Additional hepatic 166Ho-radioembolization in patients with neuroendocrine tumours treated with 177Lu-DOTATATE; a single center, interventional, non-randomized, non-comparative, open label, phase II study (HEPAR PLUS trial)

Arthur J A T Braat, Dik J Kwekkeboom, Boen L R Kam, Jaap J M Teunissen, Wouter W de Herder, Koen M A Dreijerink, Rob van Rooij, Gerard C Krijger, Hugo W A M de Jong, Maurice A A J van den Bosch, Marnix G E H Lam, Arthur J A T Braat, Dik J Kwekkeboom, Boen L R Kam, Jaap J M Teunissen, Wouter W de Herder, Koen M A Dreijerink, Rob van Rooij, Gerard C Krijger, Hugo W A M de Jong, Maurice A A J van den Bosch, Marnix G E H Lam

Abstract

Background: Neuroendocrine tumours (NET) consist of a heterogeneous group of neoplasms with various organs of origin. At diagnosis 21% of the patients with a Grade 1 NET and 30% with a Grade 2 NET have distant metastases. Treatment with peptide receptor radionuclide therapy (PRRT) shows a high objective response rate and long median survival after treatment. However, complete remission is almost never achieved. The liver is the most commonly affected organ in metastatic disease and is the most incriminating factor for patient survival. Additional treatment of liver disease after PRRT may improve outcome in NET patients. Radioembolization is an established therapy for liver metastasis. To investigate this hypothesis, a phase 2 study was initiated to assess effectiveness and toxicity of holmium-166 radioembolization (166Ho-RE) after PRRT with lutetium-177 (177Lu)-DOTATATE.

Methods: The HEPAR PLUS trial ("Holmium Embolization Particles for Arterial Radiotherapy Plus 177 Lu-DOTATATE in Salvage NET patients") is a single centre, interventional, non-randomized, non-comparative, open label study. In this phase 2 study 30-48 patients with > 3 measurable liver metastases according to RECIST 1.1 will receive additional 166Ho-RE within 20 weeks after the 4th and last cycle of PRRT with 7.4 GBq 177Lu-DOTATATE. Primary objectives are to assess tumour response, complete and partial response according to RECIST 1.1, and toxicity, based on CTCAE v4.03, 3 months after 166Ho-RE. Secondary endpoints include biochemical response, quality of life, biodistribution and dosimetry.

Discussion: This is the first prospective study to combine PRRT with 177Lu-DOTATATE and additional 166Ho-RE in metastatic NET. A radiation boost on intrahepatic disease using 166Ho-RE may lead to an improved response rate without significant additional side-effects.

Trial registration: Clinicaltrials.gov NCT02067988 , 13 February 2014. Protocol version: 6, 30 november 2016.

Keywords: 177Lu-DOTATATE; Holmium-166; Liver metastasis; Lutetium-177; NET; Neuroendocrine tumour; PRRT; Radioembolization.

Conflict of interest statement

Authors’ information

A.J.A.T. Braat, M.D., corresponding author and study physician. Department of Radiology and Nuclear Medicine, University Medical Centre Utrecht, Heidelberglaan 100, Huispostnummer E01.132, P.O. Box 85,500, 3584 CX Utrecht, the Netherlands.

Ethics approval and consent to participate

Phase 2 study was approved by the Medical Ethical Committee of the University Medical Centre Utrecht. Informed consent will be obtained of all participating patients.

Competing interests

The department of Radiology and Nuclear Medicine of the University Medical Centre Utrecht owns royalties for 166Ho-microspheres. MGEHL has acted as a consultant for BTG, Sirtex, Mirada and Bayer Healthcare. All other authors declared no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Example of 177Lu-DOTATATE in NET. Upper row: planar whole body 111In-pentetreotide scintigraphy. Lower row: venous phased CT of the liver. On the left baseline imaging and on the right imaging after 177Lu-DOTATATE treatment
Fig. 2
Fig. 2
Example of 166Ho-radioembolization in NET. A patient with a grade 2 small intestinal NET according to the WHO-criteria, treated in the prior HEPAR 2 trial. On the left, the 18FDG-PET and venous phased CT at baseline. In the middle, the imaging studies 3 months after 166Ho-RE with partial metabolic 18FDG-PET response and some tumour reduction on CT. On the right, follow-up imaging studies 6 months after 166Ho-RE with significant partial metabolic response and significant tumour reduction on CT
Fig. 3
Fig. 3
Study protocol depicting the time line and study proceedings between inclusion and hospital discharge
Fig. 4
Fig. 4
Example of lung shunt fraction overestimation by 99mTc-MAA. A patient with multiple liver metastases of a cholangiocarcinoma treated in the prior HEPAR 2 trial. Note the (visual) significant overestimation of 99mTc-MAA on planar imaging compared to the 166Ho-scout dose and 166Ho-treatment dose. Quantification of the lung shunt fraction on planar and SPECT/CT imaging confirmed the visual assessment: a99mTc-planar = 13.4%, d99mTc-SPECT = 6%, all 166Ho imaging modalities (b, c, e and f) with the scout dose and with the treatment dose showed a lung shunt fraction of < 1%

