Neuroendocrine Tumors: Answers-and Questions

September 15, 2014
Matthew Kulke, MD
Matthew Kulke, MD

Volume 28, Issue 9

The relative abundance of new data on the biological underpinnings of neuroendocrine tumors, combined with clinical trial data supporting new treatment options, is a clear sign of progress. Yet, as is so often the case, these recent studies have generated a multitude of new and different questions.

In their timely review in this issue of ONCOLOGY,[1] Drs. Cives and Strosberg provide a detailed and comprehensive description of the biology and treatment of neuroendocrine tumors. Knowledge of this diverse group of malignancies has evolved rapidly in the past few years, although the emergence of new data has perhaps raised as many new questions as it has answered.

Several of the studies reviewed by the authors describe the use of new systemic therapies for patients with advanced disease. A key theme among many of these clinical trials is the recognition that pancreatic neuroendocrine tumors and nonpancreatic gastrointestinal neuroendocrine tumors (“carcinoid tumors”) may respond differently to treatment. This difference is perhaps most evident in the response of neuroendocrine tumors to alkylating agents such as streptozocin or temozolomide. Pancreatic neuroendocrine tumors appear to be more responsive to both of these drugs than do neuroendocrine tumors that arise in other locations. Interestingly, antitumor activity associated with the mammalian target of rapamycin (mTOR) inhibitor everolimus or with the vascular endothelial growth factor (VEGF) pathway inhibitor sunitinib has also, to date, been more evident in pancreatic neuroendocrine tumors.[2,3]

Observed differences in treatment response are likely linked to differences in the underlying biology of pancreatic and nonpancreatic neuroendocrine tumors. For example, alkylating agents exert their effect by inducing DNA damage, and deficiencies in DNA mismatch repair have been found to be more prevalent in pancreatic neuroendocrine tumors than in their nonpancreatic counterparts.[4] Mutations in the tumor suppressor gene menin, as well as in DAXX and ATRX-genes implicated in chromosomal maintenance-are also prevalent in pancreatic neuroendocrine tumors but are rare or nonexistent in neuroendocrine tumors arising in other locations.[5]

The potential clinical implications of these recently identified mutations are not addressed by the authors and, in fact, remain largely unexplored. While genomic profiling is increasingly driving the selection of treatments for other cancer patients, it is unclear whether a similar approach will be effective for patients with neuroendocrine tumors. Unlike other malignancies, in which driver oncogenes can be effectively targeted, the mutations in pancreatic neuroendocrine tumors appear to be limited primarily to tumor suppressor genes. To date, no direct associations between mutational status and treatment response have been identified. It seems likely that downstream effects of these mutations, including, possibly, epigenetic modifications, may play a more direct role in regulating neuroendocrine tumor growth. The presence of epigenetic aberrations seems particularly likely in extra-pancreatic neuroendocrine tumors. Large-scale sequencing of small intestine neuroendocrine tumors, for example, revealed recurrent mutations (in the cyclin-dependent kinase inhibitor CDKN1B) in less than 10% of cases.[6]

In contrast to other systemic therapies, somatostatin analogs appear to be active across neuroendocrine tumor subtypes. Somatostatin receptors are expressed in the majority of gastroenteropancreatic neuroendocrine tumors, and somatostatin analogs have long been known to be effective in controlling symptoms of hormone hypersecretion, whether it is the classic “carcinoid syndrome” or less common syndromes, such as those associated with gastrinoma or VIPoma (neuroendocrine tumors that secrete vasoactive intestinal peptide). The PROMID study, which randomly assigned patients with midgut neuroendocrine tumors to receive either octreotide or placebo, was the first to clearly demonstrate that somatostatin analogs also have an antiproliferative effect.[7] These observations were confirmed and broadened in the larger and more recent CLARINET study, which demonstrated that treatment with lanreotide was associated with improved progression-free survival compared with placebo in patients with a range of gastroenteropancreatic neuroendocrine tumors.[8]

As highlighted by the authors, the increasing number of treatment options for patients with neuroendocrine tumors has made questions of timing and sequencing paramount. In addition to the treatments described above, other approaches include treatment with radiolabeled somatostatin analogs, which has gained acceptance in Europe and is currently being formally evaluated in an international randomized study. Hepatic artery embolization is also commonly used in patients with liver metastases and hepatic-predominant disease. While the number of available treatment options has increased, however, there are currently only limited data to guide the practitioner in making a decision about which treatment to recommend for a given patient. Molecular and genetic profiling are not yet at a stage where they can be effectively used to drive most treatment decisions. To date, few studies have compared different systemic treatments head-to-head, examined the efficacy of different sequencing strategies, or examined the relative efficacy of drug combinations. Moreover, because overall survival can be prolonged in many cases, many of the available studies have, by necessity, relied on progression-free survival rather than overall survival as a primary efficacy endpoint.

In the absence of such data, clinical judgment continues to play a critical role in guiding the care of patients with neuroendocrine tumors. The generally mild side effect profile of somatostatin analogs, together with evidence confirming their antiproliferative effect, makes them an attractive first treatment option for many patients. Even so, patients with truly indolent, asymptomatic disease may not require immediate initiation of treatment. Conversely, patients with bulky, symptomatic, or progressive disease may benefit from more aggressive treatment, either with a single modality or with a combination of approaches. In such cases, molecularly targeted drugs such as sunitinib or everolimus, treatment with an alkylating agent, or hepatic-directed therapy might be considered, depending upon tumor subtype, patient comorbidities, and the pace of the disease.

The relative abundance of new data on the biological underpinnings of neuroendocrine tumors, combined with clinical trial data supporting new treatment options, is a clear sign of progress. Yet, as is so often the case, these recent studies have generated a multitude of new and different questions. Happily, we are finally beginning to understand which questions to ask.

Financial Disclosure:Dr. Kulke serves as a consultant to Ipsen Pharmaceuticals and Novartis.


1. Cives M, Strosberg JR. An update on gastroenteropancreatic neuroendocrine tumors. Oncology (Williston Park). 2014;28:749-58.

2. Yao JC, Shah MH, Bohas CL, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514-23.

3. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501-13.

4. 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. 2009;15:338-45.

5. Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199-203.

6. Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet. 2013;45:1483-6.

7. Rinke A, Müller HH, Schade-Brittinger C, et al; PROMID Study Group. 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;27:4656-63.

8. Caplin ME, Pavel M, Ćwikla JB, et al; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224-33.