Because neuroendocrine tumors are not one disease but a continuum of diseases, ranging from well-differentiated tumors to poorly differentiated and small cell tumors, treatment approaches can vary greatly. At the 2018 Debates and Didactics in Hematology and Oncology conference, held on Sea Island, Georgia, Bassel El-Rayes, MD, of Emory University, outlined multiple options for the management of advanced-stage neuroendocrine tumors, including systemic therapy, surgery, and liver-directed therapies.1
“When treating patients with neuroendocrine tumors, it’s important to know what the goal of therapy is,” said Dr. El-Rayes, Director of the Gastrointestinal Oncology Program and Associate Director for Clinical Research at Emory Winship Cancer Institute. “The clinical course will vary depending on whether you are trying to control the symptoms related to the mass effect, the symptoms related to secretion, or the rate of disease progression.”
Treatment of Secretory Symptoms
As Dr. El-Rayes reported, although treatment for the majority of symptoms related to hormone secretion is well established, there have been recent changes to the management of carcinoid syndrome. Two randomized, placebo-controlled phase III studies, TELESTAR and TELECAST, examined the role of a telotristat ethyl (Xermelo), a tryptophan hydroxylase inhibitor, in patients with uncontrolled carcinoid syndrome. In both studies, treatment with telotristat ethyl resulted in better control of diarrhea, and the drug was well tolerated.2
“In the TELESTAR trial, doses of telotristat at 250 and 500 mg led to significantly decreased use of short-acting somatostatin analogs to control symptoms, and no new safety signals were revealed,” said Dr. El-Rayes. “Side effects were limited to mild nausea and some alteration in liver-function tests, but they were low grade.”
Somatostatin Analogs
Clinicians have several treatment options for controlling the volume of advanced disease, including minimally invasive procedures such as radioembolization (yttrium-90), transcatheter arterial chemoembolization, and ablation, but surgery is still an option in the metastatic setting for patients with limited disease. As Dr. El-Rayes reported, however, the cornerstone of treatment for neuroendocrine tumors remains systemic therapy, which rests on the somatostatin receptor.
Octreotide, which is the prototype in this class, binds to somatostatin receptor 2 and comes in two formulations: short-acting octreotide (150–250 mg), which can be used for immediate effect in patients with uncontrolled carcinoid syndrome; and long-acting release octreotide (20–30 mg), which is used to control the disease chronically. Short-acting octreotide can also be added to octreotide long-acting release for the treatment of breakthrough symptoms.
“The randomized, placebo-controlled PROMID trial changed the way we look at targeting somatostatin receptors,” Dr. El-Rayes explained.3 “In patients with midgut tumors, octreotide not only controlled symptoms, but delayed disease progression.”
The PROMID trial changed the way we look at targeting somatostatin receptors. In patients with midgut tumors, octreotide not only controlled symptoms, but delayed disease progression.— Bassel El-Rayes, MD
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These results were subsequently confirmed in the CLARINET study, which tested lanreotide (Somatuline), another somatostatin analog, in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor–positive neuroendocrine tumors of grade 1 or 2.4 In addition to the midgut, however, the CLARINET study included tumors that originated in the pancreas or hindgut or were of unknown origin.
“Even though the study included more histologies and treatment was initiated at an earlier stage of the disease, lanreotide was associated with significantly prolonged progression-free survival,” said Dr. El-Rayes. “Given these data, the somatostatin analogs are still the go-to drugs for newly diagnosed patients with this disease.”
Lu-177 Dotatate
As Dr. El-Rayes reported, the most recent development in the targeting of the somatostatin receptor is to use it as a way to deliver radiation. In patients with midgut neuroendocrine tumors whose disease progressed on octreotide (20 or 30 mg), the results of the NETTER-1 trial showed significantly higher rates of disease control in patients randomized to lutetium Lu-177 dotatate, a peptide receptor radionuclide therapy, vs escalation of octreotide therapy. Patients randomized to receive Lu-177 dotatate (administered in 4 doses every 8 weeks) had an objective response rate of 18%, vs 3% in the octreotide group, and these benefits were seen in all subgroups. Progression-free survival was also significantly improved in patients receiving Lu-177 dotatate, and adverse events were “relatively well tolerated and mild.” Furthermore, a recent article in the Journal of Clinical Oncology showed that deterioration of quality of life was much quicker for patients in the control group than in those receiving Lu-177 dotatate.5
After failure of either octreotide or lanreotide, Lu-177 dotatate will be a go-to drug in the second-line setting.— Bassel El-Rayes, MD
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“We were always worried about hepatotoxicity and renal toxicity when giving these drugs to patients who have extensive liver metastasis, but there was no signal of either,” said Dr. El-Rayes, who noted that preliminary results showed improvement in overall survival as well. “We need longer follow-up, but clearly there is an advantage to using 177Lu-Dotatate over escalating the dose of octreotide.” Based on these data, the U.S. Food and Drug Administration (FDA) approved Lu-177 dotatate for all gastrointestinal and pancreatic neuroendocrine tumors, not just for midgut tumors.
