 patients. A subsequent clinical phase II was performed in 47 patients with advanced disease who progressed after hormonal treatment and after chemotherapy (55% of patients). Grade 4 thrombocytopenia and neutropenia were observed in respectively 47% and 25.5% of patients. For efficacy, ≥50% and ≥ 30% PSA declines were observed respectively in 10.6 and 36.2% of patients. Interestingly a longer overall survival was observed in patients injected with the MTD of 70 mCi/m 2 than in those injected with 65mCi/m 2 ( 21.8 mo vs. 11.9 mo). With the aim to decrease hematologic toxicity while maintaining and possibly increasing efficacy, a phase I trial of fractionated dose was performed in 40 patients with bone metastases (85% of cases), lymph node metastases (65%) and lung/liver metastases (47.5%). Twenty-four patients received a cumulative activity of 40 mCi/m 2 × 2 or 45 mCi/m 2 × 2, namely higher than the MTD of 70 mCi/m 2 with single-dose. Grade 4 thrombocytopenia and neutropenia were observed in respectively 50% and 33% of patients. This hematologic toxicity was not higher than that observed with the single-dose MTD despite a higher cumulative activity (80 and 90 mCi/m 2 vs 70 mCi/m 2 ). For efficacy, in the 24 patients who received a cumulative activity of 40 mCi/m 2 × 2 or 45 mCi/m 2 × 2, ≥50% and ≥30% PSA declines were observed respectively in 29.2% and 41.7% of patients, namely higher than after a single dose. Overall median survival was dose-dependent and increased from 25.3 months for patients injected at all level activities to 43.5 months for patients injected at cumulative activity of 40 mCi/m 2 × 2 or 45 mCi/m 2 × 2. These very encouraging results prompt us to perform further investigation of this radiopharmaceutical in randomized studies.

S-36

Radiosynoviorthesis (Radiation Synovectomy) with special regard to treatment of small-sized joints

Gynter Mödder


Germany

Radiosynoviorthesis (RSO) is an established and efficient therapy which has been used for more than 40 years for the local treatment of chronic inflammatory joint diseases - especially rheumatoid arthritis. RSO means restoration (orthesis) of the synovium by means of radionuclides. By intra-articular injection of radioactive agents an attempt is made to influence the painful destructive synovial process favorably as an alternative to surgical synovectomy. In the anglo-american literature the term radiosynovectomy or radiation synovectomy came into use. In Germany RSO nowadays is performed in about 70.000 joints per year, as much as radioiodine therapy in thyroid diseases.

Basically, RSO is indicated for the local treatment of almost all kinds of chronic synovitis. The main indications for RSO are

  • Rheumatoid arthritis (RA)
  • Seronegative spondarthropathy (i.e. reactive arthritis, psoriatic arthritis)
  • Haemarthrosis in haemophiliac
  • Recurrent joint effusions (i.e. after arthroscopy)
  • Pigmented villonodular synovitis (PVNS)
  • Osteoarthritis (activated arthrosis)
  • After joint prosthesis: persistent effusions, polyethylene disease
  • Undifferentiated arthritis (where the arthritis is characterized by synovitis, synovial thickening or effusion).
    The most common and approved radiopharmaceuticals used for RSO are following, β-emitters:
  • [ 90 Y] yttrium-citrate or -silicate ([ 90 Y] colloid), only used for RSO of knee joints
  • [ 186 Re] rhenium sulphide ([ 186 Re] colloid), used for RSO of middle sized joints
  • [ 169 Er] erbium citrate ([ 169 Er] colloid, used for RSO of small-sized joints.
The radioactive particles in colloidal form are taken up by phagocytosis in synovial macrophages with homogenous distribution on the surface of synovium. β-radiation leads to coagulation necrosis, sclerosis and fibrosis of the synovial tissue including vessels and pain receptors, resulting in reducing effusion, swelling and pain of the joint. Cartilage has no nerves and vessels and cannot inflict pain and because of having no ability for phagocytosis this tissue is no target for the radiation effects.

Patients should be submitted after ineffective conservative local and/or systemic (rheumatic diseases) treatment. Also after surgical interventions RSO might improve the complaints of the patient, i.e. after total knee replacement or effusions after arthroscopy.

