Eur J Nucl Med Mol Imaging
`DOI 10.1007/s00259-012-2330-6
`
`GUIDELINES
`
`The joint IAEA, EANM, and SNMMI practical guidance
`on peptide receptor radionuclide therapy (PRRNT)
`in neuroendocrine tumours
`
`John J. Zaknun & L. Bodei & J. Mueller-Brand &
`M. E. Pavel & R. P. Baum & D. Hörsch & M. S. O’Dorisio &
`T. M. O’Dorisiol & J. R. Howe & M. Cremonesi &
`D. J. Kwekkeboom
`
`# The Author(s) 2013. This article is published with open access at Springerlink.com
`
`Abstract Peptide receptor radionuclide therapy (PRRNT) is a
`molecularly targeted radiation therapy involving the systemic
`administration of a radiolabelled peptide designed to target with
`high affinity and specificity receptors overexpressed on
`tumours. PRRNT employing the radiotagged somatostatin re-
`ceptor agonists 90Y-DOTATOC ([90Y-DOTA0,Tyr3]-octreotide)
`or 177Lu-DOTATATE ([177Lu-DOTA0,Tyr3,Thr8]-octreotide or
`[177Lu-DOTA0,Tyr3]-octreotate) have been successfully used
`for the past 15 years to target metastatic or inoperable neuro-
`endocrine tumours expressing the somatostatin receptor
`
`subtype 2. Accumulated evidence from clinical experience
`indicates that these tumours can be subjected to a high absorbed
`dose which leads to partial or complete objective responses in
`up to 30 % of treated patients. Survival analyses indicate that
`patients presenting with high tumour receptor expression at
`study entry and receiving 177Lu-DOTATATE or 90Y-DOTA-
`TOC treatment show significantly higher objective responses,
`leading to longer survival and improved quality of life. Side
`effects of PRRNT are typically seen in the kidneys and bone
`marrow. These, however, are usually mild provided adequate
`
`L. Bodei
`Division of Nuclear Medicine, European Institute of Oncology,
`Milan, Italy
`
`J. J. Zaknun (*)
`Nuclear Medicine Section, Division of Human Health,
`International Atomic Energy Agency, IAEA, Vienna, Austria
`e-mail: J.zaknun@hotmail.com
`
`J. J. Zaknun
`e-mail: John.Zaknun@Zentralklinik.de
`
`J. J. Zaknun
`Zentralklinik Bad Berka, Center for Molecular Radiotherapy and
`Molecular Imaging, ENETS Center of Excellence, Bad Berka,
`Germany
`
`J. Mueller-Brand
`Klinik und Institut für Nuklearmedizin, Universitätsspital Basel,
`Basel, Switzerland
`
`M. E. Pavel
`Campus Virchow Klinikum, Klinik für Gastroenterologie,
`Hepatologie, Endokrinologie, Diabetes und
`Stoffwechsel-erkrankungen, Charité Universitaetsmedizin Berlin,
`Berlin, Germany
`
`R. P. Baum : D. Hörsch
`Zentralklinik Bad Berka, Department of Internal Medicine,
`Gastroenterology and Endocrinology, ENETS Center of
`Excellence, Bad Berka, Germany
`
`M. S. O’Dorisio
`RJ and LA Carver College of Medicine, Department of Pediatrics,
`University of Iowa, Iowa City, IA, USA
`
`T. M. O’Dorisiol
`RJ and LA Carver College of Medicine, Department of Internal
`Medicine, University of Iowa, Iowa City, IA, USA
`
`J. R. Howe
`RJ and LA Carver College of Medicine, Department of Surgical
`Oncology, University of Iowa, Iowa City, IA, USA
`
`M. Cremonesi
`Service of Health Physics, European Institute of Oncology, Milan,
`Italy
`
`D. J. Kwekkeboom
`Department of Nuclear Medicine, Erasmus Medical Center
`Rotterdam, Rotterdam, The Netherlands
`
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`protective measures are undertaken. Despite the large body of
`evidence regarding efficacy and clinical safety, PRRNT is still
`considered an investigational treatment and its implementation
`must comply with national legislation, and ethical guidelines
`concerning human therapeutic investigations. This guidance
`was formulated based on recent literature and leading experts’
`opinions. It covers the rationale, indications and contraindica-
`tions for PRRNT, assessment of treatment response and patient
`follow-up. This document
`is aimed at guiding nuclear
`medicine specialists in selecting likely candidates to receive
`PRRNT and to deliver the treatment in a safe and effective
`manner. This document is largely based on the book pub-
`lished through a joint international effort under the auspices
`of the Nuclear Medicine Section of the International Atom-
`ic Energy Agency.