References

    1. Bosman FT, Carneiro F. World Health Organization classification of Tumours, pathology and genetics of Tumours of the digestive system. 4. Lyon: IARC Press; 2010.
    1. Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs. Best Pract Res Clin Gastroenterol. 2012;26(6):705–717. doi: 10.1016/j.bpg.2013.01.003.
    1. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–3072. doi: 10.1200/JCO.2007.15.4377.
    1. Pavel MBE, Couvelard A, et al. ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinol. 2012;95(2):157–176. doi: 10.1159/000335597.
    1. Fraenkel M, Kim MK, Faggiano A, Valk GD. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26(6):691–703. doi: 10.1016/j.bpg.2013.01.006.
    1. Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28(1):69–76. doi: 10.1200/JCO.2009.24.2669.
    1. Quintela-Fandino M, Krzyzanowska M, Duncan G, Young A, Moore MJ, Chen EX, Stathis A, Colomer R, Petronis J, Grewal M, Webster S, Wang L, Siu LL. In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours. Br J Cancer. 2013;108(6):1298–1305. doi: 10.1038/bjc.2013.64.
    1. Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B, International Lanreotide and Interferon Alfa Study Group Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the international Lanreotide and interferon alfa study group. J Clin Oncol. 2003;21(14):2689–2696. doi: 10.1200/JCO.2003.12.142.
    1. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC. RADIANT-2 study group: Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378(9808):2005–2012. doi: 10.1016/S0140-6736(11)61742-X.
    1. Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R, PROMID Study Group Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID study group. J Clin Oncol. 2009;27(28):4656–4663. doi: 10.1200/JCO.2009.22.8510.
    1. Kvols LK, Oberg KE, O'Dorisio TM, Mohideen P, de Herder WW, Arnold R, Hu K, Zhang Y, Hughes G, Anthony L, Wiedenmann B. Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012;19(5):657–666. doi: 10.1530/ERC-11-0367.
    1. Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG, Eastern Cooperative Oncology Group Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: eastern cooperative oncology group study E1281. J Clin Oncol. 2005;23(22):4897–4904. doi: 10.1200/JCO.2005.03.616.
    1. Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, Mäcke HR, Rochlitz C, Müller-Brand J, Walter MA. 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):2416–2423. doi: 10.1200/JCO.2010.33.7873.
    1. Kwekkeboom DJ, de Herder WW, Kam BLR, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO, Krenning EP. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–2130. doi: 10.1200/JCO.2007.15.2553.
    1. Swärd C, Bernhardt P, Ahlman H, Wängberg B, Forssell-Aronsson E, Larsson M, Svensson J, Rossi-Norrlund R, Kölby L. [177Lu-DOTA0-Tyr3]-octreotate treatment in patients with disseminated gastroenteropancreatic neuroendocrine tumors: the value of measuring absorbed dose to the kidney. World J Surg. 2010;34(6):1368–1372. doi: 10.1007/s00268-009-0387-6.
    1. Sansovini M, Severi S, Ambrosetti A, Monti M, Nanni O, Sarnelli A, Bodei L, Garaboldi L, Bartolomei M, Paganelli G. Treatment with the radiolabelled somatostatin analog Lu-DOTATATE for advanced pancreatic neuroendocrine tumors. Neuroendocrinol. 2013;97(4):347–354. doi: 10.1159/000348394.
    1. Chinol M, Bodei L, Cremonesi M, Paganelli G. Receptor-mediated radiotherapy with 90Y-DOTA-DPhe1-Tyr3-octreotide: the experience of the European Institute of Oncology Group. Semin Nucl Med. 2002;32(2):141–147. doi: 10.1053/snuc.2002.31563.