Diagnostic studies prior to RSO: Ultrasound study (obligatory prior to RSO of knee joints to rule out a Baker`s cyst)

Multiphase scintigraphy with 99m Tc-MDP is the best diagnostic tool for detecting synovitis (soft tissue scintigraphy) and bone involvement (bone scintigraphy).

Performance of RSO requires a suitable room and strict asepsis. A good puncture technique is essential. Apart from the knee all joints have to be punctured for RSO by fluoroscopy and mostly by arthrography.

After RSO distribution scintigram confirms the appropriate intra-articular distribution of the radiopharmaceutical. Only after the use of 169 Erbium no scintigram is available.

Immobilization of the treated joints by a splint is required for 48 h avoiding necrosis and leakage.

The first follow-up care is recommended about 6 months after RSO or earlier, of course, if problems (reactive inflammation, suspect of infection, swelling of Baker`s cyst) occur.

Side effects are very rarely observed: radiation necrosis in the injection channel or the adjacent soft tissue. They can be avoided by perfect precautions and injection techniques.

Results: Response rates reported in abundant literature range from about 60 to >80% for all joints. Most of the studies relating to RSO during the last 40 years do not fulfil the criteria of modern evidence-based medicine, but recently a number of well-designed trials have been carried out evaluating the efficacy of RSO. RSO provides better results in rheumatoid arthritis than in osteoarthritis, depending on stage of joint damage. Deformed or unstable joints might fail treatment and therefore surgical interventions should be considered. Close cooperation with orthopaedists and rheumatologists is necessary to consider RSO in each patient to ensure optimal medical care.

Small joints are treated with [ 169 Er] erbium citrate ([ 169 Er] colloid erbium), in the vast majority in cases of rheumatoid arthritis and activated fingerpolyarthrosis (FP). In FP the most affected joints are distal interphalangeal joints (DIP), called Herberden's, and the proximal interphalangeal joints (PIP), called Bouchard's FP. But also 1 st carpometacarpal joint (thumb base) may be involved. In rheumatic diseases metacarpophalangeal joints (MCP) are involved in many patients. Not only the hand but also in some regions of feet RSO with 69 Er is common: All joints of the toes, and tarsometatarsal and cuneonavicular joints. Candidates for 169 Er-RSO may also be acromiclavicular, sternoclavicular, distal radioulnar, and iliosacral joints.

A recent prospective multicentre study in patients with RA resistant to intra-articular corticosteroids carried out under strict evidence based medicine (EBM) criteria demonstrates significant improvement (pain, swelling and joint mobility) for 69 Er versus placebo. In Germany ethical committees refuse further EBM studies for RSO.

With an all over improvement of about 80% within several years this treatment is a safe and minor intervention with rare side effects. This therapy should be performed at an early stage of disease, where cartilage damage is minimal. In some more difficult cases fractionated RSO may lead to success.

The effective dose to the whole body is estimated to be 30 times lower than in 131 I therapy in benign thyroid diseases.

S-37

Recent Advances in the Management of Inflammatory Arthritis

Michael L. Tee


Department of Internal Medicine-Rheumatology, University of the Philippines, College of Medicine

Inflammatory polyarthritis is generally accepted to be a risk factor for bone loss. Among the central pathologies that cause this structural damage is the TNFa which directly activates cells of the osteoclast lineage and cause bone resorption. In fact, among patients with rheumatoid arthritis, the primary goal of therapy is to maximize quality of life through control of symptoms, prevention of structural damage and normalization of function and social participation. Recently, EULAR and ACR redefined the criteria for the classification of rheumatoid arthritis with the aim of informing the diagnosis and to help define a homogenous treatment population for study purposes. Corollary to this, treatment targets have also been identified to take advantage of the benefits that newer treatment modalities like biologic agents can offer. Likewise, a new set of criteria has defined disease remission. This talk will explore the roles of steroid, disease-modifying anti-rheumatic drugs and biologic agents in the management of inflammatory arthritis. A step-wise, treat-to-target approach will be presented. The management of occasional patients with monoarthritis flares of disease activity will also be discussed. A discussion of available biosimilar anti-TNF alpha will also be presented. Finally, we will explore the possible roles of modalities applied in the field of nuclear medicine to aid in the diagnosis, prognostication and monitoring.