`
`Keywords Peptide receptor radionuclide therapy . PRRNT .
`PRRNT, neuroendocrine tumours, guideline/s, renal protection
`
`Purpose
`
`This guidance document is aimed at assisting and guiding
`nuclear medicine specialists in:
`
`1. Assessing patients with neuroendocrine tumours (NETs)
`for their eligibility to undergo treatment with 90Y- or
`177Lu-radiolabelled somatostatin analogues.
`2. Providing guidance on performing peptide receptor ra-
`dionuclide therapy (PRRNT) and implementing this
`treatment in a safe and effective manner.
`3. Understanding and evaluating the outcome of PRRNT,
`namely treatment results and possible side effects in-
`cluding both renal and haematological toxicities.
`
`A committee of international experts was assembled
`under the auspices of the International Atomic Energy
`Agency (IAEA), in cooperation with the EANM Thera-
`py, Oncology and Dosimetry Committees and with the
`Society of Nuclear Medicine and Molecular Imaging.
`They worked together to create this guidance document
`on the use of somatostatin analogue-based PRRNT. This
`guidance document was compiled taking into account
`recent literature and experts’ opinion.
`
`Regulatory issues
`
`Applicable in all countries Clinicians involved in unsealed
`source therapy must be knowledgeable about and compliant
`with all applicable national and local legislation and
`regulations.
`
`Applicable in the USA The radiopharmaceuticals used for
`the diagnostic and therapeutic procedures addressed in this
`
`Eur J Nucl Med Mol Imaging
`
`guidance document are not approved by the Food and Drug
`Administration (FDA) in the USA. Therefore in the USA
`these procedures should be performed only by physicians
`enrolled in an investigational protocol pursuant to a valid
`Investigational New Drug application or Radioactive Drug
`Research Committee approval and under the purview of an
`appropriate institutional review board.
`
`Background information and definitions
`
`Definitions
`
`PRRNT
`
`Somatostatin
`
`Somatostatin
`receptors
`
`PRRNT (or PRRT) involves the systemic
`administration of a specific well-defined
`radiopharmaceutical composed of a β-
`emitting radionuclide chelated to a pep-
`tide for the purpose of delivering cyto-
`toxic radiation to a tumour. The
`oligopeptides are designed to target cel-
`lular proteins, commonly cell surface
`receptors, such as the somatostatin recep-
`tor (sstr) subtype 2 (sstr2) that is overex-
`pressed on the cell surface of NETs in a
`tumour-specific fashion, thereby ensuring
`a high level of specificity in the delivery
`of the radiation to the tumour. Hence,
`PRRNT is a molecularly targeted radia-
`tion therapy, and thus is distinct from ex-
`ternal beam radiation therapy.
`The naturally occurring somatostatin
`molecule is an oligopeptide comprising
`either 14 or 28 amino acids with a
`limited half-life in blood due to rapid
`enzymatic degradation. Somatostatin
`exerts an antisecretory endocrine and
`exocrine effect in addition to tumour
`cell-growth inhibition. Stabilized ana-
`logues of somatostatin (SSA) show
`prolonged duration of action [1].
`In humans five sstr subtypes have been
`identified. Each sstr is a transmembrane
`molecule weighing approximately
`80 kDa. Somatostatin exerts its action by
`inhibiting G-protein-dependent 3′,5′-
`cyclic monophosphate (cAMP) formation
`in a dose-dependent manner at
`subnanomolar concentrations. Sstr2 is
`overexpressed in NETs. Sstr2 is the key
`target molecule for both cold and
`radiolabelled SSA. Upon binding to its
`receptor, the complex (SSA-sstr) under-
`goes cellular internalization thereby
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`Yttrium-90
`
`Lutetium-177
`
`DOTATOC
`
`DOTATATE
`
`enhancing the therapeutic effect of the
`radiolabelled drug [2].
