|Year : 2011 | Volume
| Issue : 1 | Page : 26-59
Abstracts of Invited Lectures
|Date of Web Publication||16-Jun-2011|
|How to cite this article:|
. Abstracts of Invited Lectures. World J Nucl Med 2011;10:26-59
Ge-68/Ga-68 Generators - Past, Present and Future
Institute of Nuclear Chemistry, University of Mainz 55122 Mainz, Fritz-Strassmann-Weg 2, Germany
Gallim-68 today sees a renaissance - in terms of new 68 Ge/Ga radionuclide generators, sophisticated 68 Ga radiopharmaceuticals, and state-of-the-art clinical diagnoses via PET/CT. Why "renaissance"? 68 Ga represents one of the very early radionuclides applied to PET imaging at a time when even the wording PET itself was not established - long time before the usage of fluorine-18. Moreover, due to the availability of this positron emitter via the first 68 Ge/Ga generators, Hal Anger could create the first positron scintillation camera in the beginning of the 1960s. Driven thus by the coincidence of old-fashioned radiochemistry and dramatic improvement of tomographic detection systems, almost immediately, A Gottschalk and others applied several 68 Ga tracers for imaging of various diseases, mainly in the human brain. Hundreds of patients have been investigated in the USA with 68 Ga-EDTA and others from 1963 on. Although several publications described improved radionuclide generators, the impact of 68 Ga imaging fated away in the late 1970s, because of mainly two reasons: the generator design itself appeared not adequate to the requirements of versatile syntheses of 68 Ga radiopharmaceuticals, and the ones available through the existing technology had minor clinical relevance, in particular in view of the parallel and rapid developments of the new classes of 99mTc- and 18F-labelled diagnostics. Thanks to the pioneering achievement of radiochemists in Obninsk, Russia, a new type of 68 Ge/Ga generators became commercially available in the first years of the 20s century. Generator eluates based on hydrochloric acid provided cationic 68 Ga instead of "inert" 68 Ga-complexes, opening new pathways of Me(III) based radiopharmaceutical chemistry. Again coincidentally, the 68 Ga cation was introduced immediately into existing designs of MRI and SPECT imaging probes, namely DTPA- or DOTA-based derivatives. The impressive success of utilizing 68 Ga-DOTA-octreotides and PET/CT instead of e.g. 111In-DTPA-octroescan paved the way not only to the clinical acceptance of this particular tracer for imaging neuroendocrine tracers, but to the realisation of the great potential of the 68 Ge/Ga generator for modern nuclear medicine in general. Consequently, the last decade has seen a 68 Ga rush. Increasing applications of generator based 68 Ga radiopharmaceuticals (for diagnosis alone, but increasingly for treatment planning thanks to the inherent option as expressed by THERANOSTICS) ask for progressive developments - towards the optimization of 68 Ge/Ga generators both from chemical and regulatory points of view. Dedicated chelators may be required to broaden the possibilities of 68 Ga labelling of more sensitive targeting vectors. Last but not least, the concept of 68 Ga-radiopharmaceutical chemistry should be applied to an increasing number of targeting vectors, addressing the clinically most relevant diseases. It maybe a vision, maybe a dream: In another decade from now on, 68 Ge/Ga generator based diagnostics may approach rank 3 of clinical impact after that of 99mTc and 18F based tracers.
Pro and Cons - Some Thoughts Around Technology for Routine Production of 68 Ga-tracers
Department of Biochemistry and Organic Chemsitry, Uppsala University; Imperial College, London, UK and Syddansk Universitet, Odense, Denmark Falkvägen 17, 75756 Uppsala Sweden
The development of Molecular Imaging especially PET has reached a steady state situation and the question "why" is important. There is a need of a change from the use "long-lived" 18F tracers to more short-lived ones. These tracers have dominated the last decade due to the success of a distribution business tracer concept. The advent of getting 68 Ga available by use of the generator technology is indicating a possible change back from distribution to on site or local concept of producing tracers because the half-life of 68 Ga is pushing that in direction of site specific or local production. The fact is that the distribution of generators is already existing within the scientific and clinical nuclear medical community. This change to return on site production will also push a return back from the commercial requirements pushed by regulatory having an industrial production to a more old fashion "extempore" preparation technology. In the lecture there will be a discussion around 68 Ga-tracers and technology with regard to high specific radioactivity and but also expand this thinking into production of other short half-life radionuclides which definitely only can be produced on site.
Overview and Perspectives on Automation Strategies in 68 Ga Radiopharmaceutical Production
Department of Nuclear Medicine, Azienda Ospedaliero Universitaria S.Orsola Malpighi di Bologna, Via Massarenti 9, 40138, Bologna, Italy
The 68 Ga labelling of DOTA and other macrocyclic ligands is a promising technology for labelling peptides, proteins and many other molecules. A renaissance of 68 Ga radiopharmacy has come with the introduction of reliable generators and with the development of small tumor-affine peptides, most notably those targeting somatostatin receptors. These molecules represent the new gold standard for the imaging of neuroendocrine tumors. The initial strategy for labelling DOTA peptide was based on "manual" systems. Apart from research studies, these systems can hardly fulfil the pharmaceutical and regulatory requirements of the routine production for human use. Automation strategies now have become mandatory in order to comply the regulatory issues (GMP, local regulation etc.) and, of utmost importance, to reduce the operator exposure during routine productions of radiopharmaceutical for clinical use. Automation strategy should manage the different phases of the process: generator elution, post processing of the 68 Ga eluates (including concentration and pre purification), labelling of the conjugate considering high specific activity as a main issue and provide a purification system. The automatic module should be built on a platform capable of integrate ancillary equipments, i.e. bubble point test device, use a "user-friendly" interface and a software which should be compliant with cGMP, GLP and GAMP 5 requirements, in terms of audit trails and reporting. Several companies are now producing modules for 68 Ga radiopharmaceutical productions and the main features will be described. The use of disposable sterile cassettes ensure easy handling by click'n'run technology, better sterility assurance and avoid intense cleaning and sanitation routines. Moreover, radiopharmaceutical routine production for different tracers without cross contamination issues is feasible, allowing syntheses of radiopharmaceuticals not only for diagnostic purpose but also and for Radioimmunotherapy. Flexibility for adapting to post-processing Ga68 eluate protocols and the possibility of installing a microwave reactor will lead to a high specific activity and possibly make the purification step unnecessary. Automation strategies, together with the development of a "pharmaceutical grade" generator, will be fundamental to encourage nuclear medicine department to produce PET radiopharmaceuticals independently of an onsite cyclotron.
Post-processing via Cation Exchange Cartridges: Versatile Options
Institute of Nuclear Chemistry, 55122 Mainz, Fritz-Strassmann-Weg 2, Germany
Germanium-68 provides the positron emitter Gallium-68 (T½=67.7 min) as an easily available and relatively inexpensive source of a PET nuclide for labelling interesting targeting vectors. We have developed an effective post-processing of 68 Ge/ 68 Ga generators to provide high 68 Ga recovery, removal of 68 Ge, removal of metallic impurities, and minimized volumes for labelling. This is easily achieved by online passing the elate through a small action exchange resin. Subsequently, 68 Ga is eluted in 400 μL of a second mixture of acetone and Hal (N2) from the action exchanger. The 68 Ga recovery is as high as 95% within 3 minutes, the additional removal of 68 Ge reaches four orders of magnitude, and the removal of metallic impurities including the inherent stable Zn(II) is almost quantitative. Finally, the volume for subsequent labelling is just 400 ml at low acid concentration - resulting in excellent yields of 68 Ga-synthesis reactions. [1,2] In addition, the temporarily absorption of highly purified on the small action exchange cartridge appears to be an ideal starting point for various further options. The first approach investigated was to use it for versatile synthesis of 68 Ga tracers under non-hydrous conditions. A convenient method was investigated for 68 Ga-labelling using the solid-phase (action exchange resin) derived 68 Ga-acetylacetonate ( 68 Ga(acac)3). The initial aqueous generator elate was transferred online onto a cationic exchange resin to quantitatively absorb 68 Ga as described before. From this resin, 68 Ga was eluted with different acetone-based, non-aqueous solvent systems providing n.c.a. 68 Ga(acac)3 as labelling agent. More than 95% of the initially eluted 68 Ga was eluted form the cationic exchange resin with 600 μl of a 98% acetone / 2% acetylacetone mixture. 68 Ga-labelling of water-insoluble porphyrin derivatives were chosen as model compounds for a proof of principle for the labelling of lipophilic compounds. Labelling of these model compounds was performed in chloroform in a focused microwave synthesis system. Two different porphyrin derivatives, meso-tetraphenyl-porphyrin (Top) and (3-(1-hydroxyheptyl)deuteroporphyrin dimethylester (HHDPD), were labelled in yields of >90% within 5 minutes using 68 Ga(acac)3 and diverse co-ligands in chloroform. Radiochemical purities of >95% were achieved by solid-phase extraction.  Extending this concept, the purified, solid-phase derived 68 Ga was used to process it via subsequent anion exchange based processing to achieve 68 Ga fractions free of any organic component such as acetone.  Finally, we are currently evaluating the idea to utilize the action exchange-based 68 Ga to directly perform labelling reactions on the resin. In conclusion, the initial concept of "just" purifying elegantly the initial 68 Ga generator elates offers new options relevant for 68 Ga labelling reactions.
1. Zhernosekov et al. (2007), J. Nucl. Med. 48, 1741-1748
2. Asti et al. (2008), J. Nucl. Med. Biol. 35, 721-724
3. Zoller et al. (2010), Radiochim. Acta 98(3), 157-160
4. Loktionova et al. (2011), J. Apl. Rad. Isot., doi:10.1016/j.apradiso.2011.02.035
Automated Preparation Method for Ga-68 DOTATATE Using Anion-exchange Prepurification of the Ge-68/Ga-68 Generator Eluate
G.J. Meyer, J. Kühn, M. Fleer, L. van der Vliert 1
Medizinische Hochschule Hannover, 1 Veenstra Instruments, Carl Neuberg Str. 1, 30623 Hannover, Germany
Aim: Development of a reproducible, safe, and fast preparation method for 68 Ga-labelled DOTA-derivatized peptides using a anion-exchange prepurification of any 68 Ge/ 68 Ga generator eluate.  The method should be fully automated, while maintaining reproducibility, a high standard of safety, and high yields for clinical studies.
Materials and Methods: All currently available 68 Ge/ 68 Ga generators deliver 68 GaCl 3 in various concentrations of HCl. With our method any 68 GaCl 3 eluate is converted into 68 GaCl 4 - with concentrated HCl. This is collected on a very small strong anion exchange column (ca. 50μl). Residual HCl is removed by a stream of inert gas. The 68 GaCl 4 - complex is reconverted to 68 Ga3+ by rinsing with a small amount of water, and thus transferred to the reaction vessel.
A small amount of DOTA-derivatized peptide, dissolved in a suitable buffer, - preferably HEPES -, is added and labelled at 90° C for 2-4 min. The labelled peptide is transferred to a C18ec cartridge, washed with pure water to remove free 68 Ga3+ and eluted with ethanol into a second vessel. Any 68 Ga hydroxy-aquo complexes will remain on the cartridge. Ethanol is removed by heating at 90° C under a flow of inert gas. The dried product is redissolved with 0.9% saline and transferred via a sterilisation filter to the final product vial. The labelling module: The 68 Ga labelling synthesis module consists of 20 valves, 8 reagent glasses, 1 pressure regulator, 2 reactors, 2 cleaning cartridges, 1 elution pump, 1 sterile filter and several collecting bottles for product and waste and 5 radioactivity detectors. The radioactivity detectors monitor the elution process and any major 68 Ge breakthrough, the absorption of the 68 GaCl 4 - and the 68 Ga3+elution, any excess 68 Ga3+ in a waste vial and 68 Ga hydro aquo complexes remaining on the C18ec cartridge for the in-line quality control. A pressure holding test (or bubble point test) is also automatically performed. The apparatus is controlled by the specialized Absynth software, which also assists to create a GMP compliant production environment according to FDA 21 CFR Part 11.
Conclusion: The 68 Ga labeling module produced 86 Ga-Gallium DOTATATE in a stable and reproducible manner. The overall yields of the module are around 70%. The overall runtime is 35 min. The synthesis module can be used to produce other compounds as well, by varying the peptides, ligands and radioisotopes. Because of the built in features of prepurification via the 68 GaCl 4 complex and ethanol evaporation the process exhibits a high standard of safety.
1. Geerd-J. Meyer, Helmut Mäcke, Jochen Schuhmacher, Wolfram H. Knapp, Michael Hofmann. 68 Ga-labelled DOTA derivatised peptide ligands. Eur. J. Nucl. Med. Mol Imaging 31, 1097 - 1104 (2004)
Ge-68/Ga-68 Labeling System for Efficient and Cost Effective Labeling of Radiopharmaceuticals
Jussi Jernström, Markus Hutt, Mark Harfensteller, Sebastian Marx, Josue Moreno Bermudez, Juho Nikula, Konstantin Zhernosekov, Andreas Hey, Richard Henkelmann, Tuomo Nikula
ITG Isotope Technologies Garching GmbH, Lichtenbergstr. 1, 85748 Garching, Germany
Aim of the Study: Ga-68 can be obtained on-site from a Ge-68/Ga-68 generator. Ga-68-labeled compounds are becoming increasingly popular in clinical PET, especially in the diagnosis of neuroendocrine tumors. The results obtained with novel Ga-68-PET tracers have demonstrated high diagnostic values of this nuclide. Starting from the increasing global demands for high purity Ga-68 a Ge-68/Ga-68 generator containing a novel germanium-specific resin was developed. Factors such as elution yield, Ge-68 breakthrough and chemical purity of eluate were monitored as the key parameters of generator performance. In addition, possibility for recycling of Ge-68 from used generators was taken into account in the generator design. Moreover, a generator-associated manual labeling module was developed for efficient production of Ga-68-labeled DOTA-peptides. The key design parameters for the module were high labeling efficiency, comfort of use, compact size and high safety for the operator.
Materials and Methods: The Ge-68/Ga-68 generator is based on novel silica-based resin which has high affinity for germanium. The elution of the generator is performed with less than 4 ml of dilute hydrochloric acid (0.05 M HCl). The generator system is metal-free, and can be finally sterilized by autoclaving prior to use. The generator is produced in sizes up to 2 GBq. The developed generator-associated labeling system consists of three parts: the shielded module frame, an integrated fluidic and labeling system and the generator. The generator is integrated in the labeling module and is directly connected to the fluidic system.
Results: Major features of the Ge-68/Ga-68 generator are high and stable elution yield of more than 80%, small elution volume and low Ge-68 breakthrough of less than 0,005% of the eluted Ga-68 activity. The system provides Ga-68 eluates that can be directly used for labeling without need for prepurification. The developed labeling system allows an efficient and safe preparation of Ga-68-DOTA-peptides with high radiolabeling yield and the highest radiochemical and radionuclidic purity. The labeling module can be easily and safely utilized in clinical environment and does not necessarily require further external lead shielding.
Summary: A compact and user-friendly labeling system designed for cost effective and safe production of Ga-68-labeled biomolecules with high purity has been developed. The system is currently under evaluation for routine preparation of different Ga-68-labeled compounds.
Gallium-68 Labeled Annexin for Apoptosis Imaging
Verbruggen Alfons, Bauwens Matthias, De Saint-Hubert Marijke
University of Leuven, Lab. of Radiopharmacy, O&N2, Box 821, Gasthuisberg, BE-3000 Leuven, Belgium
Aim of the Study: To develop a site-specifically 68 Ga labeled annexin-V and evaluate its suitability for apoptosis imaging.
Materials and Methods: Variants of annexin with a cysteine residue at position 2 or 165 (cys2-AnxA5 and cys165-AnxA5) were produced by site directed mutagenesis of the cDNA of human AnxA5. 68 Ga DOTA-maleimide, prepared by reaction of 68 Ga eluate with DOTA-maleimide at pH 4 at 90°C, was reacted with the annexin variants at 37°C to obtain 68 Ga-DOTA-anxV conjugates via a sulfide-bond at position 2 or 165. 68 Ga-DOTA-succinimidyl-cys*-AnxA5 was purified using a 10-kDa MWCO filter unit and washing with 2 ml Hepes buffer. Binding of purified tracers to apoptotic cells was studied in vitro using Jurkat T-lymphocyte cells treated with anti-Fas antibody. Biodistribution and pharmacokinetics of the radiotracers were studied with μPET in healthy mice and in a mouse model of hepatic apoptosis. μPET imaging after IV injection of the 68Ga-labeled annexins in combination with μMRI was performed in Daudi tumor bearing mice before and after treatment with a combination of chemotherapy and radiotherapy.
Results: Reaction of cys*-AnxA5 with 68 Ga-Dotamaleimide at 37°C and at pH 7-7.5 resulted in a coupling yield of 70±10%.In vitro, 68 Ga-cys2-AnxV and 68 Ga-cys165-AnxV showed a well-preserved capacity of binding to phosphatidyl serine, the activity bound to anti-Fas treated Jurkat cells being about 5 times higher than to untreated cells. No significant difference was noted between the two analogues.Biodistribution data indicated a fast renal clearance with only minor hepatobilliary uptake, but also a high retention in the kidneys. Compared to Tc99m-Hynic-annexin, activity in blood and liver was clearly lower for 68 Ga-cys*-AnxA5. No radioactive metabolites were detected in animal plasma 1 h p.i., whereas activity in urine was only in the form of radiolabeled metabolites.Animals treated with anti-Fas mAb showed a 3 to 8 times higher liver uptake as compared to healthy animals with a major shift of radioactivity from kidneys to the (apoptotic) liver. Tumor uptake of 68 Ga-cys2-AnxA5 and 68 Ga-cys165-AnxA5 was low but significantly increased after therapy. Accurate tumor delineation based solely on PET images was impossible but MRI-PET fusion images allowed clear delineation of each tumor.
Summary: Site-specifically labeled 68 Ga-cys2-AnxA5 and 68 Ga-cys165-AnxA5 were prepared with a high yield, high stability and within a reasonable time period. Both compounds showed fast clearance from the blood with high retention in the kidneys. Apoptosis was clearly visualized in a model of hepatic apoptosis. PET-MRI fusion images demonstrated a statistically higher tumor uptake after cancer therapy, indicating that 68 Ga-AnxA5 may be useful for the early evaluation of tumor therapy. In view of the rather low absolute uptake of the new 68 Ga labeled annexin derivatives, resulting in suboptimal image quality and sensitivity, further optimization of these radiotracers is nevertheless required in order to improve clinical usefulness.
Ga-68 PET for Infection Imaging, Inflammation and Other Indications
Vijay Kumar, Dilip Bodetti, Scott Evans, Socrates Angelides
Department of Nuclear Medicine and PET, Westmead Hospital and The Children's Hospital at Westmead, Sydney NSW 2145, Australia
Aims: We explored the ability of 68 Ga-Citrate and 68 Ga- TF (apo-transferrin) to detect Staph A infection in rats and further studied its ability to detect intra-abdominal infections in patients.
