Abstract
Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising option for the treatment of somatostatin-receptor-positive endocrine tumors. Treatment with somatostatin analogs labeled with 111In, 90Y or 177Lu can result in symptomatic improvement, although tumor remission is seldom achieved with 111In-labeled analogs. In this Review, the findings of several studies on the use of PRRT for endocrine tumors are evaluated. Large variation in the antitumor effects of 90Y-octreotide was reported between studies: an objective response (≥50% tumor regression) was achieved in 9–33% of patients. After treatment with 177Lu-octreotate, an objective response was achieved in 29% of patients and a minor response (25–50% tumor regression) was achieved in 16% of patients; stable disease was present in 35% of patients. Treatment with 177Lu-octreotate resulted in a survival benefit of several years and markedly improved quality of life. Serious, delayed adverse effects were rare after PRRT. Although randomized, clinical trials have not yet been performed, data on the use of PRRT compare favorably with those from other treatment approaches, such as chemotherapy. If these results can be replicated in large, controlled trials, PRRT might become the preferred option in patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors.
Key Points
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Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs is a promising treatment modality for patients with somatostatin-receptor-positive gastroenteropancreatic neuroendocrine tumors
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177Lu-octreotate resulted in tumor remission in 46% and stable disease in 35% of patients; a median time to progression of 40 months and a survival benefit of several years was indicated
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PRRT is generally well tolerated if treating physicians adhere to dose limits and renal protection is administered
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PRRT can also be effective for patients with nongastroenteropancreatic tumors, such as non-radioiodine-avid thyroid carcinoma and paraganglioma; however, further studies are needed to determine PRRT's role in this setting
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Studies are ongoing to improve the antitumor effects of PRRT, reduce its adverse effects, increase patients' long-term survival prospects, and improve their quality of life
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PRRT might become the preferred option for patients with progressive gastroenteropancreatic neuroendocrine tumors if these data can be confirmed
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References
Arnold, R., Benning, R., Neuhaus, C., Rolwage, M. & Trautmann, M. E. Gastroenteropancreatic endocrine tumours: effect of Sandostatin on tumour growth. The German Sandostatin Study Group. Digestion 54 (Suppl. 1), 72–75 (1993).
Janson, E. T. & Oberg, K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 32, 225–229 (1993).
Ducreux, M. et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am. J. Gastroenterol. 95, 3276–3281 (2000).
O'Toole, D., Hentic, O., Corcos, O. & Ruszniewski, P. Chemotherapy for gastro-enteropancreatic endocrine tumours. Neuroendocrinology 80 (Suppl. 1), 79–84 (2004).
Kwekkeboom, D. J. et al. Treatment with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate in patients with gastro-entero-pancreatic (GEP) tumors. J. Clin. Oncol. 23, 2754–2762 (2005).
Kwekkeboom, D. J. et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA0, Tyr3]octreotate: toxicity, efficacy, and survival. J. Clin. Oncol. 26, 2124–2130 (2008).
Valkema, R. et al. Phase I study of peptide receptor radionuclide therapy with [111In-DTPA0]octreotide: the Rotterdam experience. Semin. Nucl. Med. 32, 110–122 (2002).
Anthony, L. B. et al. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin. Nucl. Med. 32, 123–132 (2002).
Buscombe, J. R., Caplin, M. E. & Hilson, A. J. Long-term efficacy of high-activity 111In-pentetreotide therapy in patients with disseminated neuroendocrine tumors. J. Nucl. Med. 44, 1–6 (2003).
Delpassand, E. S. et al. Safety and efficacy of radionuclide therapy with high-activity In-111 pentetreotide in patients with progressive neuroendocrine tumors. Cancer Biother. Radiopharm. 23, 292–300 (2008).
Stokkel, M. P., Verkooijen, R. B., Bouwsma, H. & Smit, J. W. Six month follow-up after 111-In-DTPA-octreotide therapy in patients with progressive radioiodine non-responsive thyroid cancer: a pilot study. Nucl. Med. Commun. 25, 683–690 (2004).
Otte, A. et al. Yttrium-90 DOTATOC: first clinical results. Eur. J. Nucl. Med. 26, 1439–1447 (1999).
Waldherr, C., Pless, M., Maecke, H. R., Haldemann, A. & Mueller-Brand, J. The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann. Oncol. 12, 941–945 (2001).
Waldherr, C. et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq 90Y-DOTATOC. J. Nucl. Med. 43, 610–616 (2002).
Waldherr, C. et al. Does tumor response depend on the number of treatment sessions at constant injected dose using 90Yttrium-DOTATOC in neuroendocrine tumors? Eur. J. Nucl. Med. Mol. Imaging 29 (Suppl. 1), S100 (2002).
Chinol, M., Bodei, L., Cremonesi, M. & Paganelli, G. Receptor-mediated radiotherapy with Y-DOTA-D-Phe-Tyr-octreotide: the experience of the European Institute of Oncology group. Semin. Nucl. Med. 32, 141–147 (2002).
Paganelli, G. et al. 90Y-DOTA-D-Phe1-Tyr3-octreotide in therapy of neuroendocrine malignancies. Biopolymers 66, 393–398 (2002).
