Neuroendocrine Tumor Treatment Options Are Growing

Matthew H. Kulke, MD

When it comes to neuroendocrine tumors (NETs), there is no shortage of nomenclature. Broad categories, such as “carcinoid,” belie the true heterogeneous nature of this group of diseases and the complexity of their management.

Important Distinctions

Primary Site

During the past several years, a wealth of positive clinical trials coupled with an evolution in understanding of the cancer type has altered the treatment landscape. At a recent OncLive Peer Exchange session entitled “Neuroendocrine Tumors: An Evidence-Based Discussion,” a panel of experts examined the latest evidence in NETs and provided valuable insight into how these advances are likely to impact clinical practice.Although carcinoid tumors and pancreatic NETs look identical under the microscope, they respond differently to treatments, said moderator Matthew H. Kulke, MD. This is due to biological differences at the molecular level.

Pancreatic NETs have somatic mutations that have a lot of recurrent chromosomal copy number changes, agreed James C. Yao, MD. Small bowel carcinoid tumors, by contrast, have very few somatic mutations that recur.

“We know now that primary site makes a big difference in terms of prognosis as well as response to some types of treatment,” Yao said. “For example, we have diseases like gastric carcinoid and rectal carcinoid tumor where most of the time they’re localized, have great prognosis, [and] they don’t recur,” he said. “But they are actually malignant, and when they do spread, they tend to have a very aggressive course.”

James C. Yao, MD

Differentiation

It is important to note, however, that what was formerly lumped into a single “carcinoid” category is now being recognized as multiple diseases, said Diane Reidy Lagunes, MD. “Now as we’re learning about the genetics, in fact, foregut may be different than the so-called midgut,” she said. The lung, gastric, and pancreatic tumors may have common genetics and seem to have clinical similarities as well, Lagunes said.In addition to primary site, NETs are classified according to whether they are well differentiated or poorly differentiated, and the treatment options for these tumor types also differ, explained, Jennifer Eads, MD. Within the poorly differentiated tumors, there are further distinctions: large cell and small cell histologies.

Systemic chemotherapy is the standard of care for poorly differentiated tumors, and no targeted agents have been found to be useful in this setting. “It’s very difficult to do clinical trials in this population,” Eads stated. “And historically, because the histology under the microscope has been similar to that seen in small cell lung cancer, we’ve really just extrapolated data from the small cell lung cancer literature to guide our treatments for the poorly differentiated population.”

Diane Reidy Lagunes, MD

For patients with well-differentiated NETs, there are more options, noted Eads. These include somatostatin analogues (SSAs), targeted therapies such as VEGF or mTOR inhibitors, and cytotoxic therapies based on primary site.

In order to more fully define the classification, Eads uses supplementary features such as the Ki67 proliferative index. Poorly differentiated tumors typically are defined by a Ki67 of at least 20% up to 100%, said Eads.

However, the panelists agreed that there are gray areas where disease burden trumps this proliferative index. “There’s this borderline in between where sometimes patients can have a well-differentiated histology but may have a Ki67 that technically classifies them as a high-grade or poorly differentiated tumor,” Eads said. “I think that gray area is difficult.”

Functional Versus Nonfunctional

Clinical features help determine the best course of treatment in these cases, Yao said. For example, patients with 60% liver involvement, a Ki67 less than 20%, and an elevated lactate dehydrogenase, should be treated as though the tumor were poorly differentiated. However, a watch and wait approach is appropriate for patients who have low-volume disease and an indolent course, even if they are found to have a poorly differentiated tumor with a Ki67 of 30%. “The tumor is behaving like a well-differentiated tumor,” Yao said.Treatments are also driven by the patient’s symptoms. Typically, patients with functional, or hormone-secreting tumors present with stage IV disease, said Lagunes. “My job is to control their disease but also maintain their quality of life,” she said. “Some of these hormone-secreting tumors can be quite debilitating.”

The Role of Surgery

Pancreatic NETs can produce insulin, which can lead to hypoglycemia that is potentially life threatening. Other tumors produce gastrin, and are associated with a high morbidity and the potential for severe ulcers. By contrast, patients with tumors that begin outside of the pancreas, such as in the small bowel or lung, can develop carcinoid syndrome. Those patients typically have flushing and diarrhea as their main symptoms.Surgery is still considered the only curative approach for NETs. It is important for surgeons to work hand in hand with the medical oncologists, radiologists, and other members of the multidisciplinary team to determine the best options for the patient. “We always say cut is the cure, but, unfortunately, neuroendocrine tumors have a very high metastatic and recurrence rate,” said Eric H. Liu, MD.

Liu explained that a different philosophy is employed with NETs compared with pancreatic adenocarcinoma or metastatic colon cancer. “We are aggressive about adenocarcinomas to try to remove them,” said Liu. “[However], we shy away when there’s metastatic disease, which is actually very different from [our approach in] neuroendocrine [tumors].” In NETs, small tumors can become very bulky disease. Despite this, patients with NETs can live a long time. Thus, quality of life is very important, Liu stated.

Liu said that the questions that arise when deciding whether to perform surgery include: Is there going to be some complication which will hurt this patient down the road? Are they going to have a small bowel obstruction?