Materials and Methods: 68 Ga-Citrate was prepared by mixing Sodium Citrate with pure 68 GaCl 3 (20MBq) post-processed from Obninsk 68 Ge/ 68 Ga generator. 68 Ga- TF was prepared by mixing the pure 68 GaCl 3 (180 MBq/0.5mL) with a solution containing 2.0 mg of TF in 1.5 ml of sodium carbonate (0.1 M, pH 7.0). The reaction vial was incubated in the water bath at 40 o C for 1 hr. The radiochemical purity (RCP) of 68 Ga-Citrate was determined by ITLC-SG/methanol:glacial acetic acid (9:1 v/v). The RCP of 68 Ga- TF was determined by TLC/alumina chromatography, using sodium citrate (0.1 M) as the solvent (free 68 Ga, Rf=1 and bound 68 Ga, Rf=0). Infection was induced in the right thigh muscle by intramuscular injection of 500,000 CFU Staph A. 68 Ga-Citrate or 68 Ga- TF (15 MBq/rat and 150 MBq/patient) was injected intravenously and the images were acquired for 10 min each with the matrix size of 256x256 using a Siemens Biograph PET-CT.
Results and Conclusion: Radiochemical purity and yield of 68 Ga-Citrate and 68 Ga- TF were always >99% and it was stable for 6 hrs. The stability was not tested beyond 6 hrs, as the half-life of 68 Ga is only 68 min. When 68 Ga-Citrate or 68 Ga- TF was injected in the infected rats, the lesion was detectable within 6 min post-injection although intense, focal uptake was seen after 60 min. The accumulation of activity at the lesion increased with time with concomitant decrease in the cardiac activity during the same period of study. There was measurable blood pool activity at 3hr post-injection. Since the background activity was washed out in a time dependent manner, the ratio of T/M increased progressively over the entire period of the study from 2.2 to 7.5 from 10 to 6hr post-injection. When 68 Ga -Citrate was injected in patients, the biodistribution of the agent indicated high blood pool, high liver and bone (growth plate) uptake with low soft-tissue activity at 60 min post-injection. More importantly, there was significant activity in the large blood vessels at 60 and 120min after injection, which is absent in rat studies. This observation may suggest high protein binding in patients and some interference with infection imaging. However, preliminary observations indicated that 68 Ga-Citrate was successful in detecting intra-abdominal infection in a post-operative patient. The infected area in the abdomen was detected within 30min post-injection of 68 Ga-Citrate, which was consistent with CT and subsequently the abscess (43mL volume) was drained from the corresponding lesion and microbiology results further confirmed the findings. The SUV max of the lesion increased from 30min to 60min post-injection period. Subsequent studies indicated that this agent has useful applications for imaging infection in patients with a number of infection conditions. These findings indicate the potential of 68 Ga-Citrate for clinical utility. We have demonstrated 99mTc-labelled glucosamine is able to detect inflammatory arthiritis in a number of patients. However, the tracer has limitations and therefore, we are extending our studies further by replacing 99mTc with Ga-68 in order to improve the resolution and sensitivity of the PET tracer. This will further enhance the diagnostic ability of the PET agent.
Development of Ga-68 Labeled Amino Acids and Nitroimidazole Derivatives
Jae Min Jeong
Seoul National University College of Medicine 101 Daehangno Jongno-gu, Seoul 110-744, Korea
Ga-68 is an excellent positron emitter for future applications. We developed Ga-68 labeled amino acid and nitroimidazole derivatives for imaging cancer and hypoxia, respectively. The chemical structures of the conjugates were proved by X-ray crystallography. Various amino acid derivatives labeled with C-11 or F-18 have been reported to image cancer tissues. These amino acid derivatives have been proved to be transported into cancer cells through the amino acid transporters. We synthesized amino acid derivatives conjugated with NOTA or DOTA. The compounds were labeled with Ga- 68 and found all of them to be stable. NOTA derivatives showed lower protein binding than DOTA derivatives, which is important for rapid washout from blood and whole body. NOTA-homoaminoalanine showed the highest tumor/non-tumor ratio among the derivatives and showed the best tumor image in xenografted mice. Hypoxic tissues are generated essentially as the tumor grows. To image the hypoxic tissues, we developed Ga-68 labeled novel nitroimidazole derivatives. Nitroimidazole was conjugated to NOTA or DOTA via various linkers. The synthesized compounds were labeled with Ga-68 and found that NOTA derivatives have lower protein binding than DOTA derivtives. These labeled compounds were tested in vitro cell uptake and in vivo tumor uptake. We proved that the Ga-68-labeled nitroimidazole derivatives were taken up by hypoxic tumor cells both in vitro and in vivo.
Ga-68-labeled Peptides Targeting G-protein Coupled Receptors: Agonists versus Antagonists
Department of Nuclear Medicine, University Hospital Freiburg, Germany
Aim: Radiolabeld peptides are important ligands for imaging and targeted radionuclide therapy. Somatostatin based peptides are the prototypes of these radiopeptides and provide distinct improvement in regard to patient care. In particular Ga-68-labeled octapeptides (such as DOTA-TOC/TATE and NOC)became the preferred modalities to image neuroendocrine tumors using PET/CT. Recently other peptides were also developed for PET imaging with Ga-68; for instance peptides of the bombesin family in particular those targeting the gastrin releasing petide (GRP) receptor overexpressed on major human tumors. Also the GLP-1 receptor proved to be of interest allowing to image and preoperatively localise small insulinomas with SPECT tracers but also labeled with Ga-68. These peptides are potent agonists, show quick receptor mediated internalisation into tumor cells and good image contrast. Agonists were therefore considered preferable to antagonists. But antagonists are known to possibly label a larger number of binding sites than agonists which may compensate for the lack of internalisation. We studied preclinically and clinically agonists and antagonists comparatively.
Materials and Methods: Peptides were synthesised using solid phase peptide synthesis. Chelators (DOTA and NODAGA) were coupled to the resin assembled peptide. Binding affinities were determined as IC(50)-values using 125I-Tyr4-bombesin as radioligand. Agonist and antagonist potency were determined using calcium flux measurements and immunofluorescence microscopy. Nude mice were xenografted with tumors expressing the respective receptors. First in-human use studies of neuroendocrine tumors and prostate cancer were performed and will be presented.
Results: Peptides were synthesised with 30-35% yield based on the first amino acid. Ga-68 labelings of the NODAGA-conjugates were done at room temperature and DOTA-conjugates at 100°C with comparable specific activities. Known structural motifs to convert an agonist to an antagonist were used to develop antagonistic peptides. The affinity of the peptides depended on chelators and even radiometal, in particular in case of somatostatin based antagonists. Tumor uptake in the xenografted mice was usually higher using radioantagonists. Surprisingly the retention time in the tumors was long despite lack of internalisation. Translation into the clinic seemed warranted and first human studies in neuroendocrine tumors and prostate cancer look very promising and confirmed the animal data in regard to tumor uptake, retention and image contrast.
Summary: Ga-68 labeled peptides seem to become a new class of radiopharmaceutical due to the availability of the radionuclide from a generator system and the appropriate half-life of Ga-68 which matches the pharmacokinetics of peptides. Surprisingly antagonistic peptides may be superior to agonists, a change in paradigm. They certainly deserve further scrutiny in preclinical and clinical studies.
Ga-68 Labeled Nanoparticles, Peptides and Phage Display Selected Peptides for PET Imaging of Cancer
Cathy Cutler, Nebiat Sisay, Melchor Cantorias, Ajit Zambre, Mark McLaughlin, Goerge Smith, Susan Deutscher, Silvia Jurisson, Raghuraman Kannan, Kattesh Katti
University of Missouri, 1513 Research Park Drive, Columbia, MO 65211, USA
Aims: The availability of Ga-68 from a generator plus its ability to be stably incorporated with a variety of chelates hold promise for expanding PET utilization to facilities unable to afford their own cyclotron. In collaboration with researchers at the University of Missouri, we have developed and evaluated nanoparticles and peptides for guided imaging and therapy.
Objectives: Receptors are over-expressed by a variety of human cancers such as breast, lung, pancreatic and prostate tumors. There has been a concerted effort to develop site-directed imaging agents using peptide vectors and nanoparticles, which demonstrate high affinity and selectivity for receptors. Our aim is to radiolabel a peptide analog or nanoparticle with high specific activity Ga-68. Gallium-68 is a positron emitter which allows for quantitative imaging. A 68 Ge/ 68 Ga generator prototype has been modified to supply carrier-free Ga-68 free of metals. Using phage display techniques we have developed peptides that are avid for galectin-3 a family of galactoside-binding animal lectins overexpressed by various types of human cancers most improtantly breast cancer. Additionally we have investigated a novel pretargeting aproach using phage display to develop peptides that are radioconjugate avid and bind a modified DOTA chelate thorugh a cyteine near its N-terminus.
Materials and Methods: Nanoparticles and peptide analogs, were radiolabeled in 0.1 M NH4OAc with Ga-68 (pH 4, 100°C) under water-bath incubation. Additionally, Ga-68 reactions were performed in a circular microwave reaction cavity (Resonance Instrument Model 520A-1) to reduce reaction time. Radiolabeling yield was determined by TLC and HPLC. The in vitro stability of the formed complex was evaluated in rat serum and hydroxyapatite at 37°C.Reversed-phase HPLC conditions were developed to purify the labeled peptides. EDTA challenges were performed to assess stability of labeling. Radiolabeled complexes were further evaluated for stability in serum over time.
Results: The synthesis of Ga-68, via water-bath incubation for 20 min, produced Ga-68 radiolabeled complexes with 87% or higher radiochemical purity. Preliminary results for the microwave labeling were similar to the water-bath technique but the labeling process was completed in about two min. Stability was assessed to be 80% or higher when chalnged by serum, hydroxyapatite and EDTA.
Conclusions: We have successfully labeled peptides and nanoparticles with high specific activity Ga-68 using the standard water-bath heating as well the circular microwave. Complexes were shown to be stable in serum over a 4 hr time period and are going to be further evaluated in animal models.
Pretargeted Immuno-PET of Colorectal Cancer with Bispecific Antibodies
Otto C. Boerman, Rafke Schoffelen, Robert M. Sharkey, C-H. Chang, William McBride, Wim J. Oyen, David M. Goldenberg
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands and Garden State Cancer Center, Belleville, NJ, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands
Aim of the Study: To improve the tumor targeting of radiolabeled antibodies pretargeting strategies have been developed. In our pretargeting strategy the tumor is pretargeted with an anti-CEA × anti-HSG bispecific antibody and the tumor is targeted with a radiolabeled di-HSG peptide. In our studies we aimed to determine the potential of pretargeted immuno-PET to image colorectal cancer.
Materials and Methods: The anti-CEA × anti-HSG trivalent bispecific antibody (TF2) was used to pretarget CEA-expressing LS174T tumors in nude mice. Mice were i.v. injected with TF2 and 16 hours later with Ga-68-labeled diHSG peptide or with F-18-labeled diHSG peptide. One or two hours after the injection of the radiolabeled peptide, PET/CT images were acquired. Pretargeted immuno-PET imaging was compared with 18F-FDG-PET imaging in mice with a s.c. LS174T tumor and contralaterally an inflamed thigh muscle. Furthermore, the sensitivity of pretargeted immuno-PET was determined in mice with intraperitoneally growing LS174T tumors.
Results: Pretargeted immuno-PET resulted in high and specific targeting of the Ga-68-labeled diHSG peptide in the tumor (10.7±3.6% ID/g), with very low uptake in the normal tissues, the CEA-negative tumor (0.35±0.35% ID/g), and inflamed muscle (0.72±0.20% ID/g). Tumors that were not pretargeted with TF2 had low uptake of the Ga-68-labeled diHSG peptide (0.20±0.03% ID/g). As early as 1 h postinjection of the radiolabeled peptide the tumor-to-blood ratio in these mice exceeded 60. The corresponding PET/CT images of mice that received Ga- 68 or F-18-labeled diHSG peptide following pretargeting with TF2 clearly showed the efficient targeting of the radiolabeled peptide in the LS174T tumor, while the inflamed muscle was not visualized. In contrast, with 18F-FDG the tumor as well as the inflammation was clearly delineated. The Ga-68-labeled peptide also accreted efficiently in the pretargeted intraperitoneally growing tumor nodules (23.4±7.2% ID/g, 1 h p.i.). Background activity levels were low: tumor/intestines 57.5±22.4, resulting in clear visualization of the small intra-abdominal tumor lesions (1.5-5 mm). F-18-FDG localized efficiently in the tumors (8.7±3.1% ID/g), but with physiological uptake in various normal tissues (tumor/intestines 4.0±0.9).
Summary: Pretargeted immune-PET imaging of CEA-expressing tumors using anti-CEA × anti-HSG trivalent bsAb in combination with the Ga-68-labeled HSG-substituted peptide reveals excellent PET images of s.c. and i.p. LS174T tumors within 1 h after injection. Pretargeted immuno-PET potentially could be a sensitive method to visualize CEA-expressing tumors in patients.
Ga-68 labeled PET Tracers for Studying Pathophysiological Properties of the P-glycoprotein
Oliver Thews, Marco Fellner, Wolfgang Dillenburg, Frank Rösch
Institute of Physiology, University of Halle, Magdeburger Str. 6, 06112 Halle (Saale), Germany
Aim of the Study: The p-glycoprotein (Pgp) is the most prominent member of active drug transporters leading to a multidrug resistant phenotype of tumors. On the other hand, solid tumors are known to exhibit an acidic extracellular pH due to forced glycolytic metabolism. In vitro it has been shown previously that the functional activity of the Pgp is markedly increased by an extracellular acidosis with pH of 6.5 (a value found in experimental an human tumors). In this Pgp activation MAP kinases (p38, ERK1/2) seem to play an important role for signal transduction. However, it was unclear whether these effects are also relevant in vivo.
Materials and Methods: For imaging the Pgp activity a new Ga-68 labeled PET tracer (the Schiff΄base ligand complex (Ga-68)MFL6.MZ) was developed which serves as a substrate of the Pgp. Therefore, its intracellular concentration is inversely correlated with the Pgp transport rate. For in vivo studies, subcutaneously implanted experimental tumors (R3327-AT1 prostate carcinoma of the rat) were imaged with the Ga-68 tracer under acidic conditions and during inhibition of p38- or ERK1/2-MAP kinases in a μ-PET system. Therefore, tumors were acidified artificially either by inspiratory hypoxia (8% O2) or by injection of lactic acid. Inhibitors of MAPKs were injected directly intratumorally.
Results: In vitro, (Ga-68)MFL6.MZ showed a high accumulation within the cells of about 20% which was increased to 30% by Pgp-inhibition using verapamil as a specific Pgp inhibitor indicating that the intracellular tracer accumulation reflects inversely the functional Pgp activity. Perfoming analog experiments in solid tumors in vivo showed a marked tracer uptake. Direct intratumoral injection of verapamil increased the tracer concentration by ~25% reflecting the functional changes of Pgp activity. Within the tumor, spatial heterogeneity of the tracer distribution was found which might reflect regional differences in Pgp-mediated transport. With increasing tumor volume the tumor pH went down and in parallel the Pgp activity was increasing almost linearly. When the tumors were acidified artificially by direct lactic acid injection, the PET-tracer accumulation was reduced by 20% indicating a higher transport rate out of the cells. Changing the inspiratory O2-fraction to 8% led dynamically to a reduction of the extracellular pH and in parallel to a reduced tracer concentration. Inhibition of the p38 pathway increased the tracer concentration by 70% indicating a reduced Pgp-mediated transport rate. However, inhibition of ERK1/2 had practically no impact.
Summary: The new Ga-68 labeled tracer is suitable for PET-imaging of the tissue Pgp activity. With this tracer it becomes possible to identify patients with multidrug resistant tumors pre-therapeutically. In vivo imaging reveals that an acidosis activates the Pgp markedly, a mechanism in which the p38-MAPK pathway seems to play a role. From these results new strategies for overcoming multidrug resistance (e.g., reducing tumor acidosis, inhibition of p38) may be developed.
Click Cyclized Ga-68 Labeled MSH Peptides for Imaging Medulloblastoma
Molly E. Martin 1 , M. Sue O'Dorisio 1 , Whitney M. Leverich 1 , Kyle C. Kloepping 2,3 , and Michael K. Schultz 2,3
1 Department of Pediatric Hematology/Oncology, Carver College of Medicine, The University of Iowa; 2 Department of Radiology, Carver College of Medicine, The University of Iowa; 3 Department of Radiation Oncology (Free Radical Radiation Biology Program), Carver College of Medicine, The University of Iowa, USA
New α-melanocyte stimulating hormone (α-MSH) peptide analogs have been synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition "click" chemistry techniques. α-MSH analogs are promising ligands for targeting the G-protein coupled receptor (GPCR) family of melanocortin receptors (MCRs), which we recently identified as upregulated in medulloblastoma - the most common form of brain tumor in children. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor bearing mice using a murine melanoma cell line that highly expresses the MC1R receptor. The new DOTA-conjugated click-cyclized analogs exhibited high binding affinity (<2 nM) to melanocortin receptor subtype 1 (MC1R) expressing cells in vitro, high stability in human serum, and produced high contrast PET images of tumor xenografts. The results indicate that the triazole linkage is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radiometals or stable metals for molecular imaging and therapy. Both the propargylglycine and azido-lysine residues were stable to all steps of the peptide synthesis and selective for the click cyclization, eliminating the need for side-chain protection/deprotection. The results of these studies advance our efforts in the development of molecular targeting for imaging and therapy of medulloblastoma in children and demonstrate a click chemistry approach for effective cyclization of these α-MSH analogs for molecular imaging and therapy applications.
Radiometals for Therapeutic Application: Availability and Future Prospects
ITG GmbH - Isotope Technologies Garching GmbH, Lichtenbergstr. 1; 85748 Garching, Germany
The increasing demand for medical radionuclides of high quality that is needed for radiolabeling has significantly accelerated efforts in radiochemical research and industrial activities. Especially the development of novel generator systems and production routes is aimed to enable access to novel PET and therapeutic isotopes. Currently 68 Ga-labeled PET-tracers and 90Y- and 177Lu-based radiotherapeutics are utilized on routine basis and are valuable diagnostic and therapeutic tools in nuclear oncology. High-energy beta emitter 90Y (T½=64.1 h; Eβ-max=2.3 MeV) can be produced via 90Sr/90Y radionuclide generator and is already commercially available in GMP-quality. An attractive alternative is the reactor produced 177Lu (T½=6.71 d; Eβ-max=0.5 MeV). The low-energy of beta particles, emitted by 177Lu results in less side-effects during the therapy. In addition the radionuclide provides a small amount of photons useful for SPECT. 177Lu can be obtained by neutron irradiation of enriched 176Lu. Since the target material cannot be separated the available specific activity is, however, limited. Due to a side reaction long lived 177mLu (T½ 160d) is accumulated during the irradiation and reduces the radionuclidic purity of the preparation. As alternative neutron irradiation of enriched 176Yb can be applied. After subsequent chemical isolation of 177Lu from the target material the radionuclide can be obtained with the highest specific activity and radionuclide purity. Recently we developed and implement high-scale production of high-quality 177Lu via the 176Yb-route at Munich facility. For further optimisation of the therapeutic treatments alpha-emitters are considered to be very useful. Limited availability of those radionuclides decelerates, however, further development of alpha radionuclide therapy. We are currently implementing high activity 225Ac/213Bi radionuclide generator systems for routine production of the short-lived alpha emitter 213Bi (T½ 45.6 min). Produced 213Bi is effectively used for radiolabeling of DOTA-conjugates. Immediate availability of medical radioisotopes of appropriate quality must be guaranteed for the systematic development and application of innovative radiopharmaceuticals.
