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ABSTRACTS
Year : 2012  |  Volume : 11  |  Issue : 3  |  Page : 121-153

ICRT-Speakers' Abstracts


Date of Web Publication10-Nov-2012

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How to cite this article:
. ICRT-Speakers' Abstracts. World J Nucl Med 2012;11:121-53

How to cite this URL:
. ICRT-Speakers' Abstracts. World J Nucl Med [serial online] 2012 [cited 2019 Dec 13];11:121-53. Available from: http://www.wjnm.org/text.asp?2012/11/3/121/103414

S-1

Subclinical Hyperthyroidism: To Treat or Not to Treat with Radioiodine

G. Kaminski


Endocrinology and Radioisotope Therapy, Military Institute of Medicine, Warsaw, Poland

Subclinical hyperthyroidism (sHT) is a condition affecting 1% (0.1-15%) of population, characterized by a decreased or undetectable thyrotropin (TSH) concentration and normal concentration of free thyroid hormones. Based on the laboratory findings, sHT is divided into two groups: Low but detectable TSH levels (0.1-0.4 mIU/l) and suppressed TSH levels (less than 0.1 mIU/l). There is more and more compelling evidence that patients with sHT experience deleterious effects of thyroid hormone excess. It was observed that even subclinical thyroid hyperfunction manifests in significant anatomical and functional changes in the heart. Patients with sHT have significantly accelerated heart rates compared to euthyroid subjects. sHT was also shown to be associated with an increased incidence of supraventricular arrhythmias, including atrial fibrillation, which is an independent risk factor of cerebral stroke, exacerbation of ischemic heart disease, heart failure, and death. It has also been observed that sHT exerts important influence on heart hemodynamic, of which left ventricular diastolic function is particularly affected. Moreover, sHT is supposed to induce prolonged hemodynamic overload and, therefore, left ventricular hypertrophy, itself associated with increased risk of cardiovascular morbidity and mortality. Although the deleterious effect of overt hyperthyroidism on the cardiovascular system is unquestionable, the clinical consequences of sHT are yet unclear because of paucity of prospective studies in large groups of patients. In fact, the diagnosis of sHT is often underestimated and the need for treatment of sHT is still discussed. The recent guidelines recommend that "treatment of sHT should be strongly considered in all individuals more than 65 years of age with TSH level lower than 0.1 mIU/l" (recommendation 65) and that "treatment of sHT should be considered in individuals less than 65 years of age with low TSH levels but 0.1 mIU/l or higher" (recommendation 66). But considering whether "to start or not to start" the treatment, besides the factors such as TSH concentration, age of patients, symptoms of thyrotoxicosis, and co-morbidity (ischemic heart disease, arrhythmia, heart failure, osteoporosis), there is a very important question about the cause of sHT. It seems that if the endogenous thyroid autonomy [toxic multinodular goiter (TMNG), toxic adenoma (TA), or disseminated thyroid autonomy] is the cause of sHT, the best choice of treatment is radioactive iodine therapy. Radioiodine treatment should be taken into consideration in patients with endogenous autonomic sHT with low but detectable TSH levels (0.1-0.4 mIU/l). Over 60% patients with sHT and with thyroid autonomous nodules need treatment during the next 5 years be cause of overt hyperthyroidism. The best predictive indicator for this is positive thyroid scintiscan (P = 0.003). However, findings based on observational data should be interpreted with great caution for clinical practice because of their limitations.

Suggested Reading

  1. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-38.
  2. Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Saccà L, et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000;85:4701-5.
  3. Sgarbi JA, Villaça FG, Garbeline B, Villar HE, Romaldini JH. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab 2003;88:1672-7.
  4. Kaminski G, Michalkiewicz D, Makowski K, Podgajny Z, Szalus N, Ruchala M, et. al. Prospective echocardiographic evaluation of patients with endogenous subclinical hyperthyroidism and after restoring euthyroidism. Clin Endocrinol 2011;74:501-7.
  5. Kaminski G, Makowski K, Michalkiewicz D, Kowal J, Ruchala M, Szczepanek E, et al . The influence of subclinical hyperthyroidism on blood pressure, heart rate variability, and prevalence of arrhythmias. Thyroid 2012;22:454-60.
  6. Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012;172:799-809.
  7. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: The Framingham Heart Study. Circulation 1998;98:946-52.
  8. Haider AW, Larson MG, Benjamin EJ, Levy D. Increased left ventricular mass and hypertrophy are associated with increased risk of sudden death. J Am Coll Cardiol 1998;32:1454-9.
  9. Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, et al. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21:593-646.
  10. Schouten B, Brownlie B, Frampton C, Turner J. Subclinical thyrotoxicosis in an outpatient population-predictors of outcome. Clin Endocrinol 2011;74:257-61.


S-2

Graves' Ophthalmopathy and Radioactive Iodine Therapy

E. A. Barrenechea


Department of Nuclear Medicine, Veterans Memorial Medical Center and St. Luke's Medical Center, Manila, Philippines

Graves' ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease and still remains a pathogenetic enigma and a therapeutic dilemma It is disfiguring and invalidating, and influences and impairs the quality of life. Based on the American Academy of Ophthalmology guidelines, GO is present if eyelid retraction occurs together with objective evidence of thyroid dysfunction, or exophthalmos, or optic nerve dysfunction, or extraocular muscle involvement. If eyelid retraction is absent, then GO may be diagnosed only if exophthalmos, optic nerve involvement, or restrictive extraocular myopathy coexists with thyroid dysfunction and no other causes for the ophthalmic features are apparent. GO is probably initiated by autoreactive T lymphocytes reacting with one or more antigens shared by the thyroid and orbit; after reaching the orbit and recognizing the shared antigen (or antigens), T lymphocytes trigger a cascade of events, including secretion of cytokines. The TSH-receptor (TSH-R) is the autoantigen involved and is shown in the orbital and pre-tibial fibroblasts. These cytokines stimulate the proliferation of orbital fibroblasts, expansion of adipose tissue, and secretion of hydrophilic glycosaminoglycans from fibroblasts. The resulting increase in orbital content explains many manifestations of GO. Genetic factors, though poorly understood, and environmental factors play a major role, as well as stressful events and smoking in the worsening of GO. Affecting autoimmunity, cascading to humoral and cellular immunity giving rise to increased production of stimulating factors (TSAb, cytokines) producing Graves'. Majority will have self-limiting and mild disease only requiring local measures for symptomatic relief. Two features of the disease-severity and activity-must be assessed if radioactive iodine treatment is in order. Optic neuropathy as seen in loss of visual acuity, marked proptosis, diplopia, or involvement of the extraocular muscles indicates severity. The question of a deleterious effect of 131 I therapy on ophthalmopathy in some patients has been raised by some, but not all, studies. The only two randomized studies (those of Talstedt and Bartalena) suggest that in patients with Graves' disease, thyroid-associated ophthalmopathy is slightly more likely to develop or worsen if the hyperthyroidism is treated with 131 I rather than thyroidectomy or antithyroid drug. Both of these studies, however, have been criticized. Investigators generally accept that most patients do not have progression of their ophthalmopathy after radioactive iodine therapy, including this author. Cigarette smoking, post-therapy hypothyroidism, and the duration and severity of the hyperthyroidism are other possible risk factors for the progression of the ophthalmopathy. In patients with established ophthalmopathy, a course of corticosteroid therapy begun at the same time as administration of 131I decreases the possibility of worsening the ophthalmopathy. Anti-thyroids remain the simplest and safest way to treat patients with GO, but they are associated with a high relapse rate of hyperthyroidism and have no effect on the course of GO. Thyroid surgery, whether total or subtotal thyroidectomy, has no effect on the course of GO. RAI should be used cautiously in those patients with severe GO and concomitant steroids, whether oral or IV, should be considered. Otherwise, the chance for worsening of GO is minimal.

S-3

Thyroid Cancer and Nuclear Accidents

Naoyuki Watanabe


Professor, Diagnostic Imaging, Gunma Prefectural College of Health Sciences, Maebashi, Gunma, Japan

Thyroid gland is thoroughly susceptible to the carcinogenic effects of high doses of ionizing radiation. A pooled analysis of studies of thyroid cancer following external radiation exposure showed a strong inverse relationship between the risk of thyroid cancer and increasing age at the time of radiation exposure. It was found that an average excess relative risk was 7.7 per Gy while the excess absolute risk was 4.4 per 10 4 person-years. Risk was about 30% lower for fractionated doses. The risk of thyroid cancer increased after a mean dose as low as 100 mGy to the thyroid gland. At lower doses, the relative risk cannot be calculated because of uncertainties regarding the absorbed dose. For higher absorbed doses up to 15 Gy, a linear relation exists between the dose and the risk of cancer. Almost no thyroid cancers prior to 5 years after exposure have been reported. It has also been suggested that the excess relative risk per Gy was the greatest about 15 years after exposure, but was still elevated 40 or more years after irradiation. The Japanese atomic bomb study has estimated age-related excess relative risk coefficients per Gy as to 9.5, 3.0, 0.3, and -0.2 at ages 0-9, 10-19, 20-39, and above 40, respectively. Females are about two to three times more likely than males to develop both benign and malignant thyroid nodules after exposure during childhood. The malignant thyroid tumors after exposure typically appear as papillary cancer in approximately 85% of the irradiated children and adolescents. Studies of the considerable population that were exposed during childhood and adolescence to radioiodines (of over 10 19 Bq of radionuclides) released as a result of the Chernobyl nuclear reactor accidents have demonstrated additional perception of the effectiveness of radioiodines which were incorporated into thyroid glands through contaminated food and water in causing thyroid cancer. WHO has reported that the risk for developing thyroid cancer due to the Chernobyl accidents is greatest in newborns and children below the age of 5. During the first 15 years after the accident, the increase in thyroid cancer cases in Belarus was 87.8-fold in children, 12.7-fold in adolescents, and 4.5-fold in adults more than expected. Fukushima nuclear power plant accidents happened following the tremendous earthquakes and Tsunami on 11 March 2011. Information about the accidents has improved in the last several months. The mean thyroid effective dose in children living in most contaminated areas appears to be far less significant than expected. However, the thyroid cancer risk of children in the contaminated areas from radioiodine exposure at lower dose rates is still not adequately quantified. An appropriate approach to medical monitoring and epidemiological follow-up for the younger members of general public being exposed at lower dose rates would be crucial to reassure the general public for a certain period of time.

S-4

Use of Rh-TSH (Thyrogen) in Thyroid Cancer

S. T. Lee


Nuclear Medicine and PET, Ludwig Institute for Cancer Research, Heidelberg, Australia

S-5

Modern Imaging in Detection of Iodine-negative, Tg-positive disease in Differentiated Thyroid Carcinoma

J. Mihailovic


Department of Nuclear Medicine, Oncology Institute of Vojvodina Sremska Kamenica, Serbia

The diagnostic imaging procedures that have a role in detection of malignant thyroid tissue include radioiodine ( 131 I) diagnostic whole-body scintigraphy (WBS), neck ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) for evaluation of the mediastinal area. Recently, 18 FDG has been added to this list. Stimulated thyroglobulin (Tg) in association with ultrasound and cytology has a high sensitivity to detect nodal metastases in differentiated thyroid carcinoma (DTC) patients. US is preferred for the detection of nodal recurrences in the central and lateral neck, but cannot detect recurrences in the mediastinal area due to interference with bone and air. Lymph node metastases usually appear on US as round, hypoechoic with microcalcifications or cystic components, and are hypervascularized at Doppler. Cytological analysis of nodal and Tg content in the aspirate also helps in detection of metastases. Radioactive iodine 131 I-WBS in association with stimulated Tg has a high specificity in the detection of DTC recurrences. However, 131 I-WBS will detect uptake in 60-80% of DTC patients with clinical lymph node metastases. One-third of recurrent DTC with rising serum Tg loses its iodine avidity and shows negative WBS. In WBS-negative patients, detection of persistent or recurrent disease is possible with CT, MRI, and 18 FDG positron emission tomography/computed tomography (PET/CT). MRI has several advantages in detection of DTC recurrences, such as multiplane evaluation, better tissue contrast, no radiation to the neck, and use of paramagnetic contrast agent that does not interfere with subsequent 131 I therapy. Despite excellent morphologic characterization of metastatic nodal recurrences, MRI cannot reliably differentiate between benign and malignant lymph nodes. Although it detects enlarged metastatic lymph nodes, there are many small nodal metastases that are usually missed. Metastatic tissue in dedifferentiated thyroid carcinomas does not concentrate radioiodine well and 131 I-WBS is negative despite elevated Tg levels. Although MRI helps in detection of these non-iodine avid metastases, 18 FDG PET/CT performs more effectively in these patients. Iodine-positive metastases are often negative with FDG-PET imaging, while iodine-negative metastases exhibit increased FDG uptake, the so-called "flip-flop" phenomenon. If a metastatic lesion is identified by FDG PET/CT, the usual approach is to refer the patient to surgery for removal of neoplastic tissue, if possible. This may be followed by re-treatment with 131 I therapy after tumor redifferentiation with retinoic acid. Recent studies in animal models and patients with non-iodine avid tumors have shown that several new chemotherapy agents may induce differentiation with restoration of radioiodine uptake sufficient to achieve a therapeutic effect. Iodine-negative thyroid cancer may express somatostatin receptors and radiopeptide therapy may be utilized. If this is the case, radiopeptide therapy may be performed. Ga-68 DOTATOC PET/CT may be helpful in the selection of these patients. FDG PET/CT is a modern hybrid imaging diagnostic tool which helps in the detection of non-iodine avid metastases. It has a role in exact localization of recurrences, which will assist in the decision to remove the malignant tissue surgically.

S-6

Therapeutic Approaches in Thyroid Cancer: What is Next to Standard Treatment?

D. Putzer, D. Waitz, S. Buxbaum, D. Kendler, C. Uprimny, A. Kroiss, I. Virgolini


Nuclear medicine, Innsbruck Medical University, Innsbruck, Austria

The incidence of thyroid cancer has risen in Austria from 3.4/100,000 inhabitants to 8.3/100,000 inhabitants from 1990 to 2008. Therefore, attention is paid to early diagnostics and accurate treatment by surgery and radioiodine treatment. However, patients not responding well to standard treatment are those suffering from radioiodine non-avid thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. In locally spread disease, surgery is the treatment of choice. Recent studies have shown, however, that 10-20% of thyroid cancer patients will suffer metastatic disease, and half of these patients will not benefit from radioiodine treatment or thyroid hormone suppressive therapy. Furthermore, the long-term survival rate of patients with a tumor characterized by loss of radioiodine avidity reduces to less than 10%. These patients are likely to show tumor sites with aerobic glycolysis in [(18)F] 2-deoxy-2-fluoro-d-glucose positron emission tomography (18F-FDG PET). Response to chemotherapy and external beam radiation is mediocre and associated with high rates of comorbidity. Durante et al. demonstrated that the median survival of patients with tumor persistence after radioiodine treatment with proven radioiodine non-avid lesions reduces to 3 years. Redifferentiation attempts have not shown significant response rates in the long-term follow-up. Phase II trials of chemotherapeutic regimens neither proved effectiveness, with doxorubicin being the substance with the highest response rates along with significant toxicity. In anaplastic thyroid cancer, a case series of five patients has shown good response rates using docetaxel in combination with external beam radiation. Early diagnosis and accurate tumor characterization is mandatory to improve prognosis in thyroid cancer patients with low radioiodine avidity and aerobic glycolysis in 18F-FDG PET. Imaging of somatostatin receptors (SSTR) using 68Ga-DOTA-Tyr3-octreotide (DOTA-TOC) as a tracer for positron emission tomography (PET) has been adapted to the diagnostic assessment of these patients. If patients are not eligible for peptide receptor radionuclide therapy, molecular targeted therapy using multikinase inhibitors or proteasome inhibitors can be taken into consideration, as chemotherapeutic protocols lack efficacy. Iten et al. proved that 90Y-DOTA-TOC response is associated with survival benefit in iodine-refractory thyroid cancer in a long-term phase 2 clinical trial. Multiple approaches in molecular targeted therapy have been reported and included also in the NCCN practice guidelines for oncology in treatment of thyroid cancer, such as sunitinib, sorafenib, bortezomib, vandetanib, motesanib, and others. We evaluated the diagnostic importance of a new somatostatin analog, 68Ga-DOTA-TOC, for PET in a total of 44 consecutive patients with papillary, follicular, oxyphilic, or anaplastic thyroid cancer (25 males, 19 females; 65 ± 14 years). Our study included patients with low differentiated thyroid cancer as well as patients who lost radioiodine avidity during the course of disease. Hence, these patients were candidates for radionuclide-peptide therapy. Fifteen patients showed signs of local recurrence of disease, 28 were negative, and 1 patient had a suspicious lesion in the thyroid region. Thirty-five patients already showed distant metastases, while nine patients had only local findings. In 68Ga-DOTA-TOC-PET, 19 patients had SSTR-positive lesions and 25 patients showed no uptake, while in 18F-FDG-PET, 35 patients showed glucose hypermetabolic lesions and only 8 patients had no and 1 patient showed very low glucose uptake in tumor lesions. Twenty patients showed high radioiodine avidity, 22 patients had no radioiodine uptake in post-therapeutic whole-body scintigraphy, and 2 patients only low radioiodine uptake. 68Ga-DOTA-TOC-PET provides a sensitivity of 50% and a specificity of 88% and an overall accuracy of 57% for the detection of thyroid cancer lesions compared to 18F-FDG-PET, while these values were 59%, 73%, and 66% compared to radioiodine avidity. 68Ga-DOTA-TOC-PET is of high diagnostic value concerning extension and localization of disease, allowing more comprehensive diagnosis in radioiodine-positive as well as radioiodine-negative thyroid cancer and also in mixed tumor patterns and allows assessment of feasibility of radionuclide-peptide therapy. Furthermore, seven patients with inoperable, metastasized progressive TC proven to be radioiodine non-avid received bortezomib i.v. with a standardized dose of 1.3 mg/m2 on day 1, 4, 8, and 11. All patients underwent three therapeutic cycles with an interval of 10 days. [(18)F] 18F-FDG PET and measurement of thyroglobulin (TG) levels were performed before, during, and after therapy, with a 6-week interval to post-therapeutic follow-up. Stable disease was seen after protease inhibitor therapy in four of the seven patients. Two of the seven patients showed decrease of SUVmax in both post-therapeutic follow-up investigations, and one of these cases also had decreasing TG levels. Two patients experienced stable disease during the post-therapeutic follow-up. Two patients showing a mixed response had an improvement in their clinical situation. One patient had rapidly progressive disease and died 3 months after the last therapeutic cycle. Adverse events included mild polyneuropathy in two patients and alterations of the blood count up to WHO grade II in five patients. To sum up, treatment with somatostatin analogs is feasible in patients with high somatostatin receptor expression. In case of further tumor progression, treatment with multikinase inhibitors or proteasome inhibitors can be taken for consideration. Treatment regimens need to be adapted to tumor entity, stage of the disease, and patient condition.

