Clinical Factors Help Define Use of Radionuclide Therapy in Neuroendocrine Tumors

Thorvardur Halfdanarson, MDe

Radiopharmaceuticals have been integrated into the treatment paradigm for patients with neuroendocrine tumors (NETs), yet there are nuances in the clinical scenarios in which they are most effective, according to Thorvardur Halfdanarson, MD.

Peptide receptor radionuclide therapy (PRRT) designed as radiolabeled somatostatin analogues (SSAs) are appropriate for midgut, non-midgut gastrointestinal and lung, and pancreatic NETs with strong somatostatin receptor expression, Halfdanarson said during a presentation at the 4th Annual School of Gastrointestinal Oncology^™ (SOGO^®) meeting.¹

The most commonly used radionuclides, lutetium 177 (¹⁷⁷Lu) and yttrium 90 (⁹⁰Y), are β emitters. The differences between the 2 radionuclides are demonstrated in energy, tissue penetration, and half-life, said Halfdanarson, a hematologist/oncologist in the Department of Oncology (Medicine) at Mayo Clinic in Rochester, Minnesota.

“Keep in mind that the energy level emitted by lutetium is lower than yttrium, tissue penetration is shorter for lutetium, and the half-life is longer for lutetium,” Halfdanarson said. This has an effect on “toxicity and possibly efficacy,” he added.

Retrospective studies² of ¹⁷⁷Lu and ⁹⁰Y suggest that complete responses are very rare and range from 0% to 6%. However, partial responses are much more common and range from 4% to 38%. Progression-free survival (PFS) ranges from 16 months to 33 months, and overall survival (OS) ranges from 22 months to 46 months. “This is a mixed bag of retrospective studies with different types of patients,” cautioned Halfdanarson. “What we need is a large prospective trial.”

The clinical scenarios for PRRT vary. The treatment appears safe for central nervous system and orbital metastases. In patients with extensive bone metastases, worsening pain has been reported after PRRT, but steroid therapy may provide relief. Worsening of carcinoid crisis has been reported. ¹⁷⁷Lu is predominantly excreted in the urine, with a half-life of 3.5 hours for elimination in blood. In general, negligible radioactivity is present in body fluids, with the exception of urine.¹

Table. NETTER-1 Population Characteristics³

Future research involving PRRT will include use in the neoadjuvant setting, in combination with chemotherapy (most likely capecitabine or temozolomide), somatostatin antagonists, targets other than somatostatin receptors, and α emitters.¹

NETTER-1 Findings

In January 2018, lutetium Lu 177 dotatate (Lutathera) became the first radiopharmaceutical to gain FDA approval for patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs in adults.

The approval was based on findings from the NETTER-1 trial³, which followed 229 patients with metastatic midgut NETs, of whom 116 were randomized to receive ¹⁷⁷Lu-Dotatate at a dose of 7.4 gigabecquerel plus best supportive care (including 30 mg octreotide long-acting repeatable [LAR]) every 8 weeks and 113 to receive 60 mg octreotide LAR alone every 4 weeks (control). The clinical characteristics of the patients were similar between the 2 treatment groups (Table).³

There were 105 patients (91%) in the lutetium arm and 101 patients (89%) in the control arm with grade 3/4 uptake of radiotracer via scintigraphy (with higher grades indicating greater somatostatin receptor expression). “As of the publication date of the study, PFS was not reached in the experimental arm, but it has been estimated to be 28.4 months,” Halfdanarson said. “For patients taking octreotide [control], PFS was reported as 8.4 months.”

Fourteen deaths were reported in the interim analysis of OS in the lutetium group, and 26 deaths were reported in the octreotide group (P = .004). The investigators reported objective response rates (ORRs) of 18% in the lutetium arm and 3% in the control arm (P <.001). In the lutetium arm, the most common all-grade adverse events (AEs) reported were nausea (59%) and vomiting (47%); grade 3/4 AEs were nausea (4%) and vomiting (7%). In the octreotide arm, all-grades AEs were nausea (12%) and vomiting (10%), with grade 3/4 AEs of nausea (2%) and vomiting (1%) reported.

