# Background
Neuroendocrine tumours (NETs) are a family of tumours, occurring with an incidence of about 5.25 cases per 100,000 1 . The incidence of NETs is increasing over the last 3 decades. NETs can arise in several organs; the most common sites are the ileum and pancreas, followed by other sites within the GI tract, the lungs, thyroid, parathyroid, adrenal glands, and pituitary gland. However, NETS can occur anywhere in the body 2,3 . NETs are often classified as functioning or nonfunctioning tumours, the latter of which do not present with hormone hypersecretion, and are often found as a bulky tumours with metastatic disease. The five-year survival rate for patients with NETs depends largely upon the location of the primary tumour and the extent of disease. Patients with localized disease can expect five-year survival rates ranging from 65% for ileal tumours to 84% for lung tumours and 90% for rectal tumours 4 . As expected, patients with distant disease carry a worse prognosis with five-year survival rates ranging from 24% in the rectum and 27% in the lungs to 54% in the ileum 5 .
Few curative options are available for patients with unresectable, progressive, or metastatic NETs. Peptide receptor radionuclide therapy (PRRT) has been studied in the clinical trial setting since about the year 2000. Several agents are potentially available, including 90Y-DOTAOC 6 , 111ln-DTPAOC 7 , 177Lu-DOTATATE 8 , which are radionuclides bound to the somatostatin analog octreotide. These agents work by binding to the tumour receptors and emitting radiation to the tumour. The Health Canada approved product (Lutathera, 177Lu-DOTATATE) is administered with a dose of 200mCi every 8 weeks for a total of four cycles. Dosing and timing may differ based on a centre's specific clinical research trial protocol. The most common side effects of treatment are nausea /vomiting, fatigue and decreased blood counts. Rare severe toxicities include myelodysplasia, acute leukemia, renal failure and hormonal crisis (if the tumour is secretory). The full listing of adverse events can be viewed further in the Lutathera product monographand/or the centre's trial protocol. The purpose of this guideline is to provide evidence-based recommendations on the use of PRRT for NETs and to define which patients are candidates for this treatment. This guideline will focus on the role of 177Lu-DOTATATE 9,10 

# Search Strategy
The National Guidelines Clearinghouse and individual cancer agencies' websites were searched for guidelines on the use of peptide receptor radionuclide therapy. Among the guidelines identified, Cancer Care Ontario's document, Radionuclide Therapy for Neuroendocrine Malignancies (August 15, 2011), was deemed appropriate by the working group for adaptation. The search strategy employed by Cancer Care Ontario was current to 2010 11 . In order to make the guideline adaptation current to 2018, the MEDLINE and EMBASE database was searched (2010 through 2021) using the same search strategy.
The search initially resulted in1530 citations after duplicates were removed. Studies that did not report response rates or survival rates were excluded, as well as prospective studies that included 30 or fewer patients or retrospective studies that included 100 or fewer patients. A total of 60 publications were deemed relevant. Evidence is summarized in the table in Appendix A.

# Target Population
The recommendations in this guideline apply to patients diagnosed with unresectable, progressive, or metastatic neuroendocrine tumours. Recommendations 1. Peptide receptor radionuclide therapy (PRRT) is an appropriate treatment option for patients with unresectable or metastatic; progressive or symptomatic, NETs. Consideration for treatment is to be determined at a multidisciplinary neuroendocrine tumour board.

# Required work up
- Confirm diagnosis and staging of NET with histopathology and biochemical assays. The tumour differentiation must be present on the pathology report: Grade 1 (ki-6720%) tumours 12 . - Images should be reviewed to assess for receptor heterogeneity. If there is discordance between imaging modalities with presence of lesions that are suspected to be dedifferentiated based on absence of uptake on somatostatin receptor imaging or if they exhibit a rapid progression pattern on anatomic imaging, an FDG PET-CT should be performed to exclude aggressive or dedifferentiated disease that would not be amenable to PRRT and for prognostic purposes.
- Baseline tumor markers should be obtained prior to initiating therapy, depending on origin and hormonal secretion status (secreting or not, ex: CgA and 5-HIAA, Insulinemia, etc).
- Somatostatin receptor imaging (SRI) using PET or SPECT, such as Ga68 DOTA PET, octreotide scan or other available SRI imaging , to determine if tumour is somatostatin receptor positive. Sufficient tumour uptake is defined as higher than normal liver uptake.
- For Higher grade tumors: ki67 >10%, it is recommended that Diagnostic imaging (CT and MRI), should be less than 3 months old.
- If PRRT is received within a clinical trial, additional work up may be required based on the study protocol.
- Conduct an appropriate laboratory assessment at baseline and before each cycle (directed at known side effects of treatment) o hematologic: CBCD (complete blood count and differential) o kidney function: electrolytes, creatinine and eGFR o liver function: bilirubin, albumin, INR, ALT o metabolic: fasting glucose - Perform cross sectional imaging (CT and/or MRI) at baseline (within 6 months of therapy initiation or less in case of suspected significant interval changes: significant elevation in tumor markers, clinical deterioration or other imaging showing significant progression) and at follow-up to assess tumour response. If PRRT is offered within a clinical trial, additional imaging may be required for tumour response assessment as per the trial protocol. 

# Development and Revision History
This guideline was reviewed and endorsed by the Alberta Provincial Endocrine Tumour Team. Members include . Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Endocrine Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook. This guideline was originally developed in 2021.

# Maintenance
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. 

# Abbreviations

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