S-7

Clinical Role of F-18 FDG PET/CT for Differentiated Thyroid Cancer before and after High-dose I-131 Therapy

H. Bom


Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, South Korea

PET/CT is not usually recommended for staging of differentiated thyroid cancer (DTC) before operation because there is no added benefit of PET/CT compared with conventional imaging. The spatial resolution of PET is one of the limitations to lower sensitivity, compared with other modalities. Moreover, normal FDG uptake has been shown in upper lateral neck region such as jugulodigastric node and posterior belly of digastric muscle. There are increasing evidences showing PET/ CT as a potential diagnostic tool for staging of DTC. FDG uptake of primary lesion is related to tumor size, capsular invasion, central LN metastasis, and histologic variants with a poor prognosis. CT findings can be helpful to discriminate between metastatic and reactive lymph node (LN) by evaluation of intact fatty hilum in FDG-avid LN. In addition, PET/CT can be helpful to evaluate extra-cervical metastases. For restaging of DTC, PET/ CT is widely accepted especially in patients showing negative I-131 scan and high serum thyroglobulin (Tg) levels. Diagnostic accuracy of PET/ CT in negative I-131 scan varies according to serum Tg levels and PET/ CT can be useful for the diagnosis of recurrent lesion especially in serum Tg level greater than 10-20 ng/ml. In addition to evaluating recurrent or metastatic lesions with high accuracy, PET/CT also provides prognostic information in patients with DTC: High FDG uptakes are known to be related with the worse prognosis. PET/ CT can be a useful tool for response evaluation. When well-differentiated thyroid cancer dedifferentiates, the capability to concentrate iodine declines while the capability to concentrate FDG increases, and high-dose I-131 therapy has little or no effect on patients with FDG avid metastases. Moreover, PET/CT can assess the therapeutic response after other kinds of therapies, such as external beam radiotherapy, radiofrequency ablation, or targeted therapies. Conventional imaging with CT, MRI, and ultrasonography (US) often cannot differentiate between recurrent lesions and postoperative changes. However, PET/CT may be very helpful in differentiating them and focal FDG uptake can help clinicians to inform the biopsy site and to choose the further therapy. Incidental FDG uptake in the thyroid gland is frequently found. Diffuse FDG uptake usually indicates chronic lymphocytic (Hashimoto's) thyroiditis, rarely acute thyroiditis or Graves' disease. On the other hand, focal thyroid uptake has been associated with malignancy, usually primary thyroid carcinoma, although there is a substantial overlap in FDG uptake to distinguish malignant nodule from benign nodule. Thyroid function study, US, and/or US-guided FNA are usually recommended if the characteristics of the thyroid disease have the potential to change patient management. In summary, PET/CT is a useful imaging modality in patients with DTC and can change the diagnosis, management, and improve outcome and survival of them.

S-8

Role of SPECT-CT in Diagnosis, Staging, and Follow-up of Patients with Thyroid Diseases

S. Sergieva, T. Hadjieva 1 , R. Pandev 1


Sofia Cancer Center, 1 UH "Queen Giovanna" Sofia, Bulgaria

Imaging techniques in ordinary nuclear medicine are well established in various thyroid diseases. Intensity of different tracers' uptake (such as 131 I, 99m Tc-pertechnetate, 99m Tc-Sestamibi, 99m Tc-Tetrofosmin, 111 In OctreScan, 99m Tc-Tektrodyt, etc.) in thyrocytes depends on the physiological distribution of applied radionuclides, metabolic activity, vascularization, oxygen consumption, and tumor's receptor status. Acquired imaging techniques: Planar and SPECT have an influence on diagnostic accuracy of thyroid scintigraphy. SPECT studies improve quality and sensitivity of planar imaging because of their higher spatial resolution. Three-dimensional reconstruction allows analyzing thyroid abnormalities in all three planes. SPECT protocols are most useful in finding small parenchyma lesions (d < 1 cm) and cervical lymph nodes. Recently, new hybrid SPECT-CT systems have become available. Combined SPECT-CT studies have grown in the past years due to the almost simultaneous acquisition of transmission and emission information, thus obtaining optimal fusion in a very short time. SPECT-CT imaging depicts precise location and the type of morphological changes that have occurred in the "hot" or "cold" scintigraphic spots. The first scientific paper of co-registered and superimposed SPECT and CT images without the use of external markers in patients with thyroid cancer was published by C. Perault et al. in 1997 (J Nucl Med 38:1234-1242). Ten of the patients had medullary (MTC) or differentiated (DTC) thyroid carcinoma. They had undergone SPECT-CT studies with 111 In OctreScan and 131 I, respectively. Authors concluded that fused CT and SPECT images increased the diagnostic power of each separate imaging modality for detection and localization of TC recurrence or metastases and could be of clinical utility in the management and care of the patients. Thyroid nodules are a common clinical problem. Patients with multiple thyroid nodules have the same overall risk of malignancy as those with solitary nodules. Scintigraphy can determine the functionality of each nodule larger than 1 cm. Fusion images allow to make comparison with CT data-exact topography and size of each nodule, to identify morphological patterns (solid or cystic, available micro-calcifications or capsulation, etc.). All these data are used by surgeons as a guide to select the most suspicious nodules for FNA or biopsy. Retrosternal thyroid amounts to 7-10% of all mediastinal masses. Sometimes due to high background activity related to surrounding blood pool, 99m Tc images are suboptimal and difficult to interpret. CT part of fusion studies may be demonstrable to detect mediastinal or retro-clavicular goiter. This is valuable information for surgical decision and planning resection. The utility of radioiodine SPECT-CT in DTC has been described in a lot of publications as an integral component of the "gold standard" before applying 131 I therapy and to follow-up patient after treatment. Many authors observed that the anatomical information from low-resolution CT images allowed characterization of equivocal lesions on planar and whole-body scanning as benign in remnant thyroid tissue or physiological uptake or as malignant in cervical nodal, local relapse or distant metastases in thoraco-abdominal regions. Findings of SPECT-CT changed the therapeutic management in these patients - to indicate surgery and further radioiodine treatment or to avoid additional radiological studies in order to reduce prescribed 131 I therapeutic dose. SPECT-CT studies could diagnose metastatic lesions in patients with elevated Tg and negative 131 I scan. Also, combined images are very useful in follow-up of patients with clinical data for disease progression but with negative Tg because of positive TAT. SPECT-CT images provide differential diagnosis of the most of malignant and equivocal foci in the 131 I whole-body scans, reducing false-positive and false-negative results and additional inconclusive studies. Anatomical cross-sectional CT data increase the diagnostic accuracy of 131 I scintigraphy which is very important for the successful treatment of the patients with DTC. MTC presents 5-10% of all thyroid malignancies. In comparison to DTC, this thyroid cancer does not concentrate radioiodine. MTC is more difficult to treat and has higher rates of recurrence and mortality. Somatostatin receptors are expressed in the MTC cells and they are potential targets for peptide receptor radiotherapy. During the last two decades, receptor scintigraphy using 111 In-OctreoScan and recently 99m Tc-Tektrotyd have been widely used for diagnosis and follow-up of patients with MTC. SPECT-CT is used in order to optimize somatostatin-receptor scintigraphic protocols. SPECT-CT allows identification of MTC and accurate pre-surgical staging in locally advanced disease in order to change the treatment strategy from surgery to conservative treatment. SPECT-CT can provide correct localization and post-treatment restaging of MTC in patients with hypercalcitoninemia. especially for metastatic foci in the thorax and abdominal cavity. Fusion images improve the diagnostic accuracy by enabling to distinguish physiological tracer activity from tumor uptake, thus also avoid the need of delay acquisitions. In conclusion, SPECT-CT studies have been reported to change clinical management in significant number of patients with thyroid diseases. Proposed changes in management include indication and the volume of surgery intervention, the need to give or withhold radioiodine treatment in DTC patients, to select patients for external beam radiotherapy or conventional chemotherapy in MTC patients, or to indicate performing alternative imaging strategies such as PET-CT.

S-9

Management of Differentiated Thyroid Cancer: A Single-center Experience-lessons learnt in the last 20 years

S. Fatima


Head, Nuclear Medicine; Oncology and Radiotherapy Institute (NORI), Islamabad, Pakistan

Management of thyroid cancer is not the same throughout the world. The practice differs considerably from country to country and from region to region. Papillary and follicular thyroid cancers are well differentiated, slow growing, and have unique characteristics. Prognosis is generally excellent and is influenced by factors related to the patient, the disease, and the therapy. Physicians benefit from the lessons learnt and improve overall patient management of thyroid cancers. NORI has been providing diagnostic and treatment facilities to the referred patients of the twin cities, suburbs, and northern parts of the country. Management of differentiated thyroid carcinomas has considerably been modified in time line of NORI. Discussions within the department have become a regular feature and management decision is taken after consensus. Furthermore, surgeons are invited in MDMs and cases are discussed in these meetings. Such discussions lead to a tailor-made patient management. We analyzed the data of 1469 patients, and based on the results, modified our existing management strategies. Guidelines for the management of differentiated thyroid cancer in adults lay great stress on the importance of aggressive early treatment. Joint meetings with surgery department have helped in planning optimal baseline surgery for the each patient. Early management practice was to give initial I131 dose, which was around 80-100 mCi, and in patients with bone metastasis it was around 120-150 mCi. We used to give knock-out I131 dose of around 30-50 mCi to carcinoma thyroid patients whose TSH was not raised due to inadequate thyroidectomy, but with experience we have learned that high first dose given to patients leads to better prognosis, survival, and less complications, as compared to low dose regimen. Patients with lung metastasis usually received smaller I131 doses to avoid possible complication of lung fibrosis; now the perception has changed and we are giving more than 180 mCi safely to these patients after lesion-specific dosimetry. Recently we have started using recombinant TSH in the diagnostic as well as therapeutic I131 doses with good results. Addition of PET-CT has added strength to the patient management. Physicians in Nuclear Medicine Department with their available resources are trying to give the best possible treatment through modifications in management protocols, which are time tested, and by well-coordinated specialist care by multidisciplinary team approach.

S-10

Intermittent Pneumatic Compression: Effect on MDP uptake. A Potential Method to Facilitate Therapy

A. H. Elgazzar, A. Owunwanne


Department of Nuclear Medicine, Kuwait University, Kuwait

Venous compression of the lower limbs obstructs outflow through the deep and superficial veins, yet inflow continues, without continual swelling of the limb. It is hypothesized that venous channels in the long bones act as collateral channels to restore outflow, and therefore general blood flow through bone increases. Such a hemodynamic change should affect the skeletal uptake of radiopharmaceuticals, though uptake changes in themselves would not indicate flow changes. Therefore, the purpose of this study was to determine whether or not bone uptake in the lower limb is affected by intermittent venous compression, irrespective of the mechanism involved. The effect of intermittent pneumatic compression of the thigh and calf on the uptake of 99m Tc-methylene diphosphonate (MDP) was studied in 24 patients. All were undergoing routine bone imaging for medical conditions that were not focused on their lower limbs, and received 1 h of the compression therapy at 60 mmHg on one limb only, after injection of the radiopharmaceutical. Three hours later, the relative difference in uptake (net counts per pixel) between the two limbs was calculated. The standard imaging protocol was otherwise unchanged. The median differences in uptake in the intermittently compressed limb compared with the contralateral limb were +7.6% [inter-quartile range +3.9% to +16.0%, P < 0.0005 (Wilcoxon)] for the anterior aspect of the femur; +11.7% (inter-quartile range +4.3% to +22.2%, P < 0.0005) posterior, femur; +10.5% (inter-quartile range +6.5% to +13.8%, P < 0.0005) anterior, tibia; and +10.6% (inter-quartile range +5.5% to +17.6%, P < 0.0005) posterior, tibia. Intermittent pneumatic compression clearly and significantly increased the uptake of Tc-99m MDP in long bones. These data are consistent with increases in blood flow through bone, though a direct mechanical influence on the bone cannot be excluded. This effect should be given consideration during routine therapeutic and thromboprophylactic use of intermittent compression.

S-11

Radionuclide Imaging of Bone Metastases: Science and Practice

G. Gnanasegaran


Consultant Physician, Department of Nuclear Medicine, Guy's and St Thomas' Hospital NHS Foundation Trust,

St Thomas Hospital, London, United Kingdom

S-12

Radiosynovectomy in the Treatment of Arthritis

K. Liepe


Nuclear Medicine GH Kassel, Kassel, Germany

Radiosynovectomy is a useful therapeutic procedure that involves radiopharmaceutical injections into joints, especially to treat rheumatoid arthritis. A problem for comparison of radiosynovectomy response is the lack of a gold standard for estimating the effect. Most papers used a subjective score by patients, which is uncertain. Therapeutic effects between 60 and 90% are described in the literature. A large problem for estimation of response is lack of a gold standard. Most papers used a subjective score by patients, which is uncertain. Objective scoring, e.g., using the results of two-phase bone scintigraphy, is a better option in this topic. Liepe et al.[1] published data of bone scans before and after radiosynovectomy in 136 patients and 424 joints. The success of Radiosynovectomy (RSO) was evaluated after 12 months by patients' estimation and comparison of the pre-and post-therapeutic uptake in blood pool phase. The subjectively estimated success rates for the small, medium-sized, and large joints were 89% (215/242), 86% (112/130), and 79% (41/52), and for Rheumatoid arthritis (RA) and Osteoarthritis OA were 89% (280/313) and 79% (88/111), respectively. The scintigraphically determined response rates for small and medium-sized joints were 81% (86/106) and 69% (35/51), respectively. There was a mismatch between patients' assessments and scintigraphic assessments in 18% (28/157) with 6 false-negative and 22 false-positive estimations using scintigraphy as the standard of reference. In another publication using a subjective score, Liepe [3] showed an excellent or good response in 57% of treated knees, 63% of shoulders, 60% of wrists, 64% of ankles, 54% of thumb bases, 55% of MCPs, 54% of PIPs, 53% of DIPs, and 54% of MTPs. Side effects associated to the RSO, i.e., swelling or transient increase of pain, were recorded in 15% of the patients that resolved within 1 month. No patient had any skin alteration after treatment. An important point for an exact indication for the treatment is an optimal pre-therapeutic diagnostic evaluation (case history, palpation of the joints, and two-phase scintigraphy). All rheumatic patients should have a local scan of the fingers (3 min) and a fast whole-body scan (20 cm/min). If the patient described pain in the ankle, then perform a lateral scan of the ankle (3 min), and in cases with pain in MTPs a local scan of planar food (3 min). The rate of side effects and radiation exposure for the patients is very low (e.g., effective radiation absorbed dose lower than 1 mSv/30 MBq of erbium-169. [4] More important is the radiation exposure of the physician, especially in large number of treated patients. Erbium-169 with a low beta energy is not a big issue since, the energy was absorbed by the syringe wall. Using rhenium-186, a 2.5-mm Perspex radiation protection of the syringe is sufficient. However, for using yttrium-90 with maximum beta energy of 2.1 MeV, a 5-mm Perspex wall and a manipulator for fixation of the needle during the therapy is necessary. Radiosynovectomy is a safe and effective treatment not only in rheumatoid arthritis, but also in other kinds of arthritis. The physician should use sufficient radiation protection to reduce the radiation exposure, especially at the finger pulp.