Bodei, L. 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 30, 207–216 (2003).
Valkema, R. 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. 36, 147–156 (2006).
Valkema, R. et al. Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0, Tyr3-octreotide and 177Lu-DOTA0, Tyr3-octreotate. J. Nucl. Med. 46 (Suppl. 1), S83–S91 (2005).
Teunissen, J. J., Kwekkeboom, D. J. & Krenning, E. P. Staging and treatment of differentiated thyroid carcinoma with radiolabeled somatostatin analogs. Trends Endocrinol. Metab. 17, 19–25 (2006).
Forrer, F., Riedweg, I., Maecke, H. R. & Mueller-Brand, J. Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma. Q. J. Nucl. Med. Mol. Imaging 52, 334–340 (2008).
Reubi, J. C., Waser, B., Schaer, J. C. & Laissue, J. A. Somatostatin receptor SST1–SST5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur. J. Nucl. Med. 28, 836–846 (2001).
Reubi, J. C. et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur. J. Nucl. Med. 27, 273–282 (2000).
de Jong, M. et al. [177Lu-DOTA0, Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int . J. Cancer 92, 628–633 (2001).
Kwekkeboom, D. J. et al. [177Lu-DOTA0Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients. Eur. J. Nucl. Med. 28, 1319–1325 (2001).
Esser, J. P. et al. Comparison of [177Lu-DOTA0, Tyr3]octreotate and [177Lu-DOTA0, Tyr3]octreotide: which peptide is preferable for PRRT? Eur. J. Nucl. Med. Mol. Imaging 33, 1346–1351 (2006).
Bodei, L. et al. Receptor radionuclide therapy with 177Lu-DOTATATE in neuroendocrine tumours. Eur. J. Nucl. Med. Mol. Imaging 33, S214 (2006).
Ezziddin, S. et al. Targeted radiotherapy of neuroendocrine tumors using Lu-177-DOTA octreotate with prolonged intervals [Abstract]. J. Nucl. Med. 48 (Suppl. 2), 394P (2007).
Kwekkeboom, D. J. et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate. Eur. J. Nucl. Med. Mol. Imaging 30, 417–422 (2003).
Sowby, F. Nonstochastic Effects of Ionizing Radiation, ICRP Publication 41 (Pergamon, New York, 1984).
de Keizer, B. et al. Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate. Eur. J. Nucl. Med. Mol. Imaging 35, 749–755 (2008).
van Essen, M. et al. Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin. Eur. J. Nucl. Med. Mol. Imaging 34, 1219–1227 (2007).
Clancy, T. E. et al. Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors. Dig Dis. Sci. 51, 877–884 (2006).
Janson, E. T. et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann. Oncol. 8, 685–690 (1997).
Quaedvlieg, P. F., Visser, O., Lamers, C. B., Janssen-Heijen, M. L. & Taal, B. G. Epidemiology and survival in patients with carcinoid disease in The Netherlands. An epidemiological study with 2,391 patients. Ann. Oncol. 9, 1295–1300 (2001).
Mazzaglia, P. J., Berber, E., Milas, M. & Siperstein, A. E. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery 142, 10–19 (2007).
Asnacios, A. et al. Indium-111-pentetreotide scintigraphy and somatostatin receptor subtype 2 expression: new prognostic factors for malignant well-differentiated endocrine tumors. J. Clin. Oncol. 26, 963–970 (2008).
Nilsson, O. et al. Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology 84, 212–215 (2006).
Teunissen, J. J., Kwekkeboom, D. J. & Krenning, E. P. Quality of life in patients with gastroenteropancreatic tumors treated with [177Lu-DOTA0, Tyr3]octreotate. J. Clin. Oncol. 22, 2724–2729 (2004).
Teunissen, J. J., Kwekkeboom, D. J., Kooij, P. P., Bakker, W. H. & Krenning, E. P. Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma. J. Nucl. Med. 46 (Suppl. 1), S107–S114 (2005).
van Essen, M. et al. Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. J. Nucl. Med. 47, 1599–1606 (2006).
Virgolini, I. et al. In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. Semin. Nucl. Med. 32, 148–155 (2002).
Forrer, F., Uusijarvi, H., Storch, D., Maecke, H. R. & Mueller-Brand, J. Treatment with 177Lu-DOTATOC of patients with relapse of neuroendocrine tumors after treatment with 90Y-DOTATOC. J. Nucl. Med. 46, 1310–1316 (2005).
Wild, D. et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur. J. Nucl. Med. Mol. Imaging. 30, 1338–1347 (2003).
Valkema, R. et al. Peptide receptor scintigraphy (PRS) with In-111-DOTANOC and peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTANOC [abstract]. J. Nucl. Med. 48 (Suppl. 2), 394P (2007).
Wehrmann, C., Senftleben, S., Zachert, C., Müller, D. & Baum, R. P. Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu DOTA-TATE and 177Lu DOTA-NOC. Cancer Biother. Radiopharm. 22, 406–416 (2007).
