Treatment of neuroendocrine tumours with ¹⁷⁷Lu‐peptide receptor radionuclide therapy: Challenging clinical scenarios and their management

Abstract

Somatostatin receptors (SSRs) are expressed on several tumours, with a high incidence and density of receptors found particularly in well differentiated neuroendocrine tumours (NETs). 1 Therapeutic applications targeting the SSRs are well established in the management of NETs. Peptide receptor radionuclide therapy (PRRT) targets the SSRs using a radioligand that contains a somatostatin analogue and a therapeutic radioactive radionuclide (e.g., 90 yttrium, 177 lutetium). 177 Lu-DOTA-octreotate (DOTATATE) is currently the most widely used PRRT compound following the successful NETTER-1 trial. 2 The NETTER-1 trial, a randomised controlled trial in progressive midgut NETs, reported a statistically significant superior progression-free survival (PFS) of 177 Lu-DOTATATE compared to high-dose octreotide LAR (28.4 months vs. 8.5 months). 2 The second major single centre phase I/II study of over 1200 patients with grade 1 and 2 bronchial and gastroenteropancreatic (GEP) NETs (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) treated with 177 Lu-DOTATATE reported a PFS of 29 months and described a favourable safety profile. 3 The data in these two studies led to the European and American Regulatory bodies licensing 177 Lu-DOTATATE in GEP-NETs in 2017/18. 177 Lu-DOTATATE has become an established therapy in welldifferentiated GEP-NETs. International guidelines have recommended PRRT as second line systemic treatment in metastatic small intestine NETS and second-fourth line treatment in metastatic pancreatic NETs. 4,5 In addition to 177 Lu-DOTATATE, several other PRRT agents produced by different pharmaceutical companies are undergoing clinical trials in NETs. 6,7 177 Lu-DOTATATE therapy is generally well tolerated and has a good safety profile. Significant subacute toxicities are usually limited to grade 3/4 haematological events in < 10% of patients. 2,3 Patient selection for PRRT should be in a multidisciplinary setting. Typically, patient selection for PRRT includes the following criteria: (a) progressive metastatic NET, (b) somatostatin receptor positivity on molecular imaging, (c) adequate safety blood markers and (d) satisfactory clinical performance status. In addition to these basic criteria, there are various scenarios where the risk-benefit analysis of PRRT needs to be carefully evaluated to mitigate any risks associated with PRRT.Although there are existing guidelines on the selection of patients for PRRT in GEP-NETs, 4,8 guidance on the use of 177 Lu-PRRT in high-risk scenarios or in scenarios of relative contraindications is less clear.This review looks at 11 critical clinical scenarios where the risk-benefit of 177 Lu-PRRT should be closely evaluated. In these

Peptide Receptor Radionuclide Therapy

“…At baseline, patients who are potential candidates for PRRT with 177 Lu-DOTATATE should have hemoglobin ≥ 5 mmol/L (8 g/dL); white blood count ≥ 2 × 10 9 /L; platelets ≥ 75 × 10 9 /L. According to the most recent SmPC the minimal threshold baseline creatinine clearance for PRRT with 177 Lu-DOTATATE is 40 mL min −1 1.73 m −2 , but in some centers patients with renal insufficiency have also been treated ( 65 ). In patients with hormone-producing NENs there is a 1% risk of hormonal crises with PRRT with 177 Lu-DOTATATE, particularly in patients with the carcinoid syndrome and VIPoma syndrome ( 65 , 66 ).…”

“…According to the most recent SmPC the minimal threshold baseline creatinine clearance for PRRT with 177 Lu-DOTATATE is 40 mL min −1 1.73 m −2 , but in some centers patients with renal insufficiency have also been treated ( 65 ). In patients with hormone-producing NENs there is a 1% risk of hormonal crises with PRRT with 177 Lu-DOTATATE, particularly in patients with the carcinoid syndrome and VIPoma syndrome ( 65 , 66 ). In patients with midgut NENs and extensive mesenteric desmoplastic reactions and/or extensive peritoneal metastases, PRRT with 177 Lu-DOTATATE can increase the risk of subacute bowel obstruction or venous ischemia, probably by provoking edema or enhancing the fibrosis ( 65 , 67–69 ).…”