Abstract
Purpose
Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (90Y) and a medium-energy beta/gamma emitter (177Lu) in patients with metastatic NET refractory to conventional therapy.
Methods
A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [177Lu]DOTA-TATE (5.55 GBq) and [90Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [177Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST.
Results
Administration of tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment
Conclusion
The results of our study indicates that combined [90Y]DOTA-TATE and [177Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.
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References
Maggard MA, O’Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg. 2004;240:117–22.
Jensen RT. Carcinoid and pancreatic endocrine tumors: recent advances in molecular pathogenesis, localization, and treatment. Curr Opin Oncol. 2000;12:368–77.
Volkert WA, Hoffman TJ. Thrapeutic radiopharmaceuticals. Chem Rev. 1999;99:2269–92.
Krenning EP, Valkema R, Kooij PP, Breeman WA, Bakker WH, de Herder WW, et al. Scintigraphy and radionuclide therapy with [indium-111-labelled-diethyltriamine pentaacetic acid-D-Phe1]octreotide. Ital J Gastroenterol Hepatol. 1999;31 Suppl 2:S219–23.
Bodei L, Cremonesi M, Zoboli S, Grana C, Bartolomei M, Rocca P, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. Eur J Nucl Med Mol Imaging. 2003;30(2):207–16.
Waldherr C, Pless M, Maecke HR, Schumacher T, Crazzolara A, Nitzsche EU, et al. Tumour response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med. 2002;43:610–6.
Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–30.
Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, et al. [177Lu-DOTA0Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients. Eur J Nucl Med. 2001;28(9):1319–25.
Bakker WH, Albert R, Bruns C, Breeman WA, Hofland LJ, Marbach P, et al. [111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci. 1991;49(22):1583–91.
Barone R, Borson-Chazot F, Valkema R, Walrand S, Chauvin F, Gogou L, et al. Patient-specific dosimetry in predicting renal toxicity with 90Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship. J Nucl Med. 2005;46:99S–106.
Wessels BW, Konijnenberg MW, Dale RG, Breitz HB, Cremonesi M, Meredith RF, et al. MIRD pamphlet No. 20: the effect of model assumptions on kidney dosimetry and response – implications for radionuclide therapy. J Nucl Med. 2008;49(11):1884–99.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.
National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE); 2006. http://www.eortc.be/services/doc/ctc/ctcaev3.pdf. Accessed 26 Sep 2013.
Rindi G, Kloppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451:757–62.
Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC, editors. World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004. p. 19–20.
Forrer F, Krenning EP, Kooij PP, Bernard BF, Konijnenberg M, Bakker WH, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0),Tyr(3)]octreotate. Eur J Nucl Med Mol Imaging. 2009;36(7):1138–46.
Nisa L, Savelli G, Giubbini R. Yttrium-90 DOTATOC therapy in GEP-NET and other SST2 expressing tumors: a selected review. Ann Nucl Med. 2011;25(2):75–85.
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(9):1427–34.
Kunikowska J, Królicki L, Hubalewska-Dydejczyk A, Mikołajczak R, Sowa-Staszczak A, Pawlak D. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? Eur J Nucl Med Mol Imaging. 2011;38(10):1788–97.
Villard L, Romer A, Marincek N, Brunner P, Koller MT, Schindler C, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol. 2012;30(10):1100–6.
Acknowledgments
This study was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) and “5 per mille” funds of Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy.
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Seregni, E., Maccauro, M., Chiesa, C. et al. Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy. Eur J Nucl Med Mol Imaging 41, 223–230 (2014). https://doi.org/10.1007/s00259-013-2578-5
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DOI: https://doi.org/10.1007/s00259-013-2578-5