Lu-177-BPAMD and Ga-68-BPAMD: THERANOSTICS for Bone Metastases
Marco Fellner, Richard P. Baum, Vikas Prasad, Vojtěch Kubíček, Petr Hermann, Frank Rösch
Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany
Aim of the Study: Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are well established ligands for 99mTc for planar and SPECT/CT imaging of osteoblastic metastases. A macroyclic bisphosphonate (BPAMD) is of high interest for PET, using the 68 Ge/ 68 Ga generator derived 68 Ga as well as for endoradiotherapy with 177Lu.
Materials and Methods: The bisphosphonate DOTA-like ligand BPAMD [1,2] was labelled first with 68 Ga. [ 68 Ga]BPAMD was investigated in vivo on healthy rats and bone metastases bearing animals by μ-PET. First clinical trials were performed to show significance of the tracer compared to [18F]fluoride PET. Changing the radionuclide from 68 Ga to 177Lu allowed following radionuclide therapy using [177Lu]BPAMD already applied to human patients.
Results: μ-PET experiments revealed high accumulation of [68 Ga]BPAMD in regions of pronounced remodelling activity like bone metastases in a bone metastases animal model. Consequently, [ 68 Ga]BPAMD was injected i.v. into a patient with known extensive bone metastases of prostate cancer. [ 68 Ga]BPAMD revealed intense accumulation in multiple osteoblastic lesions in the central skeleton, ribs and proximal extremities and high SUV max compared to [18F]fluoride. The change from 68 Ga to 177Lu showed high accumulation of [177Lu]BPAMD in bone lesions as well together with fast blood clearance in patients.
Summary: BPAMD is of great interest for diagnosis and therapy of bone metastases. Using 68 Ga for PET diagnostics and 177Lu for endoradiotherapy this bisphosphonate is a perfect example for a theranostic development. This gives medical doctors the opportunity to have diagnosis and therapy with one highly potent molecule together with the advantage of an enhanced dosimetry calculation.
1. Kubíček V et al. J Am Chem Soc. 2005;127:16477-85
2. Vitha T et al. J Med Chem. 2008;51:677-83
3. Fellner M et al. Eur J Nucl Med Mol Imag. 2010;37:834
Radiolabeled GRPR-antagonists: New Promising Tools in the Diagnosis and Therapy of GRPR Positive Tumors
Theodosia Maina 1 , Berthold A. Nock 1 , Richard P. Baum 2 , Eric P. Krenning 3 , Marion de Jong 3
1 Molecular Radiopharmacy, IRRP, NCSR "Demokritos", 2 Department of Nuclear Medicine, Center for PET/CT, Zentralklinik Bad Berka, Germany; 3 Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands, 153 10 Athens, Greece
Aim of the Study: Radiolabeled bombesin analogs have been evaluated for use in diagnostic imaging and radionuclide therapy of GRPR-expressing human tumors, such as prostate and breast cancer (GRPR: gastrin releasing peptide receptor). Owing to their high internalization efficiency radiolabeled bombesin-like agonists were believed to cause amplification of the diagnostic signal and also to enhance the therapeutic effects on tumors in animals and patients. Recent evidence, however, has shown that GRPR-antagonists exhibit a very rapid background clearance which is often combined with a high and prolonged residence time on the tumor. These qualities in combination with the observed lack of adverse reactions after iv administration of radiolabeled GRPR-antagonists may completely change our view on the clinical applicability of GRPR-antagonists. A few comparative examples on the performance of radiolabeled GRPR-antagonists versus agonists in preclinical models and in patients are presented below.
Materials and Methods: A series of bombesin (BB) and neuromedin C (NMC) analogs were synthesized, modified with tetraamines (N4) or DOTA at their N-terminus for stable binding of 99mTc or trivalent radiometals (111In, 68 Ga, 90Y, 177Lu), respectively. These analogs were compared with already well established (99mTc-Demobesin 1) and new GRPR-antagonists. Peptide analogs were labeled with 99mTc (N4-conjugates) or with 111In, 68 Ga/ 67 Ga, 177Lu (DOTA-conjugates) and their properties were studied in GRPR+-cells and animals bearing human prostate adenocarcinoma (PC-3) xenografts. Selected radioligands were administered in prostate cancer patients and diagnostic imaging was performed.
Results: All radiolabeled BB and NMC analogs showed good affinity and high internalization rates in PC-3 cells in vitro, while radiolabeled GRPR-antagonists - despite their equally high or better affinity for the human GRPR - showed poor internalization rates in PC-3 cells. In mice bearing human PC-3 xenografts the highest in vivo uptake values were achieved by antagonists. In contrast to BB and NMC-based radioligands, all radiolabeled GRPR-antagonists showed rapid body clearance, especially from kidneys and the GRPR+-mouse pancreas, thus showing excellent pharmacokinetic profiles. During preliminary "proof-of-principal" clinical studies these preclinical findings translated well into excellent delineation of metastatic lesions in prostate cancer patients. Highly sensitive detection of very small metastatic lesions, especially lymph node metastases <8 mm in diameter was possible with PET/CT.
Summary: Our perspectives on the clinical usefulness of radiolabelled GRPR-antagonists for diagnostic imaging and radionuclide therapy of human tumors underwent a profound re-assessment due to continuously emerging evidence on their superior pharmacokinetics over internalizing agonists. In addition to their better tolerability in man radiolabelled GRPR-antagonists may thus provide higher contrast images and perhaps also higher therapeutic efficacy. Ongoing studies will eventually reveal the value, benefits and limitations of their use in the clinic.
Ga-68 Imaging in Clinical Practice - The European Experience
Katharinen hospital, Klinikum Stuttgart, Kriegsbergstr. 60, 70174 Stuttgart, Germany
Since more than 20 years somatostatin receptor scintigraphy (SRS) is a well-established technique for functional imaging of neuroendocrine tumors (NET). To date, five human somatostatin receptor subtypes (ssr1-ssr5) are known showing differences in their expression on NET and their affinity for somatostatin analogues. Most of NET express the ssr2, which is mainly addressed by the scintigraphically used somatostatin analogues so far. The first and most commonly used somatostatin analogue for functional imaging using planar gamma camera scintigraphy was (In-111)DTPA-octreotide (OctreoScan® ). However, the spatial resolution of SRS, even when SPECT is performed, is comparably low (1.5 - 2 cm for In-111). The better spatial resolution of positron emission tomography (3-5 mm) and ease of quantification clearly favours PET compared to conventional scintigraphy and with the introduction of hybrid PET/CT scanners this combined morphological and functional imaging approach has become one of the most rapidly growing techniques. The possibility to label somatostatin analogues with Gallium-68, a cyclotron-independent generator product, revolutionized the role of nuclear medicine and PET/CT in the diagnostic work-up of NET. The principal and possible clinical applications of this new approach were first described in the literature by a German group in 2001. This has stimulated the development of specific peptides and the clinical investigation of Ga-68 SSR PET and PET/CT imaging in NET in many European centers. (Ga-68)DOTA-TOC, (Ga-68)DOTA-TATE and (Ga-68)DOTA-NOC are so far the most commonly used peptides in Europe which can be easily, quickly and meanwhile automated labelled with Ga-68 with high radiochemical purity. Since 2001, SSR PET and PET/CT imaging has been shown to be a valuable tool for tumor localization (in patients with suspicion for NET but no pathological findings in conventional imaging) and staging/re-staging of NET because of its high sensitivity especially for small GEP NET and for the detection of bone and lymph node metastases. Furthermore, this method and the ease of quantification have contributed to a more precise evaluation of patients eligible for specific therapies like biotherapy with cold somatostatin analogues or for peptide receptor radionuclide therapy (administration of the same peptides, however, labelled with therapeutic nuclides such as Yttrium-90 or Lutetium-177 for treatment of inoperable metastasized NET). First results on treatment monitoring with SSR PET/CT also point to advantages of PET/CT over conventional imaging alone. Ga-68-labelled somatostatin analogues, therefore, significantly improved the diagnostic work-up of NET and became the tracers of first choice for imaging in many German but also European NET centers. The development of somatostatin analogues for PET with high affinity to a broader range of ssr and also the introduction of Ga-68-labelled peptides (e.g. glucagon-like peptide, gastrin-releasing peptide) targeting other tumor specific receptors might further improve the diagnosis and therapy of NET in the future.
Ga-68 Imaging in Clinical Practice - The Indian Experience
Jaslok Hospital and Research Centre, Mumbai, India
Aim: To review the Indian experience with Ga-68 imaging.
Materials and Methods: Data was collected on Ga-68 scans performed at 3 centres in India with the facilities available for somatostatin receptor PET-CT imaging, with reference to number of scans and acquisition and reporting protocols and encountered difficulties and spectrum of cases.
Results: 3 centres in India: AIIMS (New Delhi), BIO (Bangalore) and Jaslok Hospital (Mumbai) routinely perform Ga-68 somatostatin receptor PET-CT since 2007. Approximately 1536 Ga-68 somatostatin receptor PET-CT scans have been collectively done in India to date. (881 AIIMS, 465 BIO, 190 Jaslok). Ga-68-DOTATATE is the main agent used at Jaslok while Ga-68-DOTANOC is used at AIIMS and BIO. Tracer activities range from 500uci to 3 mci. Scanning was performed at 60 minutes post injection (range 30-90 min). Mostly whole body diagnostic CT scans with oral and i.v. contrast were obtained along with the PET acquisition; each scan taking 20-25 min. Patient was off long acting somatostatin analogues for at least a month prior to scanning. Majority of the scans were non functioning neuroendocrine tumors (41%) carcinoids (27%), insulinomas (12%), and pheochromocytomas/neuroblastomas (17%). Good to excellent quality images were obtained.
Summary: Ga-68 somatostatin receptor imaging has proven very useful in diagnosis and management of a wide spectrum of neuroendocrine neoplasms in Indian setting.
68 Ga-DOTATATE PET/CT for the Evaluation and Followup of Patients with Neuroendocrine Tumors. Pioneering Experience in Latin-America
H. Amara l , M.C. Gil 2 , H. Lavados 1 , F. Redondo 1 , R. Pruzzo 1 , H. De la Fuente 1 , M. Mahave 1 , I. Coudeu 1 , S. Astudillo 1 , R. Galaz 1 , C. Chamorro 1
1 Nuclear Medicine and PET/CT, Surgery and Chemotherapy Departments of Oncologic Institute Arturo Lopez Perez Foundation; 2 CGM Nuclear; Santiago, Chile, Rancagua 878, Santiago, Chile
Introduction: Neuroendocrine Tumors (NET) share the special characteristic of over-expressing somatostatin receptors (SR) in the cell surface, especially receptor sub-type 2. These receptors can be identified on planar and SPECT images with 111In-octreotide. Since the 80's 111In-octreotide has been the most frequently used radiopharmaceutical and has become a milestone in Nuclear Medicine because of its capability of detecting specifically SR in whole body images. Nevertheless, this radiopharmaceutical has certain limitations, mainly secondary to intrinsic physical properties, limited availability and high cost. The new imaging technique consistent on fusion of positron emission tomography and computed tomography (PET/CT) has imposed around the world because of its capability to produce high resolution anatomic and functional information in just one exam. On the other hand there has been a revival of 68 Ge/ 68 Ga generators that allow local and permanent 68 Ga production with a lower cost that 111In. 68 Ga is positron emitter radionuclide with a 68 minute half life with clear advantages for the labelling somatostatin analogue peptides. The purpose of this presentation is to communicate our pioneer experience in Latin-American in the utilization of this new technology.
Materials and Methods: In the last 2 years we have performed 271 whole body 68 Ga-DOTATATE PET/CT in 201 patients, 105 men and 96 women (52.4±15.1 years) with histologically proven NETs. After the elution of a 68 Ge/ 68 Ga generator, 68 Ga-DOTATATE was obtained by means of a semiautomatic labelling process. The radiopharmaceutical was purified and filtered in C18 columns during the process. Final quality control was performed with TLC-Al SG chromatography. Fifty minutes after IV administration of 3.6±0.62 mCi of 68 Ga-DOTATATE (CGM Nuclear) PET/CT images were registered in a Siemens Biograph 6 HiRez P3D, with SUV measurement of the lesions observed. The reference diagnosis of the patients was: gastro-entero-pancreatic NET in 159, medullar thyroid cancer in 12, bronchial carcinoid in 10, rectal carcinoid in 6, carcinoid syndrome with unknown primary in 6, Cushing's syndrome in 3, MEN I in 2, GIST in 1, pheochromocytoma in 1 and thymic carcinoid in 1. The indication of the study was staging in 37%, restaging in 21.1%, unknown primary in 14.3%, follow up in 14.2% and therapy control in 13.4%.
Results: Radiochemical purity of the radiopharmaceutical was always over 99%. In all patients PET/CT images were of excellent quality allowing a precise localization of the lesions. No secondary effects or adverse reactions were observed. Tumor localization was: liver in 28.4%, abdomen and lymph nodes 18.1%, pancreas 11.0%, bone 8.9%, ileum/appendix 5.0%, mediastinum 5.0% and others 23.6%.
Conclusion: 68 Ga-DOTATATE PET/CT presents a series of advantages over traditional studies with planar or SPECT 111In-Octreotide. In our experience its main benefits are: 3D PET/CT images of substantial superior quality in less than 2 hours, semi-quantitative evaluation of tumor activity by means of SUV measurements, permanent availability of the radiopharmaceutical, simple labelling process, lower patient dosimetry and lower cost in places with no local production of 111In.
Ga-68 Imaging in Clinical Practice: The Singapore Experience
A.K. Padhy, D. Ng, S.P. Thang, T.Y. Kok, B. Magsombol, S. Yu, M.M. Saw 1 , A. Goh
Singapore General Hospital, Singapore and 1 Clinical Imaging Research Centre, National University of Singapore, Singapore
The incidence of NET in Singapore is <5 per 100,000 person per year (world-wide incidence is 1 per 100,000). Singapore is a city state with a population of about 5 million. Practice of Nuclear Medicine is of reasonably high quality with 8 nuclear medicine centres/departments/units providing routine clinical nuclear medicine service. Singapore has at present 5 centres with PET/CT facilities (Total number of PET scanners=7). With respect to radionuclide imaging and therapy of neuro-endocrine tumors, four departments in the city provide limited diagnostic imaging services with In-111 Octreotide. Very rarely we treat neuroendocrine tumors with radionuclides. From 1997 to 2009, SGH Department of Nuclear Medicine had performed only 59 Indium-111 Octreotide scans for neuroendocrine tumors. However with the introduction of Ga-68 DOTA TATE PET/CT imaging our referral rate is increasing quickly and we are performing more and more neuroendocrine tumor imaging. Since March 2009 we have performed a total of 110 studies on 87 patients. The main indications include: Initial diagnosis (reassessment after other routine investigations failed to detect the disease), staging and follow up evaluation to assess response to therapy. The most common site of NET in our series is pancreas followed by lung and bowel. We also have used the procedure in a few thyroid cancer patients to detect non-iodine concentrating and somatostatin receptor expressing thyroid cancers. Since October 2010 we also have done a few Ga-68 DOTA NOC studies. But due to non-availability of radiopharmaceutical grade DOTA NOC we have suspended this service for the time being. As a result of increasing use of Ga-68 DOTA TATE imaging for neuroendocrine tumor assessment, our visibility has also increased in the hospital's neuroendocrine tumor boards. We have recently obtained funding to build a new facility for PRRT and if everything goes according to the plan we should introduce PRRT as a clinical service in SGH in the next 3-4 months. In the form of Carcinoid and Neuroendocrine Tumor Society (CNETS) of Singapore, our region has an excellent support group for neuroendocrine tumor patients, family caregivers, researchers and physicians. The group has its headquarters in Singapore. The primary focus of this organisation is to establish an online resource which spans Asia Pacific borders to provide 24/7 support for the community. Its current online resources include a complete library of video recordings from neuroendocrine medical conferences. A wiki is planned, to tap the experience of patients, caregivers and physicians throughout the region. A few research activities, both applied as well as basic, are also currently being undertaken in the field in various institutions of the city state. These include in-house development and QC of Ga-68 DOTANOC and Ga-68 -DOTA-Bombesin for NETs at the National University Hospital Singapore. Singapore is also participating in an IAEA CRP on development and QC of Ga-68 radiopharmaceuticals. The NUH has an ongoing project on "development of automated synthesis in collaboration with Faculty of Engineering and MMS. The Singapore Bio-imaging Consortium (SBIC) is currently engaged in a few pre-clinical imaging projects (micro-PET), which include Ga-68 labeled apoptosis imaging agents and Ga-68 labeled new agents for Alzheimer's disease. All in all we are now on the verge of starting our Ga-68 SSR Imaging and PRRT clinical service in a much wider scale and in a highly comprehensive manner in Singapore, not only to serve the population of Singapore but also the region.
Ga-68 Imaging in Clinical Practice - The Australian Experience
Centre for Cancer Imaging, Translational Research Group, Molecular Imaging and Targeted Therapeutics Laboratory, The Peter MacCallum Cancer Centre, Melbourne, Australia
68 Ga-DOTATATE PET Imaging for Neuroendocrine Tumors: The First American Experience
Eric H. Liu 1 , Jeff Clanton 2 , Bill Martin 2 , Dominique Delbeke 2 , Martin Sandler 2 , Ron Walker 2
1 Departments of Surgery; and 2 Radiology and Nuclear Medicine, Vanderbilt University, Nashville, TN, USA
Background: Somatostatin analogue (SA) imaging has been used successfully in the diagnosis and evaluation of patient with neuroendocrine tumors. In the United States, the only SA imaging commercially and widely available is as the standard of care is 111In-octreotide SPECT/CT scan (Octreoscan). However, international experience with SA based PET scanning with 68 Ga has demonstrated great promise in higher sensitivity, resolution, and ease of administration.
Materials and Methods: 68-Ga was eluted from a 69 Ge/ 68 Ga generator (Eckert and Ziegler Eurotope GmbH) and labeled to DOTA-octreotate (ABX). Five millicuries were injected within 15 minutes of labeling and a fixed dynamic scan performed over the liver for forty-five minutes. Then a whole body scan was performed. Vital signs were taken before and after the scan.
