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ORIGINAL ARTICLES Q J NUCL MED MOL IMAGING 2010;54:52-60

Preliminary experience with 68Ga-DOTA-lanreotide positron emission tomography

A C I D E M ® A T V H R G E I IN YR M P O C

T. TRAUB-WEIDINGER 1, E. VON GUGGENBERG 1, G. DOBROZEMSKY 1, D. KENDLER 1, W. EISTERER 2, R. BALE 3, D. PUTZER 1, M. GABRIEL 1, I. VIRGOLINI 1

Aim. Positron emission tomography (PET) of 68Ga-radiolabelled (SST) somatostatin receptor (R) binding peptides has recently been evaluated in SSTR positive tumor patients. First promising results in lung and thyroid tumor patients with 111In-DOTA-Lanreotide (DOTA-LAN) scintigraphy have been described. We report our first experience with 68Ga-labeled DOTA-LAN. Methods. Eleven patients (3 non small cell lung cancer [NSCLC], 3 small cell lung cancer [SCLC], 3 radioiodine negative thyroid cancer, 2 medullary thyroid cancer [MTC]) were investigated. After intravenous injection of 75-150 MBq 68Ga-DOTA-LAN dynamic studies were acquired over the tumor site for the first 40 min with a dedicated PET scanner in 3 patients, and 2 partial body scans were acquired at 20 and 50 min p.i. in 2 patients. Whole body acquisitions at 90 min after injection were acquired in all 11 patients. Image reconstruction was performed by iterative reconstruction utilizing additional transmission scans for attenuation correction. Vital parameters were recorded during the PET study and up to 24 h p.i. Blood and urinary sampling was done up to 4 hr after tracer injection in 8 patients. PET results were compared to conventional imaging techniques (CIT), i.e. computed tomography (CT) and/or magnetic resonance imaging (MRI). In 5 patients, 68Ga-DOTA-LAN was compared with 2-[18F]fluoro-2-deoxyD-glucose (18F-FDG). Results. After intravenous (i.v.) injection of 68Ga-DOTALAN the radioactivity in the blood rapidly decreased to less then 20% of the injected dose (ID) within the first 20 min and further decreased to less than 9% ID after 4 h. A cumulative urinary excretion of 68Ga-DOTA-LAN up to 29.2±13.2% ID at 4 h was found. No acute side effects were observed. Tumor sites were visualized already during the first min after injection. Comparison of posiCorresponding author: I. Virgolini, MD, Prof., Department of Nuclear Medicine, Medical University of Innsbruck, Annichstrasse 35, 6020 Innsbruck, Austria. E-mail: [email protected]

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1Department of Nuclear Medicine Medical University of Innsbruck, Innsbruck, Austria 2Department of Internal Medicine Medical University of Innsbruck, Innsbruck, Austria 3Department of Radiology Medical University of Innsbruck, Innsbruck, Austria

tron emission tomography (PET) and CIT showed concordant results in 3/8 patients and partial concordant results in 5/8 patients with matched results for the primary/recurrent tumor, mediastinal lymph nodes, or adrenal gland metastases. Partial concordant results were seen for the lung, bone, liver and cervical lymph node metastases. Micronodular metastases of the lung and the cerebrum were not visualized by 68Ga-DOTALAN PET. The maximal standardized uptake values of the lung and bone tumor lesions ranged from 6 to 8 g/ml at 90 min p.i.. Conclusion. 68Ga-DOTA-LAN visualized the majority of tumor lesions. Further studies are required to assess the clinical value, and to obtain the best imaging protocol of this new PET SSTR tracer. Key words: Somatostatin - Lanreotide - Possitron-emission tomography.