References

  1. Liepe K, Zaknun JJ, Padhy A, Barrenechea E, Soroa V, Shrikant S, et al. Radiosynovectomy using yttrium-90, phosphorus-32 or rhenium-188 radiocolloids vs. corticoid instillation for rheumatoid arthritis of the knee. Ann Nucl Med 2011;25:317-23.
  2. Zuderman L, Liepe K, Zöphel K, Andreeff M, Kotzerke J, Luboldt W. Radiosynoviorthesis (RSO): Influencing factors and therapy monitoring. Ann Nucl Med 2008;22:735-41.
  3. Liepe K. Efficacy of radiosynovectomy in rheumatoid arthritis. Rheumatol Int 2012;32:3219-24.
  4. Manil L, Voisin P, Aubert B, Guerreau D, Verrier P, Lebègue L, et al. Physical and biological dosimetry in patients undergoing radiosynoviorthesis with erbium-169 and rhenium-186. Nucl Med Commun 2001;22:405-16.
S-13

Development of New Radiopharmaceuticals for Diagnosis and Treatment of Arthritis

Vijay Kumar


Department of Nuclear Medicine and PET , Radiopharmaceutical Research, Westmead and The Children's Hospital at Westmead, Sydney, Australiya

Background: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that is characterized by chronic progressive inflammation and subsequent destruction of peripheral joints, ligaments, and tendons. The inflamed RA synovium is complex and characterized by synovial proliferation, neoangiogenesis, and chronic inflammatory cell infiltration. Numerous cell surface receptors, adhesion molecules present on endothelial cells and extracellular matrix, may serve as potential targets for diagnostic purposes and therapeutic intervention. Therefore, there is a need to develop better diagnostic tools and drug delivery methods to fully utilize the advantages.

Aim: The present work is aimed at evaluating the utility of 99m Tc-glucosamine (ECDG), 99m Tc-CP-His [Core-Peptide], and 99m Tc-HAP (specific targeted peptide) to define RA lesions in an animal model. Labeled liposome-peptide conjugates were explored as delivery vehicles to explore target areas of inflammation.

Materials and Methods: 99m Tc-ECDG and 99m Tc-CP-His [Core-Peptide] were synthesized as described in the publication (Nucl Med Biol 2011;38:751-56). We have developed labeled liposomes as drug delivery vehicles as they have the ability to encapsulate large quantities of small molecules either within their aqueous interior or in the lipophilic membrane. 99m Tc-HMPAO and fluorescent probes were used as markers with liposomal vehicles to monitor drug delivery. The pearl impulse from LI-COR® was used to acquire the images and data were analyzed using LI-COR® Pearl Cam Software. Images were acquired according to the manufacturer's instructions with the resolution set at 170 mm.

Results: The arthritic joints showed significantly higher uptake of 99m Tc-ECDG and/or 99m Tc-CP-His [Core-Peptide] than normal control rats. Similar uptake patterns were demonstrated when liposomes were loaded with either 99m Tc-HMPAO or 99m Tc-CP-His [Core-Peptide]. The intensity of uptake using radiolabeled probes had two major limitations: The short half-life of 99m Tc tracers imposed limitations with liposomal preparation and the image intensity was compromised due to lower SUV values at the arthritic lesions. Therefore, fluorescence-labeled liposomes were used in these studies [RGD, (scrambled) scHAP, and HAP]. HAP-liposomes showed over a fivefold increase in uptake of in the arthritic feet compared to background. The background was 105.3 signal units; 3 h following scHAPL administration, this increased to 565.7 signal units.

Conclusion: Specific targeting of labeled liposomal drugs to the synovium is a promising approach and has the potential to increase drug efficacy and minimize extra-synovial toxicity, thereby providing a new platform for use of existing drugs.

Acknowledgement

The work was submitted as part of the PhD thesis by Anne Vanniasinghe.

S-14

Molecular Approach for Radionuclide Treatment and PET

Naoyuki Watanabe


Professor, Diagnostic Imaging, Department of Radiological Sciences, Gunma Prefectural College of Health Science, Maebashi, Gunma, Japan

Antisense labeled with radioisotopes emitting Auger electrons or positrons may be useful for targeting messenger RNA (mRNA) of activated proto-oncogene in malignant tumor cells for radionuclide treatment or imaging with PET. The success of therapy with radiolabeled antisense oligonucleotides or PET imaging depends on surmounting hurdles at a targeted delivery of radiolabeled antisense to malignant tumor in vivo and its sequential internalization into tumor cells, developing up a real new field of molecular nuclear medicine. This review covers the advances in the antisense probe development for radionuclide treatment or PET.

S-15

Treatment Response Evaluation Using Current Imaging Modalities

R. Kumar


Additional Professor, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India

Anti-cancer drug development is a major area of research. New imaging techniques provide a novel method for anti-cancer drug development and monitoring response to therapy by targeting functional metabolic activity at cellular level. Based on early treatment response evaluation, one can modify the treatment. If treatment is likely not successful, then it is important to escalate or change therapy. If treatment is likely successful, one can think of deescalating or stopping therapy early. The treatment response can be evaluated using biological markers, serial biopsies, structural imaging, functional imaging, etc. Radiological imaging modalities commonly employed for evaluation of therapy response are ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Of all, CT is the most commonly used imaging modality owing to its wide availability and the short examination time. A decrease in the uni- or bi-dimensional diameter of a tumor or in the number of tumor lesions during or after completion of treatment as compared with the pre-treatment scan is considered as a response. Two important criteria commonly used to define tumor response are the WHO criteria and the RECIST (response evaluation criteria in solid tumors) criteria. However, there were some issues with RECIST, e.g., whether fewer than 10 lesions can be assessed without affecting the overall assigned response for patients, whether or how to utilize newer imaging technologies such as FDG-PET and MRI, and how to handle assessment of lymph nodes. To overcome these limitations, new criteria, RECIST 1.1, were introduced in 2009. Despite improvement in RECIST 1.1, there are many limitations to assess the response to therapy in solid tumors which are based on measurement of the changes in tumor size. As we know, tumor shrinkage is only the final step in a complex cascade of cellular and subcellular changes after treatment and several cycles of therapy (radiotherapy fractions, chemotherapy) are needed before treatment response can be assessed by anatomic imaging. Residual mass is often present after treatment-it is hard to differentiate between viable tumor posttreatment changes, such as scarring and fibrosis. Positron emission tomography (PET) has been used to measure changes in drug-induced metabolism, cellular proliferation, and tissue perfusion. Also, changes induced by immunomodulating drugs such as apoptosis, telomere activity, growth factor levels, and many more can be studied using specific radiolabeled PET tracers. Hybrid PET/CT scanners provide both the anatomical and functional aspects of the tissue. PET and PET/CT have been found to be very useful in assessing treatment response in various cancers. In the present review, I will attempt to address the status and limitations of currently applied anatomic tumor response criteria, including WHO, RECIST, and the new RECIST 1.1 criteria. During this lecture, we will review the qualitative and quantitative approaches using PET/CT in treatment response assessment, e.g., European Organization for Research and Treatment of Cancer (EORTC) and Response Criteria in Solid Tumors (PERCIST, version 1.0) criteria.

S-16

Avibodies: A Novel Approach for Targeting Prostate and Ovarian Cancer

A. M. Scott 1,2 , F. T. Lee 1 , R. Bogdal 1 , P. Kocovski 1 , A. Rigopolous 1 , D. Cao 1 , G. O'Keefe 2 , F. Smyth 1 , M. P. Wheatcroft 3 , P. J. Hudson 3


1 Tumor Targeting Program, Ludwig Institute For Cancer Research, Melbourne, 2 Centre for PET, Austin Health, Heidelberg, 3 Avipep Pty Ltd, Parkville, Victoria, Australia

Objectives: Diabodies (Avibody™ products) are single-chain antibody fragments (scFv) that spontaneously self-associate at high yield into stable multivalent dimers. Diabody pegylation achieves increased tumor uptake by reducing renal clearance, improving the serum half-life, and achieving high tumor:blood ratios. TAG 72 is an oncofetal antigen found on the surface of many epithelial cancers. Our aim was to develop a pegylated diabody against TAG-72, which can be used for in vivo animal model studies, and human trials.

Materials and Methods: A diabody (AVP0458) was engineered from the scFv domains of mouse monoclonal antibody CC49. Production of AVP0458 was performed from  Escherichia More Details coli expression, and subsequent purification. Pegylation of AVP0458 was performed with high yields and retention of antigen binding. Preclinical studies aimed at exploring the functional properties of PEG-AVP0458 were performed. Biodistribution and PET imaging studies with 124 I-radiolabeled PEG-AVP0458 were also performed in BALB/c nude mice bearing TAG-72 positive LS174T. Results: In vitro analyses confirmed retention of antigen binding activity and serum stability. High in vivo tumor uptake >52% was observed 24-48 h p.i. with prolonged tumor retention. Normal tissues showed minimal 124 I-PEG-AVP0458 uptake, consistent with blood pool activity (<3% ID/g at 24 h p.i.). Pharmacokinetic analysis calculated a serum half-life of T 1/2α =6.7 h and T 1/2β =29.7 h. This compares with T 1/2β =72.2 h previously observed with the parent antibody, CC49, in the same LS174T human colon carcinoma xenograft model. Specific, high tumor localization of 124 I-PEG-AVP-0458 was observed by PET imaging, with tumor imaging evident by 24 h and prolonged retention with time. Optimization of radiolabeling of 124 I-PEG-AVP0458 for clinical studies was also performed.

Conclusions: 124 I-PEG-AVP0458 shows optimal blood clearance, with high, specific, and prolonged tumor uptake in vivo. A Phase I first-in-human bioimaging trial of 124 I-PEG-AVP0458 PET in patients with prostate and ovarian cancer has commenced.

S-17

Percutaneous Radionuclide Therapy

R. McCready


Nuclear Medicine Department, Royal Sussex County Hospital, Brighton, United Kingdom

Interventional nuclear medicine has yet to be defined. The major difference between the radiological approach and nuclear medicine is that the former is anatomically based while the radionuclide techniques have the benefit of usually being functional targeting specific lesions. Most lesions are now accessible percutaneously with the help of ultrasound or CT scanning. The main requirement for successful directly injected radionuclide therapy is a suitable carrier which can be labeled with a beta emitter for therapy and/or gamma emitter for dosimetry. Using a direct injection into lesions with high retention, tumoricidal doses can be given with relatively low activities. For example, the activity required to administer 100 Gy with In-111 pentetreotide would be only just over 600 MBq. This dose compares with the limitation of 60-80 Gy given by external beam radiotherapy. The increase in dose possible with the directly injected radiopharmaceutical should improve the therapeutic outcome. Patient radiation safety is ensured since if all the radiopharmaceutical in this example left the site of injection, the whole body dose would still be only 12 mGy. The choice of carrier is important. Our experience with commercially available P-32 in experimental models and human studies demonstrated an inability to diffuse through tumors, but there was total ablation of the tumor at the point of injection. The use of a somatostatin analog as the carrier is more promising since somatostatin receptors are present in a wide range of tumors and there is good diffusion through the tissues. Using labeled depreotide, good uptake has been found in metastases from breast carcinoma and a lack of retention confirmed when somatostatin receptors were absent. The direct radiopharmaceutical injection technique could be very useful in reducing the trauma of current therapy in a variety of clinical situations including breast carcinoma, lung carcinoma, and brain tumors. In patients being treated for thyroid nodules with radioioiodine-131, the technique could also be used to reduce the unnecessary radiation to the normal parts of the thyroid gland, reducing post-therapy hypothyroidism. By minimizing unnecessary irradiation of the reproductive system, it would reduce the time required to avoid pregnancy following radioiodine therapy. It would also help in patients with impaired renal function where there is delayed excretion following oral administration. Since the use of any radiopharmaceutical in a novel manner necessitates the setting up of a clinical trial with all the associated paperwork and permissions, the progress and development of interventional nuclear medicine will be slow. WARMTH provides a good opportunity for international cooperation to help speed up the spread of this exciting technique.

S-18

Current Status of PET Radiopharmaceuticals in PET/CT Guided Radiotherapy Treatment Planning

A. Balenoviæ


Head, Department of Nuclear Medicine, Poliklinika Medikol, PET/CT Center, Zagreb, Croatia

Substantial technological progress in radiation oncology enabled dose delivery to the tumor with a high geometric precision. The introduction of stereotactic radiotherapy, radiosurgery, intensity-modulated radiotherapy (IMRT), and three-dimensional brachytherapy requires a re-evaluation of the standard methods for target volume delineation. During recent years, new methods for tumor visualization have been introduced in oncology, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS). These so-called "molecular imaging" modalities are able to visualize biological characteristics of tumors, providing information on metabolism and molecular biology of tumor tissue. That information is concurrently used with the anatomical data supplied by CT and MRI. Among those, the most exploited molecular imaging method recently is PET/CT. Bringing PET into current radiotherapy (RT) practice was enabled due to the significant development in PET/CT scanners, especially by decreasing resolution of the system up to 2 mm in new generations of PET cameras, and resulted in several potential advances. First, the primary tumor can be identified more accurately which resulted in reshaping the gross tumor volume (GTV). More accurate tumor identification could lead to the better normal tissue sparing. Second important advantage is that other tumor characteristics beside size, which are relevant for radiation sensitivity, can be visualized. PET imaging can identify the degree of radiosensitivity of the tumor and hypoxic areas, which are resistant to the treatment. Finally, intratumoral biological heterogeneity can be identified and the concept of "biological target volume" has been introduced. Sub-volumes of the tumor, which are resistant to the radiation, receive an extra dose delivered with a high precision on a small volume. This represents advanced dose escalation strategy, called "dose painting," which is expected to provide better therapeutic gain, namely reducing local recurrences. The current interest focuses on three evidence-based causes of radiation therapy failure in the clinic: Tumor burden, cell proliferation, and hypoxia. Therefore, radiopharmaceuticals (RF) currently used for RT planning are stratified according to those three tumor characteristics.

a) Tumor burden and sub-volume boosting: Many studies are published on the use of 18F-FDG PET/CT to improve target definition/tumor burden in RT planning and FDG is still the most useful radiotracer in this regard. Although a non-specific agent, which traces the early steps of glycolysis, FDG is also the most effective tumor imaging agent for PET for assessing tumor burden across a wide range of cancers. The two most widely used applications where PET/CT plays a role in detecting overall tumor volume for radiation therapy planning are in the treatment of patients with lung cancer and head and neck tumors. Clinical outcome data show the importance of the volume of a cancer as a driver of local outcome after RT. PET/CT is now an integral part of radiotherapy practice in tumor protocols, and with the raising ability of PET scanners, more studies have been conducted to assess the added value of molecular imaging. Wide clinical experience accumulated over the years made FDG good surrogate for tumor cell burden in patients with different cancers: Head and neck cancer (HNC), small and non-small cell lung cancer (SCLC and NSCLC), pancreas, lymphoma, breast cancer, etc. Limited data are available on GTV delineation and RT dose adaptation with metabolic tracers other than FDG. There are some published data using aminoacids such as methionine (18F-MET) and fluoroethyl-tyrosine (18F-FET) in gliomas, 68Ga-DOTATOC in meningiomas and glomus tumors, and choline (labeled with 11C or 18F) for prostate cancer. Only modest increase in local control has been achieved by using these additional methods.

b) Proliferation: Tumor cell proliferation is a well-established cause of local failure after radiation therapy for many tumors. Controlled trials have been conducted for HNC and NSCLC. Intensive research resulted in developing 11C-labeled thymidine, but rapid biodegradation of the compound leads to radiolabeled metabolites in the blood, which affects imaging and the interpretation of the results. Therefore, another thymidine analog has been synthesized, 18F-fluorothymidine (FLT), which is often called a "proliferation tracer" and actually provides a map of growth fraction of tumor cells. FLT is retained in the cells after phosphorylation by the enzyme thymidine kinase 1 (TK1). TK1 is differently expressed in the different phases of the cell cycle, therefore is presenting active fraction of tumor cells. FLT PET can detect the growth inhibitory response induced by molecular target agents, cytotoxic drugs, or ionization radiation effect. Comparison of FLT scans at baseline and 2 weeks after the fractionated radiotherapy has been used in order to define targets for sub-volume boosting. However, to assess the proliferative response to therapy, rather than just proliferation at the baseline study, requires more knowledge, and interpretation of the result should be with some caution. Studies have demonstrated that inhibition of cell cycle progression prevents FLT uptake up to 48 h after single radiation dose, which is consistent with the well-known mitotic delay after irradiation, and can result in false-negative reports. Therefore, still many prospective randomized studies should be conducted before assessing practical guidelines when and how to use FLT studies in cancer patients in order to achieve a shortening of overall treatment time. Another strategy to counteract cell proliferation is epidermal growth factor receptor (EGFR) inhibition. EGFR expression in tumor biopsy specimens is used to select the dose fractionated scheme which could have the greatest chance of benefiting the patient. By using PET studies, EGFR expression can be assessed in vivo. New radiopharmaceuticals are developed to quantify tumor EGFR expression, e.g., 68Ga-EGF and 89Zr-cetuximab (an inhibitor of EGFR), but still only used in preclinical trials.

c) Hypoxia: Tumor hypoxia is a well-known strong contributor to radiation resistance and is associated with progression of the disease and a poor outcome after therapy. Tumor control inversely correlates with the hypoxic fraction of the tumor. For tumor imaging of hypoxia, many PET imaging agents have been developed and already have been in clinical use. The strongest evidence exists for squamous cell carcinoma of the head and neck, prostate, and uterine cervix. Tracers with the most extensive clinical experience are imidazole containing RF, 18 F-fluoromisonidazole (FMISO), and 123 I-iodoazomycin arabinoside (IAZA), and non-imidazole tracer 64Cu-diacetyl-methylthiosemicarbazone (ATSM). The overall conclusion from several correlative clinical studies is that there is a statistically significant association between PET-assessed hypoxia at baseline and tumor outcome after radiation therapy. However, there are many new hypoxia sensitive tracers under investigation in the preclinical trials. These tracers have different characteristics and retention mechanisms, but all are labeled with 18F (such as FETNIM, EF5, and FAZA). Still, it is not clear to what extent these tracers will have clinical relevance when used for PET imaging of human tumors in a population of patients. As more PET studies become available validating the various functional imaging properties, more treatment-related decisions will have to be tested in clinical trials. Integrating biological or molecular information of tumors into radiation oncology might help in deciding where, as well as how, therapy should be delivered. Introduction of FDG PET/CT has already achieved success in reduction of interobserver variability, reducing missing parts of the cancer and also reducing the irradiated volume of normal tissue and organs at risk, nearby the target volume. On top of that, molecular imaging can play an important role in developing predictive assays that can serve as selection tool before initiating radiotherapy or other treatment modalities.

