The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours

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 receptor agonists 90 Y-DOTATOC ([ 90 Y-DOTA 0 ,Tyr 3 ]-octreotide) or 177 Lu-DOTATATE ([ 177 Lu-DOTA 0 ,Tyr 3 ,Thr 8 ]-octreotide or [ 177 Lu-DOTA 0 ,Tyr 3 ]-octreotate) have been successfully used for the past 15 years to target metastatic or inoperable neuroendocrine 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 177 Lu-DOTATATE or 90 Y-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
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 contraindications 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 published through a joint international effort under the auspices of the Nuclear Medicine Section of the International Atomic 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 for their eligibility to undergo treatment with [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-or Lu-radiolabelled somatostatin analogues. 2. Providing guidance on performing peptide receptor radionuclide 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 including 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 Therapy, 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 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
PRRNT (or PRRT) involves the systemic administration of a specific well-defined radiopharmaceutical composed of a emitting radionuclide chelated to a peptide for the purpose of delivering cytotoxic radiation to a tumour. The oligopeptides are designed to target cellular proteins, commonly cell surface receptors, such as the somatostatin receptor (sstr) subtype 2 (sstr2) that is overexpressed 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 radiation therapy, and thus is distinct from external beam radiation therapy. Somatostatin
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 analogues of somatostatin (SSA) show prolonged duration of action.

## Somatostatin receptors
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 3,5cyclic 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) undergoes cellular internalization thereby enhancing the therapeutic effect of the radiolabelled drug [bib_ref] Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target..., Waser [/bib_ref]. Yttrium- [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] The radiometal [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y is a pure -emitting isotope with a physical half-life of 64 h. The maximum and mean -particle energies are 2.28 MeV and 0.934 MeV, respectively. The maximum and mean particle penetration depths in soft tissue are 11 mm and 3.9 mm, respectively. Lutetium-177 Lu is a and -emitting radionuclide with a physical half-life of 162 h (6.73 days). Compared to Lu has lower maximum and mean -particle energies (0.498 MeV and 0.133 MeV, respectively). These translate to maximum and mean soft-tissue penetration depths of 1.7 mm and 0.23 mm, respectively. 177 Lu has two main gamma emission lines: 113 keV (6 % relative abundance) and 208 keV [bib_ref] Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment, Maecke [/bib_ref].

# 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 presenting with well-differentiated or moderately differentiated neuroendocrine carcinomas, defined as NETs of grade 1 or 2 according to the WHO classification of 2010 [bib_ref] The ENETS guidelines: the new TNM classification system, Rindi [/bib_ref]. The incidence of NETs has been rising over the past 30 years, particularly those arising from the midgut and pancreas [bib_ref] Gastroenteropancreatic neuroendocrine tumors, Modlin [/bib_ref]. Anatomical imaging of NETs should be as detailed and extensive as possible to provide accurate information about site and extent of the primary tumour, and the location and extent of regional and distant metastases. 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 [bib_ref] Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for..., Sundin [/bib_ref].
Functional imaging procedures applying sstr imaging using 111 In-pentetreotide (OctreoScan) with SPECT or PET with 68 Ga-labelled SSA, combined with morphological imaging procedures, are used to collect essential information for staging, assessing sstr status and making decisions on the most appropriate therapy regimens [bib_ref] Oncology Committee of the EANM. 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging, Bombardieri [/bib_ref] [bib_ref] Procedure guidelines for PET/CT tumor imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE, Virgolini [/bib_ref]. Serial morphological examinations are mandatory to monitor therapy and detect recurrent disease. Emerging data indicate that 18 F-FDG PET may have additional prognostic value [bib_ref] 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors, Binderup [/bib_ref]. This information, however, needs validation in larger studies.
Multiple treatment approaches are now available for patients presenting with metastatic disease, considering recently introduced molecular targeted therapies and multimodality treatment options. For the choice of the most appropriate treatment, information regarding anatomical location 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 restricted 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.