D

uring the last 15 years peptide receptor targeted scintigraphy, and nowadays also radionuclide therapy, of somatostatin (SST) receptor (R) positive tumors have found increasing interest in oncology.1-4 The high level of SSTR expression on various tumor cells compared to normal tissue and blood cells has provided the basis for the clinical use of radiolabelled peptides as tracers for tumor visualization and treatment in

THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING

February 2010

PRELIMINARY EXPERIENCE WITH 68GA-DOTA-LAN PET

nuclear medicine.2, 5 In the past, the main effort was the development of radiopeptides labelled with 99mTc or 111In for SPECT and with 90Y and 177Lu- for targeted radiotherapy.1-3, 6 DOTA-lanreotide (DOTA-LAN), labelled with 111In and 90Y showed promising results for tumor visualization and tumor uptake in a variety of SSTR-positive tumor entities.7-10 Previously we reported a high affinity of DOTA-LAN to the SSTR subtypes 2-5.7, 8 Other groups confirmed a higher affinity of DOTA-LAN only for SSTR subtype 3 and 5.11 The comparison of 111In/90Y-DOTA-LAN with radiolabelled DOTA-Tyr3-Octreotide (DOTA-TOC) showed discordant results in vivo concerning tumor uptake and detection of tumor lesions, possibly based on differences in SSTR subtype expression.9, 12, 13 Although radiolabelled DOTA-TOC showed higher efficacy in neuroendocrine tumors,12 in radioiodine negative thyroid cancer patients both radiolabelled SST analogs were suitable for evaluating targeted radiotherapy with SST analogs as alternative treatment option, with a slight preference for DOTA-LAN.9 Especially for lung cancer patients, encouraging results for tumor visualization and tumor uptake were found with 111In-DOTA-LAN,14 which favours the therapeutic use of 90Y-DOTA-LAN.2, 10 A new field of interest is the application of positron emitting 68Ga-labeled DOTA-conjugated peptides for positron emission tomography (PET) with superior imaging technology.4, 15 68Ga-DOTA-TOC has shown higher tumor to non-tumor ratios, with better visualization especially of small lesions, and lower kidney accumulation as compared to the 111In-labelled counterpart.15 Additionally, the generator-based production of 68Ga, the short half-life of 68 min and the rapid tracer accumulation in the tumor lesions render this radiolabelled compound a very attractive imaging tracer for SSTR-positive tumors.16, 17 Based on these experiences the purpose of this study was to investigate the tolerability, the radiopharmacokinetics, tumor and organ distribution and visualization of 68Ga-DOTA-LAN in advanced SSTR positive lung and thyroid tumor patients.

TRAUB-WEIDINGER

were purchased from Aldrich-Sigma Chemical Co (Vienna, Austria), in pharmacopoeia quality. Peptide radiolabelling with 68Ga was performed in the following way: 20-25 µM DOTA-LAN was incubated with ~500 MBq of 68GaCl3 obtained from fractionated elution of a 68Ge/68Ga generator (Cyclotron Co Ltd, Obninsk, Russia), in 0.2 M sodium acetate at pH2 patients presented these lesions.

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The introduction of the generator-produced metallic positron emitter 68Ga for the radiolabelling of peptides,18 as well as the development of automated synthetic routes for 68Ga-peptide labelling 19 allowed to translate the clinically well established SSTR scintigraphy also to high sensitivity PET imaging. Recent PET studies have shown promising results with the


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TRAUB-WEIDINGER

7

Average SUVbw (g/mL)

