Gastrointestinal Neuroendocrine Tumors: Slow but Steady Progress

Neuroendocrine tumors (NETs), previously thought to be rare, have been steadily increasing in incidence, and their prevalence in the United States is estimated to be over 35/100,000.[1] The article by Drs. Cives and Strosberg in this issue of ONCOLOGY is a timely, comprehensive review of the current state of knowledge regarding gastrointestinal NETs (GI NETs).[2] In spite of recent encouraging developments in the setting of GI NETs, many clinical questions remain to be answered and will be highlighted in this commentary.

As the authors discuss, a key step in evaluating patients with NETs is determining the Ki-67 index. Recent work by Dr. Strosberg and others, however, suggests that the current Ki-67 cut-off value of 2% may need to be raised in order to better distinguish between patients with truly indolent disease and those with more aggressive, well-differentiated tumors.[3] In the case of poorly differentiated NETs, a higher Ki-67 cut-off of 55%, instead of the current 20%, also appears to be more predictive of response to platinum chemotherapy. Assessment of Ki-67 levels is also subject to significant intratumoral heterogeneity and interobserver variability, especially when these are “eyeballed” values instead of those obtained by digital analysis or manual counting.[4] Apart from use of Ki-67 as a biomarker, adoption of TNM classification by the American Joint Committee on Cancer (AJCC) in 2010 has also improved our ability to prognosticate, but validation studies suggest that these staging schema warrant revisions to acknowledge the unique biology of GI NETs.[3]

Drs. Cives and Strosberg also discuss the role of somatostatin analogs (SSAs) in controlling symptoms related to hormone production as well as tumor growth in patients with GI NETs. In symptomatic patients, treatment with SSAs is typically initiated at diagnosis and continued indefinitely. However, several questions remain unanswered regarding the role of SSAs as anticancer agents, namely:

(1) Do all NETs benefit from SSAs? The PROMID trial evaluated octreotide long-acting release (LAR) in 85 patients with metastatic midgut NETs and showed improvement in progression-free survival (PFS; 14.3 months vs 6 months; P = .000072; hazard ratio [HR] = 0.34; 95% confidence interval [CI], 0.2–0.59).[5] The larger CLARINET trial evaluated lanreotide in 204 patients with metastatic GI NETs irrespective of site of origin (although only 14 patients had hindgut primaries) and also showed improvement in PFS (18 months vs median not reached; P < .001; HR = 0.47; 95% CI, 0.30–0.73).[6] Together, these trials show that SSAs benefit patients with GI NETs.[6] In contrast, there are currently no data with which to evaluate the effect of SSAs in thoracic NETs, which account for about 27% of all diagnosed NETs.

(2) What is the optimal time to initiate therapy with an SSA? Based on a subgroup analysis of the PROMID trial that suggested more pronounced PFS improvement in patients with a low liver tumor burden, the authors of this study suggested early initiation of therapy.[5] However, the value of their conclusion is limited by the small study size and imbalances between the control and experimental arms. These results are also not supported by the larger CLARINET study, which showed benefit to use of SSAs regardless of the extent of liver burden.[6] In practice, it is reasonable to initiate therapy immediately in patients with extensive disease burden, while those with low-volume disease may be observed closely until progression.

(3) What is the optimal systemic therapy of nonpancreatic GI NETs following progression on SSA therapy? The RADIANT-2 trial randomized 429 patients with carcinoid syndrome, 80% of whom were previously treated with octreotide and experienced significant improvement in PFS with the addition of everolimus to octreotide (16.4 months vs 11.3 months, P < .018).[7] However, everolimus is not approved for use in patients with nonpancreatic NETs. The ongoing RADIANT 4 trial, which is accruing patients with nonfunctional, nonpancreatic NETs, may help expand the role of everolimus in this setting if the results are positive. Antiangiogenic agents, such as bevacizumab, pazopanib, various cytotoxic agents, and interferon, have been evaluated in smaller trials but their use is limited by lack of robust evidence for efficacy and/or by associated toxicities. Given that nearly 80% of well-differentiated NETs express high levels of somatostatin receptors, and based on promising retrospective data, ¹⁷⁷Lu-octreotate–based peptide-receptor radiotherapy (PRRT) is being evaluated against high-dose octreotide in a registration trial in patients with metastatic midgut NETs. While awaiting the results of ongoing trials, patients with progressive nonpancreatic GI NETs should be strongly considered for clinical trials when possible.

In contrast to other GI NETs, pancreatic NETS (pNETs) appear to have a distinct biology. There are also more treatment options for patients with pNETs. Recent phase III clinical trials have led to approval of both the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi–tyrosine kinase inhibitor sunitinib for pNETs.[8,9] The optimal sequence of these two agents is unclear, however, with the initial choice often dictated by their side-effect profile and the patient’s underlying comorbidities. For instance, since everolimus may cause hyperglycemia, patients with severe diabetes mellitus may be started on sunitinib while patients with hypertension may be considered for everolimus therapy, given sunitinib’s anti–vascular endothelial growth factor receptor (VEGF) properties. Cytotoxic agents, such as alkylating agents, anthracyclines, and/or fluoropyrimidines, also appear to have promising activity based on single-institution series, but data from larger trials are lacking. Results from the ongoing phase II Eastern Cooperative Oncology Group (ECOG) E2211 trial, which is randomizing patients with pNETs to temozolomide with or without capecitabine, may help to address this deficiency.[10]

Over a century ago, Siegfried Oberndorfer characterized NETs as “not quite a conventional adenocarcinoma.” Since that initial description, we have made significant advances in management of NETs. It is hoped that the collective progress achieved in our understanding of NETs will serve as a launch pad for rapid improvements in future therapy of this not-so-rare disease.

Financial Disclosure: Dr.Yao receives consulting fees from Ipsen, Lexicon, and Novartis, and research support from Novartis. Dr. Dasari has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26:3063-72.

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

3. Strosberg JR, Weber JM, Feldman M, et al. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. J Clin Oncol. 2013;31:420-5.

4. Tang LH, Gonen M, Hedvat C, et al. Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods. Am J Surg Pathol. 2012;36:1761-70.

5. Rinke A, Muller 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;27:4656-63.

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

7. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011;378:2005-12.

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

9. 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.

10. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42:557-77.