    1. Devcic Z, Rosenberg J, Braat AJAT, Techasith T, Banerjee A, Sze DY, Lam MGEH. The efficacy of hepatic 90Y resin Radioembolization for metastatic neuroendocrine tumors: a meta-analysis. J Nucl Med. 2014;55(9):1404–1410. doi: 10.2967/jnumed.113.135855.
    1. Zielhuis SW, Nijsen JF, de Roos R, Krijger GC, van Rijk PP, Hennink WE, van het Schip AD. Production of GMP-grade radioactive holmium loaded poly(L-lactic acid) microspheres for clinical application. Int J Pharm. 2006;311(1–2):69–74. doi: 10.1016/j.ijpharm.2005.12.034.
    1. Smits MLJ, Nijsen JFW, van den Bosch MAAJ, Lam MGEH, Vente MA, Mali WP, van het Schip AD, Zonnenberg BA. Holmium-166 radioembolisation in patients with unresectable, chemorefractory liver metastases (HEPAR trial): a phase 1, dose-escalation study. Lancet Oncol. 2012;13(10):1025–1034. doi: 10.1016/S1470-2045(12)70334-0.
    1. Smits MLJ, Elschot M, van den Bosch MAAJ, et al. In vivo dosimetry based on SPECT and MR imaging of 166Ho-microspheres for treatment of liver malignancies. J Nucl Med. 2013;54(12):2093–2100. doi: 10.2967/jnumed.113.119768.
    1. Elschot MSM, Nijsen JFW, Lam MGEH, Zonnenberg BA, van den Bosch MAAJ, et al. Quantitative Monte Carlo-based holmium-166 SPECT reconstruction. Med Phys. 2013;40:112502. doi: 10.1118/1.4823788.
    1. Response Evaluation Criteria In Solid Tumors []. Accessed Dec 2016.
    1. Central Accompaniment Institution; directive precautions with iodinated contrast / Centraal BegeleidingsOrgaan; Richtlijn Voorzorgsmaatregelen bij jodiumhoudende contrastmiddelen []. Accessed Dec 2016.
    1. Prince JF, van Rooij R, Bol GH, de Jong HWAM, van den Bosch MAAJ, Lam MGEH. Safety of a scout dose preceding hepatic radioembolization with holmium-166 microspheres. J Nucl Med. 2015;56(6):817–823. doi: 10.2967/jnumed.115.155564.
    1. Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03) []. Accessed Dec 2016.
    1. Prince JF, van den Bosch MAAJ, Nijsen JFW, Smits MLJ, van den Hoven AF, Nikolakopoulos S, Wessels FJ, Bruijnen RCG, Braat MNGJA, Zonnenberg BA, Lam MGEH. Efficacy of radioembolization with holmium-166 microspheres in salvage patients with liver metastases: a phase 2 study. J Nucl Med. 2018;59(4):582–8.
    1. Sangro B, Gil-Alzugaray B, Rodriguez J, Sola I, Martinez-Cuesta A, Viudez A, Chopitea A, Iñarrairaegui M, Arbizu J, Bilbao JI. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer. 2008;112(7):1538–1546. doi: 10.1002/cncr.23339.
    1. Lam MGEH, Banerjee S, Louie JD, Abdelmaksoud MH, Iagaru AH, Ennen RE, Sze DY. Root cause analysis of gastroduodenal ulceration after yttrium-90 radioembolization. Cardiovasc Intervent Radiol. 2013;36(6):1536–1547. doi: 10.1007/s00270-013-0579-1.
    1. Ezziddin S, Meyer C, Kahancova S, Haslerud T, Willinek W, Wilhelm K, Biersack HJ, Ahmadzadehfar H. 90Y Radioembolization after radiation exposure from peptide receptor radionuclide therapy. J Nucl Med. 2012;53(11):1663–1669. doi: 10.2967/jnumed.112.107482.
    1. SIRTeX Medical . Package insert. 2013.
    1. Filippi L, Ciorra A, Sardella B, Schillaci O, Bagni O. Sequential use of (90)Y microspheres Radioembolization and (177)Lu-Dotatate in Pluri-metastatic neuroendocrine tumors: a case report. Nucl Med Mol Imaging. 2014;48(4):321–325. doi: 10.1007/s13139-014-0292-2.
    1. Elschot M, Nijsen JFW, Lam MEGH, Smits MLJ, Prince JF, Viergever MA, van den Bosch MAAJ, Zonnenberg BA, de Jong HWAM. 99mTc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with 166Ho-microspheres. Eur J Nucl Med Mol Imaging. 2014;41(10):1965–1975. doi: 10.1007/s00259-014-2784-9.
    1. Kao YH, Steinberg JD, Tay YS, et al. Post-radioembolization yttrium-90 PET/CT - part 1: diagnostic reporting. EJNMMI Res. 2013;3(1):56. doi: 10.1186/2191-219X-3-56.
