Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

Nicolas Marincek, Ann-Catherine Jörg, Philippe Brunner, Christian Schindler, Michael T Koller, Christoph Rochlitz, Jan Müller-Brand, Helmut R Maecke, Matthias Briel, Martin A Walter, Nicolas Marincek, Ann-Catherine Jörg, Philippe Brunner, Christian Schindler, Michael T Koller, Christoph Rochlitz, Jan Müller-Brand, Helmut R Maecke, Matthias Briel, Martin A Walter

Abstract

Background: We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors.

Methods: In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols.

Results: Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03).

Conclusions: Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

Figures

Figure 1
Figure 1
The natural somatostatin receptor ligand, the 14 amino acid peptide somatostatin (A), was abridged to the biologically more stable 8 amino acid peptide Octreotide (OC, B), which is used for the treatment of symptomatic neuroendocrine tumors. Introduction of a tyrosine into the 3rd position of the Octreotide sequence resulted in Tyr3-Octreotide (TOC, C), which allows for iodination of the tyrosine residue with the γ-emitter 123I and subsequent somatostatin receptor targeted imaging. For the use in somatostatin receptor targeted radiotherapy TOC was coupled with the chelator DOTA, which led to the study drug, the octapeptide DOTA-TOC (D).
Figure 2
Figure 2
Patient flow.
Figure 3
Figure 3
Dosage protocol.
Figure 4
Figure 4
Binary logistic regression plots displaying the frequency of anemia, leukopenia and thrombocytopenia at different therapeutic [90Y-DOTA]-TOC activities (A). Cumulative incidence functions displaying the proportion of patients with renal toxicity are shown for low-dose, intermediate dose and high-dose [90Y-DOTA]-TOC treatment (B). Covariate-adjusted Kaplan-Meier estimates of overall survival are shown for low-dose, intermediate dose and high-dose [90Y-DOTA]-TOC treatment (C).

References

    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;26:3063–3072. doi: 10.1200/JCO.2007.15.4377.
    1. Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389–427. doi: 10.1210/er.2002-0007.
    1. Vale W, Rivier J, Ling N, Brown M. Biologic and immunologic activities and applications of somatostatin analogs. Metabolism. 1978;27:1391–1401. doi: 10.1016/0026-0495(78)90081-1.
    1. Bauer W, Briner U, Doepfner W, Haller R, Huguenin R, Marbach P, Petcher TJ, Pless. SMS 201–995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982;31:1133–1140. doi: 10.1016/0024-3205(82)90087-X.
    1. Oberg K. Cancer: antitumor effects of octreotide LAR, a somatostatin analog. Nat Rev Endocrinol. 2010;6:188–189. doi: 10.1038/nrendo.2010.3.
    1. Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker 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;27:4656–4663. doi: 10.1200/JCO.2009.22.8510.
    1. Krenning EP, Bakker WH, Breeman WA, Koper JW, Kooij PP, Ausema L, Lameris JS, Reubi JC, Lamberts SW. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet. 1989;1:242–244.
    1. Otte A, Jermann E, Behe M, Goetze M, Bucher HC, Roser HW, Heppeler A, Mueller-Brand J, Maecke HR. DOTATOC: a powerful new tool for receptor-mediated radionuclide therapy. Eur J Nucl Med. 1997;24:792–795.
    1. Stolz B, Weckbecker G, Smith-Jones PM, Albert R, Raulf F, Bruns C. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-DPhe1, Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur J Nucl Med. 1998;25:668–674. doi: 10.1007/s002590050268.
    1. Otte A, Herrmann R, Heppeler A, Behe M, Jermann E, Powell P, Maecke HR, Muller J. Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med. 1999;26:1439–1447. doi: 10.1007/s002590050476.
    1. Otte A, Mueller-Brand J, Dellas S, Nitzsche EU, Herrmann R, Maecke HR. Yttrium-90-labelled somatostatin-analogue for cancer treatment. Lancet. 1998;351:417–418. doi: 10.1016/S0140-6736(05)78355-0.
    1. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122.
    1. Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, Macke HR, Rochlitz C, Muller-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;29:2416–2423. doi: 10.1200/JCO.2010.33.7873.
    1. Waldherr C, Pless M, Maecke HR, 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. 2001;12:941–945. doi: 10.1023/A:1011160913619.
    1. Iten F, Muller B, Schindler C, Rochlitz C, Oertli D, Macke HR, Muller-Brand J, Walter MA. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial. Clin Cancer Res. 2007;13:6696–6702. doi: 10.1158/1078-0432.CCR-07-0935.
    1. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877–884. doi: 10.1056/NEJM199403313301301.
    1. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26:2389–2430. doi: 10.1002/sim.2712.
    1. Koller MT, Raatz H, Steyerberg EW, Wolbers M. Competing risks and the clinical community: irrelevance or ignorance? Stat Med. 2012 May 20;31(11-12):1089–1097. doi: 10.1002/sim.4384. Epub 2011 Sep 23.
    1. Oomen SP, Hofland LJ, van Hagen PM, Lamberts SW, Touw IP. Somatostatin receptors in the haematopoietic system. Eur J Endocrinol. 2000;143(Suppl 1):S9–S14.
    1. Chen PS, Terepka AR, Hodge HC. The Pharmacology and Toxicology of the Bone Seekers. Annu Rev Pharmacol. 1961;1:369–396. doi: 10.1146/annurev.pa.01.040161.002101.
    1. Iten F, Muller B, Schindler C, Rasch H, Rochlitz C, Oertli D, Maecke HR, Muller-Brand J, Walter MA. [(90)Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term results of a phase 2 clinical trial. Cancer. 2009;115:2052–2062. doi: 10.1002/cncr.24272.
    1. Pfeifer AK, Gregersen T, Gronbaek H, Hansen CP, Muller-Brand J, Herskind Bruun K, Krogh K, Kjaer A, Knigge U. Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland. Neuroendocrinology. 2011;93:189–196. doi: 10.1159/000324096.
    1. Bodei L, Cremonesi M, Grana CM, Fazio N, Iodice S, Baio SM, Bartolomei M, Lombardo D, Ferrari ME, Sansovini M. et al.Peptide receptor radionuclide therapy with (1)(7)(7)Lu-DOTATATE: the IEO phase I-II study. Eur J Nucl Med Mol Imaging. 2011;38:2125–2135. doi: 10.1007/s00259-011-1902-1.
    1. Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, Feelders RA, van Aken MO, Krenning EP. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130. doi: 10.1200/JCO.2007.15.2553.
    1. Valkema R, Pauwels S, Kvols LK, Barone R, Jamar F, Bakker WH, Kwekkeboom DJ, Bouterfa H, Krenning EP. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0, Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2006;36:147–156. doi: 10.1053/j.semnuclmed.2006.01.001.
    1. Villard L, Romer A, Marincek N, Brunner P, Koller MT, Schindler C, Ng QK, Macke HR, Muller-Brand J, Rochlitz C. et al.Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol. 2012;30:1100–1106. doi: 10.1200/JCO.2011.37.2151.
    1. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–655. doi: 10.1097/00000421-198212000-00014.
    1. Rindi G. The ENETS guidelines: the new TNM classification system. Tumori. 2010;96:806–809.
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する