“Grade 3/4 hematologic toxicities were thrombocytopenia (2%), lymphopenia (9%), leukopenia (1%), and neutropenia (1%) [in the lutetium arm],” Halfdanarson said.

“Our concern [with PRRT therapy] is with dose treatment delays as patients show up at the clinic with platelet counts of 49 or lower,” Halfdanarson said. “As a result, we cannot administer the drug, which costs $53,000. We can’t send the drug back to the manufacturer because the drug is actively decaying.” One way to avoid treatment delays is to have the patient come into the clinic a week to 10 days before administration for a complete platelet count. “At least we can cancel the shipment of the drug if the patient’s count is low,” he noted.

PPRT Retreatment

There are very few data available discussing retreatment with PRRT, but one retrospective study⁴ followed patients who had PFS ≥18 months after initial PRRT. Retreatment of 168 patients resulted in an ORR of 15.5%, and re-retreatment of 13 patients produced an ORR of 38.5%. Investigators reported hematologic toxicity, including myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML), and renal toxicity did not appear to be increased.

Halfdanarson noted that a benefit of re-retreatment in terms of cumulative OS was observed in subsets of patients with bronchial/gastroenteropancreatic and midgut NETs (P <.01 for both). Although the study authors⁴ noted a trend toward OS improvement among patients with pancreatic NETs, it did not reach statistical significance (P = .57).

Hematologic toxicities associated with PRRT have been relatively minor, with grade 3/4 AEs (other than lymphopenia) resolved within 3 months for 77% of patients in one study.⁵ The most severe complication of PRRT, however, is delayed toxicity, specifically MDS/AML.

Brabander et al⁵ reported that 9 patients (1.5%) developed MDS a median of 28 months after treatment, and 4 patients (0.7%) developed acute AML a median of 55 months after treatment. “This is a horrible complication to have because the survival with treatment-related AML is very short,” Halfdanarson said. Grade 3/4 nephrotoxicity and hepatoxicity were minor. Brabander and colleagues reported that 6 patients (1%) developed renal failure during follow-up, but all cases were attributable to other causes.

“MDS and AML are probably more common than we originally thought,” said Halfdanarson, “so keep an eye on it.” MDS and leukemia occurred in 2% of patients a median of 8 years after NET diagnosis in one study,⁶ “but a lot of these patients would not have lived 5 years if they did not receive PRRT,” he said.

References

1. Halfdanarson TR. Peptide receptor radionuclide therapy (PPRT) for neuroendocrine tumors. Presented at: Physicians’ Education Resource^®, LLC (PER^®), 4th Annual School of Gastrointestinal Oncology^™ (SOGO^®); April 27, 2019; Washington, DC.
2. van der Zwan WA, Bodei L, Mueller-Brand J, de Herder WW, Kvols LK, Kwekkeboom DJ. GEPNETs update: radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol. 2015;172(1):R1-8. doi: 10.1530/EJE-14-0488.
3. Strosberg J, El-Haddad G, Wolin E, et al; NETTER-1 Trial Investigators. Phase 3 trial of ¹⁷⁷Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.
4. van der Zwan WA, Brabander T, Kam BLR, et al. Salvage peptide receptor radionuclide therapy with [¹⁷⁷Lu-DOTA,Tyr³]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2019;46(3):704717. doi: 10.1007/s00259-018-4158-1.
5. Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy, survival, and safety of [¹⁷⁷Lu-DOTA0,Tyr³]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23(16):4617-4624. doi: 10.1158/1078-0432.CCR-16-2743.
6. Baum RP, Kulkarni HR, Singh A, et al. Results and adverse events of personalized peptide receptor radionuclide therapy with ⁹⁰Yttrium and ¹⁷⁷Lutetium in 1048 patients with neuroendocrine neoplasms. Oncotarget. 2018;9(24):16932-16950. doi: 10.18632/oncotarget.24524.