## 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, chemotherapy, molecularly targeted agents, locoregional therapies 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 beneficial 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 radiation 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. Unfortunately, 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 obstruction. 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 [bib_ref] Midgut carcinoid tumors: surgical treatment and prognosis, Kerstrom [/bib_ref] [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors: well-differentiated..., Plockinger [/bib_ref] [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors: well-differentiated..., Ramage [/bib_ref] [bib_ref] Operative resection of primary carcinoid neoplasms in patients with liver metastases yields..., Givi [/bib_ref]. Solitary 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 syndromes. Different techniques are applied depending on individual findings (number size and distribution of liver lesions, their morphology, focal or diffuse, and their vascularization), functional activity of the NET and locally available expertise. In an individual with few liver lesions with a preferably resected primary lesion, liver lesions can be treated by surgical resection with or without RFA or laserinduced interstitial thermoablation. In those with multifocal or diffuse liver disease causing a high tumour load, TACE and TAE are the preferred choices [bib_ref] Consensus guidelines for the management of patients with liver metastases from digestive..., Steinmuller [/bib_ref] [bib_ref] Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and..., Vogl [/bib_ref]. Local embolization techniques are particularly useful when treating patients with functionally active liver metastases. Following TACE, symptomatic response rates of 60-95 % and biochemical response rates of 50-90 % are achieved and radiological response of 33-80 % have been reported [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref]. Response duration is between 18 and 24 months. Similar response rates are achieved with TAE alone [bib_ref] Liver metastases of neuroendocrine carcinomas: interventional treatment via transarterial embolization, chemoembolization and..., Vogl [/bib_ref]. 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 response rates among individual centres [bib_ref] Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in..., Kennedy [/bib_ref]. Prospective studies are however lacking. In a single prospective study in 34 patients the objective response rate was 50 % [bib_ref] Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases, King [/bib_ref]. Given the lack of comparative studies of the different techniques used for local ablative and locoregional therapies, the choice of technique will be highly dependent on the physicians' experience in the different centres and on individual criteria such as number, size, vascularization and distribution 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 alongside other concurrent therapeutic options, and for supportive care. Long-acting SSA possess secretory inhibiting action, and are approved for alleviating the symptoms of the carcinoid 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 [bib_ref] Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumors, Modlin [/bib_ref]. Nevertheless, patients may become refractory to syndrome control, and need incremental dosage increases of SSA. However, most patients with tumour progression require 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 [bib_ref] Consensus guidelines for the management of patients with digestive neuroendocrine tumors -welldifferentiated..., Eriksson [/bib_ref] [bib_ref] Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in..., Rinke [/bib_ref].
Interferon-alpha (IFN-) 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 [bib_ref] Interferon in the management of neuroendocrine GEP tumors, Oberg [/bib_ref]. IFN- effectively reduces hypersecretionrelated 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 carcinoids, and stabilization in 39 %. IFN- has also been demonstrated to be effective in endocrine pancreatic tumours [bib_ref] An update of the medical treatment of malignant endocrine pancreatic tumors, Eriksson [/bib_ref]. The very common side effect of IFN-, 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 welldifferentiated 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 [bib_ref] Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major..., Moertel [/bib_ref] [bib_ref] The management of patients with advanced carcinoid tumors and islet cell carcinomas, Moertel [/bib_ref]. The standard treatment for neuroendocrine carcinoma (grade 3) is cisplatin and etoposide. The response rate with this combination is 42-67 %, and its duration is often short, ranging from 8 to 9 months [bib_ref] Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors, Fjallskog [/bib_ref]. The combination of irinotecan and cisplatin [bib_ref] A phase II study of irinotecan and cisplatin for metastatic or unresectable..., Mani [/bib_ref] or FOLFOX chemotherapy (5-fluorouracil or capecitabine and oxaliplatin) may be an alternative [bib_ref] Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade..., Bajetta [/bib_ref]. PRRNT is very rarely a suitable treatment option for neuroendocrine carcinoma (grade 3), because of the low expression of sstr but it may be considered following the failure of chemotherapy and if 111 In-pentetreotide (OctreoScan) or [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] Ga-DOTATOC/DOTATATE PET/CT demonstrates moderate to high sstr expression.
Systemic chemotherapy based on streptozotocin (Zanosar, STZ) is considered a standard therapy for progressive pancreatic NETs with low or moderate proliferative capacity. Combinations of STZ and 5-fluorouracil and/or doxorubicin have been shown to lead to partial remission rates of 35-40 % [bib_ref] Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced..., Kouvaraki [/bib_ref] [bib_ref] Treatment with combined streptozotocin and liposomal doxorubicin in metastatic endocrine pancreatic tumors, Fjallskog [/bib_ref] [bib_ref] Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma, Moertel [/bib_ref]. Recent phase II studies have shown efficacy of temozolomide based chemotherapy either with antiangiogenic drugs or capecitabine [bib_ref] First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine..., Strosberg [/bib_ref] [bib_ref] Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine..., Kulke [/bib_ref]. Standards of care for the use of chemotherapy have been defined by ENETS [bib_ref] ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: chemotherapy..., Eriksson [/bib_ref]. In recent years, the efficacy of molecular targeted therapies for treating NETs has been assessed in clinical trials. These therapies include angiogenesis inhibitors, 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 [bib_ref] A randomized, doubleblind, placebo-controlled, multicenter phase III trial of everolimus plus octreotide..., Pavel [/bib_ref]. The most developed antiangiogenic drugs are sunitinib and the anti-VEGF antibody bevacizumab. In a phase II study bevacizumab in combination with octreotide LAR led to partial tumour remission in 18 % of patients and stable disease in 77 % [bib_ref] Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment..., Yao [/bib_ref]. A recent international phase III study of sunitinib versus placebo in patients with progressive welldifferentiated endocrine pancreatic tumour was interrupted prematurely due to the striking superiority of sunitinib evident by a PFS of 11.1 vs. 5.5 months [bib_ref] Sunitinib malate for the treatment of pancreatic neuroendocrine tumors, Raymond [/bib_ref]. 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 intramuscular octreotide acetate therapy. The combination therapy group showed significantly longer PFS (16.7 vs. 9.7 months) [bib_ref] Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after..., Yao [/bib_ref]. The efficacy of everolimus has been confirmed in a large international placebo-controlled trial including 410 patients with progressive pancreatic NET (RADIANT-3) [bib_ref] Everolimus for advanced pancreatic neuroendocrine tumors, Yao [/bib_ref]. 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 [bib_ref] National Institutes of Health State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference..., Patrick [/bib_ref]. 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 111 In-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 electrons by In following the internalization of the peptidereceptor complex. Partial remissions were exceptional, and furthermore three patients developed leukaemia or myelodysplastic syndrome from the group receiving the highest cumulative dose (90-100 GBq) [bib_ref] Phase I study of peptide receptor radionuclide therapy with, Valkema [/bib_ref]. In Europe, In-pentetreotide was abandoned as a therapy option in favour of the more efficient  emitters 90 Y and 177 Lu. In-pentetreotide is, however, still used by some in the USA mainly due to the lack of availability of -emitting radiotracers. High-energy  emitters, such as 90 Y with a longer  range in soft tissue, were considered more promising for the treatment of bulky tumour. A novel analogue, Tyr 3 -octreotide, with a similar affinity profile for sstrs, was developed. Linked to a macrocyclic chelator (DOTA), it allows simple and stable radiolabelling of 111 In and 90 Y to [DOTA 0 ,Tyr 3 ]-octreotide ( 90 Y-DOTA-TOC) [bib_ref] Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers..., Jong [/bib_ref]. PRRNT using 90 Y-DOTATOC was first used in 1996 in a patient in Basel, Switzerland. The excellent subjective and objective response following several cycles of 90 Y-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 90 Y-DOTATOC [bib_ref] Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin..., Kwekkeboom [/bib_ref]. Since the year 2000, octreotate (Tyr 3 ,Thr 8octreotide), a newer analogue with improved affinity for sstr2, has been synthesized. The chelated analogue [DOTA 0 ,Tyr 3 ]octreotate (DOTATATE) can be labelled with the and emitting isotope Lu 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 [bib_ref] Somatostatin receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors, Kwekkeboom [/bib_ref] [bib_ref] Peptide receptor therapies in neuroendocrine tumors, Bodei [/bib_ref] [bib_ref] Treatment with the radiolabeled somatostatin analog, Kwekkeboom [/bib_ref] [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. 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 [bib_ref] 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma, Gains [/bib_ref] or medullary thyroid carcinoma [bib_ref] Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma, Bartolomei [/bib_ref] [bib_ref] Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized..., Iten [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas, Bodei [/bib_ref] [bib_ref] Yttrium-DOTA]-TOC response is associated with survival benefit in iodine-refractory thyroid cancer: long-term..., Iten [/bib_ref] [bib_ref] Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma, Teunissen [/bib_ref]. The ideal candidates 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 [bib_ref] Somatostatin receptors as targets for nuclear medicine imaging and radionuclide treatment, Maecke [/bib_ref]. & A patient with pending liver failure should be considered with caution before being submitted to PRRNT.