S-38

Current Status of Radiosynovectomy in India: Problems and Solutions

Birendra K. Das


India

S-39

RIT and EBRT in Lymphoma

Michael Tomblyn


USA

S-40

Boron Neutron Capture Therapy of Cancer: A New Type of Radionuclide Therapy

Jun Hatazawa


Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan

The clinical trial of accelerator-based BNCT has started in Osaka, and is prepared in Fukushima, Tsukuba, and Tokyo, Japan, for glioblastoma and head-and-neck tumor. 10 B borono-phenylalanine (BPA, ~30g/body) is first administered intravenously to patients. BPA preferentially accumulates to cancer cells by amino acid transporter. Proton beam (30MeV, ~2.0mA) is irradiated to Be or Li target, which produces neutrons by (p, n) reaction. Neutron beam is then modulated to have appropriate energy (thermal neutrons), and irradiated to patients. In tumor cells, nuclear reaction of 10 B (n, α) 7 Li produces tumor-cell killing α particle (E = 1.47 MeV, travel range = 9μm) and 7 Li (0.84 MeV, travel range = 4μm). The effect of BNCT relies on the flux of neutrons and the concentration of 10 B in tumor tissue.

To advance the BNCT, three major issues are considered. The first is to produce abundant thermal neutrons. The nuclear reactor was used as a neutron source. It is now possible to use in-house cyclotron. The second is to develop 10 B carrier to tumor cells. The third is to estimate BPA concentration in tumor tissue and surrounding normal tissue, which is critically important to set upper limit of neutron irradiation and to avoid adverse events. 18 F-fluoro-BPA ( 18 FBPA) PET is employed for this purpose. We are studying the practical method to predict 10 BPA concentration by means of 18 FBPA PET. The in-house cyclotron-based BNCT is a new type of RN therapy where internal irradiation with internally produced radionuclide is employed.

S-41

The Alpha Emitter Alpharadin: The Treatment Of Bone Metastases

Knut Liepe


Department of Nuclear Medicine, GH Kassel, Germany

Bone metastases occur in many patients with different forms of solid malignant tumors, but especially in advanced stages of prostate and breast cancer, and are commonly associated with increased morbidity and mortality. The resulting bone pain interferes with the patient's quality of life and requires effective treatment. Unfortunately, various non-radiotherapeutic modalities such as analgesics, hormone therapy, orchidectomy, cytostatic and cytotoxic drugs, bisphosphonates and surgery are not universally effective. External-beam radiotherapy is suitable only for well-defined localized bone metastases and extended field radiation is often accompanied by serious side effects. Therefore, systemic radionuclide therapy must be considered as a valuable and effective method of treatment in patients with widespread skeletal metastases. A new and interesting radiopharmaceutical is the α-emitter radium-223-based Alpharadin© , under development by Algeta ASA in collaboration with Bayer Schering Pharma AG. In three Phase I studies the biodistribution, safety and radiotoxicity of Alpharadin© were controlled. Phase II studies determined a repeated activity of 50kBq/kg BW as useful. A double blind phase III study including 921 patients was started to determine the therapeutic effect of Alpharadin© . In the therapy group 50kBq/kg of Alpharadin© were applied in 4 weeks interval 6 time. A significant longer survival (14.9 versus 11.3 months, P < 0.0001) and a longer time to the first skeletal relevant event (SRE) (12.2 versus 6.7 months, P < 0.0001) was observed in Alpharadin© group compared to placebo. Alpharadin© is effective in therapy of bone metastases with a longer survival, longer time to the first SRE, pain relief and decrease of ALP and PSA. The therapy was well tolerated with a low bone marrow toxicity of the α-emitter.

