First Randomised Study Results for Lutetium Therapy in Pancreatic Neuroendocrine Tumours

Neuroendocrine tumours (NETs) arise in hormone-producing endocrine and nerve cells of the body’s neuroendocrine system. Although often slow-growing, they may also spread rapidly. Their behaviour varies with their location and the hormones they release (see Neuroendocrine Tumours: Symptoms, Stages and Treatment).

Around 2.5 - 5 people per 100,000 are diagnosed with NETs each year. They most often arise in the stomach, pancreas, small intestine, thyroid, lungs and prostate. They are named after the organ where they originate, such as gastric or pancreatic neuroendocrine tumours.

Pancreatic neuroendocrine tumours, also called islet cell tumours, are rare cancers arising in the pancreas’s endocrine tissues. They may release peptide hormones, including insulin, gastrin, glucagon and vasoactive intestinal peptide, causing many different symptoms. However, 50 to 75 percent of pancreatic NETs are asymptomatic, meaning that they are not associated with a hormonal syndrome.

Pancreatic neuroendocrine tumours are rare overall, with an annual incidence of ≤1 case per 100,000 people, and account for 1 to 2 percent of all pancreatic tumours.

Neuroendocrine cancer cells are classified according to whether they carry a somatostatin binding receptor. Depending on whether this receptor is present, they are described as somatostatin receptor-positive or receptor-negative neuroendocrine tumours.

Promising results from the first multicentre randomised phase II study of peptide receptor radionuclide therapy (PRRT) in advanced pancreatic neuroendocrine tumours (PNETs) were presented at the 2022 ESMO Congress.

Targeted Therapy Versus Radionuclide Therapy

In OCLURANDOM, patients receiving lutetium-octreotate had longer progression-free survival than those receiving sunitinib.

Lu-DOTA-TATE is the first PRRT for advanced somatostatin receptor-positive gastroenteropancreatic NETs approved by the EMA (2017) and the US FDA (2018). Although rarely curative, PRRT has been shown to relieve symptoms, improve quality of life, shrink tumour lesions and slow disease progression.

OCLURANDOM was designed to assess the antitumour effects of PRRT with 177lutetium-octreotate versus sunitinib in patients with positive somatostatin receptor scintigraphy (SSTR) and unresectable, progressive, advanced pancreatic NETs. ECOG Performance Status of 0-2 and documented progression within 1 year before enrolment were required for previously treated patients, who were randomised 1:1 to OCLU (lutetium-octreotide) or sunitinib.

The study met its primary endpoint by achieving significantly longer progression-free survival with OCLU-based PRRT within 12 months. The 12-month progression-free survival rate was 80.5% with OCLU, compared with 42% at 11 months with sunitinib.

Figure: Progression-free survival with 177lutetium-octreotate (OCLU) versus sunitinib in OCLURANDOM among patients with positive somatostatin receptor scintigraphy and unresectable, progressive, advanced pancreatic neuroendocrine tumours.

Among the 84 enrolled patients, mean age was 63 and 52% were women. Liver involvement was present in 37%, a functional syndrome in 20%, and 43% had received two or more systemic treatments.

Grade 3 - 4 adverse effects occurred in 44% of the OCLU group and 63% of the sunitinib group.

The most frequent adverse effects, listed as OCLU versus sunitinib, were:

• Decreased blood cell counts (12% versus 23%)
• Digestive problems (12% versus 21%)
• Hypertension (12% versus 19%)
• Fatigue (7% versus 12%)

Treatment was discontinued because of adverse effects in 5% of the OCLU group and 21% of the sunitinib group.

Conclusion

Although the first clinical OCLU results in somatostatin receptor-positive gastroenteropancreatic tumours were published in 2003, randomised trials assessing meaningful clinical outcomes were lacking. Because of this lack of randomised evidence in gastroenteropancreatic NETs, the 2020 ESMO and European Neuroendocrine Tumor Society guidelines preferred molecularly targeted agents such as everolimus or sunitinib and systemic chemotherapy, with PRRT considered only after these failed. The current study therefore fills an important gap, despite limitations such as the heterogeneity of previous treatment regimens.