## Contraindications

## 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 wholebody imaging with 111 In-pentetreotide (OctreoScan) or [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] 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 proliferation 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 handling accidental contamination of the site or personnel. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-DOTATOC or 177 Lu-DOTATATE should be administered by appropriately trained medical staff with supporting 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.

## Patient preparation

## Renal protection
Together with the bone marrow, the kidneys are the critical organs in PRRNT particularly when using 90 Y-DOTATOC. Proximal tubular reabsorption of the radiopeptide and subsequent retention in the interstitium result in excessive renal irradiation. Nephrotoxicity may be aggravated by risk factors, such as preexisting hypertension or diabetes mellitus [bib_ref] Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC..., Bodei [/bib_ref]. To counteract and reduce the high kidney retention of radiopeptides, 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 % [bib_ref] New advances in peptide receptor radionuclide therapy, De Jong [/bib_ref]. 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 [bib_ref] 86YDOTA0)-DPhe1-Tyr3-octreotide (SMT487) -a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective..., Jamar [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumors, Bodei [/bib_ref].

## 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 insufficiency (e.g. carcinoid heart valve disease), in which case volume overload, possibly leading to acute exacerbation of the condition, should be avoided. Hyperosmotic solutions in particular should be avoided since they can induce dangerous electrolyte imbalances that might lead to severe metabolic acidosis and cardiac arrhythmias. An appropriate dilution is 25 g of amino acid in 1 l of normal saline.
Before beginning the amino acid infusion, appropriate measures against nausea and vomiting should be undertaken by administering an antiemetic (e.g. 5-HT3 antagonist, such as granisetron) and/or a corticosteroid (e.g. dexamethasone). Antiemetic can be repeated if needed. Amino acid infusion should be started 30-60 min before administration of the radiopeptide and should be maintained over 4 h. Particular attention and care should be given to avoiding possible electrolyte imbalance (hyperkalaemia and hypernatraemia), and the consequent metabolic acidosis, that might lead to mild nausea and vomiting [bib_ref] Effect of amino acid infusion on potassium serum levels in neuroendocrine tumour..., Giovacchini [/bib_ref]. These side effects should be managed by hydrating the patient with normal saline and possibly by repeating corticosteroid or antiemetic administrations.

## Three-day 25-g protection protocol
During day 1, a cocktail of 25 g of lysine diluted in 1 l of normal saline is infused over 4 h, starting 30-60 min before the PRRNT. This is followed by the administration of a 12.5 g lysine solution in 500 ml of normal saline over 3 h twice a day on the second and third day after therapy. This protocol is aimed at maximizing renal protection while minimizing the side effects of the amino acid infusion.
3. Three-day 50-g protection protocol A 50-g solution of lysine and arginine (25 g/25 g) diluted in 2 l normal saline infused over 4 h during the first day starting 30-60 min before therapy. This is followed by the administration of an additional 12.5 g lysine diluted in 500 ml of normal saline infused over 3 h twice a day on day 2 and day 3 after therapy.