S-42

Current and Future IAEA Programs on Radionuclide Therapy

Adriano Duatti


Radioisotope Products and Radiation Technology Section, Division of Physical and Chemical Sciences, Department of Nuclear Sciences and Applications, International Atomic Energy Agency, Wagramer Strasse, 5, A-1400 VIENNA, Austria

Radionuclide therapy is still in its infancy despite the introduction of I-131 for the treatment of thyroid cancer dates back many decades ago. There exist only a limited number of approved radioactive therapeutic agents for the therapy of metastatic bone cancer and non-Hodgkin's lymphoma, and a few radiolabeled peptides are under clinical scrutiny for the treatment of neuroendocrine tumors. However, investigational studies are flourishing and a variety of different approaches have been proposed including nanotechnology. International Atomic Energy Agency (IAEA) has been always on the forefront in constantly promoting scientific discussions and applications of therapeutic radiopharmaceuticals in Member States (MS). These efforts are pursued through the organization of Coordinated Research Projects (CRPs) and Technical Meetings (TMs), and through the publication of books and reports on various fundamental topics that may serve as both an introduction to new developments and exhaustive reviews of the status of the field.

The list of Agency's initiatives in the field of radionuclide therapy includes many different subjects ranging from (a) the investigation of new or alternative production methods for therapeutic radionuclides, (b) the development of novel radiopharmaceuticals for therapy and (c) the continuous transfer of scientific and technical knowledge to MS on therapeutic agents that were already demonstrated to possess a real clinical utility for cancer treatment. Specifically, in the recent past, a number of projects have been focused on Rhenium-188, Yttrium-90 and Lutetium-188 radiopharmaceuticals. These has led to investigate many hot topics such as radionuclide availability, production, generator technologies, radiolabelling approaches, quality control, and to study a few interesting radiocompounds for the therapy of hepatocellular carcinoma ( 188 Re-lipiodol), metastatic bone cancer ( 188 Lu-EDTMP), neuroendocrine tumors ( 177 Lu-DOTATATE) and non-Hodgkin's lymphoma ( 177 Lu/ 90 Y-Rituximab). Recently, a specific CRP project was devoted to overview production methods of Copper-64 and current availability of 64 Cu-radiopharmaceuticals, though it is still unclear whether this radionuclide may play any effective role in therapy. However, data presented at the various meetings showed unexpected uptake of copper ions in different types of tumors, a result that may pave the way to the development of new therapeutic applications, particularly based on Copper-67. Lastly, a few months ago, a comprehensive IAEA technical meeting has been organized on alpha therapy gathering a number of highly respected experts in the areas of production, radiopharmaceuticals, microdosimetry and clinical applications of alpha emitters. This initiative was partly stimulated by the recent introduction of Radium-223 chloride for the therapy of bone cancer, thus providing the first example of alpha-emitting radiopharmaceutical to be approved for clinical use. All these successful accomplishments would have not been possible without the generous, and mostly voluntary, contribution and dedication by one of the largest scientific community around the world.

S-43

Somatostatin Theragnostics Beyond Neuroendocrine Tumours

Michael S. Hofman


Molecular Imaging, Centre for Cancer Imaging and Neuroendocrine Tumour Service, Peter MacCallum Cancer Centre; Department of Medicine, University of Melbourne, Melbourne, Australia

Somatostatin receptors (SSTR) are expressed on the cell surface of neuroendocrine tumors (NETs) providing a unique target for both imaging and therapy. Ga-68 SSTR PET/CT provides high accuracy imaging compared to conventional techniques with superior sensitivity and specificity. Peptide receptor radionuclide therapy (PRRT) enables targeted delivery of particulate radioactivity with favorable efficacy and lower toxicity than conventional approaches. Current approaches have primarily been applied to gastroenteropancreatic NETs. Other tumours also express SSTR and can therefore be imaged and targeted with the same approach. This review will focus on our evolving experience of this diagnostic and therapeutic paradigm in patients with paraganglioma, pheochromocytoma, meningiomas, neuroblastoma and small cell carcinomas.