6 5 4 3 2 1

on the direct use of a fraction of the generator eluate for labelling.25 By using this approach consistent high labelling yields and radiochemical purity >98% were obtained. Administration to the patient resulted to be safe, neither acute nor delayed side effects were observed in any of the 11 patients. 68Ga-DOTA-LAN showed a rapid bi-exponential clearance from the plasma with radioactivity decreasing to less than 20% ID within the first 20 min p.i. Blood levels at later time points were higher and cumulative excretion into the urine more pronounced in comparison with 111In-DOTA-LAN.8 Higher blood pool activities of 68Ga versus 111In-labelled peptides can possibly be explained by higher protein binding,26 whereas the more efficient kidney clearance has been related to differences in the radiometal coordination chemistry.27 The decrease of radioactivity in plasma was somewhat lower also in comparison with 68Ga-DOTA-TOC 15 which is in agreement with the higher lipophilicity of DOTA-LAN. A higher whole body retention of 111InDOTA-LAN in comparison with 111In-DOTA-TOC has already been reported previously.8 No metabolites were found in the urine for the observation time of 2 h p.i. Matched imaging results of 68Ga-DOTA-LAN and CIT were found for all primary/local recurrent tumor lesions, as well as for mediastinal and cervical lymph node metastases with exception of one patient. The higher spatial resolution of a PET system keeps the promise to result in better imaging properties and this has already been proven for 68Ga-DOTA-TOC.15, 20 Additionally, preclinical studies have shown the superiority of 68Ga-labelled peptides over its 111Inlabelled congener reporting a higher subtype affinity


0 00:00

00:14

00:28

00:43

00:57

01:12

01:26

01:40

Time p.i.

Figure 5.—Combined curves of SUVs bw for tumor lesions from dynamic studies, extended by the values for the same lesions taken from the whole body scans 90 min p.i. There is only one lesion showing decrease of uptake from the last dynamic frame as compared to the late image (filled triangles, connected by dotted line).

68Ga-labeled

SST analog DOTA-TOC.15, 20-22 A significantly higher detection rate compared to conventional SSTR scintigraphy and diagnostic CT has been reported with consecutive changes in the clinical management of patients undergoing treatment with SST analogs radiolabelled with ß-emitting radionuclides.15, 20, 23, 24 Earlier promising scintigraphic results obtained with the alternative SST analog DOTA-LAN radiolabelled with 111In in patients with lung and iodine negative thyroid tumor patients encouraged us to investigate the tolerability, radiopharmacokinetics, tumor and organ distribution as well as the tumor visualization of 68Ga–DOTA-LAN.8, 9, 14 Radiolabelling of DOTA-LAN with 68Ga was based

TABLE II.—Body weighted mean standard uptake values of 68Ga-DOTA-LAN for organs and tumor lesions and maximum SUVs for all tissues. SUVbw [g/ml]

Spleen Liver GI Abdominal bkgnd Renal parenchyma Renal pelvis Spine Femur Lung tu Liver mts Bone Adrenal gland

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AVG

STDV

MAX

MED (MAX)

5.6 2.8 3.1 0.5 2.5 5.9 2.9

2.2 0.3 0.3 0.1 0.4 1.4 0.6

20.2 8.2 8.2 1.5 8.7 12.6 7.4 5.7 8.8 13.7 8.3 8.4

10.5 5.7 5.7 1.0 5.1 11.5 5.1 4.2 7.1


February 2010


on SST receptors, a significantly increased internalization rate of the 68Ga-labelled peptide and a better biodistribution.28-30 We, therefore, assume that the weak or missing tracer uptake of some tumor lesions smaller than 5 mm and/or tumor lesions with extensive necrotic components is possibly related to a lower SSTR density on the tumor cell surface. This is further supported by results of 68Ga-DOTA-LAN matching with 18F-FDG in only 2 of 5 patients. For lesions of less than 1 cm in size the partial volume effect can also lead to this phenomenon. We observed a similar tracer distribution, but superior tumor detection of 68Ga-DOTA-LAN compared to 111In-DOTA-LAN, which was also described for 68GaDOTA-TOC in comparison with 111In-DOTA-TOC by other authors.15, 20 68Ga-DOTA-LAN could potentially be superior to 68Ga-DOTA-TOC in non-neuroendocrine tumors. In the three cases of dynamic studies tumor visualization was observed within the first 40 min. All lesions visible in the late images were also visible in the last frames of the dynamic series. Comparison of the obtained SUVs showed a steady increase for tumor lesions, with one exception. The organs imaged in the dynamic studies (aorta, lung and bone marrow) showed significant differences in the uptake behaviour. The blood activity was decreasing (concordant to blood sample measurements), and the lung showed a similar decrease already in the first view minutes of imaging. The initial increase of uptake in the bone marrow until the 45 min frame, followed by decrease to the 90 min frame underlines the decision to perform imaging at a later time point. In 2 patients with additional whole body scans 20 and 50 min p.i. tumor visualization was possible and tracer accumulation showed a consistent behaviour to the one measured in the dynamic datasets, thereby yielding best visibility in the frames from the 90 min p.i. acquisition.

