Neuroendocrine Tumors: Sometimes You Need to 'Sit Tight'

New treatments are desperately needed for neuroendocrine tumors (NETs), said Leonard Saltz, MD, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, at a symposium on "New Therapies for Neuroendocrine Tumors," at the 15th Annual Meeting of the National Comprehensive Cancer Network (NCCN). These rare neoplasms arise from the diffuse neuroendocrine cell system, with carcinoid tumors occurring in the aerodigestive tract and islet cell tumors occurring in the endocrine tissues of the pancreas. Saltz discussed the presentation and treatment of the different types of pancreatic islet cell tumors, along with common sites of carcinoid tumors and related statistics and management of metastatic NET. He also compared poorly differentiated versus well-differentiated NET, noting that statements about one type were not applicable to the other.

Pancreatic Endocrine Tumors

Also known as islet cell tumors, this subgroup includes insulinoma, gastrinoma, glucagonoma, somatostatinoma, and vasoactive intestinal peptide (VIPoma). Each is named after the hormone produced.

Insulinoma patients typically present with fasting hypoglycemia. Tests show inappropriately high insulin levels, with blood glucose <50 mg/ml, and a primary mass <2.5 cm. Once diagnosis is confirmed, Saltz said pro-insulin can be administered if insulin is not elevated. Somatostatin analogues should not be used before scanning to establish receptor positivity.

Gastrinoma is typically found in the pancreas but also occurs in the cystic and common bile duct or duodenum. "We all think of this as peptic ulcer disease," Saltz said. "Fifty percent of these patients will present with chronic diarrhea and no specific upper digestive complaints." Surgical resection often cures unifocal primary, but multifocal primaries are not uncommon, particularly in patients with multiple neuroendocrine neoplasia (MEN)-1 syndrome.

Glucagonoma is very uncommon, and 20% of patients have MEN-1. "[Patients] get a classic skin rash-necrolitic migratory erythema," Saltz said. He jokingly cautioned the audience to take note because "they seem to like to ask about this association on medical boards." Plasma glucagon levels typically exceed 1000 pg/ml and it is often malignant and metastatic. Somatostatin analogues help control adverse effects.

VIPoma has one overriding characteristic: profound diarrhea. "We're talking about liters of liquid stool; we're talking about cholera-like stool," Saltz explained. Some patients manage to function despite the diarrhea. They often have hypokalemia and metabolic acidosis due to loss of bicarbonate. "They need tons of fluid," Saltz advised and said typical intravenous replacement would not suffice. He also warned clinicians not to put sodium bicarbonate in normal saline: "That's hypertonic saline," he said. In the rare instance that a tumor is localized, Saltz recommended resection with curative intent. Aggressive anti-diarrheal agents are needed and somatostatin analogues can help for some time. Tumor debulking might control hormone production.

Carcinoid Tumors

The appendix is the most common site for carcinoids, followed by the rectal, ileum, bronchus, and stomach. Between 40% and 50% of patients have elevated serotonin, 5-HIAA, and plasma chromogranin A, collectively known as carcinoid syndrome. Saltz said he prefers using 24-hour urine collection to look for the breakdown of 5-HIAA. "I don't like measuring serotonin levels as much," he said. Many patients with carcinoids have predominantly right-sided endomyocardial fibrosis. Saltz monitor their hearts if he plans to use octreotide.

Carcinoid of the appendix is often found incidentally during appendectomy and tumors <2 cm rarely metastasize. "If they're >2 cm, metastasis is a significant issue and, in the absence of evidence of metastatic disease, we would recommend a forward right hemicolectomy," Saltz said. This is done to clear the lymph node and view lymph node status. A rectal carcinoid is similar, but Saltz recommending careful consideration before performing perineal resections for distal tumors. Like appendiceal carcinoids, small bowel carcinoma is often found incidentally and is typically excised along with regional nodes.