S-44

Development Experience of Re-188 Lipiodol for Liver Cancer Therapy: Tribute Lecture

Jai-Min Jeong


Korea

S-45

Y-90 SIRT - Overview and Dosimetric Considerations

David Ng Chee-Eng


Department of Nuclear Medicine and PET, Singapore General Hospital, Outram Park, Singapore

Y-90 microspheres are a form of highly targeted radiation therapy that is used in the treatment of hepatocellular carcinomas and other intrahepatic tumors. Compliance with radiobiologic principles of radionuclide internal dosimetry is fundamental to the success of this Y-90 radioembolization. Various models have been put forward to estimate the optimal delivery of the radiation to the tumour while reducing the radiation dose to the adjacent normal hepatic tissues. These include the empirical model, the body-surface-area model and the partition model. A new paradigm of multiple subpartitions model was conceived and this is based on using vascular territory (artery-specific) subpartitions to guide radiation dose delivery. This is thought to rest on a more scientific basis and uses image-guided personalized predictive dosimetric technique, integrating selective catheter-directed intra-arterial hepatic CT angiography, Tc-99m-macroaggregated albumin SPECT/CT and subpartition modeling for unified dosimetry. Catheter-directed intra-arterial hepatic CT accurately delineates planning target volumes. The SPECT/CT tomographically evaluates Tc-99m-macroaggregated albumin hepatic biodistribution in each arterial subpartition. Our early experience shows that there was good clinical response with minimal toxicities. Multi-subpartition modelling leading to personalized predictive dosimetry achieves high clinical success rates for safe and effective Y-90 radioembolization.

S-46

3D Personalized Monte Carlo Dosimetry for Treatment Planning in 90 Y-Microspheres Therapy: Absorbed dose and Biological Effective Dose considerations

A. Petitguillaume, M. Bernardini,

C. De Labriolle-Vaylet, D. Franck, A. Desbree


Internal Dosimetry, Institute of Radiation Protection and Nuclear Safety, Fontenay-Aux-Roses, France

In the last decades, the Selective Internal Radiation Therapy (SIRT) has become an alternative in the treatment of unresectable hepatic cancers. This therapy consists in the delivery of 90 Y-microspheres to the liver via the hepatic artery; these microspheres getting trapped in hepatic capillaries. As for other targeted radiation therapies, treatment planning in SIRT is a real challenge as the activity prescription is conditioned to the irradiation of organs at risk (OARs) which has to be kept to an acceptable level to avoid adverse side effects. This one can be performed using SPECT/CT data acquired after the injection of technetium human albumin macroaggregates ( 99m Tc-MAA), realized prior to the 90 Y-microspheres injection to simulate the radiopharmaceutical distribution. The activity prescription is then established, in clinical practice, using either the BSA (Body Surface Area) method or the Partition Model. The former is an empirical approach where injected activity is calculated depending only on tumor burden and the patient's physical characteristics. The latter is based on the medical internal radiation dose (MIRD) approach, in which limit values on mean absorbed doses to OARs are considered to determine the activity to inject to the patient. In the Partition Model, mean absorbed doses are calculated from the tumor-to-normal liver ratio (T/N ratio) which is estimated from 99m Tc-MAA SPECT data. However, the main drawback of this latter method is the underlying assumption of a homogeneous distribution of the activity within the regions of interest (ROIs). Therefore, an accurate and personalized evaluation of absorbed doses to OARs and tumoral lesions must be performed to guide decisions on the activity prescription.

Materials and Methods: In collaboration with the Hôpital Européen Georges Pompidou (Paris, France), a method of 3D personalized dosimetry based on the activity distribution heterogeneity and Monte Carlo calculations has been developed. This method, called Personalized Monte Carlo Dosimetry (PMCD), enables to perform a more accurate and personalized evaluation of absorbed doses to OARs and tumoral lesions. The PMCD method was evaluated from the 99m Tc-MAA distribution of 20 patients treated for hepatic metastases or hepatocellular carcinoma. Using the OEDIPE software, developed at IRSN, regions of interest outlines, drawn on CT images, were used to create patient-specific voxel phantoms. 99m Tc-MAA SPECT data were then used to generate 3D-matrices of cumulated activity and absorbed doses at the voxel scale were calculated using the MCNPX Monte Carlo transport code. Dose-volume histograms (DVHs) and isodoses curves superimposed on patient anatomy were then generated from the 3D-distribution of absorbed doses. Moreover, radiobiological modeling was incorporated to take into account the impact of dose rate distribution and biological characteristics, such as cell repair and radiosensibility, on the evaluation of biological effects. The Biological Effective Dose (BED) was calculated at the voxel scale and then used to generate BED-volume histograms (BVHs) and isoBED curves superimposed on patient anatomy. OEDIPE was finally used to determine the maximum injectable activity (MIA) for tolerance criteria on organs at risk (OARs), i.e. the lungs and non tumoral liver (NTL). Tolerance criteria based on mean absorbed doses, mean BED, DVHs or BVHs were considered. Those MIAs were compared to the ones recommended by conventional methods: the Body Surface Area (BSA) method and the Partition Model with tolerance criteria on mean absorbed doses. Finally, several multi-injections protocols were considered and compared from a radiobiological point of view.

