Combination treatments to enhance peptide receptor radionuclide therapy of neuroendocrine tumours
The incidence of neuroendocrine tumours (NETs) is increasing, but curative therapeutic options are limited because diagnosis is often delayed until the tumour has metastasized. Peptide receptor radionuclide therapy (PRRT) is among the most effective therapeutic options for metastatic NETs because of targeted delivery of radioactivity to the tumour via the somatostatin receptor (SSTR) and relatively low systemic toxicity. However, current PRRT regimes result in palliation rather than cure, and higher doses of PRRT that might achieve remission would also be too toxic to the patients. Therefore, there is a need to improve PRRT of NETs by combining it with other agents to achieve maximum benefits from the internal radiation therapy, while sparing non-target organs from radiation toxicity. Here we review various current and potential combination strategies to improve 177Lu-octreotate-based PRRT of NET, some of which could also apply to other radionuclide therapies. These strategies include co-administered drugs that improve delivery of the radiopharmaceutical via increased tumour perfusion or through increased SSTR density at tumour surface. Other combinations are aimed at enhancing the biological effects of the radiation-induced DNA damage in tumour cells or generating additional DNA damage burden to effectively increase the cytotoxicity of PRRT. We also propose an algorithm for stratifying NET patients to receive or not combination therapies with PRRT. Considering that PRRT and many of these combination agents are already used for treating patients with NET and other cancers, the proposed strategies to improve the efficacy of PRRT could be rapidly translated into the clinic.
KeywordsNeuroendocrine tumours Peptide receptor radionuclide therapy 177Lu-octreotate 177Lu-DOTATATE Somatostatin receptor Radiosensitization Receptor upregulation Tumour perfusion DNA damage
We would like to thank Marine A. Merlin for helpful discussion to improve the manuscript.
This work was supported by research funding to J.M.B. and G.M.S. from the Canadian Cancer Society Research Institute (grant no. 705327) and the Carcinoid-NeuroEndocrine Tumor Society of Canada,; and to J.M.B. from the Education and Research Foundation for Nuclear Medicine and Molecular Imaging, Quebec Bio-Imaging Network, Fondation du CHU de Québec – Université Laval and Fonds de Recherche du Québec – Santé. S.A. received a scholarship from the Canadian Institutes of Health Research.
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflict of interest related to this work. J.M.B. has received honoraria for invited conferences from Ipsen, Novartis, and Siemens Healthineers.
Not applicable. This article does not contain any studies with human participants or animals performed by any of the authors other than those previously published and cited in this review article.
- 1.Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system: World Health Organization; 2010.Google Scholar
- 4.Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017. https://doi.org/10.1001/jamaoncol.2017.0589.
- 5.Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, et al. 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;27:4656–63. https://doi.org/10.1200/JCO.2009.22.8510.CrossRefGoogle Scholar
- 7.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: Off J Eur Soc Med Oncol. 2013;24:152–60. https://doi.org/10.1093/annonc/mds276.CrossRefGoogle Scholar
- 9.Lamarca A, Elliott E, Barriuso J, Backen A, McNamara MG, Hubner R, et al. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: a lost cause? Cancer Treat Rev. 2016;44:26–41. https://doi.org/10.1016/j.ctrv.2016.01.005.CrossRefGoogle Scholar
- 15.Cambiaghi V, Vitali E, Morone D, Peverelli E, Spada A, Mantovani G, et al. Identification of human somatostatin receptor 2 domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line. Endocrine. 2017;56:146–57. https://doi.org/10.1007/s12020-016-1026-2.CrossRefGoogle Scholar
- 22.Wang M, Caruano AL, Lewis MR, Meyer LA, VanderWaal RP, Anderson CJ. Subcellular localization of radiolabeled somatostatin analogues: implications for targeted radiotherapy of cancer. Cancer Res. 2003;63:6864–9.Google Scholar
- 23.Strosberg J, Wolin E, Chasen B, Kulke M, Bushnell D, Caplin M, et al. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with (177)Lu-Dotatate in the phase III NETTER-1 trial. J Clin Oncol. 2018;36:2578–84. https://doi.org/10.1200/JCO.2018.78.5865.CrossRefGoogle Scholar
- 25.Kim S-J, Pak K, Koo P, Kwak J, Chang S. The efficacy of 177Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis. Eur J Nucl Med Mol Imaging. 2015:1–7. https://doi.org/10.1007/s00259-015-3155-x.
