Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

Open Access 01-06-2018 | Original Article

Prospective observational study of ¹⁷⁷Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Authors: Ulrike Garske-Román, Mattias Sandström, Katarzyna Fröss Baron, Lars Lundin, Per Hellman, Staffan Welin, Silvia Johansson, Tanweera Khan, Hans Lundqvist, Barbro Eriksson, Anders Sundin, Dan Granberg

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 6/2018

Abstract

Purpose

Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

Methods

The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3–20% in 121 (60.5%) and >20% in 16 (8%).

Results

In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22–30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39–53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

Conclusions

Dosimetry-based therapy with ¹⁷⁷Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Otte A, Mueller-Brand J, Dellas S, Nitzsche EU, Herrmann R, Maecke HR. Yttrium-90-labelled somatostatin-analogue for cancer treatment. Lancet. 1998;351(9100):417–8.CrossRefPubMed

Otte A, Herrmann R, Heppeler A, Behe M, Jermann E, Powell P, et al. Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med. 1999;26(11):1439–47.CrossRefPubMed

Kwekkeboom DJ, Teunissen JJ, Bakker WH, Kooij PP, de Herder WW, Feelders RA, et al. Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol. 2005;23(12):2754–62.CrossRefPubMed

Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S, Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med. 2005;46(Suppl 1):62S–6S.PubMed

Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–30. https://doi.org/10.1200/JCO.2007.15.2553.CrossRefPubMed

Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, et al. Peptide receptor radionuclide therapy with (177)Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38(12):2125–35. https://doi.org/10.1007/s00259-011-1902-1.CrossRefPubMed

Ezziddin S, Attassi M, Yong-Hing CJ, Ahmadzadehfar H, Willinek W, Grunwald F, et al. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med. 2014;55(2):183–90. https://doi.org/10.2967/jnumed.113.125336.CrossRefPubMed

Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35. https://doi.org/10.1056/NEJMoa1607427.CrossRefPubMedPubMedCentral

Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, et al. Long-term efficacy, survival, and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23(16):4617–24. https://doi.org/10.1158/1078-0432.CCR-16-2743.CrossRefPubMed

10.

Valkema R, Pauwels S, Kvols LK, Barone R, Jamar F, Bakker WH, et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2006;36(2):147–56.CrossRefPubMed

11.

Valkema R, Pauwels SA, Kvols LK, Kwekkeboom DJ, Jamar F, de Jong M, et al. Long-term follow-up of renal function after peptide receptor radiation therapy with (90)Y-DOTA(0),Tyr(3)-octreotide and (177)Lu-DOTA(0),Tyr(3)-octreotate. J Nucl Med. 2005;46(Suppl 1):83S–91S.PubMed

12.

Bushnell DL Jr, O'Dorisio TM, O'Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28(10):1652–9.CrossRefPubMedPubMedCentral

13.

Cwikla JB, Sankowski A, Seklecka N, Buscombe JR, Nasierowska-Guttmejer A, Jeziorski KG, et al. Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): a phase II study. Ann Oncol. 2010;21(4):787–94. https://doi.org/10.1093/annonc/mdp372.CrossRefPubMed

14.

Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29(17):2416–23.CrossRefPubMed

15.

Sandstrom M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients undergoing therapy with (177)Lu-DOTA-D-Phe(1)-Tyr(3)-octreotate. Eur J Nucl Med Mol Imaging. 2010;37(2):212–25. https://doi.org/10.1007/s00259-009-1216-8.CrossRefPubMed

16.

Garske U, Sandstrom M, Johansson S, Sundin A, Granberg D, Eriksson B, et al. Minor changes in effective half-life during fractionated (177)Lu-Octreotate therapy. Acta Oncol. 2012;51(1):86–96. https://doi.org/10.3109/0284186X.2011.618511.CrossRefPubMed

17.

Sandstrom M, Garske-Roman U, Granberg D, Johansson S, Widstrom C, Eriksson B, et al. Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment. J Nucl Med. 2013;54(1):33–41.CrossRefPubMed

18.