TRAUB-WEIDINGER

to be done to investigate the clinical value of this PET tracer for tumor staging and evaluation of alternative therapeutic approaches with the same peptide labelled by ß-emitting radionuclides of lung and thyroid tumor disease.

A C I D E M ® A T V H R G E I IN YR M P O C Conclusions

68Ga-DOTA-peptides

are powerful new radiopharmaceuticals and 68Ga-DOTA-TOC can today be seen as the new golden standard for the diagnosis of SST expressing malignancies. In the patients with thyroid and lung cancer included in this study 68Ga-DOTA-LAN visualized the majority of tumor lesions known from CIT without any acute side effect. Further studies have

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References

1. Krenning EP, Kweekeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei Hy et al. Somatostatin receptor scintigraphy (111In-DOTADPhe1) and (123I-Tyr3)-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med 1993;18:1-16. 2. Virgolini I, Traub T, Leimer M, Novotny C, Pangerl T, Ofluoglu S et al. New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy. Q J Nucl Med 2000;44:50-8. 3. Virgolini I, Traub T, Novotny C, Leimer M, Fueger B, Li SR et al. Experience with 111In-and 90Y-labeled somatostatin analogs. Current Pharmaceutical Design 2002;8:1781-807. 4. Maecke H, Hofmann M, Haberkorn U. 68Ga-labeled peptides in tumor imaging. J Nucl Med 2005;46(Suppl 1):172-8. 5. Virgolini I, Yang Q, Li S, Angelberger P, Neuhold N, Niederle B et al. Cross competition between vasoactive intestinal peptide and somatostatin for binding to tumor cell membrane receptors. Cancer Res 1994;54:690-700. 6. Gabriel M, Muehllechner P, Decristoforo C, von Guggenberg E, Kendler D, Prommegger R et al. 99mTc-EDDA/HYNIC-Tyr3 -octreotide for staging and follow-up of patients with neuroendocrine gastro-entero-pancreatic tumors. Q J Nucl Med Mol Imaging 2005;49:237-44. 7. Smith-Jones PM, Bischof C, Leimer M, Gludovacz D, Angelberger P, Pangerl T et al. DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy. Endocrinology 1999;140: 5136-48. 8. Virgolini I, Szilvasi I, Kurtaran A, Angelberger P, Raderer M, Havlik E et al. 111In-DOTA-lanreotide: biodistribution, safety and radiation absorbed dose in tumor patients. J Nucl Med 1998;39:1928-36. 9. Rodrigues M, Traub-Weidinger T, Leimer M, Li S, Andreae F, Angelberger P et al. Value of 111In-DOTA-lanreotide and 111InDOTA-DPhe1-Tyr3-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with 18FFDG PET. Eur J Nucl Med Mol Imaging 2005;32:1144-51. 10. Virgolini I, Britton K, Buscombe J, Moncayo R, Paganelli G, Riva P. 111In and 90Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin Nucl Med 2002;32:148-55. 11. Reubi JC, Schaer JC, Waser B, Wenger S, Heppeler A, Schmitt JS et al. Affinity profiles for human somatostatin receptor subtypes SST1-SSt5 of somatostatinradiotracer selected for scintigraphic and radiothaerpeutic and radio therapeutic use. Eur J Nucl Med 2000;27:273-82. 12. Virgolini I, Traub T, Novotny C, Leimer M, Fueger B, Li SR et al. New trends in peptide receptor radioligands. Q J Nucl Med. 2001;45:153-9. 13. Rodrigues M, Traub-Weidinger T, Li S, Ibi B, Virgolini I. Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2006;33:532-40. 14. Traub T, Petkov V, Ofluoglu S, Pangerl T, Raderer M, Fuegger BJ et al. 111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung. J Nucl Med 2001;42:1309-15. 15. Hofmann M, Maecke H, Börner AR, Weckesser E, Schöffski P, Oei ML et al. Biokinetics and imaging with the somatostatin receptor PET radioligand 68Ga-DOTATOC: preliminray data. Eur J Nucl Med 2001;28:1751-7. 16. Hayes RL, Carlton JE, Byrd BL. Bone scanning with 68Gallium: a carrier effect. J Nucl Med 1965;6:605-10.


