Digestive Disease Interventions 2019; 03(01): 081-090
DOI: 10.1055/s-0038-1676300
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Intra-Arterial Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor Liver Metastases

Sander C. Ebbers
1   Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
,
Maarten W. Barentsz
2   Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
,
Arthur J.A.T. Braat
3   Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
,
Marnix G.E.H. Lam
4   Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
› Author Affiliations
Further Information

Publication History

27 July 2018

22 October 2018

Publication Date:
17 January 2019 (online)

Abstract

Purpose Currently, peptide receptor radionuclide therapy (PRRT) with lutetium-177 (177Lu)-DOTATATE is used in patients with progressive neuroendocrine neoplasms (NEN) as salvage therapy. The standard treatment schedule consists of multiple cycles of intravenous (IV) administration. However, patients with liver metastases suffer from reduced tumor targeting and worse response and survival. This review provides an overview of the available evidence on the intra-arterial (IA) administration of radionuclide-labeled somatostatin analogues.

Methods Databases of PubMed and Embase were searched systematically in May 2018 for studies that addressed IA PRRT. Included studies were original research publications focusing on absorbed tumor dose or tumor response after IA administration of PRRT for NEN. Publications on combined PRRT with other therapies or treatment of nonhepatic sites were excluded. Included publications were critically appraised on quality and their results reported accordingly.

Results Seven publications were included in this review, including a total of 114 patients treated IA with different types of radiopeptides. Objective response was seen in 13 to 69% of the patients and disease stabilization in 18 to 52%. Disease progression occurred in 0 to 29% of the patients. IA administration resulted in a 1.06 to 9.2-fold increase in tumor-to-nontumor dose ratios in liver tumors, while normal liver and kidney doses remained within expected ranges. The incidence of adverse events was comparable to IV administration.

Conclusion There is limited evidence that IA application of PRRT results in higher tumor-to-non-tumor dose ratios compared with IV infusion. IA administration of 177Lu-DOTATATE seems to be a promising new improvement in current clinical practice, achieving a higher absorbed tumor dose in patients with hepatic metastases of NEN.

