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New Strategies for Advanced Neuroendocrine Tumors in the Era of
Targeted Therapy
Mei Dong, Alexandria T. Phan, James C. Yao
Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson
Cancer Center, Houston, Texas, 77030
Running Title:
New Strategies in Advanced Neuroendocrine Tumors
Key words:
Neuroendocrine tumors, carcinoid, angiogenesis, mTOR
Requests for reprints: James Yao, M.D., Department of Gastrointestinal Medical Oncology,
Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe
Boulevard, Houston, TX 77030. Phone: (713) 792-2828; Fax: (713) 745-1163; E-mail:
[email protected].
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Abstract
Low to intermediate grade neuroendocrine tumor (NET) constitutes a group of indolent
malignancies that share the capacity for secreting hormones and neuroamines. Until
recently, there were few therapeutic options for oncologic control. The PROMID study
demonstrated that octreotide LAR can delay tumor growth in midgut NETs. And, recent
phase III studies showed both everolimus and sunitinib improved progression free survival
in pancreatic NETs validating the PI3K/Akt/mTOR pathway and angiogenesis as important
targets for further advances. Ongoing and planned pivotal studies targeting these pathways
in other NET subtypes may widen their therapeutic application. Development of rational
combinations may further improve therapeutic outcome. These successes and our
improved understanding of the underlying molecular biology are likely to lead to further
important advances on the horizon.
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Background
Neuroendocrine tumors (NETs) are generally classified into low-to-intermediate grade
versus high-grade tumors based on pathology. Low-to-intermediate grade NETs, the focus
of this review, are either functional or nonfunctional, depending on whether the tumor
secretes bioactive substances that leads to clinical symptoms such as flush and diarrhea.
NETs are generally further divided into carcinoid and pancreatic NETs. Carcinoids develop
from neuroendocrine cells at any location in the body and are grouped according to their
embryonic origin: the foregut (lungs, thymus, stomach, and duodenum), the midgut
(jejunum, ileum, appendix, and proximal large bowel), and the hindgut (distal colon and
rectum) (1). It is estimated that 64% of all NETs originated in the gastrointestinal tract and
28% originated in the lung (2). Pancreatic NET, traditionally called islet-cell carcinoma,
represents 1.3% of all malignancies arising from the pancreas (3).
Epidemiology
The incidence of NETs has increased significantly from 1.09 to 5.25 per 100,000 individuals
between 1973 and 2004 (4). A large, retrospective, case-control study identified only
family history of malignancy as a significant risk factor (5). Pancreatic NETs are rare,
occurring at an estimated incidence of 3 per 1,000,000 individuals (4). Infrequently, NETs
arise as part of certain genetic cancer syndromes including multiple endocrine neoplasia
type 1 (MEN1), von Hippel Lindau syndrome (vHL), neurofibromatosis (NF), and tuberous
sclerosis (TSC) (6). Most NETs, however, are sporadic.
3
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Pathology and staging
Apart from the TNM staging system endorsed by American Joint Committee on Cancer in
2010, tumor grade and primary site are important prognostic determinants of cancerrelated outcomes (7-9). Low-grade NETs follow a relatively indolent course. The cells are
well differentiated with a uniform appearance. They produce secretory granules and often
express chromogranin A (CGA) and synaptophysin. On the other hand, high-grade NETs
are aggressive tumors. Cells are poorly differentiated appearing in a sheet-like structure,
and usually nonfunctional. Indices of cell proliferation include the number of mitoses per
10 high-power microscopic fields, or the percentage of tumor cells with immunostaining
for Ki67. As management of high grade NETs fundamentally differs from that of low and
intermediate grade NETs, uniformed reporting of grade is encouraged.
Radiological imaging
Imaging modalities frequently used for NETs include computed tomography (CT), magnetic
resonance imaging (MRI), and [111In-DTPA0]octreotide scintigraphy (10). Due to the
vascular nature of NETs, tumors generally enhance intensely with intravenous contrast
during the early arterial phase with washout during the delayed venous phase. Therefore,
multiphasic CT is recommended. MRI is a good modality to assess liver metastases, which
are usually hypointense on T1-weighted images, and hyperintense on T2-weighted images
(11). Scintigraphy using radiolabeled somatostatin analog, octreotide, can detect NETs that
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express somatostatin receptor types 2 and 5, with an overall sensitivity of 80% to 90% (12,
13). While scintigraphy provides useful information about the site of disease, it does not
give accurate information about the size of tumor. Fluorodeoxyglucose position emission
tomography (FDG-PET) has been used in evaluating NETs. While its applicability for low
grade NETs is limited because of their low metabolic activity, the usage of FDG-PETs in
intermediate and high grade NETs are still being evaluated.