## Single-day 50 g+gelofusine
Renal uptake of radiolabelled somatostatin analogues can in part be attributed to the receptor-mediated endocytic renal transporter system involving megalin-mediated cubilindependent endocytosis across the proximal epithelium. Gelofusine, a succinylated bovine gelatin molecule commonly used as a plasma expander, can be administered to further reduce kidney absorbed radiation dose (by about 45 %) through its interaction with the megalin/cubilin receptor-mediated transporter system [bib_ref] Reactions to gelatin plasma expanders, Watkins [/bib_ref] [bib_ref] Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues, Rolleman [/bib_ref]. There have been some safety concerns about the use of Gelofusine following the occurrence of allergic reactions, although mild in most cases. Severe anaphylactoid reactions are described in approximately 0.04 % [bib_ref] A systematic review of the comparative safety of colloids, Barron [/bib_ref] [bib_ref] Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu..., Wehrmann [/bib_ref]. The treating physician should be aware of these effects and be prepared to treat them accordingly with antihistaminic drugs, corticosteroids or epinephrine. A protection protocol consists of a cocktail of 25 g lysine+25 g arginine diluted in 2 l of normal saline infused over 4 h starting 30-60 min before therapy, and Gelofusine infusion as a bolus of 1 ml/kg body weight over 10 min before therapy, followed by Gelofusine infusion at 0.02 ml/kg/min over 3 h after radiopeptide infusion. Due to reported adverse immunogenic reactions, vital parameters should be monitored during Gelofusine infusion [bib_ref] Reactions to gelatin plasma expanders, Watkins [/bib_ref].
Precautions in special clinical conditions In patients with severe cardiac insufficiency, volume overload that might lead to acute cardiac insufficiency and decompensation, should be avoided. Therefore, formulations with lower amounts of amino acids and hence lower volumes should be chosen (e.g. 25 g of lysine or arginine diluted in a maximum of 1 l of normal saline). In any case, a stringent monitoring regimen with participation of a cardiologist is recommended. In patients with preexisting nephrolithiasis, forced diuresis might mobilize kidney stones leading to acute renal colic. These events should be treated appropriately but, if possible, anticipated and avoided by infusing lower volumes. Phlebitis associated with the hyperosmolarity of the infused amino acid solution may occur at the site of injection. This condition can be treated with local vasoprotective creams.

## Somatostatin analogue withdrawal
Somatostatin analogues are available as short-acting or long-acting preparations. These should be discontinued prior to PRRNT as they might interfere with receptor targeting. The duration of interruption, however, depends on the halflife of the analogue used. Withdrawal periods of 4-6 weeks for long-acting release formulations and of at least 24 h for short-acting formulations are considered good clinical practice. This topic is still a matter of debate [bib_ref] Mallorca Consensus Conference participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for..., Sundin [/bib_ref] [bib_ref] Oncology Committee of the EANM. 111In-pentetreotide scintigraphy: procedure guidelines for tumour imaging, Bombardieri [/bib_ref]. In practice a long-acting release formulation is substituted by a shortacting formulation 1 month prior to PRRNT.

## Radiopharmaceutical and administration

## Quality control
Both 90 Y and 177 Lu are trivalent metals; they form a highly stable complex with the DOTA chelating molecule. "Simple" radiochemical purity (RP) testing to assess the fraction of free radionuclide using thin layer chromatography or solid phase extraction (using a Sep-Pak cartridge) is not mandatory for commercially acquired therapeutic radiopharmaceuticals. However, if such quality control is desired by the end-user, it should be conducted by adequately trained and qualified professionals. Applying this simple test, the RP should not fall below 98 %. It is worth noting that a more sophisticated method such as high-performance liquid chromatography might reveal additional impurities, and thus a RP of 98 % will be difficult to achieve. As to the amount of peptide employed for an individual treatment cycle (single infusion), the consensus is that for formulations labelled with 177 Lu the mass of peptide should be between 100 and 200 g, and should not exceed 250 g per patient dose, while for carrier-free 90 Y it should be between 100 and 150 g per patient. It is common practice to add excess sodium DTPA to the radiopharmaceutical prior to dispensing because it binds free radiometals and facilitates their fast renal clearance. The specific activity should not fall below a certain value. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y is produced as a carrier-free radionuclide from the parent radioisotope [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Sr with a theoretically maximum achievable specific activity close to 1,295 MBq/g (35 mCi/g). Metal impurities, particularly iron, lead to a significant lowering of the specific activity of the radiopeptide and can occasionally impede the labelling procedure.
The radioisotope 177 Lu is produced by a nuclear reactor either via the direct or the indirect pathway; the direct pathway involves the n-gamma irradiation of an enriched 176 Lu target. The indirect pathway involves the irradiation 176 Yb to produce the short-lived 177 Yb (T 1/2 1.9 h) that decays to 177 Lu. The latter method avoids the production of the long-lived 177m Lu (T 1/2 60 days). Few high neutron-flux reactors are capable of producing 177 Lu of a specific activity in excess of 0.74 GBq/g (20 Ci/mg). By the time of radiolabelling the specific activity is around 0.555 GBq/g (15 Ci/mg); this, however, should not fall below 10 Ci/mg. In practice, a specific activity of 37 to 74 MBq (1-2 mCi) 177 Lu per microgram of precursor is routinely achieved and is accepted for clinical use.