`The radiometal 90Y is a pure β-emitting
`isotope with a physical half-life of 64 h.
`The maximum and mean β-particle ener-
`gies are 2.28 MeV and 0.934 MeV, re-
`spectively. The maximum and mean β-
`particle penetration depths in soft tissue
`are 11 mm and 3.9 mm, respectively.
`177Lu is a β- and γ-emitting radionuclide
`with a physical half-life of 162 h (6.73
`days). Compared to 90Y, 177Lu has lower
`maximum and mean β-particle energies
`(0.498 MeVand 0.133 MeV, respectively).
`These translate to maximum and mean
`soft-tissue penetration depths of 1.7 mm
`and 0.23 mm, respectively. 177Lu has two
`main gamma emission lines: 113 keV (6 %
`relative abundance) and 208 keV (11 %
`relative abundance). The latter properties
`of 177Lu allow posttreatment imaging and
`dosimetry assessments.
`DOTATOC is a derivatized somatostatin
`analogue peptide. DOTATOC is the
`abbreviated form of [DOTA0,Tyr3]-
`octreotide, where DOTA stands for the
`bifunctional chelating molecule 1,4,7,10-
`tetraazacyclo-dodecane-1,4,7,10-
`tetraacetic acid, and Tyr3-octreotide is the
`modified octreotide. This peptide shows a
`high affinity for sstr2 (IC50 14±2.6 nM),
`but lower affinities for sstr5 (IC50 393±84
`nM) and sstr3 (IC50 880±324 nM) [3].
`DOTATATE is also a derivatized
`somatostatin analogue peptide.
`DOTATATE is the abbreviated form of
`[DOTA0,Tyr3,Thr8]-octreotide or
`[DOTA0,Tyr3]-octreotate, and DOTA
`stands for the bifunctional metal-
`chelating molecule. This peptide shows
`a six- to ninefold higher affinity for
`sstr2 (IC50 1.5±0.4 nM) than DOTA-
`TOC, but has no affinity for either
`sstr5 (IC50 547±160 nM) or sstr3
`(IC50 >1,000 nM) [4].
`
`Background
`
`NETs have proven to be ideal neoplasms for PRRNT, as the
`majority of these slow-growing malignancies overexpress
`sstrs. Appropriate candidates for PRRNT are patients present-
`ing with well-differentiated or moderately differentiated neu-
`roendocrine carcinomas, defined as NETs of grade 1 or 2
`
`according to the WHO classification of 2010 [5]. The inci-
`dence of NETs has been rising over the past 30 years, partic-
`ularly those arising from the midgut and pancreas [6]. The
`incidence of NETs in the USA rose from 10.9 to 52.4 per
`million between 1973 and 2004 (SEER database). NETs can
`occur in children and young adults, being diagnosed as early as
`at the age of 5 years, while their incidence increases with age.
`The clinical presentation may vary depending on the site of
`tumour origin. About 72 % of NETs arise in gastrointestinal
`structures, 25 % are bronchopulmonary in origin, and less than
`5 % arise at other sites (e.g. thymus, breast and genitourinary
`system). Frequently, these tumours are discovered when meta-
`static or locally advanced and therefore inoperable. NETs can
`be either functioning or nonfunctioning in nature. Functioning
`tumours are associated with clinical syndromes, such as the
`carcinoid syndrome (due to the release of serotonin). Other
`secreting tumours include insulinomas (inducing hypoglycae-
`mia), gastrinomas (inducing Zollinger-Ellison syndrome),
`VIPomas (associated with the watery diarrhoea, hypokalaemia
`and achlorhydria syndrome; WDHA syndrome).
`Anatomical
`imaging of NETs should be as detailed
`and extensive as possible to provide accurate informa-
`tion about site and extent of the primary tumour, and
`the location and extent of regional and distant metasta-
`ses. An exact assessment of liver metastases and degree
`of liver involvement using ultrasonography, CT or MRI
`is central for accurate staging and for assessing the
`response to treatment [7].