Therapeutic Options

Symptom Control

Resection may be warranted if the tumors are blocking the intestine or are symptomatic. Debulking surgery is a good option for patients with discrete lesions in the liver. Medication is required to treat any disease that remains. One cautionary note, said Liu, is that hormone-secreting tumors can cause complications during surgery, leading to carcinoid crisis. Having surgical expertise in NETs is important, he added.SSAs are the standard of care for symptom control in patients with carcinoid and pancreatic and hormone-producing NETs, said Eads. Octreotide and lanreotide are both used in this setting. For patients with breakthrough symptoms, a higher dose of the depot injection or a self-administered, short-acting SSA can help.

Telotristat etiprate, a tryptophan hydroxylase inhibitor, is a new option for patients with poorly controlled diarrhea, said Yao. In the phase III TELESTAR trial, patients with well-differentiated metastatic NETs and carcinoid syndrome as well as diarrhea that was refractory to SSAs were randomized to telotristat etiprate 3 times daily plus an SSA or placebo plus an SSA.¹

Tumor Control

Topline results from the trial, led by Kulke, were presented at the 2015 European Cancer Congress (ECC). At week 12, treatment with telotristat etiprate at 250 mg demonstrated a 29% reduction in daily bowel movement frequency compared with baseline. Patients receiving 500 mg had a 35% reduction compared with baseline. Those in the placebo arm experienced a 17% reduction in average daily bowel movements.¹Although the goal of therapy with SSAs is symptom control, the PROMID and CLARINET trials demonstrated that SSAs also have an antiproliferative effect. The PROMID study showed that octreotide LAR increased progression-free survival (PFS) among patients with locally inoperable or metastatic midgut NETs compared with placebo (14.3 months vs 6 months; P = 000072).²

Jennifer Eads, MD

The CLARINET study looked at a broader population, including patients with pancreatic, midgut, or hindgut NETs. In this study, lanreotide decreased the risk of progression by 53% compared with placebo.³ The median PFS for patients who received lanreotide was not reached compared with 18.0 months with placebo (HR, 0.47; stratified log-rank P <.001). The increase in PFS was seen in patients with midgut (HR, 0.35) and pancreatic tumors (HR, 0.58), but was not observed in patients with hindgut tumors (HR, 1.47).³

Advanced Non-Pancreatic Disease

“Essentially, for patients with pancreatic neuroendocrine tumors and bowel carcinoids, we’re able to use somatostatin analogues in an effort to try and control tumor growth as well,” Eads said.Targeted therapies, such as the mTOR inhibitor everolimus, have primarily been used for pancreatic NETS. The FDA’s 2011 approval of everolimus in this setting was based on the RADIANT-3 study.

Data from the RADIANT-4 trial, presented at the 2015 ECC, showed more than a 7-month increase in PFS with everolimus versus placebo in 302 patients with advanced, progressive, nonfunctional NETs in the GI tract, lung, or of unknown origin.⁴ The median PFS was 11.0 months among patients who received everolimus compared with 3.9 months for those on placebo (HR, 0.48; P <.001).⁴

“There was a 2.8-fold improvement in median progression-free survival, so more than 50% reduction in risk of disease progression,” said Yao, who served as principal investigator for the study.

In February, the FDA approved a new indication for everolimus for unresectable, locally advanced, or metastatic nonfunctional NETs of lung or GI origin based on the RADIANT-4 trial results.

Eric H. Liu, MD

“Now with the RADIANT-4 data, we have other therapies to consider,” Lagunes said. “So, everolimus is absolutely a very appropriate treatment which I may use more frequently now.”

Emerging Radionuclide Agent

Another targeted strategy under consideration employs antiangiogenesis drugs such as sunitinib and pazopanib. The data for sunitinib show a benefit in pancreatic NETs, said Yao, adding, “but the role of sunitinib in nonpancreatic primary [tumor] is undefined at this time point.”Peptide receptor radionuclide therapy (PRRT), which is not currently an option in the United States outside of clinical trials, is available in Europe for patients with somatostatin receptor— positive, inoperable NETs. The therapy targets tumors with radiolabelled SSA peptides. “It absorbs the radiation within the tumor itself, and then it continually radiates the tumors from the inside out,” explains Liu.

The phase III NETTER-1 trial compared PRRT using 177Lu-DOTATATE with the current standard of care (octreotide LAR) in patients with inoperable, progressive, somatostatin receptor—positive midgut NETs. After a median follow up of 30 months in the intent-to-treat population, the median PFS in the experimental arm was not reached compared with 8.4 months with the control (HR, 0.209), providing a risk reduction of 79.1% (P <.0001).⁵

Now that the results from the NETTER-1 study have been presented at the 2015 ECC, the panelists expect PRRT to become part of the armamentarium in the near future.

“I think that the opportunity to be able to integrate things that are not yet available to us, such as PRRT, is very exciting,” Eads said. “It obviously leads to a lot of unanswered questions, but I feel very grateful that we now have the options that we do available for both pancreatic neuroendocrine patients and carcinoid patients.”

References

1. Kulke MH, Hörsch D, Caplin M, et al. Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase III TELESTAR clinical trial). Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract 37LBA.
2. 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. 2009;27(28):4656-4663.
3. Caplin ME, Pavel M, Ćwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233.
4. Yao JC, Fazio N, Singh S, et al. Everolimus in advanced nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) origin: efficacy and safety results from the placebo-controlled, double-blind, multicenter, phase 3 RADIANT-4 study. Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract LBA5.
5. Strosberg J, Wolin E, Chasen B, et al. 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: results of the phase III NETTER-1 trial. Presented at: 2015 European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract LBA6.