Results: Two patients underwent 68 Ga-DOTATATE PET/CT scanning. The first patient is a 60 y/o female with known recurrence of neuroendocrine tumors in the liver with no known primary. The liver tumors were cystic on standard cross-sectional imaging (CT/MRI). The second is a 63 y/o female with known metastatic midgut carcinoid already treated with two rounds of 177Lu-PRRT. In the first patient, 68 Ga was able to demonstrate that the cysts were in fact neuroendocrine metastases. In addition, it identified four more tumors than were evident on CT (showed five). She underwent debulking surgery with all lesions seen with 68 GaDOTATATE PET/CT confirmed intraoperatively, and with no lesions missed. In the second patient, scanning confirmed metastatic neuroendocrine tumor with disease in the chest, liver, and mesentery. In both patients, United States standard of care imaging based on 111In-octreotide SPECT/CT scans could not clearly identify all the lesions.
Conclusions: 68 Ga-SA PET scanning is superior to standard SA imaging. Our two cases support its use as an imaging modality in neuroendocrine tumors. We are currently working to open a clinical trial on 68 Ga-DOTATATE PET/CT imaging in the diagnosis and staging of patient with neuroendocrine malignancies.
Ga-68 Imaging in Clinical Practice - The Mexican Experience and Rest of the World
E. Estrada Lobato
Nuclear Medicine and Molecular Imaging Department of the National Institute of Cancer, Mexico City, Mexico
Combined PET/MR Imaging for 68 Ga-Labeled Tracers: A Case Study for 68 Ga-DOTATOC in Meningioma Patients
T. Beyer, D. Thorwarth 1
Imaging Science Institute Tübingen, Germany, 1 Section for Biomedical Physics, University Hospital for Radiation Oncology, Eberhard-Karls-University Tübingen, Germany
Hybrid imaging is a stakeholder of medical diagnosis and therapy planning. Hybrid imaging relates to the correlation of two (or more) complementary imaging information, such as functional and anatomical imaging. Such correlation can be performed retrospectively - based on independently acquired data sets (software fusion), quasi-simultaneously - based on combined imaging (PET/CT, SPECT/CT) or simultaneously - based on integrated PET/MR. Here we present first results from employing a fully-integrated PET/MR tomography for intensity-modulated radiotherapy (IMRT) treatment planning in patients with meningioma using [ 68 Ga]-DOTATOC as the biomarker of choice. Combined PET/MR tomographs are available as prototype solutions for imaging the brain and upper neck region since 2006. Since late 2010 PET/MR imaging is possible also for extra-cranial applications. Combined PET/MR offers higher soft-tissue contrast, the ability to add non-imaging information (spectroscopy, dynamics, functional response) to the plain combination of MR-based anatomy and PET-based metabolic and functional information. Furthermore, fully-integrated PET/MR employs PET technology that is not available in PET-only or PET/CT systems, and, therefore, boosts higher spatial sensitivity and resolution. Our preliminary data demonstrate logistical and diagnostic benefits of integrated PET/MR-based treatment planning over PET/CT in meningioma patients.
Within the next years, we may expect to see PET/MR gaining momentum and finding a place in the realms of standalone and hybrid imaging in clinical routine. This advance can be fostered by the adoption of highly-specific PET tracers that expose less anatomical background information on PET-only as [18F]-FDG, for example. Hybrid imaging by means of PET/CT and PET/MR will be mandatory when using 68 Ga-labeled tracers. Despite the current lack of broad clinical evidence, integrated PET/MR may become particularly important and clinically useful for improved, individualized therapy planning for brain lesions and neurodegenerative diseases.
PET/CT-Guided FNAC Biopsy (Metabolic FNAC/Biopsy) Using Automated Robotic Arm
Rakesh Kumar, Sunil Jeph, Arun Malhotra
Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
A precise morphologic diagnosis is essential for the planning of treatment and the prognosis of malignant pathologies. This can be achieved by tissue sampling of suspected mass. The sampling of tissue can be obtained by various techniques depending on its location. The tissue can be obtained without much difficulty from superficial mass/es which are easily accessible. However, when suspected pathology are in the body cavities or deep seated, tissue sampling is difficult without any help of imaging modalities like computed tomography (CT), ultrasound (USG) etc. Since most of the conventional radiological imaging techniques provide only structural details, sometimes it is difficult to obtain correct tissue for diagnosis by these image guided procedures. Aspirate from necrotic and benign areas are inconclusive or false negative resulting into either a repeat study which has the same probability of inconclusive result as the previous one or incorrect staging of the disease. PET-CT provides both functional and anatomical details and helps to direct the needle to the desired site more accurately and consistently. There are some reports using PET to guide correct biopsy in the literature. We investigated the feasibility and accuracy of PET-CT guided biopsy/ fine needle aspiration cytology (FNAC) using automated robotic arm attached with PET-CT scanner. Till date more than 60 patients, underwent PET-CT guided biopsy/FNA using automated robotic arm attached with PET-CT scanner at All India Institute of Medical Sciences, New Delhi. Consent was obtained from all the patients before the procedure. All patients were suspected/confirmed cases of cancer had abnormal PET-CT scan. In all patients conventional imaging modalities like ultrasound and/ or computed tomography were either unable to demonstrate lesion or repeated biopsy/FNAC was inconclusive. Technique involved acquisition of PET-CT data of region of which Biopsy/FNAC is being planned. Transfer DICOM images to computer attached with Robotic arm. Display images and select image where lesion is best seen. Set target on lesion and point of entry on the image. All the calculations regarding depth, angle of entry of needle were sent to robotic arm attached with PET-CT scanner. We have followed all the precautions which are required to do a minor surgical procedure or biopsy like admitting patient for short duration, prothrombin time etc. We were successful to obtain good sample tissues for diagnosis in analysis in the most of the cases. We have done all cases for doing biopsy/ FNAC except brain biopsy. Only in about 4 cases we could not get enough samples which can be processed and reported. At present we are analyzing our data for a possible publication in a journal.
- Based on the results of this study we concluded that PET-CT guided biopsy/FNA using automated robotic arm attached with PET-CT scanner is unique, feasible, and easy to perform.
- Using PET-CT it is very easy to take tissue sample from viable tumor tissue.
- Automated robotic arm helps in better accuracy, precision and confidence to users.
Ventilation/Perfusion Scans Using Ga-68 Labeled Tracers
Joerg Kotzerke 1 , Michael Andreeff 1 , Gerd Wunderlich 1 , Philipp Wiggermann 2 , Klaus Zöphel 1
Department of 1 Nuclear Medicine, 2 Institute of Diagnostic Radiology, University Hospital Carl Gustav Carus, Dresden, Germany
Aim of the Study: Imaging of lung perfusion with positron emission tomography (PET) is already possible with Ga-68 labelled macroaggregated albumin (MAA). The purpose of our study was to produce and test a Ga-68 labelled aerosol (Galligas® ) for ventilation imaging with PET and Ga-68 labelled microspheres for perfusion investigations.
Materials and Methods: Galligas was produced by simmering and burning generator-eluted Ga-68 solution (100 MBq/0.1 ml) in an ordinary Technegas generator. Fifteen patients with suspected pulmonary embolism (PE) underwent PET/CT after inhalation of Galligas and injection of Ga-68 labelled microspheres. A low-dose CT was acquired for attenuation correction (AC). Images were reconstructed with and without AC. The inhaled activity was calculated with regard to the activity injected.
Results: Galligas demonstrated a biodistribution comparable to Technegas with homogeneous distribution in the lungs without hilar deposits. Artefacts at the lung bases occurred in a few attenuation corrected images. Therefore, non-corrected images were used for reporting. Three out of fifteen patients showed perfusion defects with preserved ventilation corresponding to PE.
Summary: Lung sctingraphy with PET is feasible. Galligas is simple to produce (analogous to Technegas). Ga-68 labelled microspheres are available by a modified fast process in high yields. The method is applicable to daily routine and provided clinically relevant information.
Radioguided Surgery in Neuroendocrine Tumors using Ga-68 Labeled Somatostatin Analogues- A Pilot Study
Daniel Kaemmerer, Vikas Prasad, Stefan Senftleben, Richard Paul Baum, Merten Hommann
Department of General and Visceral Surgery, Zentralklinik Bad Berka, Robert-Koch-Allee 9, 99437 Bad Berka, Germany
Aims: Previous studies of the intraoperative use of a hand-held gamma probe to localize metastases and primary tumors have shown improved assessment of tumor spread and changes in surgical management based on additional information gained by radioguided surgery (RGS).
Purpose: The aim was to test the feasibility and advantages of doing RGS using a 68 Gallium labeled with somatostatin receptor (SMS-R) analoges in the intraoperative detection of neuroendocrine tumors (NET).
Materials and Methods: 68 Ga -SMS-R PET/CT imaging was performed preoperatively in 9 patients with gastroenteropancreatic neuroendocrine tumors. Statistical analyses were performed to find out the correlation between the pathological size of the tumor lesions and the maximum standardized uptake value (SUV max ) on PET/CT as well as the target/non-target ratio (T/NT) of gamma probe counts. Thereafter the impact of the planned operation procedure and the lesion based sensitivity of tumor detection (surgical palpation vs PET/CT vs gamma probe) had been observed.
Results: Overall, 72 locations in 9 patients were examined intraoperatively using Gamma-probes. The gamma probe detected 94% of the whole histologically quantified lesions whereas the PET/CT allocated 69% and surgical palpation, 50%. RGS resulted in change in the operative procedure in 56%. There was a significant correlation between the SUV max and tumor size (0.74; P<0.005).
Conclusion: Hand-held gamma probe surgery using 68 Ga-labeled somatostatin analoges is a feasible and an attractive option for real-time detection of small metastases and primaries of neuroendocrine tumors.
Somatostatin Receptor PET vs. Its PET Competitors in the Diagnosis and Management Strategy of Patients with Neuroendocrine Tumors, According to the Clinical Context and the Type of NET
J.N. Talbot 1,3 , F. Montravers 1,3 , V. Nataf 2,3 , A. Prignon 3 , K. Kerrou 1 , V. Huchet 1 , O. Pascal 1 , L. Michaud 1 , S. Balogova 1,4
1 Médecine Nucléaire, 2 Radiopharmacie, 3 LIMP (preclinical PET), Hôpital Tenon and Université Pierre et Marie Curie, Paris, France; 4 University Comenius, Bratislava, Slovakia
Even though neuroendocrine tumors (NET) share some common histological and biochemical features, those neoplasms constitute a heterogeneous group. Well-differentiated and slowly growing tumors are the most common, but poorly differentiated and malignant neoplasms have an aggressive behaviour. NET tend to express hormonal activity according to their origin, but some NET tumors are devoid of hormonal function. In addition to a specific hormone, various tumor markers can be expressed unevenly by NET tumors, such as chromogranin A or neuron-specific enolase. Non-specific raise of their serum levels can occur and should be checked, in particular high chromogranin A levels in case of treatment by proton pump inhibitors. In our experience, there is currently no PET tracer which would be common and best for all NET. It is therefore misleading to compare the performance of PET tracers in series associating patients with different neuroendocrine tumors. According to the proportion of the various NET types in the series, very discrepant results can be obtained. In contrast, prospective studies are necessary to determine the best strategy for the diagnosis and localisation of the NET tissue, according to the clinical context and the type of NET. We will try to summarise the currently available data and evidence for a tailored strategy of PET imaging in NET.
Several PET tracers demonstrated significant performance in NET imaging:- tracers for aggressive or advanced NET, currently FDG, since FLT has been shown to be of poor sensitivity even in those aggressive types. Data support FDG as the best first line PET tracer for small cell lung cancer, Merckel cell carcinoma, patients with a mutation in the succinate-dehydogenase B subunit (SDHB) gene in search for aggressive paraganglioma or metastatic phaeochromocytoma, and more generally poorly differentiated or aggressive NET; - tracers of noradrenaline transporter, in particular fluorodopamine (18F) (FDA), accumulating similarly as MIBG, is rarely available but may become a PET equivalent for MIBG since MIBG (124I) is irradiating. It has been shown to be sensitive in case of SDHD mutation; - analogue of aminoacid DOPA tracing the cathecolamine pathway, FDOPA is a registered PET tracer. It has currently shown the best performance and impact on patient's management in case of hyperinsulinism in infants for revealing a nodular form which can be resected, in case of phaeochromocytoma or paraganglioma in particular with the SDHD mutation, in case of occult biological recurrence of medullary thyroid cancer, in case of well-differentiated carcinoid of the ileon or occult production of serotonin. Somatostatin receptor (SR) ligands for PET (DOTATOC, DOTANOC, DOTATATE.) have been shown to be the best first choice for digestive non-carcinoid NET, in particular well-differentiated gastric, duodenal or pancreatic NET (including insulinoma in adults), where they have better performance than FDOPA, and also bronchial carcinoids in combination with FDG. For post-surgical monitoring, the best tracer should be chosen according to the receptor subtypes in the resected NET. SRPEt also has the advantage to delineate targets for internal radiotherapy with 90Y or 177Lu. Having a 68 Ge/ 68 Ga generator available would make SRPET much cheaper than FDOPA, and a potential first line examination in case of abdominal phaechromocytoma or MCT where it can reveal FDOPA-negative lesions. Conversely, FDOPA can be used as an "independent" assessor of the effectiveness of internal radiotherapy with MIBG (131I) or SR ligands. In case of NE metastasis without primary tumor or of ectopic hormone production (ACTH in particluar), FDG, SRPET or FDOPA may be used to detect the primary, according to the location of the metastasis and to hormonal activity.
Glucagon-like Peptide-1 (GLP-1) Receptor PET Imaging Using Ga-68 Labeled GLP-1 Analogues
Department of Nuclear Medicine, University Hospital Freiburg, Huggstetter Strasse 55, Germany
Strong over-expression of GLP-1 receptors in human pancreatic β cells an in insulinoma provide an attractive target for imaging. This is relevant since the preoperative localisation of insulinomas remains a challenge whilst serial measurements of function β cell mass (BCM) may improve monitoring of novel diabetes therapies such as islet cell replacement. After extensive preclinical evaluation of different 111In labelled GLP-1 receptor imaging tracers, the most promising probe, 111In-DOTA-exendin-4, was selected for a first in man study. This novel probe was then prospectively evaluated in the management setting of benign and malignant insulinoma. An additional proof of concept study was performed in a patient after intramuscular transplantation of islet cells. In this study 111In-DTPA-exendin-4 planar scintigraphy could visualise functioning human islet cells autotransplanted in the forearm muscle. However, the focal radioactive signal at the transplantation site was rather low, which might limit accurate quantification of the BCM in vivo. One possibility to overcome this limitation is the use of a GLP-1 receptor PET tracer as PET imaging is superior over planar and SPECT in terms of sensitivity and spatial resolution. Future research should therefore aim at developing PET tracers for GLP-1 receptor imaging. A first GLP-1 receptor PET tracer, 68 Ga-DOTA-exendin-4, has been recently evaluated in a preclinical setting. In that study small GLP-1 receptor expressing tumors with a diameter between 1.5 and 2.3 mm could be visualised confirming the high sensitivity of the PET tracer. However, the clinical use of 68 Ga-DOTA-exendin-4 is limited by its relatively low specific activity (13 GBq/μmol). For example, more than 40 μg 68 Ga-DOTA-exendin-4 will be needed for the preparation of only 100 MBq 68 Ga-DOTA-exendin-4. The administration of such an amount of exendin-4 is not recommended because of possible GLP-1 receptor saturation and adverse effects. The DOTA chelator was therefore replaced by novel bifunctional chelators (NODAGA and CP256) that are particularly useful for 68 Ga labelling at a high specific activity (>30 GBq/μmol). CP256 is a novel Gallium chelator which allows labelling at room temperature with a very high specific activity (>100 GBq/μmol). The higher specific activity allows reducing the administration of the peptide amount, without compromising image quality. In conclusion, these data suggest that 68 Ga-NODAGA-exendin-4 and/or 68 Ga-CP256-exendin-4 will be suitable GLP-1 receptor PET tracers for GLP-1 receptor imaging.
Milestones in Preclinical Applications and Future Developments Regarding Somatostatin Analogues
Marion de Jong
Department Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands
Selective receptor-targeting radiopeptides have emerged as an interesting and powerful class of radiopharmaceuticals for molecular imaging and therapy of tumors that overexpress peptide receptors on the cell membrane. After injection in patients, such peptides labeled with gamma-emitting radionuclides bind to their receptors, allowing visualization of receptor-expressing tumors non-invasively. Peptides labeled with beta-particle emitters or other therapeutic radionuclides are applied for therapy to eradicate receptor-expressing tumors. The prototypes of radiopeptides are radiolabelled somatostatin analogues. The somatostatin analog 111In-DTPA-octreotide permits the localization and staging of neuroendocrine tumors that express the appropriate somatostatin receptors. Newer modified somatostatin analogs, including Tyr3-octreotide and Tyr3-octreotate, are successfully being used for tumor imaging and for radionuclide therapy for more than a decade. Molecular imaging using stabilized somatostatin analogues now plays an essential role in balancing the clinical benefits and risks of radionuclide-based cancer therapy. To effectively treat individual patients, careful assessment of biodistribution, dosimetry, and toxicity is essential. Advances have been made over the last decade that combine features of molecular imaging and radionuclide therapy to provide new avenues toward individualized cancer treatment. In this presentation, some of the major steps in preclinical development and clinical translation of radio-somatostatins will be highlighted. Current status and future development of new peptide analogues, use of different radionuclides for PET, SPECT and radionuclide therapy, animal models, animal imaging, reduction of renal uptake and therapeutic strategies in preclinical models will be discussed.
PRRT with Lu-177[DOTA,Tyr3]Octreotate
Erasmus Medical Center, Rotterdam, The Netherlands
Somatostatin Receptor Imaging (SRI) with [111In-DTPA0]octreotide has proven its role in the diagnosis and staging of GastroEnteroPancreatic NeuroEndocrine Tumors (GEPNETs). Treatment with radiolabeled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized, well differentiated neuroendocrine tumors. Symptomatic improvement may occur with all 111In, 90Y, or 177Lu-labeled somatostatin analogues that have been used for Peptide Receptor Radionuclide Therapy (PRRT). The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side-effects of this therapy are few and mild, and the median duration of the therapy response for these radiopharmaceuticals is 30 and 40 months, respectively. The patients' self-assessed quality of life increases significantly after treatment with [177Lu-DOTA0,Tyr3]octreotate. Lastly, compared to historical controls, there is a benefit in overall survival of several years from time of diagnosis in patients treated with [177Lu-DOTA0,Tyr3]octreotate. These data compare favourably with the limited number of alternative treatment approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable GEPNETs.