`Functional imaging procedures applying sstr imaging
`using 111In-pentetreotide (OctreoScan) with SPECT or
`PET with 68Ga-labelled SSA, combined with morpho-
`logical imaging procedures, are used to collect essential
`information for staging, assessing sstr status and making
`decisions on the most appropriate therapy regimens [8,
`9]. Serial morphological examinations are mandatory to
`monitor therapy and detect recurrent disease. Emerging
`data indicate that 18F-FDG PET may have additional
`prognostic value [10]. This information, however, needs
`validation in larger studies.
`Multiple treatment approaches are now available for
`patients presenting with metastatic disease, considering re-
`cently introduced molecular targeted therapies and multi-
`modality treatment options. For the choice of the most
`appropriate treatment, information regarding anatomical lo-
`cation and local invasion of adjacent structures, tumour
`functionality, sstr status, histological grading and staging
`are required to facilitate the decision-making process within
`the multidisciplinary tumour board. If the disease is restrict-
`ed to the liver, surgical and locoregional approaches should
`be considered primarily. Chemotherapy is appropriate for
`highly proliferating NETs and pancreatic NETs, keeping in
`mind the fact that the vast majority of NETs are rather
`insensitive to this treatment.
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`Treatment options in NETs
`
`Patients with NETs may present with local tumours, with or
`without regional or distant metastases. The common site of
`metastasis is the liver. These tumours may remain clinically
`silent until a significant liver tumour burden is present.
`Therapeutic options include surgery, SSA, interferon, che-
`motherapy, molecularly targeted agents, locoregional thera-
`pies and PRRNT. Supportive palliative care and pain control
`also play an important role in patient management. These
`options are not mutually exclusive and, for the most part, are
`interchangeable. Options of care, including PRRNT, should
`be chosen and implemented in a correct sequence by an
`experienced multidisciplinary team. This approach should
`provide the highest benefit while minimizing the risks and
`side effects and ensuring the best quality of life achievable
`for the patient. Surgery with curative intent should always
`be performed whenever feasible; in selected cases, and
`within a multidisciplinary approach, PRRNT may be bene-
`ficial as a neoadjuvant therapy to render a patient accessible
`to surgery. For functionally active tumours, cytoreductive
`strategies, e.g. transarterial chemoembolization (TACE),
`transarterial embolization (TAE), radiofrequency ablation
`(RFA) and other techniques such as selective internal radi-
`ation therapy (SIRT), should always be considered with the
`intention of ameliorating clinical symptoms. The optimal
`management of NETs is early surgical removal prior to the
`development of regional or distant metastases. Unfortunate-
`ly, many patients are diagnosed with metastatic disease,
`when complete eradication of their tumours will not be
`possible. Removal of the primary tumour is indicated to
`prevent complications such as bleeding or small-bowel ob-
`struction. Even in the presence of liver metastases, removal
`of the primary tumour has several advantages and seems to
`have a positive prognostic impact on survival [11–14]. Sol-
`itary or isolated liver metastases can be surgically removed,
`while a more diffuse liver infiltration is usually treated using
`a locoregional approach.
`Locoregional approaches or local ablative therapies target
`predominantly liver metastases aiming at achieving local
`tumour control and alleviating functional secretory syn-
`dromes. Different techniques are applied depending on in-
`dividual findings (number size and distribution of liver
`lesions, their morphology, focal or diffuse, and their vascu-
`larization), functional activity of the NET and locally avail-
`able expertise. In an individual with few liver lesions with a
`preferably resected primary lesion, liver lesions can be trea-
`ted by surgical resection with or without RFA or laser-
`induced interstitial thermoablation. In those with multifocal
`or diffuse liver disease causing a high tumour load, TACE
`and TAE are the preferred choices [15, 16]. Local emboli-
`zation techniques are particularly useful when treating
`patients with functionally active liver metastases. Following
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`Eur J Nucl Med Mol Imaging
`
`TACE, symptomatic response rates of 60–95 % and bio-
`chemical response rates of 50–90 % are achieved and radio-
`logical response of 33–80 % have been reported [17–19].
`Response duration is between 18 and 24 months. Similar
`response rates are achieved with TAE alone [16]. In general,
`the procedure may require more than one treatment session
`to ensure effectiveness and consolidation of the treatment
`and to minimize the risk of complications.