## Administration
During the administration of the radiopeptide, a physician must remain nearby. A resuscitation cart as well as a trained emergency team must be available. The radiopharmaceutical should be diluted with saline to a final volume ranging from 10 ml to 100 ml, depending on the infusion system used. The radiopharmaceutical should be administered via an indwelling catheter to ensure safe intravenous administration and prevent paravascular infiltration, and should be administered over 10 to 30 min, depending on the infusion system used. The radiopeptide may be coinfused with amino acid solution via a three-way stopcock ("piggy-back"). The line should be flushed with saline after completion of radiopeptide infusion. PRRNT may reproduce the syndromes of the respective functional tumours due to the sudden massive release of the hormones and stimulation of their corresponding receptors. The clinical manifestation is dependent on the specific hormone involved. The following measures are therefore recommended. Vital signs (at least blood pressure and pulse) should be monitored before and after therapy infusion in symptomatic patients. Therapeutic interventions should be undertaken to treat the functional syndrome effects or exacerbation (e.g. carcinoid syndrome/hypotension, hypoglycaemia, hypergastrinaemia, hypertension, hypotension, WDHA syndrome, electrolyte imbalance). Nursing personnel must be instructed in radiation safety. Any serious or life-threatening medical condition should be noted and contingency plans put in place in case radiation precautions need to be breached to allow emergency medical care. In a medical emergency, concerns about radiation exposure should not hinder the prompt delivery of appropriate medical care to the patient. During the first 2 days after PRRNT the high levels of activity excretion in the urine is of particular concern. Patients should be advised to observe rigorous hygiene to avoid contaminating persons using the same toilet facilities. A double toilet flush is recommended after urination. Patients should wash their hands after urination. If contaminated with urine, patients should wash their hands with abundant cold water without scrubbing. Once discharged, patients should be cautioned to avoid soiling underclothing or areas around toilet bowls for 1 week following PRRNT. Considerably contaminated clothing should be washed separately. Incontinent patients should be catheterized prior to PRRNT and the catheter should be kept for 2 days thereafter. Urine bags should be emptied frequently. Gloves and protective clothing should be worn by staff caring for catheterized patients (or providing any care involving close contact). Women of childbearing potential should use effective contraception while undergoing treatment and avoid pregnancy for at least 6 months thereafter. Male patients should consider sperm banking before therapy.

## The compromised patient
For the compromised patient, the administered activity may be reduced and treatment cycles are individualized with due consideration to prevailing clinical and biochemical parameters, and the results of dosimetric studies.
In patients with reduced renal function the following additional interventions are used: In patients with reduced haematological values the following additional interventions are used:
(a) Haematologist consultation. (b) When required, packed red blood cells or platelet concentrate support may be given following PRRNT. (c) If needed, growth factor support with granulocyte stimulating factors or erythropoietin (or derivatives) can be considered not earlier than 10 days after PRRNT. (d) In patients with severely compromised bone marrow reserves, peripheral stem cell harvesting as a precautionary measure could be considered before PRRNT and, if necessary, reinfusion could be performed after an appropriate time from PPRNT has elapsed.

## Special considerations for prrnt in children
NETs and neural crest tumours in children express high levels of sstrs and can potentially be treated with PRRNT. With the exception of appendiceal carcinoid, most NETs in children are metastatic at diagnosis. Children under the age of 18 years have been excluded from participation in PRRNT trials resulting in a lack of information on safety, toxicity and efficacy in this age group. Conservatively, absorbed doses to the kidney are limited to less than 21-23 Gy. [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y-DOTATOC has been used in children with administered activities of 1.5-1.85 GBq/m 2 per cycle for up to three cycles [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref]. With regard to the use of 177 Lu-DOTATATE in children, there is no widespread experience, and activities should be adapted per square metre [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref].

## Retreatment options
The decision to re-treat a patient with PRRNT should only be undertaken within the framework of the tumour board. In patients who have previously responded to PRRNT, retreatment may be considered in those with well-documented disease progression and taking into account the total previous radiation dose to the kidneys and bone marrow. This new PRRNT course will be subject to the same eligibility criteria applied to the first radiopeptide treatment cycle. The options include the use of the same or a different radiopeptide. For instance, choosing 177 Lu-labelled peptides may be warranted, especially when considering the preservation of kidney function. When designing a retreatment regimen, due consideration should be given to the possibility of exceeding the renal threshold dose especially in patients with a good prognosis and expectation of long survival. Using 177 Lu-labelled peptides, whole-body imaging should always be performed following each cycle to document the distribution of the radiopharmaceutical and to evaluate the functional response to PRRNT.