Results: Performing dosimetry using the PMCD method instead of the Partition Model enables to increase the activity prescription while ensuring OARs' radiation protection. Moreover, the availability of DVHs when using the PMCD method makes it possible to consider DVHs tolerance criteria, and thus, to further enhance treatment planning efficiency by taking advantage of the parallel characteristic of the liver and the lungs whose functions are not impaired if the level of irradiation to a fraction of the organ is kept sufficiently low. Finally, treatment efficiency could be further improved by considering multi-injection protocols, mimicking the principle of fractionation in external beam radiation therapy. Indeed, delivering irradiation through several injections enables to achieve a higher mean BED to tumoral lesions while keeping the mean BED to OARs at the same level. OEDIPE could thus be used as a tool to define the best protocol to deliver a certain BED to tumor depending on the therapeutic intent and clinical considerations. Besides its feasibility and applicability in clinical routine, the interest of a personalized Monte Carlo dosimetry for the improvement of treatment planning in 90 Y-microspheres therapies was confirmed from those patient studies. Furthermore, the PMCD can be used for other radiopharmaceuticals.

S-47

Y-90 Microsphere Treatment of Hepatic Neuroendocrine Metastases

James Warrington


Nuclear Medicine, London Health Sciences Centre, London, Canada

A high proportion of patients with neuroendocrine malignancy present with liver metastases at the time of diagnosis (up to 75%). Not only are neuroendocrine liver metastases frequently responsible for symptoms but they are also associated with significantly worse prognosis. Y-90 radioembolization will be compared with other modalities of treatment of neuroendocrine liver metastases such as transarterial chemoembolization (TACE). Efficacy, safety and survival following Y-90 radioembolization of neuroendocrine liver metastases will be discussed based on outcome data from several clinical trials.

S-48

Radionuclide Clinical Trials

J. Buscombe


Nuclear Medicine and PET, Addenbrooke's Hospital, Cambridge, UK

There has been more than 70 years of research into radionuclide therapies. Many of these experiments have been performed with good scientific vigour and careful and honest assessment of results. However, many are still not accepted by the oncological world. Therefore to address this issue we need to know how we can present data in a way which is understandable to oncologists. This is achievable through clinical trials. Clinical trials provide evidence for the efficacy and toxicity of an agent and also how it compares with either no treatment or a known standard treatment. There are several over-riding principles. Trials should be designed first and foremost with patient safety in mind. It must be decided which patients will be selected and then a pre-determined protocol should be used in all patients. There should be a consistency if the quality of the products used. Before the trial starts it should be decided how success or failure and toxicity will be measured. Traditionally there are three main phases to a trial in oncology. In the first phase a few patients (normally between 5 and 20) are tested with our new agent. It is normal to increase the amount of product or radioactivity given until toxicity is found. An example is the development of I-131 CHT25. Once the optimal activity has been decided then a phase II trial is performed to look at the effectiveness of a new agent. If this agent is very good and changes patient outcomes, formal approval of use may follow a phase II trial. An example of a phase II trial is the use of Y-90 DOTATATE in NETs. The final type of trial is where the product you are interested in is tested against standard treatment. Patients are chosen for each treatment arm randomly and the trials are normally multi-centre. These trials can involve up to 1000 patients and two examples are the recent trials using Ra-223 which was an expensive trial or the much cheaper HiLo trial. A good working knowledge of clinical trials will ensure we can do world quality research and our results will be read and understood by the wider medical audience.

S-49

A Statistician's Fond Remembrance of Ajit Padhy

Janez Stare


Biostatistics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

This talk was planned to be a joint presentation with Ajit Padhy about some statistical aspects of the project concerning Re-188 lipiodol. Given the sad circumstances, I will instead evoke my memories of Ajit, from our first meeting in New Delhi in 1995 until the last just a few days before his death.

