麻豆传媒

The most significant recent development in the treatment of patients with metastasized or inoperable neuroendocrine tumors (NETs) has been the FDA approval of peptide receptor radionuclide therapy (PRRT).

The treatment has a history dating back to the early 1990s. Since then physicians have used the molecules [¹¹¹Indium]-DTPA⁰-octreotide and [⁹⁰Yttrium]-DOTA⁰-Tyr³-octreotide for PRRT for NETs. And for much of that time, noted Erik Mittra, MD, PhD, division chief of nuclear medicine & molecular imaging at Oregon Health & Science University in Portland, PRRT had been available in certain hospitals in Europe and Australia, but not in the U.S.

That changed in 2018 with the of [¹⁷⁷Lutetium]-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE; Lutathera) for treatment of adult patients with advanced NETs that affect the pancreas or gastrointestinal tract.

"This was a big deal because there aren't many good treatment options for neuroendocrine tumors," Mittra told 麻豆传媒. "Moreover, the results of the phase III trial for PRRT were very good, with a positive primary endpoint of progression-free survival, benefits in terms of quality of life, and limited toxicity, so all around it was a very good outcome."

The drug works by binding to the somatostatin receptor, which is present on the surface of most well-differentiated NETs. After binding to the receptor, the radiopharmaceutical enters the cell and is trapped, allowing the radiation to attack the tumor cells.

FDA approval was supported by the results of two trials:

• , a randomized, multicenter, open-label, active-controlled trial involving 229 patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor-positive tumors, demonstrated that treatment with Lutathera compared with high-dose octreotide (long-acting release) resulted in a 79% reduction in the risk of disease progression

• A of 1,214 patients demonstrated a progression-free survival of 29 months, time to progression of 36 months, and overall survival of 63 months for NET patients treated with Lutathera

A study published last year in the also demonstrated the long-term efficacy of PRRT in managing NETs. The 12-year retrospective study included 44 patients (27 men, 17 women) with advanced tumors and enhanced somatostatin receptor expression and found that while median overall survival was 79 months, 32% of the patients (14 of the 44 patients -- six men, eight women) were still alive more than 12 years after starting PRRT.

Which patients are appropriate candidates for this therapy? "These patients will have metastatic -- inoperable -- gastroenteropancreatic NETs that are low- or intermediate-grade, with a proliferation (Ki-67) index of less than 20% and are progressing on first-line therapy," said Mittra. "These are the main candidates."

"That is actually a large percentage of the patients, but it excludes patients with more unusual subtypes or those with high-grade tumors," he noted.

There is also a growing literature supporting the use of PRRT in other subtypes and higher-grade tumors. For example, the World Health Organization has recently changed the classification of high-grade tumors into those that are well-differentiated high-grade and those that are poorly differentiated high-grade. "So some high-grade patients, if they show high somatostatin expression on their scan, may be reasonable candidates for this therapy as well," Mittra said.

According to the Society of Nuclear Medicine and Molecular Imaging, the most common protocol for delivering the therapy (and which was the basis for FDA and European Medicines Agency approval) includes a series of four PRRT treatments with ¹⁷⁷Lu-DOTATATE spaced approximately 2 months apart, although protocols may differ depending on the radionuclide, the number of treatments, and the dosage.

"It is actually a relatively easy treatment to give once you go through the process of selecting the right patient and the right time to administer treatment," said Rodney Hicks, MBBS, MD, director of molecular imaging at the Peter MacCallum Cancer Centre in Melbourne, Australia. "With appropriate pre-medication to relieve the nausea associated with the amino acid solution that we give to reduce radiation dose to the kidneys, most patients experience almost no acute symptoms from PRRT."

Fatigue in the first couple of weeks is the main reported symptom, Hicks told 麻豆传媒. "There can, however, be a more problematic situation with highly symptomatic patients related to release of pre-formed hormone within the tumor. This tends to be most severe with the first cycle of treatment. Although most of our patients are treated as outpatients, we generally admit patients with severe carcinoid syndrome, VIPoma [vasoactive intestinal peptide tumor], insulinoma, or catecholamine producing pheo/paraganglioma. A hormonal flare tends to begin within 24 hours, and we can discharge most patients the day after treatment."

There are also challenges with end-organ dysfunction associated with NETs, Hicks continued, explaining that he and his colleagues generally avoid treating patients with low albumin levels and that severe renal impairment is seen as a contraindication. "But with administration of a lower activity of the PRRT agent, excellent results can be obtained, since less of the agent is excreted from the body, making it more available for binding to tumor."

Hicks said the most challenging decisions come with patients who have severe carcinoid heart disease -- patients for whom the prognosis of this complication is often worse than from the NET itself.

One current area of research involving PRRT is the possibility of combining it with other modalities, such as poly-ADP ribose polymerase (PARP) inhibitors.

"My lab and others have demonstrated that the combination of PRRT and a PARP inhibitor increases cell killing by impairing faithful DNA-repair," said Hicks. "Much of the damage done to DNA by PRRT is a break in a single strand. PARP inhibitors convert many of these into double-strand breaks in a process called fork-collapse. We are investigating the combination of radionuclide therapy with PARP inhibitors in phase I studies. We are, of course, concerned that this might also increase toxicity in other cells, particularly replicating cells of the bone marrow, so safety is the primary endpoint of these trials," he said.

PRRT is also being used to treat non-gastroenteropancreatic NETs, including childhood and adult neuroblastoma, esthesioneuroblastoma, meningioma, pheochromocytoma, and paraganglioma, as well as bronchial carcinoids and small cell lung cancer, Hicks noted. "And we also use it in metastatic Merkel cell carcinoma of the skin and have an combining PRRT with immunotherapy -- itself a highly effective therapy in this disease."

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