## Dosimetry
Radiation dosimetry of normal organs and malignant lesions provides an insight for optimizing the delivery PRRNT, thereby allowing the dose delivered to the tumour to be maximized while minimizing the dose delivered to normal organs, particularly the kidney and bone marrow. If feasible, patient-specific dosimetry can provide valuable information to assess organ-specific radiation absorbed doses and to assess the risk of delayed organ toxicity, particularly of the kidneys and bone marrow in a patient with known risk factors (see. Different dosimetry methods, practical and sophisticated, can be applied depending on final objective and availability of resources. Input data include data from blood, urine, and whole-body scans adequately scheduled up to at least 3 days after PRRNT. Planar images are useful to derive biokinetics over time, while SPECT and SPECT/CT fused images, although requiring more time to acquire, provide insight into organ-specific three-dimensional activity distribution. The MIRD scheme provides reference techniques for internal dosimetry. Dedicated software (OLINDA/EXM) has been used to derive mean absorbed dose estimates for 177 Lu and 90 Y peptides; [bib_ref] OLINDA/EXM: the secondgeneration personal computer software for internal dose assessment in nuclear..., Stabin [/bib_ref].
PRRNT dose estimates in organs are generally calculated using the MIRD scheme, with the basic formula:
[formula] D 14 e A A S 14 A 0 A t A S; [/formula]
where A is the integral activity in the organ, A 0 is the initial activity in the organ,  is the residence time corresponding to the total number of decays occurring in the organ divided by A 0 , and S is a dose conversion factor depending on the properties of the radionuclide and the target. The value of S should be corrected for the actual volume and mass of the organ. Once the integral activities in the organs of interest are determined using numerical or compartmental models [bib_ref] Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in..., Siegel [/bib_ref] [bib_ref] Developing and testing integrated multicompartment models to describe a single-input multiple-output study..., Foster [/bib_ref] , absorbed doses are generally calculated using dedicated software programs that use as input the residence time  or the number of decays (OLINDA/EXM, RADAR) [bib_ref] Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in..., Siegel [/bib_ref] [bib_ref] Developing and testing integrated multicompartment models to describe a single-input multiple-output study..., Foster [/bib_ref].
The typical kinetics of radiopeptides, namely very fast blood clearance and renal elimination, determine the information required to obtain the integral activities in organs and tumour, which includes a whole dataset of scintigraphic images and data from blood and urine samples. Once the rough data are analysed, the activity in normal and tumour tissues is converted into time-activity curves for the calculation of absorbed dose estimates. The residence time for the red marrow is calculated from the residence time for blood, with the assumption that nonspecific uptake of the radiolabel takes place in the bone marrow. Uniform activity distribution and equivalent clearance in red marrow and blood are assumed. Due to the small size of the radiopeptide, the specific activity in bone marrow can be considered equal to the specific activity in blood [bib_ref] Dosimetry of internal emitters, Sgouros [/bib_ref] [bib_ref] Bone marrow dosimetry in peptide receptor radionuclide therapy with, Forrer [/bib_ref]. Overall, the dose to the red marrow results from bone marrow self-irradiation and the contribution from the remainder of the body. Tumour absorbed doses can then be estimated by assuming the lesion is a sphere and assuming a uniform activity distribution [bib_ref] Dosimetry in peptide radionuclide receptor therapy: a review, Cremonesi [/bib_ref] [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref]. For 90 Y-DOTATOC, the lack of emission by [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref] Y makes direct dosimetry quite difficult.
Bremsstrahlung images are rather difficult to quantify, requiring the application of complex corrections. For this reason two alternative options are used in clinical practice: In and 86 Y simulations. Despite some drawbacks, the extrapolated absorbed doses are reasonably similar. For dosimetric purposes 111 In-DOTATOC has been used in clinical practice as a surrogate for 90 Y-DOTATOC because of its similar chemical and kinetic properties. An alternative but far more demanding solution is to use DOTATOC labelled with the positron emitter 86 Y. PET with 86 Y-DOTATOC offers improved spatial resolution and quantitative analysis. Nevertheless, the short time window for data collection , as a consequence of the physical half-life (14.7 h) of 86 Y, the low positron abundance, the high production cost and the low availability, are a challenge to the routine utilization of this method. 111 In-pentetreotide scintigraphy and PET with 68 Ga-DOTATOC are not suitable for accurate dosimetric calculation, the former due to its different kinetic behaviour and receptor affinity profile and the latter due to the short physical half-life (68 min) of [bib_ref] Therapeutic nuclear medicine in pediatric malignancy, Schmidt [/bib_ref] Ga. Recently, a PET-based method promising quantitative imaging of 90 Y distribution was described [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref] [bib_ref] Evaluation of quantitative planar 90Y bremsstrahlung whole-body imaging, Minarik [/bib_ref] [bib_ref] Dosimetry of yttrium-labelled radiopharmaceuticals for internal therapy: 86Y or 90Y imaging?, Walrand [/bib_ref]. In the case of 177 Lu-DOTATATE, the gamma photons emission allows both imaging and dosimetry of the same compound. Therefore dosimetry is usually performed [bib_ref] Dosimetry in peptide radionuclide receptor therapy: a review, Cremonesi [/bib_ref] [bib_ref] Dosimetry for treatment with radiolabelled somatostatin analogues. A review, Cremonesi [/bib_ref] 0.070.010.170.02 [bib_ref] A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same..., Forrer [/bib_ref] 0.04 (0.02-0.06) [bib_ref] Dosimetry in patients undergoing 177Lu-DOTATATE therapy with indications for 90Y-DOTATATE, Cremonesi [/bib_ref] 0.09 (0.03-0.18) [bib_ref] Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTAlanreotide scintigraphy and dosimetry in patients with neuroendocrine..., Rodrigues [/bib_ref] 0.040.02 [bib_ref] Results of individual patient dosimetry in peptide receptor radionuclide therapy with 177Lu..., Wehrmann [/bib_ref] 0.050.00 [bib_ref] Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor..., Forster [/bib_ref] 0.020.03 [bib_ref] Bone marrow dosimetry in peptide receptor radionuclide therapy with, Forrer [/bib_ref] 0.060.02 [bib_ref] Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe 1-Tyr3-octreotide versus 111In-pentetreotide in patients with..., Helisch [/bib_ref] 0.120.02 [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref] (paediatric, 111 In) a Kidneys 6.05 (unprotected) Lu-DOTATATE.