`The recently introduced SIRT has shown variable re-
`sponse rates among individual centres [20]. Prospective
`studies are however lacking. In a single prospective study
`in 34 patients the objective response rate was 50 % [19].
`Given the lack of comparative studies of the different tech-
`niques used for local ablative and locoregional therapies, the
`choice of technique will be highly dependent on the physi-
`cians’ experience in the different centres and on individual
`criteria such as number, size, vascularization and distribu-
`tion of the lesions.
`Among the medical treatments, octreotide and lanreotide
`are the two most used sstr agonists. They play an essential
`role in the control of both symptomatic and asymptomatic
`NETs and should be regarded as first-line therapy. SSA can
`be used with virtually all of the other therapeutic options
`available. As the vast majority (87–92 %) of NETs express
`sstr2, patients should always be offered this therapy along-
`side other concurrent therapeutic options, and for supportive
`care. Long-acting SSA possess secretory inhibiting action,
`and are approved for alleviating the symptoms of the carci-
`noid syndrome, such as flushing and diarrhoea or bronchial
`obstruction, and to prevent carcinoid crisis. It is reported
`that treatment with SSA may control the clinical syndrome
`in 40–90 % of patients subject to tumour load and dosage
`[21, 22]. Nevertheless, patients may become refractory to
`syndrome control, and need incremental dosage increases of
`SSA. However, most patients with tumour progression re-
`quire an additional treatment, including the use of PRRNT.
`The recent PROMID study conducted in Germany showed
`the effectiveness of long-acting SSA as an antiproliferative
`therapeutic agent in midgut NET. In this study, time to
`tumour progression in patients given octreotide LAR
`30 mg intramuscularly monthly was more than double that
`in patients receiving only placebo (6.0 vs. 14.3 months). The
`NCCN guidelines and very recently the ENETS guidelines
`have added octreotide as an option for antiproliferative
`treatment [23, 24].
`Interferon-alpha (IFN-α) has been used for treating
`patients with NETs, especially those with the carcinoid
`syndrome, for more than 25 years. It is considered the main
`antisecretory drug used for the treatment of functional
`tumours [25]. IFN-α effectively reduces hypersecretion-
`related symptoms in patients with carcinoid syndrome in a
`similar manner to SSA. Partial tumour growth responses are
`also observed in 10–15 % of patients with malignant
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`carcinoids, and stabilization in 39 %. IFN-α has also been
`demonstrated to be effective in endocrine pancreatic
`tumours [26]. The very common side effect of IFN-α,
`namely a ’flu-like syndrome, limits both the use of high
`dosages and the duration of treatment due to intolerance
`forcing its interruption. Systemic chemotherapy is effective
`in some patients, especially those with poorly differentiated
`NET/neuroendocrine carcinoma (grade 3, WHO 2010) or
`progressive NET of the pancreas. However, in well-
`differentiated midgut NETs/NETs (grade 1/2, WHO 2010)
`the response rates to chemotherapy are low (7–20 %) and a
`survival advantage has not been demonstrated [27, 28]. The
`standard treatment for neuroendocrine carcinoma (grade 3)
`is cisplatin and etoposide. The response rate with this com-
`bination is 42–67 %, and its duration is often short, ranging
`from 8 to 9 months [32]. The combination of irinotecan and
`cisplatin [29] or FOLFOX chemotherapy (5-fluorouracil or
`capecitabine and oxaliplatin) may be an alternative [30].
`PRRNT is very rarely a suitable treatment option for neuro-
`endocrine carcinoma (grade 3), because of the low expres-
`sion of sstr but it may be considered following the failure of
`chemotherapy and if 111In-pentetreotide (OctreoScan) or
`68Ga-DOTATOC/DOTATATE PET/CT demonstrates mod-
`erate to high sstr expression.