PRRNT - The Swiss Experience
Jan Mueller-Brand, F. Forrer, H. Rasch, S. Kneifel, G. Nicolas, T. O`Dorosio, H. Maecke, M. Walter
Department of Nuclear Medicine, University Hospital Basel, Switzerland
The Peptide Receptor Radionuclide Therapy - PRRNT- was worldwide first administered in Basel to a patient in autumn 1996 using 90 Yttrium - DOTATOC. The primary goal was to stabilize progressive GEP-NET tumor in a 40 years old patient refractory to conventional chemotherapy. Since then over 1900 patients has been treated at the University Hospital in Basel. The analysis of 1.109 patients was recently published in Journal of Clinical Oncology (JCO, epub may 9 th 2011). Response to the therapy, survival and safety profile were investigated. All patients has been treated with 2 cycles of 90 Y- DOTATOC using 3.7 GBq / m 2 body surface in 6-8 weeks interval. Kidney protection with amino acid was performed in each patints following a standard protocol. Of 1,109 patients 34% experienced morphological response, 16% biochemical reponse and 30% clinical response to the 90 Y- DOTATOC therapy. Longer survival was correlated with each (morphological, biochemical and clinical) response. Thirteen percent of the patients developed transient haematological toxicity, and 9% permanent renal toxicity (grade 4 and 5). Tumoral uptake on initial scintigraphy was predictive for overall survival, whereas the initial kidney uptake was predictive for renal toxicity. In conclusion, our long term analysis on a large group of patients with NET documents a longer survival in patients who responds to the treatment. Furthermore, initial somatostatin receptor imaging is predictive for both, survival and the occurrence of renal toxicity after 90 Y- DOTATOC therapy.
Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues: The Milano Experience
Lisa Bodei, Giovanni Paganelli
Nuclear Medicine Division, European Institute of Oncology, Milano, Italy
Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues, 90Y-DOTATOC and 177Lu-DOTATATE, has been experimented in neuroendocrine (NETs) and non neuroendocrine sst2-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 90Y-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 haematological 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 90Y-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 177Lu-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 enrolment. Partial and complete responses occurred in 15/46 (32.6%) assessable patients. Median 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 undergone to 90Y-DOTATOC or 177Lu-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 haematological toxicity with the increase of the bone marrow dose, showed, for 90Y-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 90Y-DOTATOC and 177Lu-DOTATATE. We demonstrated that lymphoid toxicity mainly affected B-cells, particularly after 90Y-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 177Lu-DOTATATE plus the radiosensitizer capecitabine, administered with a metronomic schedule, in patients with aggressive NETs. Our group is developing phase II protocols evaluating the therapeutic potential of both 90Y-DOTATOC and 177Lu-DOTATATE and the optimal schedule in terms of dosage per cycle and interval between cycles. In the future, phase III protocols comparing 90Y-DOTATOC versus 177Lu-DOTATATE and PRRT versus conventional therapies will help clarifying the position of PRRT in the therapeutic algorithm of NETs.
PRRNT - The German Experience
Dieter Hörsch, R. P. Baum
ZBB Bad Berka, Robert Koch Allee 999437, Bad Berka, Germany
Peptide receptor radiotherapy is highly efficacious for treatment of somatostatin receptor expressing neuroendocrine tumors. Here we will report first results of a nationwide registry including 297 patients from Bad Berka, Rostock, Munich, Bonn and Hannover. Patients underwent 1-8 cycles with DOTA-TOC or DOTA-TATE chelated either to 99-Yttrium or 177-Lutetium. Most of the tumors originated from pancreas, small bowel or were of unknown primary. Mean age of the patients was 57 years. Most tumors were well differentiated with a mean Ki 67 of 9%. Previous therapies were available in 218 patients. Of these, 44 had no previous therapy, 112 had undergone 1 or 2 previous therapies, 44 3-4 and the rest had up to 8 previous therapies. Of these 218 patients, 93 experienced no surgery, whereas 225 were operated 1-4 times. Medical therapy prior to PRRNT was not performed in 104 patients, 1 and 2 medical therapies was performed in 17 and 34 patients respectively, and 9 patients had undergone up to 7 previous medical therapies. Local ablative therapy and external beam radiotherapy was performed seldomly in 20 and 14 of the 218 patients. Preliminary results was available for 190 patients. Of these, response was not yet available for 30 patients in the records at the institution and institution performing PRRNT and is currently investigated. Complete remission, partial remission and minor remission was reported for 10, 27 and 1 of these 190 patients. Most patients experienced stable disease (93/190) and a minority (20/190) progressive disease. These results indicate that PRRNT is highly effective when performed in specialized institutions. The register will be continued for several more years to collect results on progression free survival, overall survival and side effects.
PRRNT - The Austrian Experience
Irene Virgolini, Daniel Putzer, Dietmar Waitz, Berhard Nilica, Tatjana Traub-Weidinger, Alexander Kroiss, Michael Gabriel, Roy Moncayo, Elisabeth V. Guggenberg, Clemens Decristoforo
Department of Nuclear Medicine, Medical University of Innsbruck and Vienna, Annichstrasse 35, Australia
In Austria, PRRNT was first performed at the Vienna University in 1995 using high-dose 111In-DTPA-octreotide. In 1997, we initiated a trial named "MAURITIUS" (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative: a European Study) using 111In-DOTA-lanreotide for diagnosis / dosimetry and 90Y-DOTA-lanreotide for therapy. A total of 235 progressive NET patients received 90Y-DOTA-Tyr3-lanreotide either intravenously (n=121; accumulated dose: 0.8 - 8.5 GBq, up to 7 cycles; 1-2 GBq per cycle), intratumorally/cavitary (n=93; accumulated dose: 0.6-2 GBq, 1-6 cycles) or intraarterially (n=21; accumulated dose: 2 GBq, 1-3 cycles). Partial remission (PR) was reported in 16%, stable disease (SD) in 37% and progressive disease (PD) in 47% (major centers were Innsbruck, Cesena, London and Milano). In 1998, 90Y-DOTA-Tyr3-octreotide treatment was established at both the Vienna and Innsbruck Universities, and 177Lu-DOTA-Tyr3-octreotate PRRNT was initiated in 2003. At the new therapy ward in Innsbruck more than 1000 PRRNTs were applied in the years 2006-2010 (663 177Lu-DOTA-TATE, 497 90Y-DOTA-TOC, 18 90Y-DOTA-LAN) in a total of 255 patients (205 patients had NETs). In general, dosimetry is performed in all patients prior to PRRNT for individualized treatment. We use individually adapted doses and time intervals depending on tumor stage, tracer uptake, biochemical response, Karnofsky index, quality of life measures. Follow-up is performed every 6 months using 68 Ga-DOTA-TOC PET/CT as well as 18F-FDG PET/CT for metabolic staging, chromogranin for biochemical response assessment, as well as EORTC scoring. For NET patients the rate of PR/CR was 20% for 90Y-DOTA-TOC and 27% for 177Lu-DOTA-TATE. Minor remission (MR) was observed in 6% of patients for 90Y-DOTA-TOC and in 15% for 177Lu-DOTA-TATE. SD was seen in 50% for patients treated with 90Y-DOTA-TOC and in 35% of patients for 177Lu-DOTA-TATE. Thus, the overall response rate for both theranostics was about 75% in metastasized NET patients. Side effects were rare and quality of life was maintained in most patients.
PRRT: The UK Experience
Addenbrooke's Hospital, Cambridge, UK
The development of radiopeptide therapy in the UK paralleled the development in most other European countries. However due to the unique form of socialized medicine organised within the UK there are particular aspects that influenced how PRRT developed. These include organisation; education and peptide availability. Organisation: The main contribution of the Royal Free Hospital to the development of the treatment of NETs within the UK was the development of the first multi-disiplinary clinic in NETs which involved a holist approach to treatment. This meant that in any clinic appointment a NET patient may meet a gastroenterologist, surgeon, oncologist, nuclear medicine physician, endocrinologist, cardiologist, specialist nurse and dietician. This approach led to this clinic becoming the prime UK clinic for NET patients seeing over 1500 patients. Education: The next step was to educate both clinicians and patients. So working with colleagues across London and then UK wide 2 parallel organisations were set up. The first was UKINETS which co-ordinated care across the UK and set up central labs for Chromogranin A etc and centralised pathology reporting standards. The second was the patient's organisation "Living with carcinoid" this was run by the patient's and their families but linked to UKINETS. Peptide availability: This was the most difficult task, whilst centres such as Rotterdam and Basle kindly provided some doses of active peptide the number of available doses that could be provided represented a tiny fraction of the need. So centres such as the Royal Free and Liverpool set up manufacturing of Y-90 DOTATATE, which for legal reasons, could only be used locally. The availability of radiopeptide remains the main stumbling block to the advance of PRRT in the UK. An additional problem is financial with no clear understanding on how these complex treatments will be funded in the future.
Polish Experience in Peptide Receptor Radionuclide Therapy
Jolanta Kunikowska 1 , Leszek Królicki 1 , Anna Sowa-Staszczak 2 , Alicja Hubalewska-Dydejczyk 2 , Dariusz Pawlak 3, Renata Mikołajczak3 , Daria Handkiewicz-Junak 4, Norbert Szaluś5, Grzegorz Kamiński5, Jarosław Ćwikła6, Maciej Jakuciński7 , Anna Lukiewicz 8 , Aldona Kowalska 8, Paweł Gut10
1 Nuclear Medicine Department, Medical University of Warsaw, Poland; 2 Chair and Department of Endocrinology and Nuclear Medicine, Jagiellonian University Collegium Medicum, Cracow; 3Institute of Atomic Energy POLATOM, Świerk-Otwock, Poland; 4 Department of Nuclear Medicine and Endocrine Oncology, Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Gliwice Branch, Gliwice; 5 Nuclear Medicine Department, Military Institute of Medicine, Warsaw, 6 Department of Radiology and Diagnostic Imaging, Medical Centre for Postgraduate Education and Central Clinical Hospital of Ministry of Internal Affairs and Administration, Warsaw; 7 Nuclear Medicine Department Bródnowski Hospital; 8Department of Nuclear Medicine and Endocrine Oncology, Maria Skłodowska-Curie Memorial Cancer Center, Institute of Oncology, Warsaw Branch, Warsaw; 9 Department of Endocrinology and Nuclear Medicine Holycross Cancer Centre (HCC), Kielce; 10Department of Endocrinology, Metabolism and Internal Diseases, Poznań University of Medical Sciences, Banacha 1 a, 02-097 Warsaw, Poland
Peptide radionuclide therapy with radiolabelled somatostatin analogues (PRRT) is promising treatment options for patients with disseminated or inoperable neurondocrine tumors (NET) First PRRT in Poland was performed in April 2004 in Nuclear Medicine Department Warsaw Medical University. Now this procedure is used in 10 Nuclear Departments in Poland.The labeling procedures and quality control were performed in Institute of Atomic Energy POLATOM, Świerk-Otwock. Between 04.2004 - 12.2010 about 1200 therapeutic doses of DOTATATE labeled with 90Y, 177Lu and 90Y/177Lu were prepared (71% of 90Y-DOTATATE, 17% 177Lu-DOTATATE and 12% 90Y/177Lu-DOTATATE). During that time 339 patients underwent PRRT. Therapy was performed on an out and in -patients basis. Following protocols was used: in 3 departments calculated doses up to 7.4 GBq/m 2 in 3-5 cycles, 4-8 weeks interval in the rest fixed doses 3-4 × 2.96 GBq or 4 × 3.7 GBq each 6-10 weeks, 4 × 2.96 GBq 90Y DOTATATE, every 12 weeks; for 177 Lu DOTATATE 3-5 × 7.4GBq each 8-12 weeks. In respect of tandem therapy with 90Y/177Lu DOTATATE two protocols were used 1:1 or 3:1 activity of 177Lu DOTATATE : 90Y DOTATATE. Because of amount of patients we included to analysis the results of therapy is 5 Departments (n=239)
Majority of patients underwent 90Y DOTATATE therapy (n=177) with PFS/TTP 17 -44 months and OS was 22- 34.2 months(in 2 studies not reach). In that patients 12 months follow up revealed: stable disease(SD) in 46 - 60% patients, disease regression (RD) 16-35% patients, disease progression(PD) was observed 7-17% patients and completed response (CR) 3%.
In patients treated with 90Y/177Lu DOTATATE (n=44) PFS/TTP was 24.2- 28.3 months and OS was 49.8 - 52.8 months. On 12 months follow up revealed: SD in 62-70% patients, RD 15-20% patients, PD was observed 10-12% patients. The treatment was well tolerated. No severe adverse events occurred. According to WHO hematological toxicity criteria in patients treated with 90Y-DOTATATE grade 3 toxicity (in WBC and PLT) during therapy was seen in 6-20% patients, but on 12 months follow up only in 3-8% of patients. In that group renal toxicity grade 3 was seen in 5-12% and grade 4 in 3- 8%In patients treated with tandem therapy with 90Y/177Lu DOTATATE or 177Lu DOTATATE alone, hematological and renal toxicity grade 3 or 4 was not observed. Mean creatinine clearance (CrCl) decrease was 6.1-7.2 ml/min per year in patients treated with 90Y DOTATATE, 2.7-3.4 ml/min per year in patients treated with 90Y/177Lu DOTATATE and 1.7 ml/min per year in patients treated with 177Lu DOTATATE.
Conclusions: The results indicate that nevertheless used procedures and isotope PRRT is effective and safe therapy option for patients with metastatic or inoperable neuroendocrine tumors. Our result suggest that tandem therapy with 90Y/177Lu DOTATATE provides to longer overall survival time and event free survival time than single isotope. Hematological toxicity was rare in all treated patients. Renal toxicity grade 3 and 4 was observed only in group treated with 90Y DOTATATE. However, more extensive studies with a larger number of patients in the same protocol are required to evaluate PFS and OS, and to establish the proportion of each isotope to be used in tandem therapy.
COST Action BM0607 on Targeted Radionuclide Therapy, Oct 2007- Oct 2011
Marion de Jong
Department of Nuclear Medicine and Radiology, Erasmus MC, Rotterdam, The Netherlands
This COST EU Action in the domain of Biomedicine and Molecular Biosciences is is a collaboration of many groups from 22 countries. The main objective of this Action in to improve the potential of cancer therapy through the development and application of innovative vectors labelled with therapeutic radionuclides for 'targeted radionuclide therapy' of disseminated cancer. The vectors used are based on monoclonal antibodies (or derivatives thereof), peptides, affibodies, amino acids or small organic molecules with well-defined tumor associated molecular targets. Besides the therapeutic probes, also imaging probes based on the same vectors are and have been developed/applied in order to allow pre-therapeutic imaging for patient-specific dosimetry and therapy planning as well as for therapy monitoring. A good example of the networking capacities of the Action can be found in the CCK/gastrin project. This project was established to select the optimal gastrin/CCK analogues for targeting different tumors expressing the CCK2 receptor. Twelve compounds of interest have been identified and labelling, affinity (IC50) measurement, receptor binding and internalisation, stability determination, biodistribution studies, and small animal imaging studies using standardized protocols have been performed. This study has been described in 4 peer-reviewed papers. Other important work that has been finished comprises the building of databases of well-characterized molecular targets with potential for TRNT, ideal target characteristics, in vitro and in vivo models, and radionuclide characteristics and availability, it has been published on the website of the Action. Small animal imaging, quality control, dosimetry and radiobiology issues are also items of high interest. Collaborative work has started on different generator systems and in addition 2 training school have been organized on this subject. The so-called short term scientific missions are very popular in the Action and appeared very powerful instruments to exchange techniques and expertise. More information on the Action can be found at: http://www.cost.esf.org/domains_actions/bmbs/Actions/BM0607-Targeted-Radionuclide-Therapy-TRNT-End-date-October-2011and at http://www.irist.org/bm0607/index.php.
Bad Berka Dose Protocol (BBDP): Results in 350 Patients with a Routinely Applicable Protocol for Dosimetry in PRRNT
C. Schuchardt, H. Kulkarni, C. Zachert, R.P. Baum
Department of Nuclear Medicine, Center for PET/CT, Zentralklinik Bad Berka, Germany
Aim: There are only few treatment options for inoperable or metastasized gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). The majority of well-differentiated NETs express somatostatin receptors (SSTR) which can therefore be visualized and treated with radio-labeled somatostatin analogues (SSTA). Due to encouraging clinical results, peptide receptor radionuclide therapy (PRRNT) with radiolabelled SSTA is now a well established treatment modality in advanced NETs.
The Medical Internal Radiation Dose Scheme (MIRD-scheme) provides, together with measurements of the biological distribution, a method for calculating absorbed doses of radionuclides. But the optimal dose estimations require time-consuming and sophisticated methods, including pharmacokinetic biodistribution as well as wash-out studies. This may be difficult owing to practical purposes mostly related to patient status as well as for physical reasons. Nevertheless, to make dosimetry available for most of the patients, we developed a convenient procedure which is based on the MIRD-scheme and is quite practical in our daily clinical routine.
Materials and Methods: The kinetics of the radiopharmaceutical were determined on the basis of five planar whole body scintigraphies in defined time order after administration (p.i.): the first scan was acquired immediately after infusion, further scans at 3h, 20h, 44h and 68 h p.i. The scintigraphies were analyzed by the use of regions of interest (ROI). After geometric mean and background correction, time dependent time-activity curves were obtained and fitted to mono- or bi exponential functions. The residence time and cumulated activity as well as the uptake and effective half life were then calculated and the mean absorbed doses were estimated by using the OLINDA/EXM software. 321 dosimetric studies of 211 patients were analyzed. All patients enrolled in this study were suffering from metastatic NETs with liver, lymph node, bone or other organ involvement. Intense SSTR expression of (inoperable) primary tumors and metastases had been verified before therapy by using 68 Ga DOTANOC, DOTATOC or DOTATATE positron emission computed tomography (PET/CT). For therapy, the patients received either Lu-177 DOTATATE/-TOC or -NOC. We analyzed the dosimetric results of each peptide, compared the kinetics and mean absorbed doses between the different peptides and determined the intra- and inter-patient variability.
Results: From the studies concerning the comparison of the dosimetric results in PRRNT using the Lu-177 labelled peptides DOTATATE/-NOC and -TOC, following were the salient findings:
Additionally we found a large inter- and intra-patient variability when comparing the results of 25 patients receiving both, Lu-177 DOTATATE and -TOC in successive cycles. Also other patients, who received more than one cycle of therapy using Lu-177 DOTATATE or DOTATOC, showed variable kinetics and no increasing or decreasing order of dosimetric results for consecutive therapies was found.
- The in-vitro higher affinity of DOTANOC correlates with the in-vivo higher uptake in whole body and normal tissue, which results in the higher whole body dose and is therefore not suitable.
- Concerning kidney uptake and mean absorbed dose to normal organs and whole body, DOTATOC revealed the highest tumor to kidney ratio and is very appropriate for PRRNT.
- Lu-177 DOTATATE was shown to deliver the highest tumor dose and is also very suitable.