59


TRAUB-WEIDINGER

17. Shealy CN, Aronow S, Brownell GL. 68Gallium as a scanning agent for intracranial lesions. J Nucl Med 1964;5:161-7. 18. Fani M, André JP, Maecke HR. 68Ga-PET: a powerful generatorbased alternative to cyclotron-based PET radiopharmaceuticals. Contrast Media Mol Imaging 2008;3:67-77. 19. Decristoforo C, Knopp R, von Guggenberg E, Rupprich M, Dreger T, Hess A et al. A fully automated synthesis for the preparation of 68Ga-labelled peptides. Nucl Med Commun 2007;28:870-5. 20. Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med 2007;48:508-18. 21. Gabriel M, Oberauer A, Dobrozemsky G, Decristoforo C, Putzer D, Kendler D et al. 68Ga-DOTA-Tyr3-octreotide PET for assessing response to somatostatin-receptor-mediated radionuclide therapy. J Nucl Med 2009;50:1427-34. 22. Putzer D, Gabriel M, Henninger B, Kendler D, Uprimny C, Dobrozemsky G et al. Bone metastases in patients with neuroendocrine tumor: 68 Ga-DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy. J Nucl Med 2009;50: 1214-21. 23. Gabriel M, Hausler F, Bale R, Moncayo R, Decristoforo C, Kovacs P et al. Image fusion analysis of 99mTc-HYNIC-Tyr3-octreotide SPECT and diagnostic CT using an immobilization device with external markers in patients with endocrine tumors. Eur J Nucl Med Mol Imaging 2005;32:1440-51. 24. Virgolini IJ, Gabriel M, von Guggenberg E, Putzer D, Kendler D,

25. 26.

Decristoforo C. Role of radiopharmaceuticals in the diagnosis and treatment of neuroendocrine tumors. Eur J Cancer 2009;45(Suppl 1):274-91. Breeman WAP, de Jong M, de Blois E, Bernard BF, Konijnenberg M, Krenning EP. Radiolabelling DOTA-peptides with 68Ga. Eur J Nucl Med Mol Imaging 2005;32:478-85. Decristoforo C, Hernandez Gonzalez I, Carlsen J, Rupprich M, Huisman M, Virgolini I et al. 68Ga- and 111In-labelled DOTA-RGD peptides for imaging of alphavbeta3 integrin expression. Eur J Nucl Med Mol Imaging 2008;35:1507-15. Heppeler A, Froidevaux S, Ma?cke HR, Jermann E, Be?he? M, Powell P et al. Radiometal-labelled macrocyclic chelator-derivatised somatostatin analogue with superb tumor-targeting properties and potential for receptor-mediated internal radiotherapy. Chem Eur J 1999;5:1974-81. Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging 2007;34:982-93. Froidevaux S, Eberle AN, Christe M, Sumanovski L, Heppeler A, Schmitt JS et al. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model. Froidevaux Int J Cancer 2002;20:930-7. Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med 2000;27:273-82.


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February 2010