S-19

Assessing Tuberculosis Response to Therapy

M. Sathekge


Department of Nuclear Medicine, Pretoria University and Pretoria Academic Hospital, PO Box 667, 0001 Pretoria, South Africa

Controlling and preventing HIV/AIDS and TB are among the key global priorities. The challenge for TB control is early detection and monitoring of therapy. With the alarming rise of multidrug-resistant (MDR) and extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) infections, there is significant interest in the use of molecular imaging to monitor TB treatment in patients. Response to TB therapy in patients with bacillus-positive TB is monitored principally by serial bacteriologic examinations, whereas responses in patients with bacillus-negative TB, including smear-negative pulmonary and most cases of extra-pulmonary TB, are usually monitored clinically and/or radiologically. During TB therapy, some bacillus-negative tuberculomas do not decrease in size or may even keep growing, making it difficult for physicians to decide whether to alter treatment regimens. And the detection of extra-pulmonary TB is confounded by atypical clinical manifestations and limitations of current diagnostic strategies, more so in HIV patients. Furthermore, the optimal duration of any given combination of anti-TB drugs for treatment of MDR and XDR-TB has not been defined in controlled clinical trials. Since clinical indicators and available laboratory methods are either not feasible or are inconclusive, fluorodeoxyglucose [18F] FDG PET/CT imaging has been considered a valuable alternative. The only available studies described indicate that FDG PET/CT as a diagnostic tool could be a noninvasive method that gives additional information about the disease status, enabling improved therapeutic management of pulmonary and extra-pulmonary mycobacterial infection. Furthermore, several studies provide evidence that PET imaging could be useful in tuberculostatic therapy evaluation. Most results concur that if FDG-PET shows that uptake is increased (or in some extra-pulmonary areas), it is likely that the tuberculosis is in active status, and that treatment should be prolonged or the patient switched to other drugs. If the uptake is decreased, it is likely that the tuberculosis is responsive to anti-TB treatment, and current treatment should be continued according to standard protocols. This topic will cover the strategies available for management/therapy response of TB today. The talk will also give an update on the results of the FDG PET/CT clinical imaging studies published in recent years. Suggested imaging patterns of the responders versus non-responders will be presented and the diagnostic discrimination between them will be discussed. Undoubtedly, FDG PET/CT has potential for monitoring response to anti-tuberculosis treatment. And the quantitative assessment may indicate clinical response and guide duration of anti-microbial therapy.

S-20

History of WARMTH

A. K. Padhy


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

World Association of Radiopharmaceutical and Molecular Therapy (WARMTH) is a voluntary non-profit making organization of individuals associated for the purposes of advancing the science and education of therapeutic nuclear medicine including dosimetry, treatment evaluation, radiation physics, radiation biology, and radiation protection for the benefit of public health and humanity. The history of WARMTH dates back to early nineties when a group of nuclear medicine professionals interested in therapy initiated an informal discussion forum (Radionuclide therapy colloquium) on the sidelines of some of the larger nuclear medicine congresses like WFNMB, SNM, EANM, and AOFNMB. Subsequently, World Radiopharmaceutical Therapy Council (WRPTC) was formed in the year 1998. In the year 2002, WRPTC was formally adopted by WFNMB as one of its subsidiary bodies. WRPTC continued to remain active by organizing Colloquia and other scientific meetings. In the year 2005, WRPTC decided to hold one International Conference on Radionuclide Therapy (ICRT) every alternate year. The first ICRT was held in Limassol in 2005 (Cyprus). This was followed by the second ICRT in Ulaanbaatar (Mongolia) in 2007. Keeping in view the importance and popularity of ICRT, it was decided to hold the meetings every year, instead of every alternate year. Subsequently, ICRTs were held in Goa, India (2008), Cartagena, Colombia (2009), Cape Town, South Africa (2010), and Ho Chi Minh City, Vietnam (2011). The seventh ICRT is being held in Levi, Finland, in 2012. We also held one large regional meeting in Kuwait in the year 2011, which was attended by over 400 participants. In order to make the organization a legal entity and democratic, an association was formed in the year 2009, called WARMTH. WRPTC was dissolved and WARMTH was inaugurated at a grand opening ceremony at Cartagena, Colombia, in November 2009. It was formally registered as an international association in India in August 2010. Today, WARMTH is an independent international organization, a legal entity with its own constitution, governing body, and bank account. Right now, we are in the midst of our first elections for electing the members of the next governing body, which will take over the responsibility of running the organization for the next two years (2013-2014). Within a short span of 3 years, WARMTH has forged alliances with Society of Nuclear Medicine (SNM), IAEA, WFNMB, AOFNMB, ARCCNM, and various national and regional professional bodies. There has been a proposal to organize an SNM-WARMTH joint CME on Nuclear Oncology during the annual meeting of SNM every year. If everything goes well, we will have our first joint CME at Toronto next year. Besides organizing international congresses and workshops, WARMTH is also providing travel fellowships to scores of professionals from developing countries to participate in our ICRTs. We are exploring the possibilities of conducting various research activities in the field of radionuclide therapy, especially in the field of liver cancer. Currently we have a paid membership of over 300 and it is growing. World Journal of Nuclear Medicine is the official journal of WARMTH (www.wjnm.org). WJNM is a quarterly peer-reviewed journal. Journal's full text is available online. The journal allows free access to its contents. The journal is also available in printed version. We do not charge for submission, processing, or publication of manuscripts, or even for color reproduction of photographs. With active participation and contributions from members, we hope to build a world-class organization dedicated to the science of nuclear medicine therapy.

S-21

IAEA Perspectives on Radionuclide Therapy

A. Duatti


Nuclear Applications, IAEA, Vienna, Austria

At the most fundamental level, cancer can be viewed as a perfect example of "molecular disease." However, it is also an example of "holistic" molecular disease involving the chemical interaction of a single cell with the whole organism. Actually, the disease originates when the inner biochemical fabric of the cell is abnormally altered, thus escaping the control mechanisms regulating the harmonic growth of the various tissues through a complicate signaling network. It is exactly the breakdown of this holistic molecular machinery that makes both the understanding and treatment of cancer so difficult. An outstanding result of this complexity is the discovery of the intrinsic heterogeneity of the cellular population within the same tumor, indicating the occurrence of a broad spectrum of genetic alterations, presumably, not all associated with the action of a single oncogene. Thus, despite some important progress, finding an effective and definitive treatment for cancer still remains a tremendous task. However, in our search for a consistent therapeutic approach, we should not avoid pursuing the basic molecular paradigm and, in this context, radionuclide therapy employing single-molecule radiolabeled substances still constitutes a promising tool for cancer treatment due to its intrinsic molecular nature. In fact, radionuclide therapy is unique in its ability to deliver selectively to cancerous cells a therapeutic dose of radioactivity by means of rationally designed molecular carriers. This strategy offers a relevant example of genuine molecular delivery exploiting some selected components of the holistic molecular machinery. Thus, a key advantage of molecular radionuclide therapy is that it does not need to have the full molecular picture, but just some relevant piece of the entire puzzle that allows targeting selectively the tumor. After uptake by some cancer cells, radioactivity does not make distinction between different cellular types and, at least in principle, the therapeutic effect can be extended to the whole tumor mass. Unfortunately, it is not easy to find a satisfactory matching between the chemical and biological properties of a radiolabeled agent and some bio-molecular mechanism capable of uploading the required amount of radioactivity for removing all cancerous cells. In this respect, iodine-131 based therapy still remains a unique, unmatched example. IAEA is constantly promoting projects and scientific discussions on the applications of therapeutic radiopharmaceuticals in oncology. These programs are pursued through the organization of Coordinated Research Project and Technical Meetings on selected topics such as the use of antibodies, peptides, and other molecular species for targeting cancer with a variety of both diagnostic and therapeutic radionuclides, or assisting member states in promoting the widespread use of target-specific radiopharmaceuticals for the diagnosis and treatment of different types of cancers. Another important aspect currently attracting much interest at IAEA is the investigation on efficient production methods for new radionuclides or on alternative approaches for producing well-established radionuclides. In this lecture, an overview of some of the most successful IAEA accomplishments and future projects in the field of therapeutic radiolabeled agents will be presented, with emphasis on the contribution brought about by a large scientific community around the world.

S-22

WFNMB Perspectives on Radionuclide Therapy

Andrew Scott


President-elect, WFNMB, Australia, (2014-18)

S-23

Future Prospects of Radionuclide Therapy in Korea

Lee Dong Soo


Nuclear Medicine, Seoul National University Hospital, Seoul, Korea

The prospects of cure of intractable diseases are closely associated with the progress of the related scientific fields and the infrastructure, which supports their application to the medicine in each country. Recently, cancer treatment evolved to have various combination therapies such as targeted therapy, immunotherapy, and classical destructive chemo-radio-radionuclide therapy. Classical destructive chemotherapy, radiotherapy, and radionuclide therapy are now re-interpreted for their role of treating cancer, and appropriate combinations of these treatment modalities are seriously being considered along the disease course. However, in clinical practice, not many new combination therapies are available. Recently, nanotechnology (NT) moved far forward to find the medical application in clinical setting and this is called "technological push." But to be used properly for clinical purposes, this technology should prove its feasibility of use with other modalities. Nanostructures should not be loaded too much in vivo for therapeutic use, and their whereabouts and in vivo effects should be understood in more detail before their possible prevalent use in clinics. In this sense, for therapeutic and/or theragnostic purposes, nanostructures need to be associated with radionuclides/radiopharmaceuticals. We call this "marriage of NT and RT" (radiation technology) in Korea. If this prospect is given successfully to the public, fused NT/RT can draw attention from government officials and lawmakers, who are to support and establish the budget and infra. In Korea, we have 35 cyclotrons and one research-purpose reactor running, and the new reactor for production of medical radioisotopes is to be installed in 2016. This reactor will produce Lu-177 and Y-90 for clinical purposes. Korean scientists pioneered Re-188 Lipiodol or colloid therapy for liver cancer and rheumatoid arthritis back in late nineties; however, that was the time when Korean FDA was firmly established, and we needed to wait for a decade to promote this technology further for clinical purposes. In the meantime, Re-188 brachytherapy for coronary artery disease was tried rapidly, but faded with the introduction of drug-eluting stent. We learned that neuroendocrine tumors can be treated with Y-90/Lu-177 DOTATATE or others, and we tried I-131 labeled rituximab for intractable DLBC, a lymphoma. As the investigators have advanced NT to the limit in Korea, and we have multiplexing technology combining NT and RT (and also ligand, linkers, etc.), we are now about to open a new arena of radiolabeled theragnostic (Lu-177 Cu-64 co-labeled) nanoparticles to be targeted to the cancers. In conclusion, I can say that we, the Koreans, are entering the era of combining targeted-therapeutic small chemicals or nanoparticles labeled with diagnostic and therapeutic radioisotopes. What will be the target diseases is the thing that we need to determine or persuade our clinician colleagues.

S-24

Personalized Radionuclide Therapy of Cancer: Will it Remain a Dream or Become Reality?

R. P. Baum


Director, Theranostics Center for Molecular Radiotherapy/Imaging, Zentralklinik Bad Berka, Bad Berka, Germany

Molecular imaging in oncology with PET and SPECT involving use of specific probes directed against the tumor or its environment determines the molecular phenotypes in neoplasms and is the decisive step to guide a personalized therapeutic regimen. In the context of radionuclide therapy, theranostics implies that a molecular targeting vector, e.g., a peptide or antibody or small molecule, when labeled with a positron or gamma emitter, can be used for molecular imaging using PET/CT or SPECT, and when labeled with a beta or alpha emitter, may be followed by molecular personalized radiotherapy of a particular tumor. Theranostics of thyroid cancer using I-131 (also I-123 or I-124 for diagnosis) has stood the test of time. Another case in point is the theranostics of neuroendocrine neoplasms, which express somatostatin receptors type 2 (SSTR2), with radiolabeled somatostatin (SMS) analogs. Molecular imaging (PET/CT) using Ga-68 can be effectively followed by peptide receptor radionuclide therapy (PRRNT) using Lu-177 or Y-90 labeled with the same vector, response to which can also be monitored by Ga-68 somatostatin receptor PET/CT (SSTR PET/CT). Dosimetry (pre- and post-therapeutic imaging) also helps to individualize the therapy. These paradigms have shown that personalized radionuclide therapy of cancer no longer remains only a dream, but has the potential to realize in case of other cancers as well.

Neuro endocrine tumor (NET) patients need highly individualized interdisciplinary treatment and long-term care, and therefore PRRNT should only be performed at specialized centers. The Bad Berka ENETS Center of Excellence is a multidisciplinary neuroendocrine tumor center. We, at the Theranostics Center for Molecular Radiotherapy and Molecular Imaging, have now experience with more than 6800 PET/CT studies performed with Ga-68 labeled peptides and more than 1000 patients treated with PRRNT. Patient selection for PRRNT should be based on both clinical aspects pertaining to the patient and molecular features of the tumor. The therapy regimen for each patient is individualized with frequent therapy cycles (4-6 and up to 8) being applied at low or intermediate doses of radioactivity for these relatively slow-growing tumors ("long-term low-dose concept"). For kidney protection, patients are well hydrated and receive an amino acid infusion containing lysine and arginine given intravenously for 4 h beginning 30 min before PRRNT. 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 of personalized radionuclide therapy is dosimetry to ensure that maximum dose is delivered to the tumors, sparing normal organs, and therefore optimizing further treatment protocol for a particular patient. We have experienced significant (i.e., end-stage renal insufficiency) renal toxicity in only 1 out of the more than 1000 patients (less than 0.1%) treated at our center (>3500 treatment cycles). We also have treated patients (n = 26) with progressive NET metastases and a single functional kidney, and 2 patients on hemodialysis using fractionated low-dose PRRNT (to the best of our knowledge, this was the first ever worldwide experience). Therefore, the probability and magnitude of renal toxicity can be significantly reduced (or completely avoided) when PRRNT is administered in fractionated doses in patients without any pre-existing risk factors and under appropriate nephroprotection. Systematic use of Y-90 and Lu-177 DOTATATE (DUO PRRNT) in sequence and concurrently is highly effective, with Lu-177 being predominantly used for small metastases or in patients with impaired renal or hematological function. Long-term follow-up of up to 7 years after DUO PRRNT showed no significant grade 3 or grade 4 nephrotoxicity attributed to concurrent or sequential DUO PRRNT. Intra-arterial PRRNT (>50 treatments already performed up to now) is more effective for selectively targeting liver metastases and large inoperable primary tumors. Neoadjuvant PRRNT could also be administered in cases of inoperable NET so as to render the tumor operable by inducing radiation-induced necrosis. PRRNT can be effectively combined with transarterial chemoembolization (TACE), radiofrequency ablation (RFA), chemotherapy (e.g., using Capecitabine, Temazolomide, or Doxorubicin), and kinase inhibitors (e.g., Everolimus, Sunitinib, or Sorafenib). Thus, in patients with progressive NETs, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period of time (Bad Berka Protocol) is effective even in advanced cases, results in excellent therapeutic responses, and a significant benefit in overall survival can be achieved (in our experience, 210 months from the time of first diagnosis and 59 months after the first PRRNT). Up to 8 cycles of PRRNT, 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. A number of novel Ga-68 labeled tracers have recently become available for theranostics. The possibility of treatment using Lu-177 or Y-90 labeled with the same agent is a truly personalized approach to therapy. These include non-peptidic tracers such as the biphosphonate-based agent BPAMD ((4-{[bis-(phosphonomethyl))car-bamoyl]ethyl}-7,10 bis(carboxymethyl)-1, 4, 7, 10-tetraazacyclododec-1-yl) acetic acid for theranostics of skeletal metastases from prostate cancer. Peptides first to be used in humans at our center were gastrin releasing peptide receptor (GRP-R) selective bombesin analog AMBA (DO3A-CH2CO-G-4-aminobenzoyl- Q-W-A-V-G-H-L-M-NH2), and the GRP-R antagonist demobesin in metastatic breast, lung, and prostate cancers for both diagnosis (using Ga-68) and therapy (using Lu-177). Other Ga-68 radiopharmaceuticals that have been used by our group as first in human studies were DOTA-alpha-MSH (melanocyte stimulating hormone) in a patient with metastatic ocular melanoma, affibody molecule targeting HER2 in breast cancer, RGD for imaging angiogenesis, and growth hormone releasing hormone (GHRH) antagonist in lung cancer. Our experience confirms that Ga-68 is a very useful, practical, and affordable radionuclide for high-resolution PET/CT imaging and holds great promise for the future. We have also recently performed a biodistribution study with minibody to the prostate-specific membrane antigen (PSMA) labeled with In-111 and Lu-177 in a patient with prostate cancer (worldwide first), with excellent results (high specific uptake in metastases). This offers an excellent prospect of therapy. A major landmark in the treatment of gliomas with I-131 4-iodo-L-phenylalanine (IPA) was the first ever I-124 IPA PET/CT for pre-therapeutic dosimetry planning, which confirmed the favorable results of our past therapy experience. A more accurate and truly individualized approach to dosimetry would be with development of newer methods for 4D calculation of dose. Pre-therapeutic organ and tumor dosimetry using receptor PET/CT can be accomplished using longer-lived positron emitters, e.g., Sc-44, Y-86, or Cu-64, and comparison of these results with those obtained from Ga-68 is needed. The appropriate peptide and radionuclide for individualized therapy ("personalized medicine") can be then selected by pre-therapeutic measurement of organ and tumor doses. The first human study using the longer-lived, generator-derived, trivalent metallic positron emitter Scandium-44 (Sc-44) coupled to DOTATOC was performed in Bad Berka in 2009. Sc-44 has a half-life of 3.9 h and is derived from a Titanium-44/Scandium-44 generator, which has a half-life of 60 years. This may inspire the development of new radiopharmaceuticals for covering longer imaging periods.