S-50

Nuclear Medicine - I have seen it all

Y. Sasaki


Japan

S-51

Nuclear Medicine - The Future

Irene Virgolini and Clemens Decristoforo


Department of Nuclear Medicine, Medical University of Innsbruck, Austria

Since the 1950s radionuclide therapy was introduced with the clinical adoption of iodine-131 iodide for the diagnosis and therapy of differentiated thyroid carcinoma. This early theranostic concept reflects a prime example for the inherent capabilities of Nuclear Medicine (NM): To use the same biomolecule for both assessing the extent of a disease and subsequent image-guided therapy, only by labelling it with a different radioisotope. In fact, NM has been rapidly developing as an additional treatment modality in the oncologic field. Many specific tumour-seeking radiopharmaceuticals are being applied for both diagnosis and therapy, using multiple routes and mechanisms to target tumour cells. The response observed to a number of these applications, the non-invasiveness and the procedure and relative lack of toxicity and late effects in comparison to chemotherapy and external beam radiation therapy make nuclear medicine therapy with radionuclides an important treatment option. Following 131I-Iodide for differentiated thyroid cancer, 131I-MIBG (meta-iodobenzyl-guanidine) has been adopted into the routine for treatment of adrenomedullary-originating tumours and neuroendocrine tumours, as well as some other radiopharmaceuticals based on radiolabelled phosphonates and Ca ++ -analogues (against bone metastases) or Yttrium-90-radiolabelled particles/microspheres (against liver metastases). Yttrium-90 microsphere radioembolization, also known as selective internal radiation therapy (SIRT ® ), is today an FDA-approved, non-surgical procedure used to treat inoperable liver cancer and metastases in patients who cannot have the tumours surgically removed. This innovative minimally invasive procedure can slow the cancer's progression, extend survival, downsize a tumour and can provide symptomatic pain relief. Several radiolabelled antibodies and somatostatin (SST) analogues were also presented, but only a few have found their way towards the clinic. It was only in 2012 that the FDA approved the first yttrium-90-radiolabelled anti-CD20-antibody ibritumomab-Tiuxetan (Zevalin ® ) for patients with non-Hodgkin's lymphoma and in May 2013 the radium-223 alpha radiation emitter Xofigo ® for hormone-refractory prostate cancer patients with bone metastasis. Today, first radiolabelled SST analogues (such as Yttrium-90-DOTA-Tyr3-Octreotide and Lutetium-177-DOTA-Tyr3-Octreotate) are in clinical phase III trials for neuroendocrine tumour patients with high SSTR expression. An alternative route to bring radioactivity into close contact with tumours is to inject the radiopharmaceutical directly into the cavity. Intracavitary radionuclide therapy can be applied to the pleural, pericardial and peritoneal cavities as well as intrathecally into the cerebrospinal fluid and into cystic tumours. By moving radionuclide therapy forward PRRT (peptide receptor related therapy) has recently been used locally in patients with liver metastases from neuroendorine tumours and in patients with recurrent brain tumours. In future, the overall management of oncological therapy is going to be more and more optimized. NM treatment modalities can favourably compare with chemotherapy, immunotherapy or external beam radiotherapy. Also, from an imaging perspective, NM has a lot to add to the management of patients. The clinical success of 18 F-FDG PET/CT has resulted in the wider acceptance of NM imaging, as a means to provide biological signals as an integral part of disease management. FDG PET has definitely changed the therapeutic approach to oncologic patients, for primary diagnosis as well as for the assessment of tumour response to therapy. In addition to the clinical benefits, dual-modality imaging offers a number of methodological benefits such as vastly increased system performance and completely revised system designs. The recent introduction of combined and even fully-integrated PET and MRI can be seen as an instrument to advance NM. There is no doubt that concerted multi-disciplinary actions are required to prepare NM for the future, to increase the clinical acceptance of NM applications leading to a more widespread use. Continued growth of the field will require cost-effectiveness data and evidence that nuclear medicine procedures affect mortality. Finally, the specialization models for future NM physicians must be realized.




 

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