Management of hormonal syndrome
NETs are characterized by their ability to produce bioactive peptides and neuroamine, such
as serotonin, histamine, prostaglandins, substance P, insulin, gastrin, glucagon, and
vasoactive intestinal polypeptide (14, 15). Most patients with early -stages NETs are
asymptomatic, some may present with nonspecific abdominal symptoms due to local effect
of serotonin or mechanical effect of the primary tumor. Patients with advanced stages
NETs can manifest with symptoms of carcinoid syndrome, classically consists of facial
flushing, diarrhea, and occasionally bronchospastic wheezing. Carcinoid syndrome can be
debilitating, and is usually seen in the setting of advanced or metastatic disease.
Somatostatin analogs, such as octreotide and lanreotide, block sst2 and sst5, effectively
reduce the release of bioactive peptides and neuroamines (Figure 1). These agents are
used for the management of carcinoid syndrome or symptoms of hormonal overproduction
from NETs. Octreotide comes in two forms, the long-acting release (LAR) form, and the
short acting rescue form. It is generally well-tolerated. Side effects including cholelithiasis,
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hypothyroidism, bradycardia, and hyperglycemia are generally manageable, infrequently
affecting the patients’ quality of life.
Interferon-α binds to receptors on NET cells and can lead to degradation of secretory
peptide and tumor growth suppression. It has been used to control carcinoid syndrome
with or without octreotide (16-18). It has delayed onset of response and more side effects
compared to octreotide, so it is not usually the front-line agent for symptomatic patients
with NETs.
Oncologic management of NETs
High-grade or poorly differentiated NETs are treated with platinum-based chemotherapy.
For low-to-intermediate NETs, surgical resection of the primary tumor offers cure of
localized disease; while complete metastectomy has been associated with longer survival
among patients with advanced disease and should be considered where possible (19, 20).
Systemic therapy options for tumor control remain limited for NETs.
Systemic therapy for pancreatic NETs
Streptozocin-based chemotherapy was approved by the Food and Drug Administration for
the treatment of pancreatic NET nearly three decades ago. Analyses of 2 large case-series
using Response Evaluation Criteria of Solid Tumors (RECIST) criteria have reported
objective tumor response rates of 38 and 39% (21, 22).
Genetic cancer syndromes (TSC-2, NF-1, and vHL), somatic mutations identified using an
exome sequencing approach, and expression profiling have consistently implicated a
6
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dysfunction of the mammalian target of rapamycin (mTOR) pathway as a critical event in
pancreatic NETs (Figue 1) (23-25). Everolimus, an oral inhibitor of mTOR, was studied in a
multi-national double blind placebo controlled phase III study (Table 1) (26). The study
demonstrated that everolimus significantly prolonged median progression free survival
(PFS) from 4.6 to 11 months compared to placebo (Hazard Ratio [HR] = 0.35, 95%
Confidence Interval [CI], 0.27 - 0.45; P<0.0001). Everolimus also significantly reduced
insulin, glucagon and gastrin secretions among patients with functional pancreatic NETs
(27, 28).
NETs are vascular tumors. Hence, there is also strong rationale to study anti-angiogenic
agents in NETs (Figure 1). Sunitinib, an inhibitor of vascular endothelial growth factor
(VGEF) and platelet-derived growth factor (PDGF) receptors, was also studied in a doubleblinded placebo-controlled phase III study (Table 1) (29). Treatment with sunitinib 37.5
mg daily was associated with an improvement in median PFS from 5.5 to 11.4 months (HR
= 0.42, 95% CI, 0.26 - 0.66) (29). Although the study failed to achieve statistical significance
due to unplanned interim analyses and early termination, its results are supported by other
studies of VEGF inhibitors in pancreatic NET (30-32).
Results from these two randomized phase III studies lead to the approval of everolimus
and sunitinib for the treatment of pancreatic NET and changed the treatment paradigm.