Suggested Reading

  1. 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.
  2. Baum RP, Kulkarni HR, Carreras C. Peptides and receptors in image-guided therapy: Theranostics for neuroendocrine neoplasms. Semin Nucl Med 2012;42:190-207.
  3. Baum RP, Roesch F. First World Congress on Ga-68 and Peptide Receptor Radionuclide Therapy (PRRNT), June 23-26, 2011, Zentralklinik Bad Berka, Germany. World J Nucl Med 2011;10:1-2.
  4. Roesch F, Baum RP. Generator-based PET radiopharmaceuticals for molecular imaging of tumors: On the way to THERANOSTICS. Dalton Trans 2011;40:6104-111.
  5. 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. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins; 2008. p. 411-37.
  6. Baum RP, Prasad V, Hommann M, Hörsch D. Receptor PET/CT imaging of neuroendocrine tumors. Recent Results Cancer Res 2008;170:225-42.
  7. Kaemmerer D, Peter L, Lupp A, Schulz S, Sänger J, Prasad V, et al. Molecular imaging with 68 Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 2011;38:1659-68.
  8. Wehrmann C, Senftleben S, Zachert C, Müller D, Baum RP. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother Radiopharm 2007;22:406-16.
  9. 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.
  10. Baum RP, Kluge A, Gildehaus FJ, Bronzel M, Schmidt K, Schuchardt C, et al. Systemic Endoradiotherapy with Carrier-Added 4-[131I] Iodo-L-Phenylalanine: Clinical Proof-of-Principle in Refractory Glioma. Nucl Med Mol Imaging 2011;45:299-307.


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Innsbruck Medical University: Long-Term Results in Patients Undergoing Peptide Receptor Radionuclide Therapy

I. Virgolini


Nuclear Medicine and PET, Medical University of Innsbruck, Innsbruck, Austria

We are reporting our experience with peptide receptor radionuclide therapy (PRRT) in the period of IV/2005-XII/2011 at the University of Innsbruck. Long-term data from 288 patients are presented. Median applied activities for 177Lu-DOTA-TATE were 23.0 GBq (mean 22.5 ± 11.7 GBq; acc. activity A 1.7-61.2 GBq) and 11.7 GBq for 90Y-DOTA-TOC PRRT (mean 11.5 ± 6.0 GBq; acc. activity 1.5-31.2 GBq). In patients with stable disease, median survival was 26.7 ± 11.2 months and time to progression was 16.3 ± 8.3 months. In patients with partial response, median survival was 43.5 ± 31.8 months, and in patients with progressive disease median survival was 11.8 ± 6.5 months. All patients were followed by 68Ga-DOTA-TOC as well as 18F-FDG PET/CT. Patients with FDG-positive lesions during the follow-up period had a higher probability for developing progressive disease as well as reduced quality of life parameters. "Music listening" induced a positive psychological effect during the acute administration of radioactivity as demonstrated in a randomized study in NET patients.

S-26

NETs: Labeled Somatostatin Analogs in Therapy

C. M. Grana, G. Paganelli


Nuclear Medicine Division, European Institute of Oncology, Milano, Italy

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs, 90 Y-DOTATOC and 177 Lu-DOTATATE, has been experimented in neuroendocrine (NETs) and non-neuroendocrine sst 2 -positive tumors for more than 15 years. PRRT can deliver significant absorbed doses to tumors, able to cause volume reduction, as reported in published studies. Our preliminary dosimetric studies showed that the kidneys are the critical organs in PRRT and that bone marrow toxicity should be also taken into consideration. Later on, our phase I escalating studies of 90 Y-DOTATOC, with dosimetric analysis, with and without renal protection with amino acids, showed no major acute reactions up to an administered dose of 5.55 GBq per cycle. Reversible grade 3 hematological toxicity was found in 43% of patients injected with 5.18 GBq, which was defined as the maximum tolerated dose per cycle. Between 1997 and 2002, our group treated 141 patients affected mainly by NETs, with a cumulative activity of 7.4-26.4 GBq of 90 Y-DOTATOC, divided into 2-16 cycles, administered 4-6 weeks apart. Objective response rate was 26%. Disease stabilization was observed in 55% of the patients and disease progression in 18%. The mean duration of response ranged between 2 and 59 months (median 18). The majority of the patients who responded had gastro-entero-pancreatic NETs. We recently completed our phase I-II study with 177 Lu-DOTATATE on 51 patients with mainly NETs, including bronchial, duodenum, ileum, appendix, rectum, pancreatic endocrine carcinomas, as well as NETs of unknown origin, paragangliomas, and one case of meningioma. Patients were treated with 3.7-7.4 GBq per cycle up to a maximum cumulative activity of 3.7-29.2 GBq, divided in 1-7 cycles. No major acute or delayed renal or hematological toxicity occurred. Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). Cumulative bone marrow doses were <1.5 Gy. Thirty-nine patients were progressive at enrollment. Partial and complete responses occurred in 15/46 (32.6%) assessable patients. Median time to progression (TTP) was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumor involvement showed lower survival. Regarding safety, our group has been committed in evaluating the dosimetric and clinical aspects toxicity to the target organs, the kidneys, primarily, and the bone marrow. The long-term evaluation of renal parameters in patients who had undergone 90 Y-DOTATOC or 177 Lu-DOTATATE therapy and dosimetric studies showed that patients with risk factors for late renal toxicity showed a lower renal absorbed dose threshold (28 Gy) than did those without risk factors (40 Gy). The evaluation of the hematological toxicity with the increase of the bone marrow dose showed, for 90 Y-DOTATOC, a mild but progressive impoverishment of the bone marrow reserves. As to the commonly observed G2-3 lymphocytic toxicity, we studied the course of lymphocyte subsets after 90 Y-DOTATOC and 177 Lu-DOTATATE. We demonstrated that lymphoid toxicity mainly affected B-cells, particularly after 90 Y-DOTATOC. This phenomenon was transient and resolved completely at the end of the 90-day follow-up. Due to the selective targeting of B-cells, no increase in infections is normally observed after PRRT. These findings open interesting perspectives in the treatment of B-cell lymphoproliferative disorders. Presently our group is evaluating the effect of combination therapies, specifically of 177 Lu-DOTATATE plus the radio-sensitizer capecitabine, administered with a metronomic schedule, in patients with aggressive NETs. Our group is developing phase II protocols evaluating the therapeutic potential of both 90 Y-DOTATOC and 177 Lu-DOTATATE and the optimal schedule in terms of dosage per cycle and interval between cycles. In the future, phase III protocols comparing 90 Y-DOTATOC versus 177 Lu-DOTATATE and PRRT versus conventional therapies will help clarify the position of PRRT in the therapeutic algorithm of NETs.

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Clinical Trial Evaluation of Radiopeptide Therapy of NET

J. H. Turner


Department of Nuclear Medicine, The University of Western Fermantle Hospital, Australia

In the continued absence of a randomized controlled trial or registrational trial of Peptide Receptor Radionuclide Therapy (PRRT) of Neuroendocrine Tumor (NET) and consequent lack of level 1, or even level 2, evidence of efficacy and safety, medical oncologists generally refer to PRRT as an "evidence-free zone." No approved agent is in routine clinical practice and current European Neuroendocrine Tumor Society (ENETS) guidelines accord PRRT no place in first-line treatment of NET, and it is generally considered appropriate only after failed medical therapy. Paradoxically, whilst most PRRT is given after failure of all other treatments, in the majority of patients, it achieves the best overall response. The efficacy of PRRT is greatly enhanced by multimodality treatment with radio-sensitizing chemotherapy and/ or biological agents, such as tumor signaling pathway inhibitors, and the non-overlapping toxicities are manageable. Our experience of multimodality PRRT of well-differentiated Neuro endocrine tumor (NET) with 177 Lu-octreotate/capecitabine/temozolomide with Overall response rate (ORR) 82% in pancreatic NETS [1] will be reported. Our phase I clinical study of multimodality 177 Lu-octreotate/Everolimus, mTOR inhibitor will also be reported with a view to improving outcome of PRRT of metastatic carcinoid. These early phase clinical trials constitute a paradigm for demonstrating the potential for PRRT control of advanced NET and may be used to develop a strategy for obtaining the level of evidence required by medical oncologists to incorporate PRRT into routine clinical management of NET.

References

  1. 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 Biother Radiopharm 2012:27:561-9.


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An Update on PRRT in India

V. Lele


Nuclear Medicine, Jaslok Hospital and Research Centre, Mumbai, India

S-29

Somatostatin Analogs as Possible Theragnostic Molecules for Advanced Prostate Cancer

G. Dos Santos, R. Castro, E. Savio, A. Paolino, A. Quagliata, H. Balter, V. Trindade, J. Giglio, J.P. Gambini, H. Engler, O. Alonso


Nuclear Medicine, University of Uruguay, and Uruguayan Center of Molecular Imaging (CUDIM), Montevideo, Uruguay

Objectives: In the framework of an ongoing trial aiming to assess the value of Ga-68-DOTATATE PET-CT (GALPET) as a possible theragnostic agent for patients with prostate cancer, we performed an intra-individual comparison of this technique with C-11 choline PET-CT (CHOLPET).

Materials and Methods: We studied seven patients with prostate cancer during follow-up: Two with known bone metastases confirmed by a previous bone scan (PSA: 79-480 ng/mL) and five with biochemical recurrence after treatment (PSA: 0.7-10 ng/mL). Within 1-2 weeks, a PET-CT study was performed with Ga-68-DOTATATE and C-11 choline with a dose of 110 MBq and 420 MBq, respectively, using a 64-slice PET-CT with time-of-flight correction. The maximum SUV (SUVm) was measured in all abnormal foci.

Results: Both techniques were negative in three patients with biochemical recurrence. GALPET and CHOLPET were positive in 63/64 bone lesions corresponding to both patients with known bone disease and to one patient with biochemical recurrence. Two discordant bone abnormal foci were found (positive for GALPET or CHOLPET only). Additionally, in two patients with bone metastases and in the other with biochemical recurrence, six pelvic lymph nodes were positive by means of GALPET whereas CHOLPET detected four of them. CHOLPET SUVm values were higher than those from GALPET (7.7 ± 3.9 vs. 3.8 ± 1.4, n = 70, P < 0.0001). However, a significant correlation was found among both tracers' SUVm (r = 0.74, n = 70, P < 0.0001).

Conclusions: In advanced prostate cancer patients, Ga-68-DOTATATE uptake in lesions expressing somatostatin receptors seemed to correlate with C-11 choline uptake. More studies are needed in order to test for the possible complementary value of these techniques and for the potential of receptor-mediated therapies with appropriate ligands labeled with Y-90 and/or Lu-177.

S-30

Phase II Study of First-line Iodine-131-Rituximab Radioimmunotherapy of Follicular Non-Hodgkin's Lymphoma: The Initial Study

W. B. G. Macdonald, A. D. McQuillan, J. H. Turner


Departments of Nuclear Medicine and Department of Haematology, The University of Western Australia, Fremantle Hospital, Fremantle, Australia

Background: Non-Hodgkin lymphoma (NHL) is the seventh most common adult malignancy. Follicular NHL is the second most common subtype. None of the available treatments is curative and so low-toxicity alternatives to combination chemotherapy are required. Radioimmunotherapy is effective in relapsed and refractory NHL, but has had only limited evaluation as first-line therapy.

Materials and Methods: Sixty-two consecutive, treatment-naïve patients with newly diagnosed follicular NHL were studied. Following initial staging with 18F-FDG PET/CT scans, patients received four infusions of rituximab 375 mg/m 2 at weekly intervals and an individualized therapy dose of 131I-rituximab, predicated on a whole-body absorbed radiation dose of 0.75 Gy. Radionuclide treatment was administered on an outpatient basis. Further infusions of unlabeled rituximab were administered 3-monthly for 12 months. Blood parameters were monitored weekly for 8 weeks and then at the discretion of the referring hematologist. Response was assessed at 3 months with repeat 18F-FDG PET/CT scans and then again at 12 months.

Results: Median follow-up was 34 months (range 6-72 months). The overall response rate assessed by 18F-FDG PET/CT scans at 3 months was 98%, with complete response (CR) in 51 patients (82%) and partial response (PR) in 10 patients (16%). Prognostic variables at study entry were not predictive of response, while the 3-month PET/CT scan was highly predictive of the need for further treatment (P = 0.001). Among the patients achieving initial CR, 95% remained in remission throughout follow-up and no patient achieving CR required re-treatment, while 8 of the 10 patients with relapse or disease progression required further treatment at a median interval of 17 months. Among the patients achieving initial PR, four subsequently converted to CR at 12 months and have remained in remission; three patients have remained in stable partial remission without further treatment and three have progressed and have received combination chemotherapy. Two-year overall survival was 96%, and median overall, progression-free, and treatment-free survival was not reached. There were three deaths during follow-up, only one from lymphoma; this patient did not respond to radioimmunotherapy or to subsequent combination chemotherapy. Grade IV neutropenia occurred in 8%, but there were no serious infections. Grade IV thrombocytopenia occurred in 8%, but there were no episodes of bleeding and only one patient required platelet transfusion. One other patient required red blood cell transfusion for mild anemia complicating severe emphysema. Nine patients (15%) developed subclinical hypothyroidism during the follow-up period and were commenced on thyroxine. There were no cases of myelodysplastic syndrome during follow-up.

Conclusion: Radioimmunotherapy with 131 I-rituximab is effective first-line therapy for follicular NHL when combined with maintenance rituximab and achieves remission rates equivalent to chemotherapy-based regimens but with lower overall toxicity.

S-31

Low-dose, Involved Field Radiotherapy Just Prior to Radioimmunotherapy for Relapsed/Refractory B-cell Lymphoma

M. Tomblyn


Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, USA

Introduction: Radioimmunotherapy (RIT) is an effective and increasingly utilized therapy for patients with B-cell non-Hodgkin lymphomas (NHL). In the relapsed/refractory setting, patients may have measurable disease in only a few sites. Many relapsed patients have been heavily pretreated with rituximab and exhibit a down-regulation of expression of CD20. Emerging evidence suggests that oxidative stress (such as low-dose radiotherapy) has the ability to up-regulate CD20 expression on B-cell NHL and to stimulate intrinsic cell death pathways. Such low-dose radiation could sensitize bulkier sites of NHL prior to RIT.

Methods: Between July 1, 2009, and June 30, 2012, we treated 21 patients with a combination of low-dose, involved-field radiotherapy (IFRT) and RIT for relapsed/refractory B-cell NHL: 9 transformed, 7 follicular, 2 marginal zone, 2 CLL/SLL, and 1 lymphoplasmacytic NHL. All patients received 4 Gy in 2 fractions IFRT to sites of active disease greater than 2.5 cm. 131 I-tositumomab was used in 9 patients and 90 Y-ibritumomab tiuxetan in 12 patients. In all cases, IFRT was delivered just prior to the RIT therapeutic injection. The median age of patients was 61 (38-82). The median number of prior therapies was 2 (1-4). The median size of IFRT targets was 5.2 cm (2.5-19.5).