`Systemic chemotherapy based on streptozotocin (Zano-
`sar, STZ) is considered a standard therapy for progressive
`pancreatic NETs with low or moderate proliferative capac-
`ity. Combinations of STZ and 5-fluorouracil and/or doxoru-
`bicin have been shown to lead to partial remission rates of
`35–40 % [31–33]. Recent phase II studies have shown
`efficacy of temozolomide based chemotherapy either with
`antiangiogenic drugs or capecitabine [34, 35]. Standards of
`care for the use of chemotherapy have been defined by
`ENETS [36]. In recent years, the efficacy of molecular
`targeted therapies for treating NETs has been assessed in
`clinical trials. These therapies include angiogenesis inhib-
`itors, single or multiple tyrosine kinase inhibitors and the
`novel SSA analogue pasireotide, for which clinical trials are
`ongoing. The drugs with the highest evidence of efficacy are
`sunitinib and everolimus (RAD-001). Both lead to extension
`of progression-free survival (PFS) of patients with advanced
`pancreatic NET. For everolimus, an mTOR inhibitor, there
`is evidence of efficacy in controlling NET arising from other
`sites associated with the carcinoid syndrome [37]. The most
`developed antiangiogenic drugs are sunitinib and the anti-
`VEGF antibody bevacizumab. In a phase II study bevacizu-
`mab in combination with octreotide LAR led to partial
`tumour remission in 18 % of patients and stable disease in
`77 % [38]. A recent international phase III study of sunitinib
`versus placebo in patients with progressive well-
`differentiated endocrine pancreatic tumour was interrupted
`prematurely due to the striking superiority of sunitinib evi-
`dent by a PFS of 11.1 vs. 5.5 months [39]. The objective
`
`remission rate was less than 10 %. The drug was recently
`approved by the US FDA and the European Medicines
`Agency for the treatment of advanced and progressive
`well-differentiated pancreatic NETs.
`Everolimus has been studied in more than 1,000 patients
`with NET and has been included in several clinical trials
`(RADIANT-1, RADIANT-2, RADIANT-3 trials, RAM-
`SETE trial). Antitumour activity of everolimus has been
`confirmed in RADIANT-1 in patients with progressive
`metastatic pancreatic NETs after failure of at least one line
`of cytotoxic chemotherapy. The trial studied 160 patients
`divided into two groups with or without monthly intramus-
`cular octreotide acetate therapy. The combination therapy
`group showed significantly longer PFS (16.7 vs. 9.7 months)
`[40]. The efficacy of everolimus has been confirmed in a
`large international placebo-controlled trial including 410
`patients with progressive pancreatic NET (RADIANT-3)
`[41]. Everolimus significantly reduced the risk of disease
`progression and led to a prolongation of PFS by 6.4 months
`(11 vs. 4.6 months) compared to placebo. Objective tumour
`response was low (4.8 % partial remissions). Disease control
`rate (partial response + stable disease) was, however, higher
`with everolimus than with placebo with best supportive care
`(77.7 % vs. 52.7 %). Side effects were rarely grade 3 or 4;
`the most frequently reported side effects included stomatitis,
`anaemia and hyperglycaemia. In May 2011 the US FDA
`approved everolimus for the treatment of progressive NETs
`of pancreatic origin in patients with nonresectable, locally
`advanced, or metastatic disease.
`In the global supportive approach to the patient, and
`when delivering PRRNT, nutrition and pain control are an
`essential component of care. Treatment of pain in patients
`with NET follows the general principles followed in adult
`and paediatric oncology [42]. Effective treatment of NETs,
`such as PRRNT, may alleviate pain, including bone pain.
`Treatment of painful bone metastasis is also mandatory with
`the administration of bisphosphonates as supportive therapy.
`
`PRRNT a historical overview
`
`PRRNT using radiolabelled octreotide was first attempted in
`the 1990s. The initial phase I trial investigated the safety and
`efficacy of using high activities of the diagnostic compound
`111In-octreotide as a therapeutic radiopharmaceutical. The
`results in terms of clinical efficacy were attributed to the effect
`of intracellular emission of the Auger and conversion elec-
`trons by 111In following the internalization of the peptide–
`receptor complex. Partial remissions were exceptional, and
`furthermore three patients developed leukaemia or myelodys-
`plastic syndrome from the group receiving the highest cumu-
`lative dose (90–100 GBq) [43]. In Europe, 111In-pentetreotide
`was abandoned as a therapy option in favour of the more
`efficient β emitters 90Y and 177Lu. 111In-pentetreotide is,
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`however, still used by some in the USA mainly due to the lack
`of availability of β-emitting radiotracers. High-energy β emit-
`ters, such as 90Y with a longer β range in soft tissue, were
`considered more promising for the treatment of bulky tumour.