## Side effects

## Acute
Side effects of PRRNT are usually mild, if necessary precautions are taken. Side effects may be acute, related to the administration of amino acids or to the radiopeptide itself, or chronic. The coinfusion of amino acids enlarges the safety margin for treating with higher activities enabling higher tumour radiation doses to be attained safely. Side effects such as nausea, headache and rarely vomiting due to metabolic acidosis induced by the amino acid coadministration do occur in the majority of patients [bib_ref] 86YDOTA0)-DPhe1-Tyr3-octreotide (SMT487) -a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective..., Jamar [/bib_ref] [bib_ref] Safe and effective inhibition of renal uptake of radiolabelled octreotide by a..., Rolleman [/bib_ref]. Particular attention and care should be given to avoiding possible electrolyte imbalance (hyperkalaemia, hypernatraemia), and the subsequent metabolic acidosis, that might lead to mild nausea and vomiting. The latter side effects should be managed by hydrating the patient with normal saline and possibly by repeating corticosteroid or antiemetic administrations. PRRNT may exacerbate the syndromes related to the respective functional tumours, due to the sudden massive release of the hormones and receptor stimulation. The clinical manifestation is dependent on the specific hormone involved. The following measures are therefore recommended. Vital signs (at least blood pressure and pulse) should be monitored before and after radiopeptide infusion, especially in symptomatic patients. Therapeutic interventions should be undertaken to treat the for functional syndrome effects or exacerbation (e.g. carcinoid syndrome/hypotension, hypoglycaemia, hypergastrinaemia, hypertension, hypotension, WDHA syndrome, electrolyte imbalance) [bib_ref] Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate, De Keizer [/bib_ref]. In patients without or with minor metastatic liver involvement, no significant hepatic toxicity has been reported. However, in patients with massive liver metastases and impaired liver function, liver toxicity may occur, and this should be considered, along with preexisting conditions affecting the liver, when choosing the appropriate radioisotope and dosing. In such cases, 177 Lu-labelled peptides should be used and the administered activity should be reduced accordingly. After treatment, patients should avoid pregnancy for at least 6 months. Due to a temporary impairment of fertility, related to a transient damage to Sertoli cells, male patients should consider sperm banking before therapy.

## Delayed side effects

## Renal toxicity
The kidneys are the dose-limiting organs at the activities normally reached with PRRNT. Proper kidney protection, as discussed, is currently mandatory. However, despite kidney protection, loss of kidney function can occur after PRRNT, with a creatinine clearance loss of about 3.8 % per year for 177 Lu-DOTATATE and 7.3 % per year for 90 Y-DOTATOC [bib_ref] Long-term follow-up of renal function after peptide receptor radiation therapy with 90Y-DOTA0,..., Valkema [/bib_ref]. In a series of 1,109 patients treated with 90 Y-DOTATOC, the incidence of grade 4 and 5 kidney toxicity was found to be 9.2 % [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. Delayed renal toxicity following 90 Y-DOTATOC treatment was observed more frequently in patients with predisposing risk factors including longstanding and poorly controlled hypertension and diabetes mellitus [bib_ref] Peptide receptor radionuclide therapy for non-radioiodine-avid differentiated thyroid carcinoma, Teunissen [/bib_ref].

## Bone marrow toxicity
Severe (grade 3 and 4), mostly reversible, acute bone marrow toxicity is observed in less than 10-13 % of treatment cycles with 90 Y-DOTATOC, and in 2-3 % of cycles with 177 Lu-DOTATATE. Nevertheless, sporadic cases of myelodysplastic syndrome or overt acute myelogenous leukaemia have been reported [bib_ref] Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin..., Kwekkeboom [/bib_ref] [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref].

## Endocrine systems
Despite the presence of sstr in normal pituitary, thyroid and adrenal glands and Langerhans cells, no significant alteration in endocrine hormone function have been reported [bib_ref] Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate on endocrine function, Teunissen [/bib_ref].

# Results
PRRNT with the somatostatin analogues 90 Y-DOTATOC and 177 Lu-DOTATATE has been explored in NET for more than a decade. Present knowledge and clinical studies indicate that it is possible to deliver tumoricidal absorbed doses (e.g. >200 Gy) to neoplastic tumours expressing sst2 receptors, leading to partial or complete objective responses in up to 30 % of patients. The best objective responses have been reported in gastroenteropancreatic NETs (with partial responses ranging from 9 % to 29 % and complete remission from 2 % to 6 %), and similar rates have been achieved in thorax (lung) NETs and neuroectodermal tumours (phaeochromocytomas, paragangliomas). Less favourable results have been reported for thymic NETs, medullary thyroid carcinoma and dedifferentiated thyroid carcinomas. Encouraging results have also been reported for sstr-positive tumours including meningiomas, medulloblastomas and astrocytomas .
Survival analyses have shown that patients with high sstr tumour expression at study entry, treated with either 177 Lu-DOTATATE or 90 Y-DOTATOC, show significantly higher objective responses that translate into significantly longer survival [bib_ref] Treatment with the radiolabeled somatostatin analog, Kwekkeboom [/bib_ref] [bib_ref] Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue..., Imhof [/bib_ref]. A favourable biochemical response was also shown to be predictive of improved overall survival in patients with medullary (calcitonin) and dedifferentiated iodide-negative thyroid cancer (thyroglobulin) undergoing 90 Y-DOTATOC treatment [bib_ref] Peptide receptor radionuclide therapy with (90)Y-DOTATOC in recurrent meningioma, Bartolomei [/bib_ref] [bib_ref] Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas, Bodei [/bib_ref]. Symptomatic response, particularly a durable improvement in diarrhoea after 90 Y-DOTATOC treatment, proved to have an impact on PFS [bib_ref] 90Y-Edotreotide for metastatic carcinoid refractory to octreotide, Bushnell [/bib_ref]. Initial data indicate that combination treatments with the two isotopes 90 Y and 177 Lu linked either to DOTATOC or to DOTATATE administered in sequential treatment cycles or as a cocktail infusion for several cycles improve survival [bib_ref] Cohort study of somatostatin-based radiopeptide therapy with, Villard [/bib_ref] [bib_ref] Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem..., Kunikowska [/bib_ref]. However, larger prospective randomized trials are needed to confirm these results. In children and young adults only one controlled clinical phase I trial of PRRNT has been conducted utilizing 90 Y-DOTATOC at activity levels of 1.11, 1.48 and 1.85 GBq/m 2 per cycle in three cycles at 6-week intervals [bib_ref] Phase I trial of 90Y-DOTATOC therapy in children and young adults with..., Menda [/bib_ref]. Three patients showed a partial response, five a minor response, five stable disease and two progressive disease. Dosimetry results were similar to the dosimetry estimates in adults.
The evaluation of response to PRRNT includes the assessment of functional and morphological responses, biochemical and symptomatic responses, and quality of life. Response is assessed by morphological and functional imaging techniques. Posttherapeutic 177 Lu-DOTATATE scans provide valuable information on the intensity of uptake and localization of the tracer, and thus can be used to assess the response to the prior therapy cycles. The time-line to assess response may vary according to clinical needs (aggressiveness and extent of disease), but usually the first follow-up examination is recommended after 3 months, and subsequent follow-up examinations should be performed after 3-6 months. The reader is also referred to the ENETS guidelines for a more detailed discussion of the standards of care in NET follow-up and documentation [bib_ref] ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: follow-up..., Arnold [/bib_ref].