- 27.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;42:5–19. https://doi.org/10.1007/s00259-014-2893-5.CrossRefGoogle Scholar
- 28.Bergsma H, Lom KV, Konijnenberg M, Kam B, Teunissen J, Herder W, et al. Therapy-related hematological malignancies after peptide receptor radionuclide therapy with 177Lu-DOTA-Octreotate: incidence, course & predicting factors in patients with GEP-NETs. J Nucl Med: Off Publ, Soc Nucl Med. 2017. https://doi.org/10.2967/jnumed.117.189712.
- 32.Del Prete M, Buteau FA, Arsenault F, Saighi N, Bouchard LO, Beaulieu A, et al. Personalized (177)Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019;46:728–42. https://doi.org/10.1007/s00259-018-4209-7.CrossRefGoogle Scholar
- 33.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. https://doi.org/10.1007/s00259-017-3678-4.
- 36.Froidevaux S, Hintermann E, Torok M, Macke HR, Beglinger C, Eberle AN. Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment. Cancer Res. 1999;59:3652–7.Google Scholar
- 37.Haug AR, Rominger A, Mustafa M, Auernhammer C, Goke B, Schmidt GP, et al. Treatment with octreotide does not reduce tumor uptake of (68)Ga-DOTATATE as measured by PET/CT in patients with neuroendocrine tumors. J Nucl Med: Off Publ, Soc Nucl Med. 2011;52:1679–83. https://doi.org/10.2967/jnumed.111.089276.CrossRefGoogle Scholar
- 38.Cherk MH, Kong G, Hicks RJ, Hofman MS. Changes in biodistribution on (68)Ga-DOTA-Octreotate PET/CT after long acting somatostatin analogue therapy in neuroendocrine tumour patients may result in pseudoprogression. Cancer Imaging. 2018;18:3. https://doi.org/10.1186/s40644-018-0136-x.CrossRefGoogle Scholar
- 39.Bernhardt P, Oddstig J, Kolby L, Nilsson O, Ahlman H, Forssell-Aronsson E. Effects of treatment with (177)Lu-DOTA-Tyr(3)-octreotate on uptake of subsequent injection in carcinoid-bearing nude mice. Cancer Biother Radiopharm. 2007;22:644–53. https://doi.org/10.1089/cbr.2007.333.CrossRefGoogle Scholar
- 40.Oddstig J, Bernhardt P, Lizana H, Nilsson O, Ahlman H, Kolby L, et al. Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice. Tumour Biol. 2012;33:229–39. https://doi.org/10.1007/s13277-011-0268-0.CrossRefGoogle Scholar
- 41.Dalmo J, Spetz J, Montelius M, Langen B, Arvidsson Y, Johansson H, et al. Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1. EJNMMI Res. 2017;7:6. https://doi.org/10.1186/s13550-016-0247-y.CrossRefGoogle Scholar
- 43.Oddstig J, Bernhardt P, Nilsson O, Ahlman H, Forssell-Aronsson E. Radiation induces up-regulation of somatostatin receptors 1, 2, and 5 in small cell lung cancer in vitro also at low absorbed doses. Cancer Biother Radiopharm. 2011;26:759–65. https://doi.org/10.1089/cbr.2010.0921.CrossRefGoogle Scholar
- 45.Veenstra MJ, van Koetsveld PM, Dogan F, Farrell WE, Feelders RA, Lamberts SW, et al. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells. Oncotarget. 2016. https://doi.org/10.18632/oncotarget.9462.