Conclusion: The dosimetric results of our large cohort of patients demonstrate that the estimation of mean absorbed doses to critical organs and tumor lesions is an important factor to evaluate the risks of PRRNT and therefore to describe the clinical benefit for the patient. But as large ranges of the results emerge even in the relatively large group of patients, it is recommended that median values of absorbed doses among patients should not be the only criterion to plan the PRRNT. Besides, the inter-individual differences should be taken into account, particularly organ functionality, metabolism or receptor density in organs and tumor lesions. Finally we conclude that individual patient dosimetry in PRRNT is absolutely necessary in order to find the optimal therapy procedure.
4D SPECT/CT Acquisition for 3D Dose Calculation and Dose Planning in Lu-177-Peptide Receptor Radionuclide Therapy
Kalevi Kairemo, Timo Kiljunen, Joakim Pyyry, Aki Kangasmäki
Internationational Comprehensive Cancer Center Docrates; Saukonpaadenranta 2, FI-00180 Helsinki, Finland
Molecular radiotherapy combines the potential of a specific tracer (vector) targeting the tumor cells within the local radiotoxicity. Designing a specific tumor-targeting/killing combination is a tailor-made process. Radionuclides with imaging capacity serve best in selecting the targetor molecule.
The potential of targeted therapy with radiolabeled peptides has been reported in many conditions, peptide receptor radionuclide therapy (PRRT) is already part of Scandinavian guidelines in treating neuroendocrine tumors. Lu-177 and Y-90 labelled somatostatin analogs, to which DOTATOC, DOTANOC and DOTATATE belong, are most commonly used and have turned out to be effective. For routine use an efficient, rapid and reliable dose calculation tool is needed, which is here described.
In this work we studied serial pre- and post-therapeutic scans for dose calculation and for predicting therapy doses. Our software for dose radionuclide dose calculation is a 3-dimensional, voxel based system. The 3D dose calculation requires co-registered SPECT image sets from several time points after the infusion to reconstruct time activity curve for each voxel. The image registration is done directly by SPECT image registration using the first time point as a target. From time-activity curves, initial activity and total half life maps are calculated to produce cumulated activity map. The cumulated activity map is then convolved with voxel-dose kernel to get 3D dose map. We performed dose calculation similarly for both therapeutic and pre-planning images. Preplanning dose was the extrapolated to predicted therapy dose using ratio of administered activities. Our 3D dose calculation results were also compared with OLINDA.We used approximately 200 MBq Lu-177-DOTA-FCFWLTCTate for serial imaging at 1, 24 and 72 and/or 1 68 hrs using amino acid kidney protection (25 g L/l, 25 g R/l). Similar conditions were applied for post therapeutic scanning after receiving approximately7.4 GBq of the Lu-177-labelled compound. We used OLINDA and own software for actual dose calculation. Tumor to background -ratios based on SPECT/CT in liver varied from 4:1 to 15:1.The tumor doses varied from 2 to 100 Gy and normal organ doses in kidneys 3 -12 Gy, normal liver 2-15 Gy, spleen 2-20 Gy per cycle using post-therapeutic scans. Our preliminary results indicate dose planning pre-therapeutic scanning can predict critical organ and tumor doses. In some cases the dose planning prediction resulted in a slight, and slightly dose-dependent, overestimation of final therapy dose. Real tumor dose was similar in both pretherapeutic and posttherapeutic scans using our software. The OLINDA software and our programme gave similar normal organ doses, whereas tumor doses could be calculated in a more detailed manner using the 3-D program. Thus dose planning in advance requires new tools. Basic problem is the possible change in radiopharmacokinetics when the activity comes 40-fold and the specific activity is the same. Also improvement of the pre-planning image quality could result in better predictions. In a multicenter study, this extrapolation factor may be calculated in an appropriate manner.
Dosimetry Assessment in Y-90 Peptide Targeted Radiotherapy: Y-86 and Y-90 Imaging
Stephan Walrand, Stanislas Pauwels, François Jamar
Nuclear Medicine Center, Université Catholique de Louvain, Brussels, Belgium
The essential step for dosimetry assessment in 90Y internal radiotherapy is to quantify the therapeutic compound distribution. This can be achieved by pre-therapeutic PET imaging of the 86Y labeled compound, or by directly imaging, using PET or SPECT, the therapeutic compound after a first cycle considered as safe. Quantitative 86Y PET imaging is hampered by the low positron fraction (30%) and the huge abundance of high energy prompt single γ rays (300%) inducing spurious coincidences not removed by the random coincidences correction techniques. This results in tissue activity overestimation that can overpass 100% depending on the patient corpulence. Correction methods can be divided into two major classes: projection tail fitting (linear or quadratic interpolation) and global tail fitting (modified scatter, empiric or analytical kernel convolution). Global tail fitting methods have the benefit to be more robust and, contrary to projection tail fitting, were validated on realistic size phantoms. In 90Y-DOTATOC therapy, the empiric kernel convolution provided fine dose-toxicity relationship for the kidney and red marrow, and good dose-response relationship for the tumors. These last 2 years, quantitative imaging of the low positron emission branch of 90Y (3 10-5) by PET was proved feasible. A PET acquisition of a phantom modeling a 90Y-DOTATOC 120mCi cycle provided an accurate kidney and tumor dosimetry. But the sensitivity was too low to allow the red marrow dosimetry assessment that can however be monitored by measuring the platelet count reduction at the nadir. Very recently, pinhole collimator proved superior to parallel hole collimator in 90Y bremsstrahlung SPECT and should also allow kidney dosimetry assessment. Compared to 86Y, 90Y imaging after each cycle has the benefit to account for the tumor shrinkage and kidney function alteration between the different cycles. In conclusion different methods exist to assess the individual patient dosimetry in 90Y internal radiotherapy. Their systematic use should allow optimizing the activity to be injected, resulting in an improvement of the patient outcome and in return, to a further development of internal radiotherapy.
Renal Protection and Toxicity Related to Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumor
Vikas Prasad, Richard P. Baum
Department of Nuclear Medicine, Center for PET/CT, Zentralklinik Bad Berka, Germany
Peptide receptor radionuclide therapy (PRRNT) with radiolabeled somatostatin analogs is effective in patients with somatostatin receptor-positive neuroendocrine tumors. However, because these peptides are primarily eliminated through the kidneys, fear of nephrotoxicity often limits the amount of radioactivity that can be safely administered. Loss of renal function and end-stage renal disease (ESRD) have been reported after PRRNT with 90Y-1, 4, 7,10-tetraazacyclododecane- N,N',N'',N'''-tetraacetic acid (DOTA),Tyr3-octreotide (90Y-DOTATOC). Radiolabeled somatostatin analogs are efficiently reabsorbed by cells in the proximal tubule of the nephron, where a significant amount of radioactivity is retained. Data acquired during external-beam radiation therapy indicate that a radiation dose of 23 Gy to the kidneys, in fractions of about 2 Gy, leads to a 5% risk of renal failure in patients within 5 years, which increases to 50% when the dose is increased to 28 Gy. However, these figures cannot be directly translated to PRRNT with radiolabeled somatostatin analogs, since PRRNT is characterized by a sustained but lower radiation dose rate, for a longer duration, as compared to radiation therapy. It is, therefore, important to observe renal function over a long period of time after PRRNT in order to assess the long-term risk of clinically significant loss of renal function and to ascertain the co-existing risk factors which might independently influence the effect of PRRNT on kidney function. Additionally better understanding of the mechanism of blocking the uptake and retention of radiolabelled peptides in the kidney for nephroprotection during PRRNT has resulted reduction in the incidence of PRRNT associated delayed or acute kidney insufficiency. At present amino acid combination of lysine and arginine is the most commonly nephroprotection solution. Encouraging results have been obtained also with the use of plasma expanders like Gelofusal.
Kidney function can be followed up using several methods like serum creatinine, creatinine clearance, glomerular filtration rate and tubular extraction rate. For the purpose of follow-up after PRRNT, tubular extraction rate determined using clearance of Tc-99m MAG3 along with dynamic scintigraphy appears to be the most promising. However as there is a difference in the pathlength of Y-90 (approx 12 mm) and Lu-177 (approx 2 mm), the PRRNT induced changes in nephron and kidney can vary depending upon the type of radionuclide being used. The kidney function can itself be affected by several coexisting risk factors can lead to structural changes in the nephrons which in turn may enhance and aggravate the PRRNT associated kidney damage. This is probably the reason that several studies have shown that there is no direct correlation between the cumulative dose to kidney and nephrotoxicity. However the biological effective dose has been found to have significant correlation with functional changes of kidney after PRRNT. In an analyses of long term follow up (up to as long as 8 years) of renal function of 416 patients treated with PRRNT at Zentralklinik Bad Berka, it was observed that by taking appropriate renal protection using sometimes a combination of amino acid solution with gelofusal and long term good hydration, the incidence of PRRNT associated nephrotoxicity could be reduced to less than 1%. Advanced age, arterial blood pressure, carcinoid heart disease, diabetes mellitus, previous chemotherapy (specially platinum based) and tumor induced cachexia and tumod induced hypercalcemia were found to be the co-existing risk factors. Although Lu-177 was preferred in patients with reduced renal reserve prior to first PRRNT cycle, Y-90 was found to be equally user friendly when Bad Berka Protocol of PRRNT (fractionated regime over longer duration of interval between two therapy cycles).
Radiation Protection Issues in PRRNT and Results of the ORAMED Project Name of presenter
A. Rimpler, I. Barth, P. Ferrari, S. Baechler, A. Carnicer, L. Donadille, M. Ginjaume, M. Mariotti, M. Sans Merce, G. Gualdrini, S. Krim, X. Ortega, N. Ruiz, F. Vanhavere
Bundesamt für Strahlenschutz, Fachbereich Strahlenschutz und Gesundheit, Waldowallee 120-130, 10318 Berlin, Germany
Aim: Radiopharmaceuticals that are labelled with emitters of beta-radiation, in particular Y-90 and Lu-177, offer promising prospects for therapies of particular tumors in nuclear medicine. Moreover, positron emitters as Ga-68 are increasingly used for special diagnostic purposes. The preparation and administration of radiopharmaceuticals for peptide receptor radiotherapy (PRRNT) and radioimmunotherapy (RIT) require handling of high activities of the radionuclides. Hence, technicians and physicians may receive high exposures, mainly to the skin at the hands, when preparing and performing these therapies. Therefore, dedicated radiation protection standards have to be observed to avoid excessive skin exposures.
Materials and Methods: In the first part of the paper, some basic physical and radiological characteristics of relevant radionuclides are presented. Respective data for Y-90, Lu-177 and Ga-68 are related to those of Tc-99m, the most widely used nuclide for conventional diagnostics. The comparison underlines the markedly enhanced potential of radiation exposure in handling of beta and positron radiation emitters. The second part of the talk gives an overview on real skin exposures of nuclear medicine staff, which were measured within a comprehensive European study, the ORAMED project. The data presented here are focussed on staff performing RIT and PRRNT with Y-90-labelled substances such as Zevalin and DOTATOC/DOTATATE. In RIT with Y-90/Zevalin about 100 measuring series were performed in 16 European hospitals involving 40 staff members. 33 measuring series were made in PRRNT during labelling and administration of Y-90/DOTA. The local skin dose was measured with special thermoluminescence dosemeters (TLD), fixed at 11 positions on each hand.
Results: The measured local skin dose maximum shows a large variation in the dose between different staff members doing the same job, as well as across the hands of a single person during different sets of measurements ranging from 10 μSv up to some 100 mSv per working day. In PRRNT, a mean specific dose of 2.1 mSv/GBq (0.1 to 7.4) was found for staff performing labelling of Y-90/DOTA and 1.9 mSv/GBq (0.4 to 4.9), during administration to patients. When considering the mean Y-90 activity used for labelling (10.3 GBq) and administration (5.5 GBq), the total maximum skin dose of staff in PRRNT exceeds those in RIT, where the mean dose was 11.0 mSv/GBq and 4.8 mSv/GBq for 1.5 GBq and 1.0 GBq, respectively. Generally, exposures during the preparation were higher than during the administration of the radiopharmaceuticals to the patients, both in PRRNT and RIT.
Summary: The findings indicate that the exposure of staff can exceed the annual skin dose limit of 500 mSv if radiation protection standards are not strictly kept. Thus, adequate safety measures, including extremity monitoring of personnel, are needed. The study has also shown that there is enough potential to further improve radiation protection standards and to decrease exposure of staff.
Lu177 Octreotate in GEP NET: Outcome with Special Regard to Tumor Grade and Bone Metastases
Samer Ezziddin, A. Sabet, F. Heinemann, C. Yong-Hing, H. Ahmadzadehfar, S. Guhlke, T. Höller, W. Willinek, H-J. Biersack
University Hospital Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
Aim of the Study: Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NET), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastases (BM). The same applies for the impact of the Ki67 index on PRRT outcome in general, which is being addressed by a separate study.
Materials and Methods: We retrospectively analyzed a consecutive subgroup of n=42 patients with BM of GEP NET treated with PRRT; 177Lu-octreotate, 4 intended cycles at 3 monthly intervals (10-14 weeks), mean activity per cycle 8.1 GBq. Availability of restaging and outcome data were required for patient inclusion. Baseline characteristics including age, tumor origin, performance score, Ki67 index, tumor load, tumor uptake, plasma CgA and NSE, were analyzed regarding impact on tumor regression (modif. MDA criteria) and time-to-progression. Survival analyses were performed using Kaplan-Meier curves, log-rank test at a significance level of P <0.05, and Cox proportional-hazards model for uni- and multivariate analyses.
Results: Median follow-up was 32 months. The observed response of BM consisted of CR in 2 (4.8%), PR in 14 (33.3%), MR in 5 (11.9%), SD in 16 (38.1%), and PD in 5 (11.9%) patients. Median progression-free survival (PFS) and overall survival (OS) were 35 months (26-44, 95%CI) and 51 months (37-65, 95%-CI), respectively. Patients with responding BM (CR, PR, or MR) exhibited a trend towards better OS (median OS not reached after 53 mo) than non-responding patients (39 mo, p=0.076). Only Ki-67 index (>10%) and CgA level (>600 ng/ml) contributed to regression analysis.
Summary: Bone metastases of GEP NET are very effectively controlled by PRRT with long progression-free and overall survival. Poor patient condition and multifocality of bone metastases do not affect treatment efficacy, which might encourage the use in advanced bone metastatic disease. In addition, results of a larger series assessing the impact of the proliferation index Ki67 at baseline on outcome will be presented.
A Schema of Therapeutic Options for Neuroendocrine Tumors and the Value of Biomarker
T.M. O'Dorisio, J.R. Howe, T.R. Halfdanarson, Y. Menda, J.R. Weatherford, M. Sue O'Dorisio
Departments of Internal Medicine, Surgery, Radiology and Pediatrics; Holden Comprehensive Cancer Center, Neuroendocrine Tumor Clinic; University of Iowa, Iowa City, IA 52242, USA
The evaluation of Neuroendocrine Tumor Therapy, as we know it today, is enframed in a remarkable 109 year history beginning with the isolation of secretin and the description of the "blood borne chemical messengers" termed " hormone" (W.M. Bayless and E.H. Starling, Lancet 1902; 1:813-814). Five years later S. Oberndorfer coined the term "karzinoide" tumors of the small intestine (Frankf Z. Pathol 1907; 1:425-9). It wasn't until 1955 when R.M. Zollinger and E.H. Ellison described the first two cases of the Zollinger-Ellison Syndrome (gastronoma) defining the clinical era of the gastroentero-pancreatic tumor axis(Am J Surg, 1955;142:709-723). Isolation of highly pure GEP Peptides by R.A. Gregory and H.J. Tracy (J. Physiol, 1961;156: 523) and V. Mutt and J.E. Jorpes Biochem, 1952;52:328) and the description of the radioimmuno assay (RIA) by R. Yalow and S Berson(Nature, 1959;184:1648) helped to establish the important isolation of somatostatin (P. Brazeau, et al. Science, 1973;179:77) and the innovative and resourceful exploitation of the peptide-membrane receptor (radio-receptor) mechanisms by the European Scientific community(D. Kwekkenboom, E. Krenning, et al. J Nuc Med, 1999;40:762 and A. Imhoff, J. Mueller-Brand, et al. J Clin Oncol 2011, May 9 [Epub]). Caring for patients with neuroendocrine tumors (NETs) involves regular monitoring and management of several inter-related, non-mutually exclusive, and repeatable options. Biomarkers such as serotonin, chromogranin A (CgA), pancreastatin, and neurokinin A can be both predictive of tumor location and determination of liver tumor burden and activity (E. Ardill and T. O'Dorisio. Endocrine MetabClin N Am 2010;39:779). Somatostatin congeners (analogs) are essential for both control of symptoms/syndromes and for anti-proliferative effects (A. Rink, R. Arnold, et al. J Clin Oncol. 1:27(28):4604). Surgery of the primary tumor, even in the face of known metastases to the liver, impacts overall survival and time to progression for both pancreatic and mid-gut NETs (Sarmiento, et al. J Amer Coll Surg 2003;197(1):29 and F. Dahdalah, J. Howe, et al. 2011 Ann Surg Oncol; 18:524). Local-regional approaches include radiofrequency ablation (RFA) and transcatheter arterio-bland or chemo-embolization (TAE/TACE) and selective arterial radio therapy (SIRT) (Kamat et al. 2008 Cardiovasc Intervent Radiol. 2008;31(2):299 and King et al. Cancer 2008;113:921). Other important options of care include the now-approved anti-angiogenic tyrosine kinase antagonist and mTOR inhibitors as well as novel chemotherapeutic combinations. These will be discussed by E. Wolin during the session. In conclusion, we now have several very good options of care with which to manage patients suffering neuroendocrine tumors, a chronic cancer, who may have several years of quality life. While all the options of care are good options, good options at the wrong time may not be the best option. The 19 or so European N/E Centers of Excellencewill inspire the formation of their model for multi-disciplinary centers in the U.S. and around the world.