However, it should be noted the combination of daily everolimus and sunitinib is poorly
tolerated and should not be combined in routine clinical use (33).
Systemic therapy for carcinoid
Cytotoxic chemotherapy has minimal benefit for advanced carcinoids. With no new agent
approved over the past 3 decades, treatment options for these indolent tumors are very
7
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limited. The PROMID study (Figure 1, Table 1) showed that long-acting octreotide
significantly improved time to progression in treatment-naïve patients with midgut
carcinoids (HR = 0.34, 95% CI, 0.2 - 0.59) (34). However, the utility of somatostatin analogs
such as octreotide for control of tumor growth in NETs of other primary sites remains
undefined.
Anti-tumor efficacy and survival outcome with interferon in carcinoids are limited and
controversial. Based on its anti-tumor activity observed in preliminary studies, interferon
is currently used either alone or in combination with somatostatin analogs for patients
with symptomatic carcinoids (35).
Liver directed therapy approaches
Taking advantage of the liver’s regenerative capacity and its dual blood supply from both
the hepatic artery and portal vein, liver directed therapies have long been used in the
management of NETs. These approaches associated with moderately higher complications
rates are best employed for symptomatic NET patients with indolent disease course. Partial
hepatectomy can be considered for patients when more than 90% of tumor can be
removed safely (36). Hepatic arterial embolization and chemoembolization can be
considered as palliative measures in place of surgery (37). Newer radio-embolization
techniques may have reduced acute toxicity but have not been prospectively compared
with other established liver directed modalities.
8
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On the Horizon
Improved diagnostics
With increasing recognition of the differences in biology and clinical behavior between
pancreatic, thoracic, and gastrointestinal NETs, advanced imaging and molecular
diagnostics will play progressively important roles in the classification and optimal
management of NETs.
Much of the proof of concept for novel molecular diagnostics has already been done. For
example, studies using comparative genomic hybridization and single nucleotide
polymorphism have shown distinct patterns of allelic alternation for pancreatic and ileal
NETs (38, 39). These as well as differences in expression of site dependent transcription
factors, such as TTF1, CDX2, could be leveraged to identify occult primary tumors.
Advances in cross-sectional and nuclear imaging are allowing us to peer into the human
body with unprecedented spatial resolution, and characterize abnormalities with
increasing precision. Advanced techniques in computed tomography using negative bowel
contrast are allowing us to detect small primary tumors of the luminal gut that previously
have been inaccessible to endoscopy examination. Novel positron emission tomography
agents such as [11C]-5-HTP, 18F-FDOPA, 68Ga-DOTA-TOC, and 68Ga-DOTA-NOC are offering
significantly improved spatial resolution for functional imaging (40, 41).
Novel systemic therapy approaches
Major advances in the systemic therapy of NETs have been seen in the past several years.
The recent completion of three randomized phase III studies has demonstrated that
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rigorous evaluation of novel agents in this disease is both feasible and can lead to practicechanging outcomes.
Therapy targeting PI3K-Akt-mTOR pathway in pancreatic NET
The substantial efficacy of everolimus and the link of multiple germline and somatic
mutations in the PI3K-Akt-mTOR pathway genes to pancreatic NETs demonstrate the
importance of this pathway in tumorigenesis (Figure 1) (24, 26). Nonetheless, therapeutic
resistance frequently emerges over time. A number of strategies having potential to
overcome such resistance are under development. Inhibition of TORC1 by everolimus may
lead to up-regulation of Akt through an IGF-PI3K dependent pathway. Strategies to downregulate IGF with somatostatin analogs such as octreotide and pasireotide or inhibit IGF1
signaling with monoclonal antibody such cixutumumab are being developed in
combination therapy with everolimus. The PI3K-Akt-mTOR pathway can also be blocked at
multiple points by using serine-threonine kinase inhibitors that simultaneously inhibit
PI3K and mTOR such as BEZ235 or agents that inhibit both TORC1 and TORC2 such as
INC128.
Therapy targeting angiogenesis in pancreatic NET
Pancreatic NETs is also among the few malignancies where a VEGF inhibitor, sunitinib, has
demonstrated benefit in a pivotal trial (29). Nonetheless, much of the initial promise of
anti-angiogenic therapy remains unfulfilled. Resistance to anti-angiogenic therapy
eventually develops. Pre-clinical studies suggest resistance mechanisms may involve upregulation of transcription factors that control the expression of multiple pro-angiogenic
molecules (42-44). Further development strategies are taking advantage of agent or
10
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combination of agents that target multiple pro-angiogenic pathways. Strategies targeting
VEGF along with FGF or MET are already in development for other malignancies.