`A novel analogue, Tyr3-octreotide, with a similar affinity
`profile for sstrs, was developed. Linked to a macrocyclic
`chelator (DOTA), it allows simple and stable radiolabelling
`of 111In and 90Y to [DOTA0,Tyr3]-octreotide (90Y-DOTA-
`TOC) [44]. PRRNT using 90Y-DOTATOC was first used in
`1996 in a patient in Basel, Switzerland. The excellent subjec-
`tive and objective response following several cycles of 90Y-
`DOTATOC led to high expectations as to the therapeutic
`potential of PRRNT in patients with NET. Since then other
`centres worldwide have conducted clinical trials with 90Y-
`DOTATOC [45]. Since the year 2000, octreotate (Tyr3,Thr8-
`octreotide), a newer analogue with improved affinity for sstr2,
`has been synthesized. The chelated analogue [DOTA0,Tyr3]-
`octreotate (DOTATATE) can be labelled with the β- and γ-
`emitting isotope 177Lu and has been used in clinical studies.
`
`Indications and contraindications
`
`Indications
`
`PRRNT is indicated for the treatment of patients with
`positive expression of sstr2, or metastatic or inoperable
`NET [46–50]. Candidate patients for PRRNT using
`radiolabelled somatostatin analogues are mainly those
`with sstr2-expressing NET of the gastroenteropancreatic
`and bronchial tracts, but may also include patients with
`phaeochromocytoma, paraganglioma, neuroblastoma [51]
`or medullary thyroid carcinoma [52–56]. The ideal can-
`didates for PRRNT are those with well-differentiated
`and moderately differentiated neuroendocrine carcinomas
`defined as NET grade 1 or 2 according to the recent
`WHO 2010 classification [4].
`
`Contraindications
`
`Absolute
`
`&
`&
`&
`
`Pregnancy.
`Severe acute concomitant illnesses.
`Severe unmanageable psychiatric disorder.
`
`Relative
`
`& Breast feeding (if not discontinued).
`&
`Severely compromised renal function: for PRRNT with
`a 90Y-labelled peptide age-adjusted normal renal func-
`tion is essential. Patients with compromised renal func-
`tion may still be considered for 177Lu-labelled peptide
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`Eur J Nucl Med Mol Imaging
`
`treatment. For 177Lu-labelled peptide a mild to moderate
`grade of renal impairment can be tolerated (e.g. creati-
`nine ≤1.7 mg/dl). Glomerular filtration rate (GFR) and
`tubular extraction rate (TER) should be at least 60 % of
`mean age-adjusted normal values.
`Severely compromised bone marrow: noncompromised
`haematological reserve should be present before
`PRRNT. Suggested reference values are:
`
`&
`
`WBC <3,000/μl, with absolute neutrophil count <1,000/μl
`PLT <75,000/μl for 177Lu-DOTATATE, <90,000/μl for
`90Y-DOTATOC,
`RBC <3,000,000/μl.
`
`Special warnings
`
`Renal function
`
`the activities
`The kidney is the dose-limiting organ at
`normally used for PRRNT. Side effects involving the
`kidney and the bone marrow are mild if adequate renal
`protection and fractionation are used. Renal function
`should be assessed by means of laboratory tests (creat-
`inine and BUN), or calculation of creatinine clearance
`(e.g. Cockroft-Gault formula). Additional studies, e.g.
`measurement of GFR with 24-h urine collection or
`nuclear medicine methods (e.g. 99mTc-MAG3 with
`TER determination, 99mTc-DTPA GFR or effective renal
`plasma flow using hippuran), should be performed in
`patients with risk factors for
`renal
`toxicity or with
`compromised renal function, and in all children.
`
`Aggravating conditions (caveats)
`
`&
`
`& Renal outflow obstruction, potentially leading to
`hydronephrosis, and, ultimately,
`to loss of
`renal
`function, should always be ruled out or otherwise
`corrected before PRRNT.