Systemic Therapy of Neuroendocrine Tumors in 2011 and in the Future
Edward M. Wolin
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Boulevard Los Angeles CA 90210, USA
Personalized and biologically targeted chemotherapy is playing an increasingly important role in (Neuroendocrine Tumors) NET treatment. Chemotherapy for low-grade NET does not usually cause a major reduction in tumor size. Time to progression, however, can be markedly prolonged, extending survival and increasing quality of life. The more metabolically active carcinoid/ NET (intermediate grade, moderately differentiated, atypical carcinoid) are much more likely to respond to chemotherapy by major tumor shrinkage. Streptozotocin plus doxorubicin plus 5-FU and cisplatin combinations are more toxic and appear to have a lower response rate than modern regimens like capecitabine plus temozolomide. In addition, response to the latter program can be predicted by measurement of methyl guanine methyl transferase, which is low in responders. Everolimus, a derivative of rapamycin, disrupts tumor cell growth, proliferation and survival, and prolongs progression-free survival from 4.6 months to 11 months in patients with pancreatic neuroendocrine tumors. It also seems quite effective in carcinoids. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, blocks ligand binding and receptor signaling and has a response rate of approximately 25 percent in NET. An ongoing Southwest Oncology Group trial is comparing octreotide plus bevacizumab vs. octreotide plus interferon in carcinoid/NET. Sunitinib blocks molecular targets needed for the growth and metastasis of NET. It inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor, which play a crucial role in angiogenesis and acquisition of blood vessels, oxygen and nutrients needed for growth. A randomized trial of sunitinib increased progression-free survival in pancreatic neuroendocrine tumors from 5.5 months to 11.1 months. In an exciting new development, there is now proof that somatostatin analogs can stop the growth of neuroendocrine cells, paving the way for their use as anti-cancer drugs. In the PROMID study, 85 patients with midgut carcinoids were randomized to octreotide LAR 30mg/month vs. placebo. The average progression-free survival period was 14.3 months with octreotide vs. six months with placebo. At six months, 64percent of the octreotide-treated patients remained without cancer progression vs. 37.2 percent of the placebo-treated patients. This study established octreotide as standard therapy for all patients with metastatic carcinoid, whether or not a syndrome of diarrhea and flushing is present. Another important advance has been the development of new, highly effective somatostatin analogs. One, known as lanreotide, can be combined with water to form stable molecular aggregates that dissemble over a period of four weeks, continuously releasing lanreotide into the circulation after a single subcutaneous injection. In addition to being less painful than deep intramuscular (IM) injection of octreotide LAR, subcutaneous injection of lanreotide Autogel® allows for the administration of higher and potentially more effective doses in a smaller volume. It also provides more reliable blood levels in obese people, since octreotide LAR doses intended for IM use can unintentionally be injected into fat instead of muscle, thus impairing absorption. Lanreotide Autogel can also be easily administered to thin individuals who do not have adequate muscle mass for repeated deep IM injections. Randomized clinical trials exploring lanreotide in carcinoid/neuroendocrine tumors, with or without carcinoid syndrome, are ongoing. The third exciting somatostatin analog now being studied in clinical trials is called pasireotide (SOM-230). Pasireotide binds to more types of somatostatin receptors on carcinoid/NET cells, and binds with higher affinity than either octreotide or lanreotide. Pasireotide LAR, the long-acting formulation, is given every four weeks and is generally well-tolerated. In many patients whose carcinoid syndrome could not be controlled with octreotide or lanreotide, the syndrome can be controlled with pasireotide. Side effects are similar for all three of these somatostatin analogs, except for slightly more blood sugar elevation in patients receiving pasireotide. A multi-institutional study is currently underway, comparing symptom control and tumor control with pasireotide LAR vs. octreotide LAR. New approaches to the use of these and other systemic therapies in the future, and integration of these modalities with peptide receptor radionuclide therapy will be explored.
Australian Experience of Radiopeptide Therapy of NET
Turner School of Medicine and Pharmacology, Department of Nuclear Medicine Fremantle Hospital, Alma Street, FREMANTLE WA 6959, Australia
Australian centres have more than a decade of experience of radiopeptide therapy of NET using 90Y-octreotide, 111In-octreotide and 177Lu-octreotate. Over the past 5 years addition of radiosensitizing chemotherapy with capecitabine and temozolomide at Fremantle Hospital has improved objective response, particularly in pancreatic primary, disseminated well-differentiated progressive unresectable gastro-entero-pancreatic (GEP) NETs. The recently commenced NeuroEndocrine Tumor Therapy with Lutetium-177 octreotate and Everolimus (NETTLE) is a phase I clinical study of multimodality radiopeptide and biological therapy at Fremantle Hospital. Given acceptable toxicity and preliminary evidence of efficacy a Phase II study will follow. A multicentre Phase II randomised controlled trial of 177Lu-octreotate with capecitabine/temozolomide versus 177Lu-octreotate with everolimus may then be contemplated. Meanwhile, designated centres in Melbourne, Brisbane, Adelaide, Sydney and Perth now routinely offer 177Lu-octreotate radiopeptide therapy as standard recommended treatment of unresectable well-differentiated disseminated progressive GEP-NETs in accordance with the Consensus Guidelines of the Clinical Oncologists Society of Australia (COSA) 2011. Compassionate usage of 177Lu-octreotate radiopeptide therapy of medullary thyroid cancer, thymoma, phaeochromocytoma, paraganglioma, and other disseminated malignancies shown to be 68 Ga-octreotate-avid on PET imaging, is also available for selected patients under the Special Access Scheme of the Therapeutic Goods Administration of the Commonwealth of Australia. Radiopeptide therapy is administered on an outpatient basis in Australian hospitals, avoiding logistical bed constraints, and the main limitation on availability is funding. Patient prioritisation is conducted through multidisciplinary teams and in some centres, eligibility for formal study protocols is a key factor in provision of radiopeptide therapy.
Neuroendocrine Tumor Treatment with Somatostatin Analog Peptides Labeled with Radionuclides: Latin-American Pioneer Experience
Amaral H. 1 , M.C. Gil 2 , R. Pruzzo 1 , H. Lavados 1 , F. Redondo 1 , H. De la Fuente 1 , M. Mahave 1 , R. Rossi 3 , A. Majlis 1 , S. Kleinman 3 , I. Coudeu 1 , S. Astudillo 1 , R. Galaz 1 , C. Chamorro 1
1 Nuclear Medicine and PET/CT, Surgery and Chemotherapy Departments, Oncologic Institute Arturo Lopez Perez Foundation; 2 CGM Nuclear; 3 Oncologic Department, Clinica Alemana; Santiago, Chile
Introduction: Neuroendocrine tumors (NET) are low incidence neoplasms, but in considerable increase in the last 30 years. The only curative option for these patients is surgery in localized stages, however, a high proportion of them are diagnosed in advanced stages. Therapeutic options in patients with disseminated disease include: medical treatment with somatostatin (SST) analogues, chemotherapy, arterial embolization, chemo-embolization, immunotherapy, radiofrequency ablation, radiotherapy and molecular therapy with SST analogs labelled with radionuclides. Well differentiated NETs have very low response to external radiotherapy and conventional chemotherapy. Owing to their special characteristic of over-expressing somatostatin receptors (SR) in the cell membrane surface, specially sub-type 2, SST analogue peptides labelled with beta emitter radionuclides represent a promising tool in the treatment of advanced stages by the means of allowing systemic radiation specifically focused on neoplαsicas lesions. In this study we analyze our experience, pioneer in Latin-American, using SST analogues labelled with 90Y or 177Lu in patients with advanced stages of NETs.
Materials and Methods: We evaluated 46 patients, 22 women and 24 men (mean age 51.3, range 12-74) with histologically proven well differentiated advanced stage NETs, who had completed 4 therapy cycles. All patients had over-expression of SR demonstrated with 111In-DOTATOC or 68 Ga-DOTATATE PET/CT. Their biochemical, haematological and renal function was evaluated.
Patients received through an iv teflon catheter a total of 189 doses, 63 of 90Y-DOTA-[Tyr3, Thr8]-Octreotide (DOTATOC), 29 of 90Y-DOTA-[Tyr3]-Octreotate (DOTATATE) and 97 of 177Lu-DOTATATE (CGM Nuclear, Chile), in doses that ranged between 925 and 8880 MBq (25-240 mCi), mean 3533 MBq (95.5 mCi).
Results: Radiochemical purity of radiopharmaceuticals used was always over 99%. We observed progression of disease in 11 patients (23.9%), partial remission in 28 (60.9%), stable disease in 4 (8.7%) and complete remission in 3 (6.5%). One patient developed self limited grade 4 hematological toxicity. No patients, except one, developed significant changes in plasmatic levels of creatinine.
Conclusion: The use of 90Y/177Lu-DOTATATE allows the treatment of a significant number of patients with advanced stage NETs without significant secondary effects. In this series we have observed a favorable effect in 76.1% of the patients (stable disease, partial or complete remission) and improvement in the quality of life in most of them. Response to treatment in medium to long term has not been determined. Our experience, in line, with that of other authors, indicates that treatment based on molecular complexes labeled with radionuclides directed to specific targets it΄s a safe method that represents a new modality in the treatment of low grade advanced stage NETs.
The US Experience in Providing PRRT to Children, Adolescents and Adults
M.S. O'Dorisio, T.M. O'Dorisio; Y. Menda, D. Bushnell, M. Madsen
Departments of Pediatrics, Medicine, and Nuclear Medicine; University of Iowa, Iowa City, IA 52242, USA
PRRT was first introduced in the United States in 2001 when an international Phase II clinical trial of 90Y-edotreotide (90Y-DOTATOC) was opened at the University of Iowa. A total of 188 patients were entered worldwide, 40 of whom were entered in our institution. Metastatic carcinoid tumor (Grade 1 or 2 NET by WHO criteria) was the most frequent diagnosis and we report on results of these 90 patients (Bushnell et al., JClinOnc 28:1652, 2010). Eligibility criteria included: 1) metastatic malignancy; 2) somatostatin receptor positive Octreoscan; 3) at least one symptom refractory to Octreotide; and 3) age >18 years. Treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-DOTATOC each, once every 6 weeks. Of these 90 patients, morphologic response or stable disease was observed in 74%, while two subjects experienced reversible Grade 3-4 renal toxicity. Among 56 patients with severe diarrhea, PRRT induced durable resolution of diarrhea was highly predictive of progression-free survival (18.2 months in 38 subjects with durable response vs 7.9 months in 18 clinical non-responders). PRRT has generally been restricted to treatment of adults. A Phase I trial of 90Y-DOTATOC in children and young adults with recurrent or progressive somatostatin receptor positive tumors was conducted at the University of Iowa (Menda et al., JNucMed. 51:1524, 2011). Seventeen patients with NET, neuroblastoma, and brain tumors were treated using a 3×3 dose escalation design from 1.11-1.85 MBq/m 2 /cycle with a limit of 21Gy dose to kidneys. Morphologic response or stablization of disease was observed in 76% of patients with ten surviving at last followup (29-96 months). Gastrinoma was the most responsive tumor with 2 patients surviving >5 years with no evidence of disease following partial liver resection and liver transplant, respectively. No renal toxicity was observed, yet dosimetry on 5 adolescent subjects revealed high variability in both tumor and renal uptake of 90Y-DOTATOC. PRRT is not yet FDA approved in the US. Registration trials for both 90Y-DOTATOC and 177 Lutate are pending and scheduled to open in 2012.
Effect of Peptide Receptor Radionuclide Therapy with Tandem Isotopes - Y-90/Lu-177nDOTATATE - in Patients with Disseminated Neuroendocrine Tumors
Jolanta Kunikowska 1 , Leszek Królicki 1 , Dariusz Pawlak 2, Norbert Szaluś3, Renata Mikołajczak2, Grzegorz Kamiński3
1 Nuclear Medicine Department, Medical University of Warsaw, Poland; 2IEA POLATOM, Świerk, Poland; 3 Nuclear Medicine Department, Military Institute of Medicine, anacha 1a, 02-097 Warsaw, Poland
Introduction: Peptide Receptor Radionuclide Therapy (PRRT) is a new treatment modality for inoperable or disseminated neuroendocrine tumors (NET). De Jong was the first one to have described the use of combination treatment consisting of 50% 177Lu-DOTATATE and 50% 90Y-DOTATOC in rats; which demonstrated that survival rates were 3 times longer. The aim of the study was to evaluate the tandem 90Y/177Lu-DOTATATE therapy.
Materials and methods: 44 patients with disseminated NET were included in the study prospectively. 34 patients was treated with the administered activity was based on 1:1 90Y/177Lu-DOTATATE 3.7 GBq/m 2 body surface area (1.85 GBq of 90Y + 1.85 GBq of 177Lu) in 3-5 cycles, 10 patients with fixed 3-4 doses 7.4 GBq, 1:3 90Y/177Lu-DOTATATE (1.85 GBq of 90Y + 5.55 GBq of 177Lu). Blood tests for hematology, kidney and liver function, and CgA were evaluated before therapy. All patients underwent CT scans and somatostatin receptor imaging with 99mTc-HYNIC-TOC (99mTc-Tektrotyd) or 68 Ga-DOTATATE. Mixed amino-acids infusion over 8 hours was used for kidney protection.
Results: At the time of treatment all patients showed progressive disease confirmed by CT examination, somatostatin receptor imaging and/or increasing blood concentration of chromogranin A (CgA). In group treated with 1:1 90Y/177Lu DOTATATE the median overall survival (OS) time was 49.8 months and time to progression (TTP) was 24.2 months; in group treated with 1:3 90Y/177Lu-DOTATATE OS was 52.8 months, and TTP 28.3 months. In group treated with 1:1 90Y/177Lu DOTATATE 23 patients before PRRT received chemotherapy. In group with chemotherapy before PRRT TTP was 18.7 months and OS 29.8 months, while in group without chemotherapy before PRRT the TTP was 24.3 months and OS was not calculated due to insufficient statistical levels. Nevertheless, analysis of Kaplan-Meyer curves showed significantly longer median OS in group without chemotherapy before PRRT (P=0.028); the differences between both groups in TTP was not statistically significant. On the 12 months follow-up was observed in group treated with 1:1 90Y/177Lu DOTATATE vs 3:1 177Lu/ 90Y DOTATATE : stable disease (SD) in 62% vs 70% patients, disease regression (RD) in 15% vs 20% patients, disease progression (PD) in 12% vs 10% patients. No hematological or renal toxicity grade 3 and 4 was observed.
Conclusions: The results indicate that tandem radioisotopes (90Y/177Lu DOTATATE) therapy is safety treatment option for patients with disseminated or inoperable neuroendocrine tumors. The further observation is needed.
PRRT Combined with Chemotherapy and Kinase Inhibitors
J. Harvey Turner
Department of Nuclear Medicine, Fremantle Hospital, Fremantle, Australia
TACE and SIRT combined with PRRT or Intra-arterial PRRT
Petrovitch, Alexander, Hommann, Merten, Schneider, Arnold, Hörsch, Dieter, Baum, Richard
Interventional Radiology and Neuroradiology Zentralklinik Bad Berka, Germany, Robert Koch-Allee 9, 99437 Bad Berka, Germany
TACE and PRRT: Due to long term therapy of NET with PRRT a complete loss of receptor bearing cells could be observed in still active residual tumors with persisting FDG-uptake and progression in CT. Patients who had a previous treatment with PRRT can be treated with postponed superselective TACE (3 months or more after last PRRT) with DC-Beads plus doxorubicine as an escape strategy. Limit for this kind of treatment is only liver function and possible biliary obstruction. In our own series of now 42 patients with more than 150 local TACE-treatments after PRRT in no case loss of liver function or harm to the kidneys could be observed. Moreover 6 cases with reduced glomerular filtration rate under PRRT recovered during local treatment of the liver-lesions with TACE. This kind of treatment is safe. In 7 cases with high tumor-burden (>50 - 75%) a simultaneous treatment with PRRT and TACE was done: Patients were first treated with PRRT and one week later superselective local treatment with TACE (like above) was done. In no case a total of 100 mg Doxorubicine, 2 ml DC-beads 100 - 300μm and 300 - 500μm was exceeded. In all cases an overadditive effect with large tumor destructions and devascularisation of the tumor masses could be observed, but 5/7 cases developed cholangitis. All patients were treated with ciprofloxacine, in 4/7 cases biliogenic abscesses occurred which were tretated by drainage. All patients suffered from increased pain for a time period of 5 - 7 days an needed higher amounts of opioids and NSAIDs. In an overall-evaluation also this type of simultaneous treatment could be an useful option because of its strong antitumoral effects: in all cases in the following weeks a reduction of the tumor mass of more than 50% could be observed. Anyway this type of simultaneous treatment has to be judged as a high-risk-treatment which should be limited to very selective cases with fast tumor progression or carcinoid-crisis under PRRT, refractory to other treatments. SIRT and PRRT: Previous treatment with PRRT (more then 3 months) in a small series of patients (32 cases) is not a contraindication for embolising SIRT (SIRTEX) with local administration of 3 GBq cumulative radiation dose with SIRTafter PRRT: in no case RILD (radiation induced liver disease) or loss of liver function was observed. In 31/32 cases a good tumor response with devascularisation of the tumorlesions and tumor-mass reduction (20-40%) were detected. A reduction of dosage for the SIRT-therapy was not necessary, when a total dosage of 3 GBq in the SIRT was not exceeded. So under the restriction of a small number of patients this combination seems to be safe. However for this combination no general recommendation could be given, it has to be judged as an experimental approach. For time windows with an interval shorter then 3 months between PRRT and SIRT or for simultaneous treatments no practical experience exists.
Intraarterial PRRT and TACE/SIRT: Generally we observed in all cases of intraarterial PRRT a ~ 30% higher uptake of activity to the tumor lesions then in intravenous PRRT. The results of local treatment and observed side effects in combination of intraarterial PRRT and TACE or SIRT were similar. In the overall evaluation the combination of PRRT with local embolising therapies (TACE or SIRT) is safe with promising results for the future.
Intra-arterial Bi-213 DOTATOC Alpha-peptide Therapy in Patients with Neuroendocrine Tumors Refractory to Beta-radiation
Clemens Kratochwil, F. Giesel, A. Morgenstern, F. Bruchertseifer, W. Mier, C. Zechmann, C. Apostolidis, U. Haberkorn
University Hospital of Heidelberg, Heidelberg, Germany / Institute for Transuranium Elements, European Commission JRC, Karlsruhe, Germany
Department of Nuclear Medicine; University Hospital of Heidelberg; INF 400; 69120 D-Heidelberg
Background: Radiopeptide therapy using beta-emitter labeled somatostatin analogs such as 90Y- or 177Lu-DOTATOC is a therapeutic option in neuroendocrine cancer. However, some patients become refractory to that treatment. Alpha-emitting nuclides were able to break radioresistance to beta-emitters in vitro. Nevertheless, unfavorably half-lives constrain their clinical application in systemic therapies. Recently, we demonstrated an accelerated tumor uptake of DOTATOC by regional arterial administration. This promotes the use of 213Bi-DOTATOC in human beings.
Materials and Methods: 14 patients with neuroendocrine liver metastases, refractory to a previous treatment with 90Y-/177Lu-DOTATOC, were enrolled. The cumulative activity administered was up to 10.4 GBq Bi-213 per patient. The activity of a single treatment was escalated from 1 to 7.9 GBq per cycle and was injected in fractions of 0.5 - 1.5 GBq into a catheter placed in the hepatic artery. Response was assessed with MRI, DSA, 68 Ga-DOTATOC-PET/CT and tumor markers. Hematologic, kidney and endocrine toxicity was assessed according to CTCAE criteria initial and after the final treatment.
Results: The minimal effective activity inducing partial remission (>30% of the diameter) was 1 GBq 213Bi-DOTATOC (treatment of a single liver segment). Higher activities are needed for whole liver treatment. No acute kidney, endocrine or hematologic toxicity higher than grade 0/I were observed in the first escalation steps. Nevertheless, some patients already demonstrated a positive treatment response.