Baum, R. P., Soldner, J., Schmucking, M. & Niesen, A. Peptidrezeptorvermittelte radiotherapie (PRRT) neuroendokriner tumoren klinischen indikationen und erfahrung mit 90Yttrium-markierten somatostatinanaloga [German]. Der Onkologe 10, 1098–1110 (2004).
Baum, R. P., Soldner, J., Schmucking, M. & Niesen, A. Intravenous and intra-arterial peptide receptor radionuclide therapy (PRRT) using Y-90-DOTA-Tyr3-octreotate (Y-90-DOTA-TATE) in patients with metastatic neuroendocrine tumors. Eur. J. Nucl. Med. 31 (Suppl. 2), S238 (2004).
Rolleman, E. J., Valkema, R., de Jong, M., Kooij, P. P. & Krenning, E. P. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur. J. Nucl. Med. Mol. Imaging 30, 9–15 (2003).
Rolleman, E. J. et al. Molecular imaging of reduced renal uptake of radiolabelled [DOTA0, Tyr3]octreotate by the combination of lysine and Gelofusine in rats. Nuklearmedizin 47, 110–115 (2008).
Sasse, A. D., Clark, L. G., Sasse, E. C. & Clark, O. A. Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int. J. Radiat. Oncol. Biol. Phys. 64, 784–791 (2006).
Rolleman, E. J. et al. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0, Tyr3]octreotate. Eur. J. Nucl. Med. Mol. Imaging 34, 763–771 (2007).
De Jong, M. et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin. Nucl. Med. 32, 133–140 (2002).
Behe, M. et al. Irradiation-induced upregulation of somatostatin and gastrin receptors in vitro and in vivo. Eur. J. Nucl. Med. Mol. Imaging 31 (Suppl. 2), S237 (2004).
Oddstig, J., Bernhardt, P., Nilsson, O., Ahlman, H. & Forssell-Aronsson, E. Radiation-induced up-regulation of somatostatin receptor expression in small cell lung cancer in vitro . Nucl. Med. Biol. 33, 841–846 (2006).
Capello, A. et al. 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 32, 1288–1295 (2005).
Melis, M. 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 51, 324–333 (2007).
Hofland, L. J., Capello, A., Krenning, E. P., de Jong, M. & van Hagen, M. P. Induction of apoptosis with hybrids of Arg-Gly-Asp molecules and peptides and antimitotic effects of hybrids of cytostatic drugs and peptides. J. Nucl. Med. 46 (Suppl. 1), S191–S198 (2005).
Capello, A. et al. Increased cell death after therapy with an Arg-Gly-Asp-linked somatostatin analog. J. Nucl. Med. 45, 1716–1720 (2004).
Bernard, B. et al. Radiolabeled RGD-DTPA-Tyr3-octreotate for receptor-targeted radionuclide therapy. Cancer Biother. Radiopharm. 19, 173–180 (2004).
Capello, A. et al. Anticancer activity of targeted proapoptotic peptides. J. Nucl. Med. 47, 122–129 (2006).
Ginj, M. et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc. Natl Acad. Sci. USA 103, 16436–16441 (2006).
Breeman, W. A. et al. Anti-tumor effect and increased survival after treatment with [177Lu-DOTA0, Tyr3]octreotate in a rat liver micrometastases model. Int. J. Cancer 104, 376–379 (2003).
Wong, J. Y. et al. A phase I trial of 90Y-anti-carcinoembryonic antigen chimeric T84.66 radioimmunotherapy with 5-fluorouracil in patients with metastatic colorectal cancer. Clin. Cancer Res. 9, 5842–5852 (2003).
Kong, G., Lau, E., Ramdave, S. & Hicks, R. J. High-dose 111In-octreotide therapy in combination with radiosensitizing 5-FU chemotherapy for treatment of SSR-expressing neuroendocrine tumors. J. Nucl. Med. 46 (Suppl. 2), 151P (2005).
Rich, T. A., Shepard, R. C. & Mosley, S. T. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J. Clin. Oncol. 22, 2214–2232 (2004).
Dunst, J. et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J. Clin. Oncol. 20, 3983–3991 (2002).
van Essen, M. et al. 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 35, 743–748 (2008).
Acknowledgements
The authors thank personnel from the departments of Nuclear Medicine and Internal Medicine of the Erasmus Medical Centre for their expert help and cooperation, especially research nurses Daniëlle Verwaal, Agnes van Uden and Els Montijn.
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E. P. Krenning declares associations with the following companies: BioSynthema (consultant, stock holder/director, patent holder/applicant), Covidien (consultant, grant/research support) and Novartis (grant/research support, patent holder/applicant).
D. J. Kwekkeboom declares an association with the following company: BioSynthema (stock holder/director).
M. van Essen, B. L. R. Kam, M. de Jong, and R. Valkema declare no competing interests.
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van Essen, M., Krenning, E., Kam, B. et al. Peptide-receptor radionuclide therapy for endocrine tumors. Nat Rev Endocrinol 5, 382–393 (2009). https://doi.org/10.1038/nrendo.2009.105
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DOI: https://doi.org/10.1038/nrendo.2009.105