Garkavij M, Nickel M, Sjogreen-Gleisner K, Ljungberg M, Ohlsson T, Wingardh K, et al. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer. 2010;116(4 Suppl):1084–92. https://doi.org/10.1002/cncr.24796.CrossRefPubMed

19.

Sward C, Bernhardt P, Ahlman H, Wangberg B, Forssell-Aronsson E, Larsson M, et al. [177Lu-DOTA 0-Tyr 3]-octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: the value of measuring absorbed dose to the kidney. World J Surg. 2010;34(6):1368–72. https://doi.org/10.1007/s00268-009-0387-6.CrossRefPubMed

20.

Larsson M, Bernhardt P, Svensson JB, Wangberg B, Ahlman H, Forssell-Aronsson E. Estimation of absorbed dose to the kidneys in patients after treatment with 177Lu-octreotate: comparison between methods based on planar scintigraphy. EJNMMI Res. 2012;2(1):49. https://doi.org/10.1186/2191-219X-2-49.CrossRefPubMedPubMedCentral

21.

Barone R, Borson-Chazot F, Valkema R, Walrand S, Chauvin F, Gogou L, et al. Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship. J Nucl Med. 2005;46(Suppl 1):99S–106S.PubMed

22.

Bodei L, Kidd M, Paganelli G, Grana CM, Drozdov I, Cremonesi M, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42(1):5–19. https://doi.org/10.1007/s00259-014-2893-5.CrossRefPubMed

23.

Mariniello A, Bodei L, Tinelli C, Baio SM, Gilardi L, Colandrea M, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol Imaging. 2016;43(3):441–52. https://doi.org/10.1007/s00259-015-3190-7.CrossRefPubMed

24.

Bodei L, Cremonesi M, Ferrari M, Pacifici M, Grana CM, Bartolomei M, et al. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors. Eur J Nucl Med Mol Imaging. 2008;35(10):1847–56. https://doi.org/10.1007/s00259-008-0778-1.CrossRefPubMed

25.

Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–22.CrossRefPubMed

26.

Konijnenberg M, Melis M, Valkema R, Krenning E, de Jong M. Radiation dose distribution in human kidneys by octreotides in peptide receptor radionuclide therapy. J Nucl Med. 2007;48(1):134–42.PubMed

27.

Eberlein U, Cremonesi M, Lassmann M. Individualized dosimetry for theranostics: necessary, nice to have, or counterproductive? J Nucl Med. 2017;58(Suppl 2):97S–103S. https://doi.org/10.2967/jnumed.116.186841.CrossRefPubMed

28.

Benua RS, Cicale NR, Sonenberg M, Rawson RW. The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. Am J Roentgenol Radium Ther Nucl Med. 1962;87:171–82.PubMed

29.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed

30.

Krenning EP, de Jong M, Kooij PP, Breeman WA, Bakker WH, de Herder WW, et al. Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy. Ann Oncol. 1999;10(Suppl 2):S23–9.CrossRefPubMed

31.

Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014;120(18):2814–23. https://doi.org/10.1002/cncr.28721.CrossRefPubMed

32.

Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152–60.

33.

Fazio N, Grana C, Pelosi G, Torrisi R, Di Meglio G, Tradati N, et al. Successful chemotherapy and 90Y-DOTATOC in a patient with mediastinal highly aggressive neuroendocrine carcinoma. Acta Oncol. 2006;45(5):627–9.CrossRefPubMed

34.

Ezziddin S, Opitz M, Attassi M, Biermann K, Sabet A, Guhlke S, et al. Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2011;38(3):459–66. https://doi.org/10.1007/s00259-010-1610-2.CrossRefPubMed

35.

Garske U, Sandström M, Johansson S, Granberg D, Lundqvist H, Lubberink M, et al. Lessons on tumour response: imaging during therapy with 177Lu-DOTA-octreotate. A case report on a patient with a large volume of poorly differentiated neuroendocrine carcinoma. Theranostics. 2012;2(5):459–71.CrossRefPubMedPubMedCentral

36.