- 47.Sun L, Qian Q, Sun G, Mackey LV, Fuselier JA, Coy DH, et al. Valproic acid induces NET cell growth arrest and enhances tumor suppression of the receptor-targeted peptide-drug conjugate via activating somatostatin receptor type II. J Drug Target. 2016;24:169–77. https://doi.org/10.3109/1061186X.2015.1066794.CrossRefGoogle Scholar
- 48.Fueger BJ, Hamilton G, Raderer M, Pangerl T, Traub T, Angelberger P, et al. Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells. J Nucl Med: Off Publ, Soc Nucl Med. 2001;42:1856–62.Google Scholar
- 49.Nayak TK, Atcher RW, Prossnitz ER, Norenberg JP. Enhancement of somatostatin-receptor-targeted (177)Lu-[DOTA(0)-Tyr(3)]-octreotide therapy by gemcitabine pretreatment-mediated receptor uptake, up-regulation and cell cycle modulation. Nucl Med Biol. 2008;35:673–8. https://doi.org/10.1016/j.nucmedbio.2008.05.003.CrossRefGoogle Scholar
- 50.van Essen M, Krenning EP, Kam BL, de Herder WW, van Aken MO, Kwekkeboom DJ. Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2008;35:743–8. https://doi.org/10.1007/s00259-007-0688-7.CrossRefGoogle Scholar
- 51.Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging. 2010;37:1869–75. https://doi.org/10.1007/s00259-010-1483-4.CrossRefGoogle Scholar
- 53.Kong G, Thompson M, Collins M, Herschtal A, Hofman MS, Johnston V, et al. Assessment of predictors of response and long-term survival of patients with neuroendocrine tumour treated with peptide receptor chemoradionuclide therapy (PRCRT). Eur J Nucl Med Mol Imaging. 2014;41:1831–44. https://doi.org/10.1007/s00259-014-2788-5.CrossRefGoogle Scholar
- 54.Kashyap R, Hofman MS, Michael M, Kong G, Akhurst T, Eu P, et al. Favourable outcomes of (177)Lu-octreotate peptide receptor chemoradionuclide therapy in patients with FDG-avid neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2015;42:176–85. https://doi.org/10.1007/s00259-014-2906-4.CrossRefGoogle Scholar
- 60.Bison SM, Pool SE, Koelewijn SJ, van der Graaf LM, Groen HC, Melis M, et al. Peptide receptor radionuclide therapy (PRRT) with [(177)Lu-DOTA(0),Tyr(3)]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model. EJNMMI Res. 2014;4:21. https://doi.org/10.1186/s13550-014-0021-y.CrossRefGoogle Scholar
- 62.Elf AK, Bernhardt P, Hofving T, Arvidsson Y, Forssell-Aronsson E, Wangberg B, et al. NAMPT inhibitor GMX1778 enhances the efficacy of 177Lu-DOTATATE treatment of neuroendocrine tumors. J Nucl Med: Off Publ, Soc Nucl Med. 2016. https://doi.org/10.2967/jnumed.116.177584.
- 66.Jin XF, Auernhammer CJ, Ilhan H, Lindner S, Nolting S, Maurer J, et al. Combination of 5-fluorouracil with epigenetic modifiers induces radiosensitization, somatostatin receptor 2 expression and radioligand binding in neuroendocrine tumor cells in vitro. J Nucl Med: Off Publ, Soc Nucl Med. 2019. https://doi.org/10.2967/jnumed.118.224048.
- 70.Viallard C, Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017. https://doi.org/10.1007/s10456-017-9562-9.
- 74.Kratochwil C, Stefanova M, Mavriopoulou E, Holland-Letz T, Dimitrakopoulou-Strauss A, Afshar-Oromieh A, et al. SUV of [68Ga]DOTATOC-PET/CT predicts response probability of PRRT in neuroendocrine tumors. Mol Imaging Biol: MIB: Off Publ Acad Mol Imaging. 2015;17:313–8. https://doi.org/10.1007/s11307-014-0795-3.CrossRefGoogle Scholar
- 75.Ilan E, Sandstrom M, Wassberg C, Sundin A, Garske-Roman U, Eriksson B, et al. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE. J Nucl Med: Off Publ, Soc Nucl Med. 2015;56:177–82. https://doi.org/10.2967/jnumed.114.148437.CrossRefGoogle Scholar
- 77.Vidal C, Rauly I, Zeggari M, Delesque N, Esteve JP, Saint-Laurent N, et al. Up-regulation of somatostatin receptors by epidermal growth factor and gastrin in pancreatic cancer cells. Mol Pharmacol. 1994;46:97–104.Google Scholar
- 78.Riaz H, Dong P, Shahzad M, Yang L. Constitutive and follicle-stimulating hormone-induced action of somatostatin receptor-2 on regulation of apoptosis and steroidogenesis in bovine granulosa cells. J Steroid Biochem Mol Biol. 2014;141:150–9. https://doi.org/10.1016/j.jsbmb.2014.02.001.CrossRefGoogle Scholar