“I think the approval of Lu-177 dotatate will have a major impact on the field,” Dr. El-Rayes added. “After failure of either octreotide or lanreotide, Lu-177 dotatate will be a go-to drug in the second-line setting.”
Antiangiogenic Therapy
In a phase III Trial of patients with advanced, well-differentiated pancreatic neuroendocrine tumors, continuous daily administration of the oral, multitargeted tyrosine kinase inhibitor sunitinib (Sutent; 37.5 mg/d) improved progression-free survival, overall survival, and the objective response rate compared with placebo.6 Using the same randomized, double-blind, placebo-controlled design, the subsequent RADIANT-4 trial studied the effects of the mTOR inhibitor everolimus (Afinitor).7 In patients with lung or gastrointestinal tumors, everolimus was associated with significant improvement in disease control and progression-free survival, said Dr. El-Rayes, and the FDA approved the drug across neuroendocrine tumors.
Cytotoxic Therapy
Dr. El-Rayes Reported advances with cytotoxic therapy as well. Although temozolomide had long shown activity in neuroendocrine tumors and several single-institution trials had studied the drug as a single agent or in combination with thalidomide (Thalomid), bevacizumab (Avastin), everolimus, or capecitabine, prospective data were lacking, according to Dr. El-Rayes. Recent research, however, has shown a link between levels of expression of the DNA repair enzyme O6-methylguanine-methyltransferase (MGMT) and responsiveness to temozolomide.8
“MGMT is key in sensitivity to temozolomide,” said Dr. El-Rayes, who noted that patients who have MGMT-deficient tumors respond much better to temozolomide than patients who do not have these tumors. MGMT deficiency is more common in pancreatic tumors than in carcinoid tumors.
In my practice, I tend to use it [temozolomide] predominantly in pancreatic neuroendocrine tumors.— Bassel El-Rayes, MD
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“Now, not only do we understand that temozolomide has activity, but we understand why the activity is different in pancreatic neuroendocrine than in nonpancreatic neuroendocrine tumors. In my practice, I tend to use it predominantly in pancreatic neuroendocrine tumors,” he said.
Presented at the 2018 ASCO Annual Meeting, a trial of the ECOG-ACRIN Cancer Research Group (E2211) randomized patients with pancreatic neuroendocrine tumors to receive either temozolomide alone or temozolomide plus capecitabine.9 Temozolomide plus capecitabine yielded improved progression-free and overall survival compared with temozolomide alone. The results, said Dr. El-Rayes, strongly favored the combination regimen, which should be the standard that other chemotherapy regimens are compared against in the future.
“If you’re treating these patients in the clinic, I think it’s important to remember that those with carcinoid tumors live a long time,” Dr. El-Rayes added. “Drugs like temozolomide and, potentially Lu-177 dotatate, could have long-term risks for myelodysplastic syndromes and other hematologic problems. You want to be cautious and not put patients on these treatments indefinitely.” ■
DISCLOSURE: Dr. El-Rayes has received honoraria from Lexicon, Ipsen, Novartis, Bayer, and Bristol-Myers Squibb; and has received research support from Merck, Bristol-Myers Squibb, Pfizer, Boston Biomedical, Roche, and Novartis.
REFERENCES
2. Kulke MH, Hörsch D, Caplin ME, et al: Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 35:14-23, 2017.
3. Rinke A, Müller HH, Schade-Brittinger C, et al: Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol 27:4656-4663, 2009.
4. Caplin ME, Pavel M, Cwikla JB, et al: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224-233, 2014.
5. Strosberg J, Wolin E, Chasen B, et al: Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-Dotatate in the phase III NETTER-1 trial. J Clin Oncol 36:2578-2584, 2018.
6. Raymond E, Dahan L, Raoul JL, et al: Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501-513, 2011.
7. Yao JC, Fazio N, Singh S, et al: Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): A randomised, placebo-controlled, phase 3 study. Lancet 387:968-977, 2016.
8. Kulke MH, Hornick JL, Frauenhoffer C, et al: O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338-345, 2009.
9. Kunz PL, Catalano PJ, Nimeiri H, et al: A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211). 2018 ASCO Annual Meeting. Abstract 4004. Presented June 4, 2018.