Results: With a median follow-up of 30 months (5-41), 19 of 21 (90.5%) patients obtained a complete response (CR), and 18 of 19 (94.7%) obtaining a CR continue to be free of recurrence. No patients have failed within the IFRT fields. The two patients not obtaining a CR, overall exhibited progression of disease outside of the IFRT regions. Both underwent bone marrow transplant and died of transplant-related mortality. All 21 patients tolerated the combination of IFRT and RIT very well without unexpected complications. Only the expected transient Grade 2/3 myelosuppression from RIT was noted.

Conclusion: The addition of low-dose IFRT to sites of active disease ≥ 2.5 cm just prior to RIT in patients with relapsed/refractory B-cell NHL is very well-tolerated, adds no toxicity to that of RIT alone, and results in excellent progression-free survival, particularly for patients who obtain a CR. As the only failures seen were outside of IFRT portals, the addition of IFRT to larger sites of active disease may play an important adjunctive role to RIT. Prospective studies are necessary to further evaluate this novel combined therapeutic approach. Correlative studies should be pursued to determine the mechanism for this improved tumor control.

S-32

Radioimmunotherapy of Follicular Non-Hodgkin's Lymphoma:

The State of the Art

I. Garty


Professor of Nuclear Medicine, Central Emek Hospital, Afula, Israel

S-33

Paving the Way to Personalized Medicine for Treatment of Cancer and Inflammatory Disorder

S. Srivastava


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

A major advantage of radionuclides is that they emit radiation of different radiobiological effectiveness and range of action. This offers the possibility of choosing a nuclide, the physical and nuclear characteristics of which are matched with a particular tumor type or the disease under treatment. This presentation introduces a relatively novel paradigm that involves specific individual radionuclides or radionuclide pairs that have emissions that allow pre-therapy low-dose imaging plus higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such dual-purpose theragnostic radionuclides and radionuclide pairs that offer this exciting potential of low-dose imaging followed by higher-dose treatment, and thus possibly bringing us a major step closer to personalized medicine. [1] This approach would empower the age-long dream of performing individualized or tailored radionuclide therapy in cancer patients, as well as in the treatment of many other disorders that respond to radionuclide therapy. However, an increased and reliable availability of theragnostic radionuclides remains a major issue, which must be addressed before we can successfully put this paradigm into routine clinical practice. It is worth emphasizing that our nuclear medicine modality is the only modality that can fulfill the dream of carrying out tailored personalized medicine by way of enabling diagnosis followed by therapy in the same patient with the same radiopharmaceutical. It should be stressed that ideally, it would be best to use the same theragnostic radionuclide, or its close congeners with the same electronic structure, and therefore with the same chemical and biochemical properties, so that imaging predicts biodistribution and dosimetry in a reliable, individualized fashion, and thus also predicts as to which patients will respond to the radionuclide therapy procedure being considered and which will not. In the second best situation, a radionuclide pair (imaging photon emitter, either gamma or positron, and therapeutic particle emitter, with the same electronic structure) can be used as well. A low-dose administration using radiopharmaceuticals based on these theragnostic radionuclides or radionuclide pairs would initially allow molecular imaging (SPECT/CT or PET/CT) to provide the necessary pre-therapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, and the maximum tolerated dose (MTD), etc. If the imaging results then warrant it, it would be safe and appropriate to follow-up with dose ranging experiments to allow higher-dose targeted molecular therapy with the greatest effectiveness. This is especially important in order to be able to do tailored imaging plus therapy (personalized medicine) in individual patients. Tin-117m (T 1/2 14.0 d; g 159 keV, 86%), is a very promising radionuclide for the development of theragnostic radiopharmaceuticals. In contrast to most other therapeutic 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 g-photon, tin-117m is perfect for pre-therapy imaging in the same patient. At BNL, our work on radionuclide therapy has for some time focused on the development of this radionuclide for application to several distinct clinical areas. These include palliation of bone pain from osseous metastases, treatment of metastatic bone disease, radiation synovectomy, radioimmunotherapy, and cardiovascular applications. The results of our previous Phase II clinical trial of tin-117m DTPA (using reactor-produced low specific activity material) for the treatment of metastatic bone pain have been published. No-carrier-added (NCA) tin-117m is also being developed and tested for the therapy of bone metastases and for use in radioimmunotherapy. A phase II/III clinical trial for the imaging and treatment of bone metastases in prostate cancer patients using NCA tin-117m is in the planning stage for 2013-2014. In the United States, cardiovascular disease is at the top of our most devastating health problems. There are about 875,000-1,000,000 new heart attacks every year, resulting in a very high patient morbidity and extremely high healthcare costs (~$475B in 2008). These attacks are caused by two different types of atherosclerotic disease - luminal calcified plaque and extra luminal active atheromatous disease leading to the formation of vulnerable plaques (VP). The luminal calcified plaques are easily detected by existing diagnostics, and the patient has a number of treatment options. However, VP develops positively outside the arterial lumen and cannot be detected by existing techniques. Unfortunately, over 70% of all significant cardiac events including sudden death are caused by the rupture of these VP lesions. Thus, new non-invasive diagnostic methods and new strategies for therapeutic intervention are needed to detect and treat VP, in order to reduce cardiovascular disease morbidity and the associated patient care costs. The high-LET short-range conversion electron emitter tin-117m, in addition to being a good therapeutic for cancer, also shows promise for the non-invasive molecular imaging and treatment of VP and of occluded coronary arteries through the use of 1) coronary stents electroplated with tin-117m, or ii) specific tin-117m labeled molecules systemically targeted to VP components. As mentioned above, unlike the beta electron emission with most therapeutic radioisotopes, tin-117m conversion electrons are mono-energetic and have a fixed and absolute distance in tissue of slightly less than 300 microns. This conversion electron energy is ideal for cardiovascular applications as its range in tissue is approximately the same as the wall thickness of human coronary arteries that contain vulnerable plaque and their therapeutic advantage enables them to provide localized energy within the arterial wall with virtually no effect to the surrounding tissue. A novel radioactive stent stably electroplated with tin-117m was developed as a therapeutic tool for the treatment of atherosclerotic coronary arteries. Effects on vessel wall inflammation from various doses of electroplated tin-117m were studied in hyperlipidemic rabbits. Three days following implants in the rabbit abdominal aorta [4 doses: 0 (cold tin), 30-, 60-, and 150-mCi tin-117m], immunohistochemical analysis of proliferating macrophages and smooth muscle cells demonstrated that inflammatory cells in the tin-117m stented segments were dramatically reduced in a dose-dependent fashion. A preliminary study in pigs [24 pigs, 72 stent implants (BMS, 0-400 mCi tin-117m per 15 mm stent)] was also carried out to investigate the effects on in-stent neointima formation. The electroplating process appeared benign since the response from "cold" tin plated stents was indistinguishable from what was observed in the case of routinely used bare metal, 316L surgical stainless steel stents. A profound and unique radiation effect was consistently observed in the higher-dose implants, which consisted of a discrete zone of dense connective tissue consolidation in the tunica adventitia, of ~0.25-0.30 mm thickness, corresponding to the anticipated tissue penetration of the tin-117m conversion electron energy. Focal suppression of in-stent neointima formation was also seen, but more investigations will be needed to determine this with certainty. A clinical trial with Sn-117m-Annexin, begun in 2010, is currently in progress. At present, the phase IIa study (15 subjects) involves human carotid endarterectomy patients who are dosed and imaged for VP, with histology as the comparison. Further clinical trials (phase IIb and phase III) are in the planning stage. In recent studies in an Apo-E mouse VP model, tin-117m-Annexin has demonstrated a significant anti-inflammatory therapeutic effect. The plaque composition showed significantly less expression of macrophages in the low-, middle-, and high-dose treatment groups as compared to the control group. In contrast, smooth muscle cell expression was greater in the middle- and high-dose groups as compared to the control, and in the low-dose group, the difference was statistically significant between the low-dose versus middle- and high-dose groups. In conclusion, our preliminary data demonstrate that tin-117m could be very promising as a means to reduce inflammatory events following stent implantation. In addition, when delivered systemically to atherosclerotic tissue using specific targeting molecules (e.g., Annexin-V), Sn-117m would also provide a means in low doses to image and in higher doses to reduce the vulnerability of the active atheromatous disease in the coronary arteries as well as in other areas in the vasculature.

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

Reference

  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.
S-34

Personalized Image-based Dosimetry for Radionuclide Therapies

A. Celler


Radiology, UBC, VGH Research Pavilion, Vancouver, Canada

S-35

Computational Analysis of the Dose-Response in Peptide Receptor Radionuclide Therapy: A New Concept for a Personalized Therapy Approach

M. Blaickner, H. R. Kulkarni, S. Wiessalla 1 , R. P. Baum 1


Health and Environment Department, AIT Austrian Institute of Technology, 1 THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, ENETS Center of Excellence, Zentralklinik Bad Berka, Germany

Peptide receptor radionuclide therapy (PRRT) has proved to be an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NET). Nevertheless, very little is known about the correlation between the three-dimensional (3D) dose distribution in tumor and healthy tissue on the one hand and the clinical response rates on the other. This project aims to retrospectively process the imaging data of patients treated with PRRT using advanced computer models in order to determine the 3D dose distribution of the individual lesions and the overall tumor mass, as well as other clinically relevant quantities like tumor burden and standardized uptake values (SUV). The patient data will be supplied by two clinical institutions and comprises diagnostic somatostatin receptor PET/CT scans (using 68 Ga-DOTA-TATE and 68 Ga-DOTA-TOC) as well as SPECT/CT scans obtained after PRRT with 177 Lu-DOTA-TOC and 177 Lu-DOTA-TATE. The scans will be processed twofold. First, a common voxel-based 3D dosimetry will be performed, using the STRATOS software, applying manual tumor delineation and convolution with the software's dose kernels. Secondly, advanced computer models will be applied that involve: (i) the segmentation of organs on the CT scan using a gradient vector flow (GVF) algorithm, (ii) the non-uniform deformation of subdivision surfaces (SubD) body phantoms to match the individual patient anatomy, (iii) tumor volume estimation by segmentation of PET and SPECT data, applying statistical algorithms, and (iv) 3D voxel-based dosimetry by convolution of the time-integrated activity distribution with in-house calculated dose kernels. The output of the advanced computer models and the common 3D dosimetry comprises the mean absorbed dose, the biologically effective dose (BED), the equivalent uniform dose (EUD), and the SUV with regard to lesions, as well as the tumor burden for organs and the whole body, the latter being computed by the advanced models. Above quantities will be correlated with the individual tumor response, measured as change in tumor volume, the course of the disease of the individual patient according to the RECIST (Response Evaluation Criteria In Solid Tumors) and PERCIST (PET Response Criteria In Solid Tumors), as well as the progression free survival (PFS) and the overall survival (OS). Furthermore, the advanced models enable the calculation of an individual kidney dose and the correlation with renal impairment. The results will provide new insights into the dose-response relationship of GEP-NET treated with PRRT, particularly the dependence on spatial dose distribution, dose rate, and tumor uptake. Together with the improved reproducibility of dosimetry calculations and the enhanced knowledge about renal toxicity, this will allow for a more personalized therapy approach. The results will also have an impact on the dosimetry in other forms of radionuclide therapy.

S-36

New Options to Label Biomolecules with Trivalent Radiometals Adding Non-aqueous Solvents

F. Roesch


Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany

Objectives: Radiopharmaceuticals are typically synthesized in pure aqueous solutions. Labeling yields are defined by temperature, period of labeling, amount of labeling precursor, pH, etc. In case of 68Ga and when utilizing the cation-exchanged post-processing of 68Ge/68Ga radionuclide generators, we noticed that the presence of acetone increased the labeling yields (compared to pure aqueous solutions). Consequently, the effect of adding non-aqueous solvents to the aqueous solutions was investigated systematically.

Materials and Methods: 68Ga eluates obtained from an EZAG/Obninsk generator were used with and without cation-exchange based post-processing. The fraction of non-aqueous solvents added was varied in the range from 10 to 40 volume %. Solvents such as methanol, ethanol, isopropanol, octanol, acetonitrile, DMF, DMSO, PEG-derivatives, etc., were added to aqueous solutions containing DOTA- and NOTA-conjugated precursors such as octreotide derivatives (TOC, TATE, NOC) and bisphosphonates. Labeling parameters according to standard protocols were modified in terms of lower temperature, shorter reaction time, and lower amount of precursor. Labeling yields were analyzed by TLC and HPLC.

Results: For many non-aqueous solvents, labeling yields improved significantly at lower temperatures, shorter reaction times, and less amounts of precursor. For example, while aqueous systems at 70°C, 30 mg DOTANOC, and 10 min reaction time give 40% radiochemical yield for 68Ga-DOTANOC, these yields are 55%, 75%, and 90% for 10, 30, and 40 vol-% of ethanol, isopropanol, and acetonitrile, respectively. When amounts of precursors are reduced from 30 to 20 or 5 mg, labeling yields (exemplified for 68Ga-DOTATATE) are higher for 30 vol-% isopropanol or ethanol mixtures by factors of about 2, 3, and 5, respectively, which represents significantly increased specific activities.

Conclusions: There is experimental evidence that mixtures of aqueous + non-aqueous solvents significantly improve 68Ga labeling efficacies in terms of temperature, time, and concentration. For specific parameters, yields improve by a factor of 2 or more. It may result in higher specific yields of the lab eled products and may allow labeling reactions at significantly lower temperature which is relevant for sensitive biological molecules such as proteins. The most probable explanation is the perturbation of the hydration sphere of the central cation, which allows easier access to complex formation with the ligands present. Whether this is a general aspect and holds true for other radio-metals such as β-emitting 177 Lu or #945;-emitting 225 Ac or 213 Bi is currently under investigation.

S-37

Review of Available and Future Radionuclides Useful for Radiotherapeutics: Industrial and Regulatory Limitations

R. Zimmermann


Manager Chrysalium Consulting, Saint Remy les chevreuse, France

Most of the academic researchers and developers have experienced difficulties in communicating with industrial investors. It seems that academics and industrialists are working in two different worlds that will never understand each other. The limited interest industry shows in new molecules, and hence in radiotherapeutics, in other words, the criteria industry uses to select potential drugs in which they accept to invest, have never been explained clearly. On the other hand, pharmaceutical industries tend to consider academics as partner not at all interested in economic considerations. Unfortunately, or better, fortunately, both groups need to work closely together. While industry needs to bear the financial risk, university researchers have the freedom to explore new technical and scientific challenges, which is also a kind of risk. The number of new radiolabeled molecules that have been developed in the past 20 years is quite amazing. One can only be astonished when it is compared to the number of new radiopharmaceuticals that came on the market during the same period. Good science is not sufficient to transform a molecule in a marketed drug. The budget required to demonstrate the value of the molecule in human discourages investors to enter in this area if the market itself is not potentially huge. The dream of a blockbuster still exists in nuclear medicine. In fact, there are a series of other limitations and constraints that have to be taken into account before deciding to start human tests. Researchers believe that passing all the hurdles of their own selection criteria should be rewarded by the investment in clinical trials. Their criteria are, however, fully driven by technology and science, not economics. Industries, and more precisely investors, need to be convinced about the potential of the market and the chances of success. The budget required to bring the molecule on the market after successful preclinical tests is of another order of magnitude than for the research steps. Criteria used by radiopharmaceutical industries to select potential marketed drugs include the choice of the best radionuclide, the analysis of the market viability in the frame of the overall competition, the increasing safety constraints when working with multi-doses, the investment in usually non-existing manufacturing tools for a worldwide access to the new drug, as well as the limiting regulatory aspects. Unfortunately, it must be noted that each of these criteria is mainly driven by financial parameters and an expectation of a certain return on investment. Among these criteria, the selection of radionuclides by industry is not anymore linked to physical properties or the chemistry. The ideal radionuclide with the best profile does not exist. Is there a chance to find something better than what already exists? Nowadays, the most important criteria include long-term availability, manufacturing capacity, pharmaceutical quality, and adaptation to nuclear safety constraints or regulations. The radionuclides presently available already went through a kind of natural selection and it is important to understand the difference between radionuclides that can be used without questioning and radionuclides that still need further evaluation, manufacturing development, and large investments. This presentation will focus on the selection of radionuclides for therapy under the aspect of these different uncommon criteria. It can be helpful for research centers to better control and orient their programs (basic research vs. applied research) and should explain the reasons of the lack of interest by industry for some even a priori interesting molecules, targets, radionuclides, or indications.

S-38

Nanostructures and Their Multiplex Labeling with Targeting Ligands and Radioisotopes

J. M. Jeong


Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea

Nanoparticles can be used as a multiplex carrier of imaging ligands and therapeutic radionuclides, and surface modification is essential for production of such nanoparticles. For radionuclide therapy, the nanoparticles should be accumulated in the cancer tissue efficiently and specifically. To achieve these goals, various ligands such as peptides, sugars, aptamers, polyethylene glycols, and chelating agents should be conjugated to the surface of nanoparticles. However, conjugation of ligands one-by-one by traditional method has serious problems. Each conjugation step by chemical reaction would be influenced by reproducibility of reaction yield due to subtle change of reaction conditions such as concentration, pH, temperature, reaction time, light, and impurities. Moreover, dilution of reactants by purification procedure after each reaction step is even worse. These problems could be solved by an encapsulation method of hydrophobic nanoparticles using specific amphiphiles. The specific amphiphiles were produced by conjugating a long alkyl chain to each specific ligand such as peptide, sugar, aptamer, polyethylene glycol, and chelating agent. Actually, an amphiphile containing polyethylene glycol, Tween 60, could be obtained commercially. In order to prepare a multiplex nanoparticle, the necessary amphiphiles could be selected from the portfolio and be used for encapsulating nanoparticles. Using this method, various hydrophobic nanoparticles such as quantum dots and iron oxides could be encapsulated with various selected specific amphiphiles. Then the above problems were easily solved because the surface modification of nanoparticle was performed in one step. And thus, we established a straightforward method of producing multiplex medical nanoparticles with high reliability and reproducibility.