With 5-year median disease-free survival at 80% and an 8-year median recurrence, patients do not need adjuvant therapy, Saltz said. "There's no data to show it works and, to my mind, no good rationale for that." NETs rarely cause obstruction. Instead of adjuvant therapy, he suggested serial scanning every 1 to 2 years to follow patients who undergo resection for a small node-negative carcinoid. "We do not need to make them lifelong cancer patients, because the likelihood that their cancer is going to come back is small," he said. No other workup is required for resected tumors <1 cm.

High-Grade Neuroendocrine Carcinoma

Like lung cancer, these have small and large cell variants. Small cell tumors are associated with poor prognosis and Saltz typically uses regimens indicated for small cell lung cancer. He prefers cisplatin with etoposide or irinotecan but sometimes substitutes carboplatin. "We'll treat for maybe 4 months or so and then back off and give a chemo holiday because they give a good initial response," Saltz said. There are few options for treating large cell tumors.

Well-differentiated Gastrointestinal NET

In patients with small volume, asymptomatic tumors, Saltz prefers to "watch and wait," reserving treatment for patients that show substantial progression or present with symptoms caused by malignant hormone or tumor bulk. "We can't cookbook these patients and we have to--a watchword in oncology these days--individualize," Saltz said. He suggested asking patients whether they are comfortable with watching and waiting since median survival tends to be good with low-grade tumors. Survival with this tumor is somewhat skewed because the clock tends to start from diagnosis, yet many patients have been living it for some time, he explained.

To confirm metastatic NET, Saltz recommended biopsy. Saltz said dramatic improvements in computed tomography (CT) scanning and MRI have made MSKCC less reliant on somatostatin receptor imaging for workup. In asymptomatic patients, Saltz is not concerned with whether the tumor is an islet cell or pancreatic and recommends getting biomarker data only if it will change how you treat that patient.

For initial management of metastatic NET, Saltz says "sit tight" unless the patient reports pain from tumor bulk. Beware of mistaking CT contrast artifact for progression. Saltz showed CT scans taken minutes apart that appear to show alarming progression. "The hint is when the radiologist says to you, 'The lesions that we've been following are stable but I see new ones.' That's almost always artifact," Saltz said.

There are no approved targeted agents for metastatic NET. Based on data from the PROMID trial comparing octreotide to placebo, Saltz said rationale exists for using octreotide in functional and nonfunctional NET. He had concerns about the study protocol, the findings, and the lack of follow-up, however, and said it does not make clear when to start octreotide. He prefers to start patients on 20-mg only after real progression or symptoms.

Saltz cautioned the audience to question where data comes from before allowing it to influence practice. He pointed to a Novartis NET alliance ad that asks "Is watch and wait out of date?" Saltz said online searching turned up a want ad for director of NET alliance that described it as a marketing position requiring an MBA. "You're going to see ads from a lot of educational providers that are going to tell you to treat this disease aggressively. I'm very concerned about that," said Saltz. "Watching and waiting may be the right approach for some patients," he added.

Saltz said no compelling evidence shows asymptomatic patients benefit from chemotherapy early on. The activity of interferon, he said, is overstated and its toxicity makes it a "nonstarter" for Saltz. Streptozocin therapy is minimally active and fairly toxic. He mentioned a 2006 study of temozolomide with thalidomide (Kulke, JCO) in which more than half the patients discontinued because of toxicity. "This is not something I use in my practice," he said. He also ruled out hepatic artery embolization in gastrointestinal NET for asymptomatic patients without progression, saying its risks are too great for this population.

Saltz expressed hope for mTOR inhibitors like temsirolimus and everolimus. He said bevacizumab and sunitinib had also shown interesting activity, but neither is approved for NET, though he expects that to change. He also said he was excited about radiolabeled somatostatin analog therapy, which has been "a long time coming." Saltz concluded that new treatments are desperately needed and encouraged clinicians to support clinical trials of new agents and new treatment modalities.