Pauwels S, Barone R, Walrand S, Borson-Chazot F, Valkema R, Kvols LK, et al. Practical dosimetry of peptide receptor radionuclide therapy with (90)Y-labeled somatostatin analogs. J Nucl Med. 2005;46(Suppl 1):92S–8S.PubMed

37.

Ilan E, Sandstrom M, Wassberg C, Sundin A, Garske-Roman U, Eriksson B, et al. Dose response of pancreatic neuroendocrine tumours treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE. J Nucl Med. 2015;56(2):177–82. https://doi.org/10.2967/jnumed.114.148437.CrossRefPubMed

38.

Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med. 2011;52(9):1361–8.CrossRefPubMed

39.

Sundlov A, Sjogreen-Gleisner K, Svensson J, Ljungberg M, Olsson T, Bernhardt P, et al. Individualised 177Lu-DOTATATE treatment of neuroendocrine tumours based on kidney dosimetry. Eur J Nucl Med Mol Imaging. 2017;44(9):1480–9. https://doi.org/10.1007/s00259-017-3678-4.CrossRefPubMedPubMedCentral

40.

Cremonesi M, Botta F, Di Dia A, Ferrari M, Bodei L, De Cicco C, et al. Dosimetry for treatment with radiolabelled somatostatin analogues. A review. Q J Nucl Med Mol Imaging. 2010;54(1):37–51.PubMed

41.

Sandstrom M, Garske-Roman U, Johansson S, Granberg D, Sundin A, Freedman N. Kidney dosimetry during 177Lu-DOTATATE therapy in patients with neuroendocrine tumors: aspects on calculation and tolerance. Acta Oncol. 2017. https://doi.org/10.1080/0284186X.2017.1378431.PubMed

42.

Svensson J, Ryden T, Hagmarker L, Hemmingsson J, Wangberg B, Bernhardt P. A novel planar image-based method for bone marrow dosimetry in (177)Lu-DOTATATE treatment correlates with haematological toxicity. EJNMMI Phys. 2016;3(1):21. https://doi.org/10.1186/s40658-016-0157-0.CrossRefPubMedPubMedCentral

43.

Bodei L, Modlin IM, Luster M, Forrer F, Cremonesi M, Hicks RJ, et al. Myeloid neoplasms after chemotherapy and PRRT: myth and reality. Endocr Relat Cancer. 2016;23(8):C1–7. https://doi.org/10.1530/ERC-16-0258.CrossRefPubMed

44.

Brieau B, Hentic O, Lebtahi R, Palazzo M, Ben Reguiga M, Rebours V, et al. High risk of myelodysplastic syndrome and acute myeloid leukemia after 177Lu-octreotate PRRT in NET patients heavily pretreated with alkylating chemotherapy. Endocr Relat Cancer. 2016;23(5):L17–23. https://doi.org/10.1530/ERC-15-0543.CrossRefPubMed

Title: Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity
Authors: Ulrike Garske-Román
Mattias Sandström
Katarzyna Fröss Baron
Lars Lundin
Per Hellman
Staffan Welin
Silvia Johansson
Tanweera Khan
Hans Lundqvist
Barbro Eriksson
Anders Sundin
Dan Granberg
Publication date: 01-06-2018
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 6/2018
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-018-3945-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Prospective observational study of ¹⁷⁷Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2018

11C–acetate PET/CT: a potential alternative of transcranial biopsy for grading cerebral gliomas

The roles of 11C-acetate PET/CT in predicting tumor differentiation and survival in patients with cerebral glioma

Assessment of alteration in liver 18F–FDG uptake due to steatosis in lymphoma patients and its impact on the Deauville score

Cancer metastasizes to the bone marrow and not to the bone: time for a paradigm shift!

68Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer

A first-in-man PET study of [18F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5