S-39

Prospects of Lu-177/Y-90 Production and Future Radionuclide Therapy in Korea

S. J. Choi


Director, Radioisotope Research Division, KAERI, Daejeon, Korea

S-40

Experience of Platform Construction and Clinical Trial of New Radionuclide Therapy in Korea

G. J. Cheon


Department of Nuclear Medicine, Korea University, Seoul, Korea. E-mail: larrycheon@gmail.com

S-41

Introducing the Animal Models for Evaluation of New or/and Already Existing Radiopharmaceuticals

E. Janevik-Ivanovska


University "Goce delcev," Faculty of Medical Sciences, Republic of Macedonia

S-42

Alpharadin (radium-223) in Bone Metastatic Prostate Cancer - Basic Concepts and Clinical Results

Øyvind S. Bruland


Professor of Clinical Oncology, University of Oslo,

The Norwegian Radium Hospita, Oslo, Norway

Skeletal metastases are present in >90% of patients with castrate resistant prostate cancer (CRPC). The pronounced bone-tropism in this cancer and the sclerotic phenotype of the metastases provide the basis for bone-targeted radionuclide therapy. Based on experiences with beta-emitting variants of such bone-seeking radiopharmaceuticals (BSR), we proposed; 13 years ago, the use of the alpha-emitting BSR radium-223 in its chloride formulation. The presentation will highlight aspects of the production technology (Bruland et al., 2006), some pre-clinical observations (Henriksen et al., 2002, 2003), but focus primarily on results from clinical trials; one phase-1, two randomized phase-2 and the recently completed pivotal phase-3 ALSYMPCA-trial. In the phase-1 dose-escalation trial dose-limiting toxicity was not reached (Nilsson et al. 2005). In the subsequent phase-2 trial patients with CRPC and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of 223Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks (Nilsson et al., 2007). Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. 223Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. No patient discontinued 223Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p0 =0.048) for 223Ra versus placebo, respectively. Median overall survival was 65.3 weeks for 223Ra and 46.4 weeks for placebo ( p0 =0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p0 =0.020, Cox regression). In another phase 2 dose-response study with 223Ra treatment, pain response was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets (223Ra, n=614; placebo, n=307), 223Rasignificantly improved overall survival vs placebo (median 14.0 vs. 11.2 mo; HR=0.695; P=0.002) and was well tolerated.

Selected Reading

  1. Henriksen G, Breistøl K, Bruland ØS, Fodstad Ø, Larsen RH (2002): Significant anti-tumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res, 62 (11), 3120-5.
  2. Henriksen G, Fisher DR, Roeske JC, Bruland ØS, Larsen RH (2003): Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med, 44 (2), 252-9.
  3. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS (2005): First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res, 11 (12), 4451-9.
  4. Bruland ØS, Nilsson S, Fisher DR, Larsen RH (2006): High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res, 12 (20 Pt 2), 6250s-6257s
  5. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS (2007): Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol, 8 (7), 587-94.
  6. Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, Staffurth J, Vasanthan S, Andersson C, Bruland ØS (2012): A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer, 48 (5), 678-86.
  7. Sartor O, Hoskin P, Bruland OS (2012): Targeted radio-nuclide therapy of skeletal metastases. Cancer Treat Rev, http://dx.doi.org/10.1016/j.ctrv.2012.03.006.


S-43

Glioblastoma Therapy with Substance P Labeled with Bismuth-213: Initial Experience

L. Krolicki, J. Kunikowska


Head, Department of Nuclear Medicine, Medical University of Warsaw, Warsaw, Poland

S-44

Contribution of Nuclear Medicine in Early Breast Cancer: From Sentinel Node to IART® (Intraoperative Avidination for Radionuclide Therapy)

C. M. Grana, G. Paganelli


Division of Nuclear Medicine, European Institute of Oncology, Milan, Italy

The contribution of Nuclear Medicine to improve surgery in early breast cancer started about 15 years ago with the sentinel node biopsy (SNB) challenge. The revolution in breast cancer treatment began in the 1980s with the Milan I trial which randomized 701 patients to either breast-conserving surgery (quadrantectomy, complete axillary dissection plus breast radiotherapy, QUART) or Halsted mastectomy. The results, which ushered in the era of conservative surgery for all types of cancer, showed no difference in survival between the two arms, with the data confirmed after more than 20 years of follow-up. Before the validation of SNB, complete axillary dissection was a cornerstone of the Veronesi breast conservation protocol. If the nodes are clinically positive, they must be treated; however, the indications for and techniques of axillary clearance in a clinically clear axilla have been matters of intense controversy. Following these discussions, in the 1990s, IEO Nuclear Medicine, in collaboration with IEO senology team, started the first trials to understand if lymphoscintigraphy with radioguided SNB could replace axillary dissection in early breast cancers. Nowadays, after many published papers and many lymphoscintigrapies, SNB is the standard of care for axillary staging in breast cancer. SNB can be performed in a wide range of practice settings, providing good results, notwithstanding considerable variations in technique. SNB increases staging accuracy, mainly because sentinel nodes undergo exhaustive pathologic analysis, have less morbidity than complete axillary dissection, and afford local control comparable to that of axillary dissection, when indicated.

The following step in the conservative program of breast cancer surgery has been radioguided occult lesion localization (ROLL): It is a simple-to-perform surgical technique employing radioactive tracer and a g-ray-detecting probe for the intraoperative localization and removal of non-palpable breast lesions. The technique, developed at the IEO, involves injection of immobile radioactive tracer (as opposed to the mobile radiotracer used to identify sentinel nodes) into the lesion under mammographic or ultrasonographic control. The g-ray probe is used intraoperatively to locate the lesion and guide its removal. ROLL has proved to be an accurate method for localizing occult lesions, which facilities complete lesion removal, yet minimizes the amount of healthy tissue removed. Breast conservative surgery (BCS) plus external beam radiotherapy (EBRT) is considered the standard treatment for early breast cancer. We have investigated the possibility of irradiating the residual gland using an innovative nuclear medicine approach named IART® (Intraoperative Avidination for Radionuclide Therapy).

IART is a new partial irradiation technique under development at the IEO. There are two steps. The first is "avidination" in which native avidin is injected by the surgeon directly into and around the tumor bed. The second step is intravenous injection of 90 Y-labeled biotin (3.7 GBq), 1 day later. Avidin injection requires no more than 10 min and is done after cancer removal (quadrantectomy), while the surgeon is waiting for the result of the intraoperative pathological analysis of the sentinel node, or after axillary dissection.

Following avidination, the wound is closed as normal. Radiolabeled biotin, injected intravenously the day after surgery, binds to the avidin in the operated breast, bringing a significant quantity of radionuclide whose radioactive decay kills residual tumor cells.

In preliminary studies, scintigraphic images demonstrated fast and stable uptake of radiolabeled biotin at the injection site, but without significant localization of radioactivity in the rest of the body. A phase II study demonstrated that IART combined with reduced EBRT (40 Gy) is a safe procedure without systemic toxicity that produces a good esthetic outcome to the treated breast. The tolerance to reduced EBRT was also good. The highest grade of transient local toxicity was G3, which occurred in 3/32 pts after the completion of WB-EBRT. The combination of IART® + EBRT was well accepted by the patients, without any changes in their quality of life. No local recurrences occurred after 20-44 months of follow-up (media 35.7, median 36). One patient underwent BCS for a contralateral tumor after 15 months. The results of these first studies support the hypothesis that IART® may represent a valid approach to accelerated whole breast irradiation after BCS and is an interesting nuclear medicine approach that may have a role in the management of early breast cancer. It provides a radiation boost that reduces the duration of conventional EBRT and allows patients who have difficulty attending a radiotherapy center (particularly the elderly, and those who live at a considerable distance from the facility) to be treated optimally. In a following retrospective study, a voxel-dosimetry analysis was performed to investigate heterogeneity in distribution of the absorbed dose. The aim of this work was to compare dosimetric and radiobiological evaluations derived from average absorbed-dose versus voxel absorbed-dose approaches. Voxel Dosimetry Method (VDM) highlighted the absence of significant heterogeneity in absorbed dose in the target and is recommended for improving accuracy, taking into account actual activity distribution in the target region. The radiobiological model applied allowed us to compare the effects of IART® with those of EBRT and to match the two irradiation modalities.

S-45

Positron Emission Mammography: A Perspective

P. Bernal


Nuclear Medicine, Fundacion Santa Fe de Bogota, Bogota

S-46

Statistics: Interesting and Useful

Janez Stare


Professor of Biostatistics, University of Ljubljana, Ljubljana, Slovenia

Statistics is all around us. Sports, economics, politics, traffic, and so on, they all come with numbers describing all kinds of aspects of our daily lives. And, of course, it is difficult to imagine science, medicine in particular, to manage without statistics. Statistics is usually recognized as being indispensable, so useful, but a non-interesting, if not boring, discipline. In this talk, I will try to convince you otherwise. Being a convert myself (there was time when I thought statistics was boring), I may have a chance. In the talk, I will present real examples from everyday life where statistics was used in a wrong way. Some of the mistakes are, unfortunately, typical also in serious research, medicine included.

S-47

Role of Nuclear Medicine in Oncological Surgery

B. Birkenfeld


Department of Nuclear Medicine, Pomeranian Medical University, Szczecin, Poland

S-48

Clinical Use of Rhenium-188 from the Tungsten-188/Rhenium-188 Generator

K. Liepe


Nuclear Medicine, GH Kassel, Germany

Rhenium-188 is one of the most readily available generator-derived and useful radionuclides for therapy which emits α particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gamma photons (155 keV, 15.1%). The 188W/188Re generator is an ideal source for the long-term (4-6 months) continuous availability of 188Re suitable for the preparation of radiopharmaceuticals for different radionuclide therapies. The most common therapy in nuclear medicine using 188Re is the treatment of liver metastases or primary liver cancer. Bernal et al.[1] published data from an IAEA-sponsored trial, which included 185 patients treated with 188Re-lipiodol with a mean applied activity of 4 GBq. Among these patients, the objective response rate was 25%; stable disease was observed in 53% and tumor progression in 22%. With a median follow-up of 455 days, the estimated 12- and 24-month overall survival was 46% and 23%, respectively. Higher activities with a mean activity of 14 GBq (max. of 20.5 GBq) of 188Re microspheres were used in a similar liver cancer therapy study published by Liepe et al. [2] These high activity levels were well tolerated by all patients, and also in cases with repeated administration. An effort of the microspheres is the significant lower urinary excretion rate in comparison to lipiodol (8.9-44.1%). Another interesting indication is the therapy of metastatic bone pain with 188Re-HEDP. The first preliminary data were published by Maxon et al. [3] A later study published by Palmedo et al.[4] described an optimal activity of 3.3 GBq for therapy. Liepe et al. found a response rate of 81% of patients and a decrease of pain level from 4.1 ± 1.8 to 2.5 ± 1.9, 12 weeks after 188Re-HEDP treatment. Application in a repeated manner increases the median survival from 7.0 months after single treatment to 12.7 months after twice administration. [5] Also, the use of 188Re-microspheres for treatment of arthritis showed similar results to those of 90Y in radiosynovectomy of the knee. [6] Two German groups used 188Re liquid-filled balloons for the intravascular radiation therapy (IRT) approach to prevent restenosis in patients after PTCA. [7],[8] Hoher et al.[7] found a significant lower restenosis rate of 18% using IRT in patients compared to a placebo balloon instillation, with a response rate of 37%. Also, the event-free survival in patients with IRT was significantly longer compared to the placebo patients. More recently, the successful use of 188Re liquid-filled balloons has been shown feasible in stenosis of the peripheral vessels. Other indications include skin patches impregnated with 188Re for treatment of squamous cell carcinoma, [9] bone marrow ablation using 188Re-labeled antibody anti-CD20, [10] or labeling of peptides and proteins, e.g., the 188Re-labed P2045 peptide targeted to the somatostatin receptor for the targeting of small cells and on small-cell lung cancer. [11] In another recent example, Phase I studies have recently been completed for the targeting of 188Re-labeled antibody PTI-6D2 to melanin excreted from metastatic melanoma cells. [12]

References

  1. Bernal P, Raoul JL, Stare J, Sereegotov E, Sundram FX, Kumar A, et al. International Atomic Energy Agency-sponsored multination study of intra-arterial rhenium-188-labeled lipiodol in the treatment of inoperable hepatocellular carcinoma: Results with special emphasis on prognostic value of dosimetric study. Semin Nucl Med 2008;38:S40-5.
  2. Liepe K, Brogsitter C, Leonhard J, Wunderlich G, Hliscs R, Pinkert J, et al. Feasibility of high activity rhenium-188-microsphere in hepatic radioembolization. Jpn J Clin Oncol 2007;37:942-50.
  3. Maxon HR, 3 rd , Schroder LE, Washburn LC, Thomas SR, Samaratunga RC, Biniakiewicz D, et al. Rhenium-188 (Sn) HEDP for treatment of osseous metastases. J Null Med 1998;39:659-63.
  4. Palmedo H, Guhlke S, Bender H, Sartor J, Schoeneich G, Risse J, et al. Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases. Eur J Nucl Med 2000;27:123-30.
  5. Palmedo H, Manka-Waluch A, Albers P, Schmidt-Wolf IG, Reinhardt M, Ezziddin S, et al. Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: Tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol 2003;21:2869-75.
  6. Liepe K, Zaknun JJ, Padhy AK, Barrenechea E, Soroa VE, Shrikant S, et al. Radiosynovectomy using yttrium-90, phosphorus-32 or rhenium-188 radiocolloids vs. corticoid instillation for rheumatoid arthritis of the knee. 2011;25:317-23.
  7. Hoher M, Wohrle J, Wohlfrom M, Kamenz J, Nusser T, Grebe OC, et al. Intracoronary beta-irradiation with a rhenium-188-filled balloon catheter: A randomized trial in patients with de novo and restenotic lesions. Circulation 2003;107:3022-7.
  8. Wohrle J, Krause BJ, Nusser T, Mottaghy FM, Habig T, Kochs M, et al. Intracoronary beta-brachytherapy using a rhenium-188 filled balloon catheter in restenotic lesions of native coronary arteries and venous bypass grafts. Eur J Nucl Med Mol Imaging 2006;33:1314-20.
  9. Sedda AF, Rossi G, Cipriani C, Carrozzo AM, Donati P. Dermatological high-dose-rate brachytherapy for the treatment of basal and squamous cell carcinoma. Clin Exp Dermatol 2008;33:745-9.
  10. Buchmann I, Bunjes D, Kotzerke J, Martin H, Glatting G, Seitz U, et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-antibody for conditioning of high-risk leukemia patients prior to stem cell transplantation: Biodistribution, biokinetics and immediate toxicities. Cancer Biother Radiopharm 2002;17:151-63.
  11. Magram MY, Edelman MJ, Forero A, Meredith RF, Shen S, Stubbs JB, et al. A novel rhenium-188 labeled somatostatin receptor (SSTR) targeting peptide, P2045, as potential targeting therapy for lung cancer. J Nucl Med 2003;44:137P.
  12. Klein M, Shibli N, Friedman N, Thornton GB, Chisn R, Lotem P. Imaging of metastatic melanoma (MM) with a 188Re-Labeled melanin binding antibody. J Nucl Med 2008;49:52P.


S-49

SIR-Spheres in HCC

J. B. Cwikla


Nuclear Medicine, Faculty of Medical Science, University of Varmia and Masuria, Olsztyn, Poland

S-50

Re-188 Lipiodol Therapy for HCC: A New Approach and Perspective from the Rhenium Users' Group

A. K. Padhy


Nuclear Medicine & PET, Singapore General Hospital, Singapore

S-51

I-131-Lipiodol Therapy in Local Disease Control and Survival in Patients with Advanced Hepatocellular Carcinoma and Metastatic Liver Disease from other Primary Tumors: Our Initial Experience

K. Kallur


Nuclear Medicine, Healthcare Global Enterprises Pvt Ltd, Bangalore, India

S-52

Therapy of Colorectal Cancer Tumors with an Agonist DR5 Antibody

A. M. Scott 1,2 , I. J. G. Burvenich 1, F. T. Lee 1 , G. A. Cartwright 1 , G. A. O'Keefe 2 , R. V. Roemeling 3 , A. Rigopoulos 1 , K. Fujiwara 4 , M. W. Brechbiel 5 , R. A. Beckman 3

1 Tumor Targeting Program, Ludwig Institute for Cancer Research, 2 Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia; 3 Clinical Development-Oncology, Daiichi Sankyo Pharmaceutical Development, Edison, NJ, USA; 4 Global Project Management Department, Daiichi Sankyo Co. Ltd., Tokyo, Japan; 5 Radioimmune Inorganic Chemistry Section, Radiation Oncology Branch, Cancer Research Centre, Bethesda, MD, USA

Objectives: CS-1008 (tigatuzumab), an anti-human death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. CS-1008 is currently in various phase I/II studies. Tumor concentration of CS-1008 in vivo and the impact of dose on tumor saturation of DR5 receptors remain key questions in the determination of the optimal dosing schedule for therapeutic benefit. This study reports on the validation of radiolabeled anti-DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 receptor occupancy in a colorectal cancer xenograft model, and establish dose ranges for receptor saturation kinetics in vivo.