    1. Kao YH, Steinberg JD, Tay YS, et al. Post-radioembolization yttrium-90 PET/CT - part 2: dose-response and tumor predictive dosimetry for resin microspheres. EJNMMI Res. 2013;3(1):57. doi: 10.1186/2191-219X-3-57.
    1. van den Hoven AFPJ, de Keizer B, Vonken EJPA, Bruijnen RCG, Verkooijen HM, et al. Use of C-arm cone beam CT during hepatic Radioembolization: protocol optimization for extrahepatic shunting and parenchymal enhancement. Cardiovasc Intervent Radiol. 2015;39(1):64–73. doi: 10.1007/s00270-015-1146-8.
    1. Louie JDKN, Kuo WT, Hwang GL, Hofmann LV, Goris ML, et al. Incorporating cone-beam CT into the treatment planning for Yttrium-90 Radioembolization. J Vasc Interv Radiol. 2009;20:606–613. doi: 10.1016/j.jvir.2009.01.021.
    1. Krishnamurthy GT, Krishnamurthy S. Nuclear hepatology: a textbook of hepatobiliary diseases. 2. New York: Springer; 2000.
    1. Lam MGEH, Goris ML, Iagaru AH, Mittra ES, Louie JD, Sze DY. Prognostic utility of 90Y Radioembolization dosimetry based on fusion 99mTc-macroaggregated albumin–99mTc-sulfur colloid SPECT. J Nucl Med. 2013;54(12):2055–2061. doi: 10.2967/jnumed.113.123257.
    1. Lam MGEH, Banerjee A, Goris ML, Iagaru AH, Mittra ES, Louie JD, Sze DY. Fusion dual-tracer SPECT-based hepatic dosimetry predicts outcome after radioembolization for a wide range of tumour cell types. Eur J Nucl Med Mol Imaging. 2015;42(8):1192–1201. doi: 10.1007/s00259-015-3048-z.
    1. van de Maat GH, Seevinck PR, Elschot M, et al. MRI-based biodistribution assessment of holmium-166 poly(L-lactic acid) microspheres after radioembolisation. Eur Radiol. 2013;23(3):827–835. doi: 10.1007/s00330-012-2648-2.
    1. Seevinck PR, Seppenwoolde JH, de Wit TC, Nijsen JF, Beekman FJ, van Het Schip AD, Bakker CJ. Factors affecting the sensitivity and detection limits of MRI, CT, and SPECT for multimodal diagnostic and therapeutic agents. Anti Cancer Agents Med Chem. 2007;7(3):317–334. doi: 10.2174/187152007780618153.
    1. Smits MLJ, Elschot M, Sze DY, Kao YH, Nijsen JF, Iagaru AH, de Jong HWAM, van den Bosch MAAJ, Lam MGEH. Radioembolization dosimetry: the road ahead. Cardiovasc Intervent Radiol. 2015;38(2):261–269. doi: 10.1007/s00270-014-1042-7.
    1. Bergsma H, van Vliet EI, Teunissen JJ, Kam BL, de Herder WW, Peeters RP, Krenning EP, Kwekkeboom DJ. Peptide receptor radionuclide therapy (PRRT) for GEP-NETs. Best Pract Res Clin Gastroenterol. 2012;26(6):867–881. doi: 10.1016/j.bpg.2013.01.004.
    1. Pool SE, Kam BL, Koning GA, Konijnenberg M, Ten Hagen TL, Breeman WA, Krenning EP, de Jong M, van Eijck CH. [(111)in-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: an overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy. Cancer Biother Radiopharm. 2014;29(4):179–187. doi: 10.1089/cbr.2013.1552.
    1. Chamberlain RS, Canes D, Brown KT, Saltz L, Jarnagin W, Fong Y, Blumgart LH. Hepatic neuroendocrine metastases: does intervention Alter outcomes? J Am Coll Surg. 2000;190(4):432–445. doi: 10.1016/S1072-7515(00)00222-2.
    1. Yao KA, Talamonti MS, Nemcek A, Angelos P, Chrisman H, Skarda J, Benson AB, Rao S, Joehl RJ. Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors. Surgery. 2001;130(4):677–682. doi: 10.1067/msy.2001.117377.
    1. Gupta S, Johnson MM, Murthy R, Ahrar K, Wallace MJ, Madoff DC, McRae SE, Hicks ME, Rao S, Vauthey JN, Ajani JA, Yao JC. Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors variables affecting response rates and survival. Cancer. 2005;104(8):1590–1602. doi: 10.1002/cncr.21389.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel