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Accepted Preprint first posted on 12 August 2014 as Manuscript EJE-14-0488
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Radionuclide therapy in neuroendocrine tumors
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Wouter A. van der Zwan1, Lisa Bodei2, Jan Mueller-Brand3, Wouter W. de Herder1,
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Larry K. Kvols4, Dik J. Kwekkeboom1.
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Rotterdam, the Netherlands.
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Tampa, Florida, USA.
Department of Nuclear Medicine, Erasmus MC, University Medical Center,
Department of Nuclear Medicine, European Institute of Oncology, Milan, Italy. Department of Nuclear Medicine, University Hospital Basel, Basel, Switzerland. Department of GI Oncology, H. Lee Moffitt Cancer Center and Research Institute,
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Corresponding Author:
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W.A. van der Zwan
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Department of Nuclear Medicine, Erasmus MC, University Medical Center,
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s-Gravendijkwal 230, 3015CE Rotterdam, the Netherlands.
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Tel: +31-10-704 01 32
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Fax: +31-10-703 46 47
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Email:
[email protected]
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Short title: PRRT in neuroendocrine tumors
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Key words: Neuroendocrine tumour, Carcinoids, Radionuclide therapy, PRRT
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Word count of full article: 2585
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1 Copyright © 2014 European Society of Endocrinology.
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Abstract
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Peptide Receptor Radionuclide Therapy (PRRT) is a promising new treatment
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modality for inoperable or metastasized GastroEnteroPancreatic NeuroEndocrine
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Tumors (GEPNET) patients. Most studies report objective response rates in 15-35%
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of patients. Also, outcome in terms of PFS and OS compares very favourably with
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that for somatostatin analogues, chemotherapy, or new, “targeted” therapies. They
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also compare favourably to PFS data for liver-directed therapies.
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Two decades after the introduction of PRRT there is a growing need for randomised
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controlled trials comparing PRRT to “standard” treatment, that is treatment with
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agents that have proven benefit when tested in randomised trials.
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Combining PRRT with liver-directed therapies, or with targeted therapies could
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improve treatment results. The question to be answered, however, is whether a
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combination of therapies performed within a limited time-span from one another,
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results in a better PFS than a strategy in which other therapies are reserved until
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after (renewed) tumor progression.
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Randomized clinical trials comparing PRRT with other treatment modalities should be
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undertaken to determine the best treatment options and treatment sequelae for
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patients with GEPNETs.
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Introduction
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The majority of GastroEnteroPancreatic NeuroEndocrine Tumors (GEPNETs) express
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somatostatin receptors and can be treated with radiolabeled somatostatin analogues.
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The majority of patients that have been treated with this socalled Peptide Receptor
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Radionuclide Therapy (PRRT) had inoperable metastatic disease, and 70-90% of
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them had liver metastases.1-5
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PRRT: Efficacy
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Because at that time somatostatin analogues labeled with beta-emitting radionuclides
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were not available for clinical use, early studies in the 1990s used high activities of the
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Auger electron emitting [111In-DTPA0]octreotide (111In-octreotide) for PRRT. These
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treatments
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NeuroEndocrine Tumors (NETs), but objective tumor responses were rare (table 1).6, 7
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The next generation of analogues used in PRRT consisted of a modified
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somatostatin analogue, [Tyr3]octreotide, and a different chelator, DOTA instead of
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DTPA, which allows stable binding of the β-emitting radionuclide
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maximal tissue penetration is 12 mm and its half life is 2.7 days. [90Y-
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DOTA0,Tyr3]octreotide (90Y-DOTATOC) was used in several phase-1 and phase-2
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PRRT trials in various countries (Table 1). The registered objective responses range
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from 4% to 33%. Differences in cycle doses and administered cumulative dose, as
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well as differences in patient characteristics (included tumor types, patient
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performance status) make it virtually impossible to compare these studies. Different
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studies report median Progression Free Survival (PFS) varying from 17 to 29
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months, and median Overall Survival (OS) from 22 to 37 months (Table 2).1-5 In a
often resulted in symptom
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relief
in patients
with metastasized
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Yttrium (90Y). Its
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90
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recent report on the treatment effects of
Y-DOTATOC in a large group of patients,
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the response to 90Y-DOTATOC was associated with longer survival.11
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177
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of 2 mm.
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dosimetry using the same, therapeutic, compound. The somatostatin analogue
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[DOTA0,Tyr3]octreotate differs from [DOTA0,Tyr3]octreotide only in that the C-terminal
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threoninol is replaced with threonine, resulting in a higher affinity for the somatostatin
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receptor
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DOTA0,Tyr3]octreotate (177Lu-octreotate) therapy were described in a large group of
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GastroEnteroPancreatic NET (GEPNET) patients.5 Complete Remission (CR) was
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found in 5 (2%) patients, Partial Remission (PR) in 86 (28%) and Minor Response
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(MR) in 51 (16%) patients (Table 2). Prognostic factors for predicting tumor remission
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(CR, PR, or MR) as treatment outcome were high uptake on the Octreoscan,
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Karnofsky Performance Score > 70, and low metastatic load to the liver. Median time
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to progression was 40 months from start of treatment. Progression of disease was
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more common in patients with an extensive disease or in a poor general clinical
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condition (Karnofsky score