`Previous myelotoxic chemotherapy and extended ex-
`ternal beam irradiation fields to the bone marrow
`(pelvis, spine), particularly if performed in the
`weeks preceding the PRRNT, do increase the risk
`of bone marrow failure after PRRNT. In doubtful
`cases of haematological compromise, a bone marrow
`biopsy might be indicated to assess bone marrow
`status in pretreated patients and to assess the risk
`when planning for multiple PRRNT cycles (e.g.
`intervals between cycles). Depending on the amount
`of 90Y-DOTATOC or 177Lu-DOTATATE activity
`injected, persisting depressed platelets values follow-
`ing prior PRRNT cycle(s) can impede the timing and
`dosing of subsequent cycles.
`
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`& A patient with pending liver failure should be consid-
`ered with caution before being submitted to PRRNT.
`
`Patient preparation
`
`Renal protection
`
`Procedure
`
`Pretherapy assessment
`
`The availability of the following information is mandatory
`when considering a patient for PRRNT:
`& NET proven by histopathology (immunohistochemistry).
`& High sstr expression determined by functional whole-
`body imaging with 111In-pentetreotide (OctreoScan) or 68
`Ga-DOTA-peptide PET/CT or immunohistochemistry.
`
`The following criteria should be taken into consideration
`when deciding whether or not to perform PRRNT.
`
`& Karnofsky/Lansky performance status above 60 % or
`ECOG performance status less than 2.
`& Tumour differentiation, preferably grade 1/2.
`& Tumour proliferation rate, preferably with a Ki-67/mitotic
`index ≤20 %. In addition, the rate of tumour growth, as
`determined by CT or MRI, could be considered. Note that,
`in general, less-differentiated tumours showing high pro-
`liferation rates are better candidates for chemotherapy.
`
`Facility and personnel
`
`PRRNT is still considered an investigational treatment and
`its implementation must comply with national legislation
`and local requirements, as well as with ethical principles
`regarding human studies. The decision to provide PRRNT
`should be taken within a multidisciplinary tumour board,
`including all the specialists involved in the care of patients
`with NET. The facility requirements will depend on national
`legislation on the therapeutic use of radioactive agents. If
`inpatient therapy is required by national legislation, the
`treatment should take place in an approved facility. The
`facility must have appropriate personnel, radiation safety
`equipment, and procedures for waste management and han-
`dling accidental contamination of the site or personnel.
`90Y-DOTATOC or 177Lu-DOTATATE should be admin-
`istered by appropriately trained medical staff with support-
`ing nursing staff with a medical physics expert available.
`Physicians responsible for treating patients should have a
`general knowledge of the pathophysiology and natural history
`of the respective diseases, should be familiar with alternative
`forms of therapy, and should be able to closely liaise with
`other physicians involved in managing the patients. Clinicians
`involved in the utilization of unsealed radionuclide sources for
`therapy must also be knowledgeable about and compliant with
`applicable national legislation and local regulations.
`
`Together with the bone marrow, the kidneys are the critical
`organs in PRRNT particularly when using 90Y-DOTATOC.
`Proximal tubular reabsorption of the radiopeptide and subse-
`quent retention in the interstitium result in excessive renal
`irradiation. Nephrotoxicity may be aggravated by risk factors,
`such as preexisting hypertension or diabetes mellitus [57]. To
`counteract and reduce the high kidney retention of radiopep-
`tides, positively charged amino acids, such as L-lysine and/or
`L-arginine, are coinfused to competitively inhibit the proximal
`tubular reabsorption of the radiopeptide. The coadministration
`of these amino acids leads to a significant reduction in the
`renal absorbed dose, which ranges from 9 % to 53 % [58].
`Renal absorbed dose is further reduced by up to 39 % by
`extending the infusion time of the amino acid solution over
`10 h, and up to 65 % by extending the protection over 2 days
`following radiopeptide administration, thereby covering the
`renal elimination phase more efficiently [59, 60].
`
`Amino acid protection protocols
`
`Lysine and/or arginine should be diluted appropriately in
`large volumes of normal saline in order to hydrate the
`patient, unless the patient suffers from cardiac in