 
  • References

  • 1 Fraenkel M, Kim MK, Faggiano A, Valk GD. Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol 2012; 26 (06) 691-703
  • 2 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97 (04) 934-959
  • 3 Modlin IM, Oberg K, Chung DC. , et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008; 9 (01) 61-72
  • 4 Lepage C, Bouvier AM, Faivre J. Endocrine tumours: epidemiology of malignant digestive neuroendocrine tumours. Eur J Endocrinol 2013; 168 (04) R77-R83
  • 5 Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004; 25 (03) 458-511
  • 6 Chu QD, Hill HC, Douglass Jr HO. , et al. Predictive factors associated with long-term survival in patients with neuroendocrine tumors of the pancreas. Ann Surg Oncol 2002; 9 (09) 855-862
  • 7 Ho AS, Picus J, Darcy MD. , et al. Long-term outcome after chemoembolization and embolization of hepatic metastatic lesions from neuroendocrine tumors. AJR Am J Roentgenol 2007; 188 (05) 1201-1207
  • 8 Frilling A, Clift AK. Therapeutic strategies for neuroendocrine liver metastases. Cancer 2015; 121 (08) 1172-1186
  • 9 Pavel M, O'Toole D, Costa F. , et al; Vienna Consensus Conference participants. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 2016; 103 (02) 172-185
  • 10 Strosberg J, El-Haddad G, Wolin E. , et al; NETTER-1 Trial Investigators. Phase 3 Trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 2017; 376 (02) 125-135
  • 11 Kam BLR, Teunissen JJM, Krenning EP. , et al. Lutetium-labelled peptides for therapy of neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2012; 39 (Suppl. 01) S103-S112
  • 12 Kwekkeboom DJ, de Herder WW, Kam BL. , et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26 (13) 2124-2130
  • 13 Moher D, Liberati A, Tetzlaff J, Altman DG. ; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (07) e1000097
  • 14 Whiting PF, Rutjes AW, Westwood ME. , et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155 (08) 529-536
  • 15 Kratochwil C, Giesel FL, Bruchertseifer F. , et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging 2014; 41 (11) 2106-2119
  • 16 Pool SE, Kam BLR, Koning GA. , et al. [(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 (04) 179-187
  • 17 Kratochwil C, Giesel FL, López-Benítez R. , et al. Intraindividual comparison of selective arterial versus venous 68Ga-DOTATOC PET/CT in patients with gastroenteropancreatic neuroendocrine tumors. Clin Cancer Res 2010; 16 (10) 2899-2905
  • 18 Kratochwil C, López-Benítez R, Mier W. , et al. Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases. Endocr Relat Cancer 2011; 18 (05) 595-602
  • 19 Kontogeorgakos DK, Dimitriou PA, Limouris GS, Vlahos LJ. Patient-specific dosimetry calculations using mathematic models of different anatomic sizes during therapy with 111In-DTPA-D-Phe1-octreotide infusions after catheterization of the hepatic artery. J Nucl Med 2006; 47 (09) 1476-1482 http://www.ncbi.nlm.nih.gov/pubmed/16954556
  • 20 Limouris GS, Poulantzas V, Trompoukis N. , et al. Comparison of 111In-[DTPA0]octreotide versus non carrier added 177Lu- [DOTA0,Tyr3]-octreotate efficacy in patients with GEP-NET treated intra-arterially for liver metastases. Clin Nucl Med 2016; 41 (03) 194-200
  • 21 McStay MK, Maudgil D, Williams M. , et al. Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy. Radiology 2005; 237 (02) 718-726
  • 22 Limouris GS, Chatziioannou A, Kontogeorgakos D. , et al. Selective hepatic arterial infusion of In-111-DTPA-Phe1-octreotide in neuroendocrine liver metastases. Eur J Nucl Med Mol Imaging 2008; 35 (10) 1827-1837
  • 23 Ezziddin S, Khalaf F, Vanezi M. , et al. Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging 2014; 41 (05) 925-933
  • 24 Delpassand ES, Samarghandi A, Zamanian S. , et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience. Pancreas 2014; 43 (04) 518-525
  • 25 Sabet A, Dautzenberg K, Haslerud T. , et al. Specific efficacy of peptide receptor radionuclide therapy with (177)Lu-octreotate in advanced neuroendocrine tumours of the small intestine. Eur J Nucl Med Mol Imaging 2015; 42 (08) 1238-1246
  • 26 Demirci E, Kabasakal L, Toklu T. , et al. 177Lu-DOTATATE therapy in patients with neuroendocrine tumours including high-grade (WHO G3) neuroendocrine tumours: response to treatment and long-term survival update. Nucl Med Commun 2018; 39 (08) 789-796
  • 27 Valkema R, Pauwels S, Kvols LK. , 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 (02) 147-156
  • 28 Bergsma H, Konijnenberg MW, Kam BLR. , et al. Subacute haematotoxicity after PRRT with (177)Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging 2016; 43 (03) 453-463
  • 29 Bergsma H, Konijnenberg MW, van der Zwan WA. , et al. Nephrotoxicity after PRRT with (177)Lu-DOTA-octreotate. Eur J Nucl Med Mol Imaging 2016; 43 (10) 1802-1811
  • 30 Sabet A, Ezziddin K, Pape U-F. , et al. Long-term hematotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate. J Nucl Med 2013; 54 (11) 1857-1861
  • 31 Brabander T, van der Zwan WA, Teunissen JJM. , 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) 4617-4624
  • 32 Strosberg J, Wolin E, Chasen B. , et al; NETTER-1 Study Group. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated With 177Lu-Dotatate in the phase III NETTER-1 trial. J Clin Oncol 2018; 36 (25) 2578-2584
  • 33 Reubi JC, Schär J-C, Waser B. , 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 (03) 273-282
  • 34 Brogsitter C, Faulhaber D, Kotzerke J. Intraarterial treatment of GEP NET: (68)Ga-DOTATOC SUV cannot predict (90)Y-DOTATOC uptake. Clin Cancer Res 2011; 17 (07) 2065-2065
  • 35 Kwekkeboom DJ, de Herder WW, Krenning EP. Somatostatin receptor-targeted radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am 2011; 40 (01) 173-185 , ix
  • 36 Limouris GS, Karfis I, Chatzioannou A. , et al. Super-selective hepatic arterial infusions as established technique (‘ARETAIEION’ Protocol) of [177Lu]DOTA-TATE in inoperable neuroendocrine liver metastases of gastro-entero-pancreatic (GEP) tumors. Q J Nucl Med Mol Imaging 2012; 56 (06) 551-558
  • 37 Cornu C, Kassai B, Fisch R. , et al; CRESim & Epi-CRESim Project Groups. Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet J Rare Dis 2013; 8 (01) 48
  • 38 ClinicalTrials.gov. [Internet]. Identifier NCT03590119, Intra-arterial Lutetium-177-dotatate for Treatment of Patients With Neuro-endocrine Tumor Liver Metastases (LUTIA). https://clinicaltrials.gov/show/NCT03590119 . Published 2018