Current Therapy for Neuroendocrine Disease: When is Lutetium-177 Peptide Receptor Radionuclide Therapy Indicated?

Because overall survival of patients with metastatic neuroendocrine tumors (NET) is usually longer than other types of metastatic cancers, deciding which treatment can best control the disease over a long period of time without causing long-term side effects that might affect survival or quality of life can be challenging, according to Dr Ghassan El-Haddad, Associate Member of Vascular and Interventional Radiology and Section Head of the Radionuclide Therapy Program at the Moffitt Cancer Center and Research Institute, University of South Florida.

Surgery is considered standard of care for patients with NET who are candidates and for patients with >90% of tumor burden that can be surgically removed. In patients who are not candidates or do not want surgery, tumor debulking or metastatectomy can be performed if there is limited disease using ablative techniques, Dr El-Haddad said.

Patients with slow growing limited NET can sometimes be observed without therapy but are typically placed on a somatostatin analog (SSA) if they progress.

“If the patient progresses on SSA, then depending on the rate, extent and location of the disease progression considerations could be made for PRRT (Lu-177 DOTATATE), Everolimus, Sunitib, or Capecitabine/Temozolomide. In patients who have liver only or liver dominant disease, embolotherapy is indicated for symptomatic or progressive (non surgical, non ablatable disease). Bulky liver dominant metastatic disease might benefit more from embolotherapy since the overall response rate is higher than peptide receptor radionuclide therapy (PRRT), (about 50% vs 18%),” Dr El-Haddad said.

Lutetium-177 Peptide Receptor Radionuclide Therapy

On January 26, 2018, the Food and Drug Administration approved lutetium Lu-177 dotatate (Lutathera) for patients with metastatic or inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grade 1-2 who are somatostatin receptor (SSTR) positive progressing on standard dose long acting SSA or despite SSA and everolimus. There is no data comparing PRRT to everolimus in patients progressing on long acting SSA.

“GEP-NETs usually overexpress somatostatin receptors, which are the target of somatostatin analogs. Lu-177 dotatate is a radiolabeled SSA that binds to SSTR then gets incorporated into the neuroendocrine tumor cell by endocytosis, thereby delivering ionizing radiation to the cell nucleus causing DNA breaks and cell death,” Dr El-Haddad said.

The approval was based off the results of the phase 3, randomized NETTER-1 trial which compared Lu-177 dotatate versus high-dose octreotide LAR in patients with progressive, metastatic midgut NETs, demonstrating efficacy and tolerability. Results were published in the New England Journal of Medicine.1 Data from ERASMUS Medical Center, where an international, single-institution, single-arm, open-label trial was performed on patients with bronchial and GEP-NET somatostatin receptor-positive tumors was also used in the FDA decision.

Dr El-Haddad explained that although the Lu-177 dotatate is only approved by the FDA for GEP-NETs, it may be useful in SSTR-positive bronchial NET and well-differentiated grade 3 NET who failed or who cannot tolerate chemotherapy.

“In patients with liver-dominant or liver only disease that involves greater than 75% of the liver, embolization is contra-indicated due to high risk of hepatotoxicity. PRRT can be used in these cases since hepatotoxicity is about 1% following PRRT, and based on NETTER-1 data the patients still benefited from PRRT regardless of the degree of liver involvement,” he said.

The First Approved Radiopharmaceutical

Lu-177 dotatate is the first radiopharmaceutical approved by the FDA for NETs. The approval provides new hope for these patients of controlling their disease where there once was limited treatment options.

“Thousands of patients have been treated in the past with PRRT outside the United States, mainly in Europe, and we are very happy that we can finally treat our patients locally with this therapy that has been proven to improve progression free survival, all while maintaining the patients’ quality of life,” Dr El-Haddad said. According to him, early analysis of NETTER-1 trial data suggest that this drug might also improve overall survival, but the final results have not been released.

There are a number of considerations providers must make prior to considering Lu-177 dotatate. First, they should make sure that patients referred for PRRT have SSTR positive tumors on Octreoscan or NETSPOT or else the drug will not target the tumors. Second, providers should make sure all progressing tumors are SSTR positive. Patients can have a mixed population of NET with some not responding to PRRT. Lastly, there needs to be collaboration between medical oncologists, nuclear medicine physicians, interventional radiologists, and surgeons to determine the best management for this category of patients since the patient could have metastases from a different tumor type.

“The major question remains about sequencing of PRRT with other NET therapies. There is an upcoming trial, the COMPETE trial which is going to compare the efficacy and safety of Lu-177 DOTATOC (another PRRT radiopharmaceutical) to Everolimus in patients with non-functional GEP-NET. When deciding about different therapies, one should keep in mind the differentiation of NET, rate of progression, potential short and long term side effects of PRRT in order to decide the most appropriate type of therapy including PRRT,” Dr El-Haddad said.
 

Reference

1. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine rumors. N Engl J Med. 2017;376(2):125-135.