## Follow-up
The assessment of renal function is of paramount importance, as the kidney, together with the bone marrow, is the critical organ in PRRNT. The follow-up should include the evaluation of serum creatinine levels and the determination of creatinine clearance. In patients with pre-existing risk factors for delayed renal toxicity (high-risk group), in particular long-standing and poorly controlled hypertension and diabetes mellitus, single kidney or previously documented renal insult, mainly nephrotoxic chemotherapy, more precise methods to assess renal function are recommended. These techniques may include GFR measurements by means of 99m Tc-DTPA, [bib_ref] 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma, Gains [/bib_ref] Cr-EDTA or measurement of 99m Tc-MAG3 clearance.

## Between-cycle follow-up
A complete blood cell count should be performed every 2-4 weeks. A higher frequency can be adopted if clinically required. Renal and liver function tests should be available before confirming subsequent cycles. Following careful clinical assessment, patients with blood values lower than the limits indicated for the first PRRNT cycle should receive a lower activity and/or the interval to the following PRRNT cycle should be extended. In severe cases, interruption of PRRNT might be considered.
Intermediate and long-term follow-up A complete blood cell count (including mean corpuscular volume), and renal and liver function tests should be performed every 8-12 weeks for the first 12 months, and thereafter twice a year if clinically indicated. Evaluation of response to treatment includes consideration of the clinical, biochemical, morphological and PET/SPECT functional status, and wellbeing of the patient. Morphological response is determined by contrast-enhanced CT or MRI. Objective response can be determined using the WHO, SWOG and RECIST criteria [bib_ref] Southwest Oncology Group standard response criteria, endpoint, definitions and toxicity criteria, Green [/bib_ref] [bib_ref] RECIST revised: implications for the radiologist. A review article on the modified..., Van Persijn Van Meerten [/bib_ref]. For assessing morphological response, CT is the preferred imaging technique, but this does not rule out the use of MRI. In some patients, CT and MRI may provide complimentary information. In any case, the same imaging modality should be employed during the follow-up of the individual patient. Depending on the disease duration and on tumour biology, these examinations are repeated every 3-6 months, but may be extended up to once every 12 months in the long-term follow-up in patients with a durable response.
Functional imaging is a valuable instrument to assess the course of the disease, and it has been demonstrated to be able to predict morphological response. Combined functional and morphological imaging may in many cases better reflect the true behaviour of the tumour following PRRNT. Such imaging includes 111 In-pentetreotide (OctreoScan) and, if available, PET/CT with 68 Ga-DOTA peptides or metabolic monitoring with, for example, 18 F-DOPA. However, functional imaging is not yet accepted as a substitute for morphological imaging as a means to assess tumour response to a treatment.

## Disclaimer
This guidance document is a compilation of recent published evidence on the use of PRRNT in NETs and the personal experience of leading experts in the field reflecting personal opinion based on unpublished data. It pays special attention to and emphasizes gastroenteropancreatic presentations. The guidance is not provided as an inflexible set of rules and is not intended, nor should it be used, to establish legal standards of care. For these reasons as well as those set out below, this guidance should not be used in litigation in which the clinical decisions of practitioners are being called into question.
The EANM and the IAEA have written and approved guidelines to promote the cost-effective use of high-quality nuclear medicine therapeutic procedures. These generic recommendations cannot be rigidly applied to all patients in all practice settings. The guidelines should not be deemed inclusive of all proper procedures or exclusive of other procedures reasonably directed to obtaining the same results. Advances in medicine occur at a rapid rate. The date of a guideline should always be considered in determining its current applicability.

## Further reading
For additional reading, the book published by the Nuclear Medicine Section, IAEA, entitled "Practical guidance on peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumours" (Human Health Series no. 12) is available for download using the link http://www.iaea.org/Publications/