Materials and Methods: CS-1008 was radiolabeled with 111 In via the bifunctional metal-ion-chelating agent CHX-A″-DTPA and was characterized for DR5 binding and labeling efficiency on DR5-positive human colorectal cancer cells (COLO 205). Pharmacokinetic and biodistribution studies were performed in BALB/c nu/nu mice bearing COLO 205 or DR5-negative mouse colon tumor CT26 using antibody dose levels of 0.2, 1, or 10 mg/kg. Planar gamma camera imaging and computerized tomography (CT) images were obtained at 2 days post injection to study the receptor occupancy in vivo.

Results: Scatchard analysis showed high and specific binding affinity (K d , 1.05 ± 0.12 nmol/L) of 111 In-labeled CS-1008 and a low number of DR5 receptors expressed per COLO 205 cell (B max , 6578 ± 284 receptors/cell). 111 In-labeled CS-1008 is specifically taken up in mice bearing COLO 205 tumor xenografts with prolonged tumor retention (percentage injected dose per gram tumor at 336 h post injection, 21.05 ± 2.00% ID/g; n = 5 , SD). No differences in serum clearance were observed between different antibody dose levels (0.2 mg/kg, 1 mg/kg vs. 10 mg/kg) with mean values (n = 15, SD) for alpha half-life (t1/2a) of 5.71 ± 0.91 h and beta half-life (t1/2b) of 141.78 ± 20.69 h. DR5 receptor saturation was demonstrated in vivo via both biodistribution and planar gamma camera imaging of 111 In-labeled CS-1008. Saturation of DR5 receptor corresponds to maximal preclinical efficacy, with saturation occurring between the 1 mg/kg and 3 mg/kg dose levels.

Conclusions: 111 In-CHX-A″-DTPA-CS-1008 is a potential novel SPECT imaging tracer that can be used to determine DR5 receptor occupancy and effective dose levels of CS-1008 therapy in the clinic.

S-53

Outside the Box: Challenging Cases for Radioimmunotherapy

M. Tomblyn


Radiation Oncology, Moffitt Cancer Center & Research Institute, Tampa, USA

Radioimmunotherapy (RIT) represents the most effective single agent against B-cell non-Hodgkin lymphomas (NHL). Indications currently exist for relapsed/refractory indolent B-cell NHL, transformed B-cell NHL, and as front-line consolidation following a response to induction chemoimmunotherapy for indolent B-cell NHL. Evidence accumulates for its use in aggressive B-cell lymphomas and as part of hematopoietic stem cell transplantation preparative regimens as well. Still, many unanswered clinical questions remain for many RIT users, with very little data to support the appropriate off-label uses for these agents. In this presentation, we will describe our experience with four challenging RIT scenarios: the HIV+ patient; the patient with highly refractory lymphomatoid granulomatosis; the patient with chemo-refractory diffuse large B-cell lymphoma with involvement of the kidneys, liver and lungs; and the patient with primary central nervous system lymphoma.

S-54

Ancient Features of Personalizing Cancer Treatment: Learning from Radionuclide Therapy in the Era of Targeted Therapies

S. W. Oh, D. S. Lee


Nuclear Medicine, Seoul National University Boramae Hospital, Seoul, Korea

Numerous targeted cancer drugs have been developed based on the tremendous advances in understanding of cancer biology during the past few decades. However, conquering cancer seems to be far beyond the reality in spite of the introduction of targeted therapies. Targeted therapy often fails when a specific target may be absent or irrelevant in a given tumor. Even in the right patient at the right time, prolongation of survival times induced by targeted therapy is not so long, mainly due to the development of drug resistance. To overcome this conundrum, it is required to develop combination therapies involving various steps of cancer pathophysiology, together with molecular biomarkers that identify patients with the specific targets. Radionuclide therapy could be an alternative to overcome hurdles lain in cancer control. Since radionuclide therapy was firstly applied for the treatment of differentiated thyroid cancer, it has continuously evolved to radioimmunotherapy, peptide targeted therapy, etc. Recently, radionuclide therapy has increasingly been developed for solid tumors. These versatile applications of radionuclide therapy are mostly attributed to the advancement of radiopharmacology. Radionuclide therapy should be appropriately modified in order to be delivered properly so that it may exert an influence on target tissues. In this regard, radionuclide therapy has great potential to become a powerful medium for combining various treatment modalities, as well as adding to its own radiation effect. Besides, radionuclide therapy is advantageous in controlling surrounding tissues as well as primary cancers because it can give collateral damages to the surrounding tissues via crossfire effect. It has been reported that stromal cells in the surrounding tissues are recruited to tumors not only to enhance growth of primary cancers but also to facilitate metastatic dissemination to distant organs. Radionuclide therapy was undervalued due to its narrow indications and lack of interest of clinicians. Recently, radionuclide therapy has regained attention from researchers and clinicians as it has several advantages; such as versatility based on pharmaceutical modifications and killing effect caused by ionizing radiation. It thus seems that development of combination therapy fully utilizing the advantages of radionuclide therapy would be the promise for personalizing cancer treatment.

S-55

Quantitative Imaging of Radiotracer Biodistributions

A. Celler


Radiology, UBC, VGH Research Pavilion, Vancouver, Canada

S-56

Quality of Life Assessment in Neuroendocrine Tumor Patients

E. M. Gamper, L. M. Winter, D. Putzer, R. Orjiukwu, B. Holzner, I. Virgolini


Departments of Psychiatry and Psychotherapy and Nuclear Medicine, Medical University of Innsbruck, Innsbruck, Austria

In treatment evaluation, aspects of morbidity as well as the patient's quality of life (QOL) have traditionally been assessed by physician ratings. These usually focus on the disease process and associated symptoms and are prone to influences by a number of variables such as the physician's clinical experience or their relationship to the individual patient. However, especially in a chronic disease like cancer, the individual patient will appraise his personal trade-off between treatment benefit and treatment-related burden also in dependency of his/her ability to maintain functioning and well-being. The past decades have witnessed a rapidly growing recognition of the importance of the patients' subjective perception of their health status. It became the gold standard to complement traditional outcome parameters, such as response to therapy or disease-free and overall survival, by health issues reported by the patients themselves, the so-called patient-reported outcomes (PROs). A PRO instrument may be a questionnaire or interview and needs to provide a patient's self-report without interpretation by anyone else. In fact, QOL constitutes the beginning of PRO research and still is its core concept. Broad systematic research on QOL in oncology started in the early 1980s. Definition problems due to the use of the term "quality of life" for describing individual notions of a good life in general as well as for describing a scientific concept were the first issues to be dealt with. Some early definitions encompass a range of aspects such as self-esteem, meaning in life, and a minimum of stress and fear. Boosted by the development of psycho-oncology as a discipline in medical care, intensive conceptualization was done and the development of valid and adequate instruments was fostered. The nowadays widely acknowledged operationalization of health-related QOL (HrQOL) comprises issues which are directly related to a patients' health status and which can be influenced by treatment, i.e., provides a measure that assesses a patient's psychological, social, and somatic status and is expected to predict the effect of therapy. Additional relevant subjective aspects, such as a spiritual dimension, may be included. This operationalization has always to be regarded as such in the context of cancer treatment evaluation (in the medical literature, HrQOL and QOL usually are used synonymously). A patient's adaptation to his/her situation, including all intra-psychological and social factors, is an important mediator in how he/she perceives his/her condition and to some extent is thought to be reflected in QOL scores. However, these processes cannot be comprehended entirely by QOL assessment. Issues such as "meaning in life" and "value of life" and their meaning for the individual patient are major topics when working with cancer patients and need to be given attention in patient-physician communication, psychological counseling, and pastoral care. PROs, that is to say, are not thought to replace communication with patients. Giving value to a range of different concepts of QOL springing from different professional backgrounds and perspectives, the medical operationalization is not contrary. It rather aids the identification of problem areas and aspects of QOL which can be influenced by therapy and which are able to create an understanding of the patient's perspective beyond pre-defined clinical endpoints. QOL was even found to be useful as a predictor of survival, in some studies more accurate than clinical variable. Thus, although QOL has to some extent always been an objective of medical intervention, it is only since the systematic assessment of patient self-reports that it can be incorporated into research and clinical practice in a scientifically sound way. NETs typically are slow-growing tumors and despite the fact that there is still much to be learned in the treatment of NETs, current therapies such as treatment with octreotide enable prolonged survival. Thus, a patient can live with the disease for years. As with all cancer diseases, whether the aim of cancer therapy is to cure or to prolong progression, adverse effects and impaired QOL often accompany treatment benefit. Long lives with the disease and treatment sequelae call for comprehensive approaches in care as well as in the evaluation of therapies, focusing on long-term supportive care and treatment outcomes. In most cases, NETs are a chronic disease where aside from prolonging survival, a main treatment aim is to maintain a reasonable QOL. NET patients may suffer from various clinical symptoms, such as gastrointestinal problems, wheezing, flushing, or joint pain. In addition, they sicken in a relatively young age, entailing a range of social and financial consequences. Being diagnosed with a comparatively rare disease, their situation often is characterized by a substantial amount of uncertainty and distress, including concerns about quality of care. This highlights the importance of assessing QOL in NET patients as an additional outcome in treatment evaluation as well as in clinical practice for adverse event detection, drug safety reports, and to support medical decision making. However, there are only isolated studies that report on QOL in NET. Applied assessment methods range from interview questions on specific symptoms, visual analog scales, to validated QOL profiles. A range of reliable and valid QOL instruments is available for use in cancer patients. The most widely used and influential cancer-specific measurement systems till date have been developed by the CORE in Chicago and the EORTC Quality of Life Group (QLG). Both systems consist of a core questionnaire, the FACT-G and the EORTC QLQ-C30, respectively, which comprise questions on functioning on a physical, emotional, social, and role level, as well as on symptoms of the disease and side effects of treatment. These core questionnaires can be applied to all cancer types and conditions and can be complemented with cancer type-, treatment-, and symptom-specific modules. Further, modules for other important QOL issues have been developed, such as patient information and satisfaction, and spiritual well-being. Both measurement systems are available in different languages, whereat the EORTC QLG does not merely aim at translating questionnaires, but at a cross-cultural development process.

S-57

Quality of Life in Oncological Patients and Radionuclide Therapy

W. Claxton


President and Co-founder, CNETS, Singapore

Neuroendocrine tumor-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 the 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 center of excellence, and ensure that their treatment follows consensus guidelines. Such patients can live long and productive lives.

S-58

Radionuclide Therapy: From Radium to Radium

A. C. Perkins


Professor, Radiological and Imaging Sciences, Nottingham University Hospital, Nottingham, United Kingdom

S-59

Outpatient Therapeutic Oncology

J. H. Turner


Professor of Nuclear Medicine, Department of Nuclear Medicine, Fremantle Hospital, University of Western, Fermantle, Australia

Therapeutic nuclear oncology has evolved into molecular tumor-targeted control of metastatic cancer. Safe, efficacious, clinical practice of radionuclide therapy may now be based upon accurate personalized dosimetry by quantitative gamma SPECT/CT imaging to prescribe tumoricidal activities without critical organ toxicity. Preferred therapy radionuclides such as Iodine-131, Samarium-153, Holmium-166, Rhenium-186, Rhenium-188, and Lutetium-177 possess gamma emission of modest energy and abundance to enable quantitative SPECT/CT imaging for calculation of the beta therapy dosimetry, without radiation exposure risk to hospital personnel, carers, family, or members of the public. Measured activity release rates and radiation exposure to carers of treated patients and the public are all within recommendations and guidelines of international regulatory agencies and, when permitted by local regulatory authorities, allow cost-effective, safe, outpatient radionuclide therapy of cancer without isolation in hospital. Additional advantages include timely radionuclide treatment independent of hospital bed availability, and facilitation of multimodality chemotherapy, which enhances efficacy in therapeutic nuclear oncology.

Suggested Reading

  1. Turner JH. outpatient therapeutic nuclear oncology. Ann Nucl Med 2012;26:289-97.
S-60

Radiosynovectomy: Procedure Review and Description of a Multicenter Study to Measure the Safety and Efficacy of Radiosynovectomy Performed with Y-90 Citrate Colloid or Re-186 Sulfide

J. Warrington


Medical Imaging, University of Western Ontario, Canada

Radiosynovectomy has been demonstrated to be efficacious in the treatment of arthropathy with synovitis which is resistant to both systemic medical therapies and intra-articular steroid injection and compares favorably with surgical synovectomy. This presentation will both review radiosynovectomy as a treatment modality and describe a current phase III, open label, multicenter, prospective Canadian trial to assess the safety and efficacy of radiosynovectomy performed with Yttrium-90 citrate colloid or Rhenium-186 sulfide in patients suffering from arthritis.

S-61

Tin-117m-DOTA-Annexin for Imaging and Treating Vulnerable Plaque

G. Gonzales


Clear Vascular, Inc., New York, USA

The Clear Vascular, Inc. product uses a radioisotope tin-117m linked to a targeting molecule, annexin V. It is injected systemically and selectively binds to components of vulnerable plaque, enabling chemical identification of vulnerable plaque. The product provides both images of localized vulnerable plaque and potential systemic therapy of vulnerable plaque. Although this product has application to other inflammatory diseases, the company is focused on the vulnerable plaque imaging and therapeutic markets. Annexin V is a naturally occurring human protein that specifically binds to phosphatidylserine (PS), a compound that occurs naturally on the inner cell membrane of healthy cells. When inflammatory cells undergo apoptosis, the PS flips to the outer cell membrane and is exposed for binding to the annexin V. The specific targeting molecule for vulnerable plaque therapeutics is tin-117m-DOTA-annexin or "Tin-Annexin" and it has been produced under cGMP, and production methods of the Tin-Annexin have been established. Preclinical studies performed to date include (1) normal mouse biodistribution studies, (2) atherosclerotic rabbit normal rabbit biodistribution studies, (3) tin-117m-radioactive electroplated stent studies in the porcine model, (4) SPECT imaging and simulated imaging, (5) hyperlipidemic rabbit tin-117m stent studies, (6) mouse sterile abscess model, (7) Apo-E casted carotid mouse model and therapy with tin-117m Annexin, and (8) high-quality images in animals using tin-117m and SPECT have been achieved. Preliminary ApoE therapy trial using Tin-Annexin indicated a statistically significant therapeutic effect on vulnerable plaque in animal models of vulnerable plaque. A second ApoE mouse therapy study using a cold tin control and low doses of Tin-Annexin (i.e., 1.0 mCi, 1.7 mCi, and 3.4 mCi) suggests a therapeutic benefit of plaque stabilization in the absence of lesion regression, indicating the potential clinical utility of Tin-Annexin therapy for the rapid stabilization of vulnerable plaque. Human dosimetry has calculated that the human equivalent therapy dose of the ApoE mouse dose of 1.7 mCi will be in the 3-5 mCi range. This cGMP Tin-Annexin product is currently being used in vulnerable plaque safety and imaging trials in human carotid endarterectomy subjects and doses of 500 mCi and 3 mCi have been given with no adverse events. Phase 1 and phase 2 clinical studies have provided histology as a comparison and measure of Tin-Annexin binding and localization. Additionally, in vivo imaging of a human aortic aneurysm using Tin-Annexin has been achieved. These human imaging studies are ongoing.

S-62

Oncolytic Viral Therapy

A. Hemminki


K. Albin Johansson Research Professor for the Finnish Cancer Institute, Cancer Gene Therapy Group, University of Helsinki, Finland, and Specialist in Oncology and Radiotherapy, Docrates Oncology Hospital, Helsinki, Finland

Advanced, recurrent, and metastatic cancers remain difficult to treat effectively and it is unlikely that currently available modalities solve the issue. Novel approaches such as oncolytic viruses might be useful in the context of cases currently incurable. Such viruses are able to infect, replicate in, and lyse tumor cells. Recent data from clinical trials have shown that they are safe and can be effective when combined to standard therapy. Oncolysis induces antitumor immunity and this can be enhanced by arming the virus with transgenes. Immune responses against the virus and the tumor have emerged as the critical variables with regard to efficacy or lack thereof. This talk will introduce some strategies that are being used to improve tumor cell transduction and antitumor efficacy, including arming of the virus with immunostimulatory transgenes. Furthermore, an overview of the most important clinical approaches with oncolytic adenoviruses will be given, including our own experience in using oncolytic virus for targeting radionucleotides to tumors in vitro, in animals, and in a patient.




 

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