Summary: Regional administered 213Bi-DOTATOC demonstrated to be effective by inducing tumor remission for NETs refractory to 90Y- and 177Lu-DOTATOC, while no severe toxicity was observed with the activities administered until now. Moreover, the maximum tolerable dose was not reached so far and dose escalation continues.
Intra-arterial PRRT using Y-90 DOTATATE: The Warsaw Experience
Jaroslaw B. Cwikla
Zaklad Medycyny Nuklearnej,CSK MSWiA, Warsaw, Poland
Purpose: Prospective evaluation of the efficacy of i.a. hepatic 90Y DOTATATE peptide receptor radionuclide therapy (PRRT), in patients with advanced, progressive liver involvement of somatostatin receptor-positive neuroendocrine carcinoma (GEP-NET). Primary end point of this study was to assess OS and PFS.
Patients and Methods: The study had local ethics committee approval, 28 patients, with histological proven extensive non-resectable liver metastatic GEP-NET, with clinical or radiological progression. [90Y]-DOTATATE was given selectively into main hepatic artery or if there was unilobar disease in to left or right hepatic artery without embolisation.
Clinical responses were assessed 6 weeks after completing therapy, and then after each of the 3 - 6 months intervals. The objective radiological response was classified according to RECIST criteria.
Results: At 6 months after treatment RECIST PR was observed in 5 subjects (19%), 19 presented SD (70%) and 3 had DP (11%). Overall clinical response to therapy at 6 months follow-up was observed in 18 patients (64%), SD in 6 patients (21%) and PD in other 4 (14%). A year after PRRT radiological (RECIST) PR was seen in 4 patients (19%), SD had 14 subjects (67%) and DP was noted in 3 patients (14%). Clinical benefits in terms of PR and SD were noted in 18 patients (75%) after 12 months. Median OS in whole group was 20.5 months and PFS was 17 months. In the group of patients with clinical response noted 6 weeks after therapy median OS and PFS were 22.5 and 20.5 in those with SD median OS and PFS 27.0 and 15 months and in those who had DP median OS and PFS were 13.0 and 5.5 months.
Conclusion: i.a. 90Y-DOTATATE seems to be effective in patients with extensive non-resectable and progressive metastatic liver GEP-NET, as initial therapy and in those who had previous i.v. PRRT and developed further progression. Most of them had significant clinical response after therapy after 6 months and then after a 12 months. Objective response of PRRT, based on RECIST, underestimate benefits of this type of therapy.
Engineered Bacteria for Cancer Theranostics
Jung-Joon Min, Vu H. Nguyen, Seung Hwan Park, Dong-Yeon Kim, Hee-Seung Bom
Department of Nuclear Medicine, Chonnam National University Medical School, 160 Ilsimri, Hwasun, Jeonnam 519-809, Republic of Korea
Use of microbial system has attributed to the recent advances in targeted molecular therapy application especially for its tumor-specific accumulation and proliferation. In an attempt to investigate tumor-specific targeting, we used an in vivo optical imaging system to monitor the spatial and temporal migration of light-generating E. coli or attenuated Salmonella More Details typhimurium (carrying pLux) following injection into mice models carrying a variety of tumors. In addition to optical imaging, we employed PET-based molecular imaging strategy to visualize bacteria through targeting of bacterial DNA synthesis. The phenomenon of selective targeting and proliferation of bacteria was observed in a diverse range of tumors with multimodal imaging technologies with optical imaging and PET, as it accumulated in every type of grafted tumor we tested. In addition, the bacteria was capable of targeting both primary tumors and metastases. Bacterial therapy possesses many unique applications for treating cancer that are unachievable with standard methods. Bacteria can specifically target tumors, actively proliferate there, are easily detected and can controllably induce cytotoxic proteins. When using tissue specific or inducible system, bacteria could be engineered to express target genes specifically in the tumor area, rather than other organs, leading to maintenance of therapeutic efficacy and reduction of toxicity. The combination with engineered bacteria (BT) and radiotherapy (RT) had an synergistic effect to completely remove the subcutaneously grafted tumor. Bacterial surface engineering can be employed to enhance targeting capability of specific cancer biology. Bacterial outermembrane protein was engineered to express RGD peptide to target αvβ3 integrin that is over-expressed in cancer vasculature. The engineered bacteria revealed 10-fold increased adhesion to the cancer cells in vitro. In this research, we propose that synthetic biology techniques can be used to solve many key challenges that are associated with bacterial therapies, such as toxicity, stability and efficiency, and can be used to tune their beneficial features, allowing the engineering of 'perfect' bacteria for cancer treatment.
Old and New Peptide Receptor Targets in Cancer: Future Directions
Institute of Pathology Division of Cell Biology and Experimental Cancer Research, University of Bern, Bern, Switzerland
Novel Targets for Peptide Receptor Based Imaging and Therapy
Department of Nuclear Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany
Radiolabeled peptides binding to somatostatin receptors are now widely used for diagnosis and therapy of patients with neuroendocrine tumors. This clinical success has stimulated the interest in using peptides for targeting other receptors expressed by tumor cells. A large number of peptides have been evaluated preclinically and some are in ongoing clinical trials. Perhaps the most extensively studied "novel" target is the alpha-v beta-3 integrin. Alpha-v beta-3 integrins mediate the migration of endothelial cells during angiogenesis and also play an important role in tumor cell migration and metastasis formation. In these processes alpha-v beta-3 integrins act as adhesion molecules, but also as receptors: Binding of alpha-v beta-3 integrins to the extracellular matrix activates several intracellular signalling pathways that are important for the survival of endothelial and cancer cells. To inhibit these biological functions of alpha-v beta-3 integrins various peptidic and non-peptidic ligands have been developed. Most of these ligands are based on the cyclic pentapeptide c(RGDfV) which specifically binds to alpha-v beta-3 integrins, but not to related integrins such as alpha-iib beta-3 integrins which are expressed on thrombocytes. A large number of radioligands has been derived from the c(RGDfV) peptide and tested preclinically for imaging and radionuclide therapy. Three fluorine-18 labeled RGD peptides are in clinical trials. The clinical studies have shown that alpha-v beta-3 integrins can be imaged in patients and that the intensity of tracer uptake correlates with the amount alpha-v beta-3 integrin expression as determined by immunohistochemistry. Based on the available preclinical and clinical data it is expected that PET imaging with radiolabeled RGD peptides will be used clinically for biological characterization of malignant tumors (i.e. for radiation treatment planning and dose painting) and for monitoring therapies inhibiting angiogenesis or tumor cell invasiveness. In addition to alpha-v beta-3 integrins several other integrins, such as alpha-v beta-6 and alpha-4 beta1 are overexpressed in malignant tumors. Ligands for these integrins are in preclinical development. G-protein coupled receptors provide a large number of potential targets for radiolabeled peptides. Among these bombesin or gastrin releasing peptide receptors have been extensively studied preclinically. High expression levels of bombesin receptors are found in common malignant tumors such as prostate, breast and ovarian cancer. Imaging with bombesin receptor agonists has been limited by insufficient metabolic stability and high uptake in the gastrointestinal tract. Newer bombesin receptor antagonist demonstrate a much more favourable biodistribution resulting in high tumor to organ ratios in murine tumor models. Furthermore, bombesin receptor antagonists have shown encouraging results for radionuclide therapy of prostate cancer in experimental models. Clinical testing of these antagonists is currently ongoing.
THERANOSTICS - Where Do We Go from Here?
Richard P. Baum
Department of Nuclear Medicine, Center for PET/CT, Zentralklinik Bad Berka, Germany
The first aim of THERANOSTICS is the molecular imaging and accurate diagnosis of a disease. This can be achieved by using a specific vector (e.g. G protein coupled peptides like the somatostatin analogues or antibodies) - the KEY - targeting specific ligands - the LOCK - e.g. somatostatin receptors or antigens); an easily available generator-derived diagnostic trivalent radiometal with convenient labeling characteristics like Ga-68 can then be attached by a linker to the KEY which enables the visualization of specific molecular properties of a cell (e.g. of cell surface or intracellular structures). The single most imperative aspect of PET/CT is its ability to quantify a disease at the molecular level. The second goal - personalized treatment - is achieved by utilizing the same molecular vectors as used for imaging and by substituting the generator-derived radionuclide by a therapeutic radionuclide (e.g. applying beta emitters like Lu-117 or Y-90). Thirdly, individualized patient dosimetry can be performed by using a longer lived PET radioisotope before therapy and serial PET scanning or (with less accuracy, but more practically) by post-therapeutic dosimetry using the administered therapeutic radioisotope and taking advantage of the gamma emission of radiotherapeutics like Lu-177. Finally, post-therapeutic follow-up and therapy control can be performed using again quantitative PET/CT and generator-derived positron emitters.
Today, the most notable example are neuroendocrine tumors (NET) - imaged and treated with radiolabeled peptides forming a diagnostic-therapeutic pair like Ga-68/Lu-177 labeled somatostatin (SMS) analogues. Another emerging application is the treatment of bone metastases - imaged with bisphosphonate-based agents (e.g. Ga-68 BPAMD) and treated by the same vector labeled with Lu-177.
The Bad Berka experience: At the Neuroendocrine Tumor Center Bad Berka (which has been certified as ENETS Center of Excellence in March 2011) we are working extensively in the field of diagnosis and treatment of NET in a multidisciplinary team, especially over the last 10 years (in Germany, the first patient was treated by us in July 1997). Over 3,000 treatment cycles of Peptide Receptor Radionuclide Therapy in nearly 1000 patients have been performed up to now. First Y-90 and later Lu-177 (in use in our center since 2004) labeled somatostatin analogues have been administered alone or in combination to patients with progressive neuroendocrine tumors, non-responsive to other treatments like surgery, octreotide/interferon treatment, kinase inhibitors or chemotherapy (we are using mainly DOTATATE and DOTATOC and have administered also Lu-177 DOTANOC to a few patients). Lu-177 DOTATATE or -DOTATOC are predominantly used for smaller metastases or in patients with impaired renal or hematological function. Our group was the first to systematically administer Lu-177 and Y-90 consecutively in the same patient (DUO-PRRNT) and to concurrently apply PRRNT with Y-90 and Lu-177 peptides on the same day (TANDEM PRRNT). We were also among the first to administer (in 1999) intra-arterial PRRNT using Y-90 (IA-PRRNT) for enhancing the delivery to large, inoperable primary tumors and bone and hepatic metastases. We also inaugurated the combined use of internal (PRRNT) and external (EBRT) radiotherapy (COMBIERT) for the treatment of neuroendocrine tumors (e.g., bone invading glomus tumors, progressive meningiomas as well as large mediastinal tumors or pleural carcinosis or extensive bone metastases).
In all patients, Ga-68 DOTA-SMS analogue receptor PET/CT is performed before and after PRRNT (over 5,700 Ga-68 DOTA-SMS PET/CT studies have been performed until now). The decision for administering PRRNT is undertaken based on high Somatostatin receptor (SSTR) expression. We have extensive experience with imaging (and therapy) using the three somatostatin analogues DOTATATE, DOTATOC and DOTANOC, and recently had the chance of using a Ga-68 labeled SSTR antagonist first time in humans (JR10, kindly provided by Helmut Mäcke).
Analysis of long term follow-up after PRRNT has been performed in 454 patients (mean age 59.1 years, 248 male, 206 female), who received a total of 1,303 treatment cycles (mean activity 4.1 GBq, min. 1.05 GBq, max. 7.5 GBq per cycle, time between cycles 3 to 6 months) The number of patients/cycles are: 111 pts/1 cycle; 106/2; 74/3; 75/4; 42/5; 23/6; 9/7; 1/8. For kidney protection, patients were well hydrated and received an L-lysine/L-arginine solution infused intravenously for 4 hours beginning 30 minutes before PRRT. In addition, patients treated with Y-90 SMS analogues are pretreated with GELOFUSIN since 2008 (overall we have experience in using this nephroprotecting agent in over 1,500 treatment courses). Before each new treatment cycle, restaging was performed by morphologic (CT/MRI) and molecular imaging (Ga-68 DOTA-SMS PET/CT, in selected cases also FDG or fluoride PET/CT were performed), and blood chemistry and tumor markers (CgA, serotonine, specific hormones) were determined. Renal function was serially determined by Tc-99m MAG3 scan/clearance (TER) and by Tc-99m DTPA (GFR) measurements. Tumor and normal organ dosimetry (MIRD/OLINDA) was performed after PRRNT (using Lu-177-DOTA-SMS analogues). All data of patients treated by PRRNT are entered in a structured ACCESS database (284 items /patient) for prospective evaluation since the very beginning.
Tumor response in patients with NETs of non-pancreatic origin and pancreatic NET (pNET) after a mean follow-up of 2 years was as follows: Complete remission (CR), partial remission (PR), minor response (MR) after 3 cycles (progressive disease before) was seen in 52% of patients with pNET (48% in other non pancreatic NET); diseased was stabilized in 39% of pNET as compared to 45% in non pancreatic NET. 36 patients with advanced disease died of PD. Objective tumor responses (including improvement of clinical symptoms) were seen in 93% (91% pNET) of the patients. Significant hematological toxicity (mainly erythrocytopenia, rarely neutropenia, and severe thrombocytopenia) occurred in less than 15% of all patients. MDS developed in 5 patients (all of them received also chemotherapy before). End stage renal insufficiency was not observed in any of the patients with normal kidney function before PRRT. In most patients receiving Lu-TATE alone (n=417 cycles), serum creatinine and TER/GFR did not change. Therefore, the probability and magnitude of renal toxicity can be significantly reduced when PRRT is administered in fractionated doses in patients without any preexisting risk factors and under appropriate nephroprotection. As risk factors we identified chemotherapy, diabetes mellitus, hypertension, Hedinger's syndrome, and cachexia.
We also have been treating patients with a single functional kidney (24 patients) and 3 patients on hemodialysis due to renal insufficiency (worldwide first experience in 2009) with fractionated low dose PRRNT. None of these patients (with still functioning single kidney) showed grade 3 or 4 nephrotoxicity. PRRNT resulted in PR in 36% and stable disease (SD) in 36% of the pts, 28% had PD. 14 had grade 1 erythrocytopenia, 3 grade 1 leukocytopenia and 3 had grade 1 thrombocytopenia. No significant hematotoxicity was observed in the three patients on dialysis.
Thus, in patients with progressive neuroendocrine tumors, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period of time (Bad Berka Concept) results in good therapeutic responses and severe hematologic and/or renal toxicity can be avoided. Quality of life of the patients can be highly improved. A recent analysis of 416 patients (all NET subtypes) treated at the Bad Berka Neuroendocrine Tumor Center showed a median overall survival from the time of first diagnosis of 210 months and a median survival after 1 st PRRT of 59 months (published Rotterdam data 46 months). Our experience confirms a previous report that - compared with historical controls - there is a benefit in overall survival from the time of diagnosis of several years.
Following the concept of THERANOSTICS, we have been using clinically a number of other peptides and radiopharmaceuticals for both diagnosis and therapy of tumors (most of these as "first in humans"). Very promising is the bisphosphonate-based agent BPAMD. PET/CT with Ga-68 DOTA-BPAMD is more sensitive and results in much a high resolution images as compared to the conventional bone scan using Tc-99m MDP. We have treated meanwhile >10 patients with widespread, painful skeletal metastases, presenting with progressive disease and refractory to conventional treatment administering Lu-177 BPAMD. Dosimetry shows that due to the long half life of the radiopharmaceutical in the metastases (>80 hours), the tumor doses delivered were quite high (ranging from 2.4 - 209 mGy/MBq, the wide range is due to the different size of the lesions). A significant reduction in osteoblastic activity of the bone metastases was seen on the follow up PET/CT. The treatment was very well tolerated by all patients without any significant adverse effects. There were only minor changes in blood cell counts (not needing any intervention), and no significant alterations of serum creatinine/BUN or other lab parameters were observed.
In 2009, our group was pioneering the use of a positron emitter labeled gastrin-releasing Peptide (GRP) selective bombesin antagonist for GRP receptor PET/CT imaging of metastatic breast, lung and prostate cancers using Ga- 68 Demobesin. The first ever Lu-177 Demobesin therapy was also administered in 2009 in a patient with metastatic prostate cancer.
Many other Ga-68 labeled compounds have been first used - gastrin for NET, the GRP-R agonist AMBA for imaging (and therapy) of cancers of the breast, lung and prostate, Ga-68 DOTA Tyrosine for imaging brain tumors, Ga-68 MAA for lung perfusion scintigraphy, Ga-68 alpha-MSH (melanocyte stimulating hormone) in a patient with choroid melanoma and Ga-68 labeled glucose (without success) aimed for determining the metabolic status of tumors. This essentially underlines the emergence of Ga-68 as an effective radionuclide for high resolution PET imaging (the author named it in 2004 "the Tc-99m for PET").
Novel therapeutic approaches include the first antiangiogenesis therapy using Lu-177 RGD peptide and I-131 phenylalanine endoradiotherapy of brain tumors. The first human study using the longer-lived (3.93 h half-life), generator-derived (Ti-44/Sc-44) trivalent metallic positron emitter Sc-44 (Scandium-44 obtained from a Ti-44/Sc-44 generator with a very long half life of Titanium-44 of 59.2 years) DOTATOC was performed in 2009. This should definitely inspire the development of new longer-liver PET radioisotopes in order to cover longer imaging periods (which is of special interest for predictive, personalized dosimetry). The objectives of THERANOSTICS could be achieved by the additional use of Sc-47, a beta emitter, for therapy.
Looking into the future - towards personalized medicine: It is worth emphasizing again that every patient is different not only when it comes to be able to tolerate a particular therapy or the degree to which a patient responds, but also concerning diagnostics. Hence, it becomes imperative to choose the appropriate modality for THERANOSTICS. In this context, as we move towards personalized medicine, we must first improve the diagnostic information obtained from PET/CT, i.e., by adequate quantification.
We have developed the Bad Berka Molecular Imaging Tool (BBQ-MIT), an automatic user-independent routine for segregation and quantification (e.g. molecular tumor volume - MTV) of receptor positive neoplastic lesions detected by molecular PET/CT using Cognition Network Language (CNL) and software package provided by Definiens. This prototype routine built on CNL for DICOM PET/CT images enables the automatic analysis and quantification of lesions. It seems especially promising for shortening the time needed to evaluate a PET/CT scan showing many lesions, and will improve reproducibility as well as increase sensitivity of lesion detection. BBQ-MIT seems to be a quantum step forward towards fast and accurate analysis of serial PET/CT studies, allowing to assess tumor response early in the course of therapy and monitoring further follow-up, thus enabling effective personalized patient management.
Another very important future aspect of personalized medicine and THERANOSTICS is dosimetry, which is the single most important factor to ensure maximum dose delivered to the tumor and has decisive influence on the treatment dose/activity. Newer protocols for 3D dosimetry are developed and must be applied clinically to ensure a more individualized and accurate treatment approach. Dose assessment and predicting the molecular response on the basis of pre-therapeutic PET/CT studies is the final goal which can be accomplished by the use of longer lived PET tracers for dosimetry.
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