- 79.Nelson LE, Sheridan MA. Insulin and growth hormone stimulate somatostatin receptor (SSTR) expression by inducing transcription of SSTR mRNAs and by upregulating cell surface SSTRs. Am J Physiol Regul Integr Comp Physiol. 2006;291:R163–9. https://doi.org/10.1152/ajpregu.00754.2005.CrossRefGoogle Scholar
- 80.Kimura N, Takamatsu N, Yaoita Y, Osamura RY, Kimura N. Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation. J Mol Endocrinol. 2008;40:75–91. https://doi.org/10.1677/JME-07-0108.CrossRefGoogle Scholar
- 83.Zimmermann N, Lazar-Karsten P, Keck T, Billmann F, Schmid S, Brabant G, et al. Expression pattern of CDX2, estrogen and progesterone receptors in primary gastroenteropancreatic neuroendocrine tumors and metastases. Anticancer Res. 2016;36:921–4.Google Scholar
- 85.Presky DH, Schonbrunn A. Somatostatin pretreatment increases the number of somatostatin receptors in GH4C1 pituitary cells and does not reduce cellular responsiveness to somatostatin. J Biol Chem. 1988;263:714–21.Google Scholar
- 86.Liu Z, Marquez M, Nilsson S, Holmberg AR. Incubation with somatostatin, 5-aza decitabine and trichostatin up-regulates somatostatin receptor expression in prostate cancer cells. Oncol Rep. 2008;20:151–4.Google Scholar
- 87.Degirmenci M, Erdogan AP, Bulut G, Atmaca H, Uzunoglu S, Karaca B, et al. Octreotide in combination with AT-101 induces cytotoxicity and apoptosis through up-regulation of somatostatin receptors 2 and 5 in DU-145 prostate cancer cells. Tumour Biol. 2016;37:4939–44. https://doi.org/10.1007/s13277-015-4331-0.CrossRefGoogle Scholar
- 88.Basu S, Ostwal V. Observation on enhanced avidity on somatostatin receptor targeted 68Ga-DOTATATE PET-CT following therapy with everolimus and capecitabine-temozolamide: is redifferentiation akin phenomenon a reality in neuroendocrine tumors? Nucl Med Commun. 2016;37:669–71. https://doi.org/10.1097/MNM.0000000000000507.CrossRefGoogle Scholar
- 89.Thakral P, Sen I, Pant V, Gupta SK, Dureja S, Kumari J, et al. Dosimetric analysis of patients with gastro entero pancreatic neuroendocrine tumors (NETs) treated with PRCRT (peptide receptor chemo radionuclide therapy) using Lu-177 DOTATATE and capecitabine/temozolomide (CAP/TEM). Br J Radiol. 2018;91:20170172. https://doi.org/10.1259/bjr.20170172.CrossRefGoogle Scholar
- 91.Melis M, Forrer F, Capello A, Bijster M, Bernard BF, Reubi JC, et al. Up-regulation of somatostatin receptor density on rat CA20948 tumors escaped from low dose [177Lu-DOTA0,Tyr3]octreotate therapy. Q J Nucl Med Mol Imaging. 2007;51:324–33.Google Scholar
- 92.Behe MKS, Pqsken M, Gross M, Alfke H, Keil B, et al. Irradiation-induced upregulation of somatostatin and gastrin receptors in vitro and in vivo. Eur J Nucl Med Mol Imaging. 2004;31:S237–8.Google Scholar
- 93.Capello A, Krenning E, Bernard B, Reubi JC, Breeman W, de Jong M. 111In-labelled somatostatin analogues in a rat tumour model: somatostatin receptor status and effects of peptide receptor radionuclide therapy. Eur J Nucl Med Mol Imaging. 2005;32:1288–95. https://doi.org/10.1007/s00259-005-1877-x.CrossRefGoogle Scholar
- 94.Driessen CM, de Boer JP, Gelderblom H, Rasch CR, de Jong MA, Verbist BM, et al. Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil followed by randomization to two cisplatin-based concomitant chemoradiotherapy schedules in patients with locally advanced head and neck cancer (CONDOR study) (Dutch Head and Neck Society 08-01): a randomized phase II study. Eur J Cancer. 2016;52:77–84. https://doi.org/10.1016/j.ejca.2015.09.024.CrossRefGoogle Scholar
- 96.Kong G, Johnston V, Ramdave S, Lau E, Rischin D, Hicks RJ. High-administered activity In-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience. Cancer Biother Radiopharm. 2009;24:527–33. https://doi.org/10.1089/cbr.2009.0644.CrossRefGoogle Scholar
- 99.Watson M, Roulston A, Belec L, Billot X, Marcellus R, Bedard D, et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol. 2009;29:5872–88. https://doi.org/10.1128/MCB.00112-09.CrossRefGoogle Scholar
- 103.Hovstadius P, Larsson R, Jonsson E, Skov T, Kissmeyer AM, Krasilnikoff K, et al. A phase I study of CHS 828 in patients with solid tumor malignancy. Clin Cancer Res. 2002;8:2843–50.Google Scholar