Alternatively, targeting VEGF along with transcription factors such as HIF or Sp1 can be
another strategy against eventual therapeutic resistance.
Cytotoxic chemotherapy in pancreatic NET
In contrast to carcinoid tumors, recent prospective and retrospective studies have
suggested that oral cytotoxic alkylating agent temozolomide is active in pancreatic NETs
(45-47). In one retrospective series, for example, temozolomide-based therapy was
associated with an overall response rate of 34% in patients with pancreatic NETs (45). In
smaller case series, higher response rates have been reported for the combination of
capecitabine and temozolomide.(48) However, an adequate prospective controlled study to
define the role of temozolomide or temozolomide-based combination in pancreatic NET is
lacking, and promising activity of this cytotoxic agent awaits confirmation.
Therapy targeting angiogenesis in carcinoid
Several single arm phase II studies have demonstrated activity for angiogenesis inhibitors
in advanced carcinoids. While most studies using VEGF TKI have reported a lower response
rate in carcinoids compared pancreatic NETs, potential for delay of tumor growth remains
(Figure 1) (30-32). In a small-randomized run-in study, patients with advanced carcinoid
tumors were randomly assigned to treatment with bevacizumab or pegylated interferonalpha 2b (49). Clinical activity of bevacizumab was evidenced by a response rate of 18%
and an improved PFS rate at week 18 (95% versus 68%). These encouraging results led to
the development of a pivotal phase III study led by the Southwest Oncology Group (Table
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1), in which patients are randomized to receive either interferon-α-2b or bevacizumab in
addition to octreotide. Results of this study will likely define the role of VEGF inhibitors in
carcinoids.
Therapy targeting mTOR pathway in Carcinoid
Parallel to its development in pancreatic NETs, everolimus was also evaluated in a phase III
study among patients with progressive well differentiated NETs and carcinoid syndrome
(Table 1). Patients received octreotide LAR plus everolimus or placebo(50). The study
demonstrated a clinically important 5.1 (from 11.3 to 16.4 months) months improvement
in PFS (HR = 0.77; 95% CI, 0.59–1.00)(50). The observed P value=0.026, however, missed
the pre-specified boundary 0.0246. The efficacy of everolimus in NETs of non-pancreatic
origin will need to be confirmed in a future study.
Future development of immunotherapy in carcinoid
Immunotherapy is another promising area for advance. Past studies have demonstrated
relevant clinical activity for interferon and subcutaneous interleukin-2 (51, 52). The
expression of multiple cancer-testis antigens provides additional rationale. Although there
has been little systematic and rigorous development of immunotherapy in NETs, the recent
advances in targeting of CTLA-4 and PD-1 provide opportunities for future advances.
Personalizing therapy in NETs
NETs are heterogeneous in their biologic behavior and aggressiveness. This along with the
recent emergence of multiple active therapies has led to considerable interest in predictive
and prognostic biomarkers that may allow us to tailor therapy. In addition to the known
prognostic value of tumor grade, recent studies have also confirmed the prognostic value of
12
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plasma levels of CGA and neuron specific enolase (NSE). In a multi-national study with
central radiology review, patients with baseline elevated CGA or NSE had significantly
shorter PFS and OS.(53) Further, early CGA or NSE response was linked favorable
therapeutic benefit (21, 53). If these findings are validated in subsequent studies,
biomarkers can be used select patients for therapy versus active surveillance among newly
diagnosed patients with significant tumor burden, and guide frequency of monitoring
among patients on active therapy.
Emerging data also suggests that high methylguanine-DNA methyltransferase (MGMT)
expression is associated with therapeutic resistance to temozolomide (45, 54). If confirmed
in future prospective studies, low MGMT expression could help select patients for
treatment.
Predictive biomarkers of therapeutic benefits for mTOR and VEGF inhibitors remain
elusive. Multiple somatic mutations in the mTOR pathway, however, have been identified
(24). Expression levels of PTEN and TSC2 have also recently linked to outcome (25). Taken
together, these suggest future studies evaluating the function of the mTOR pathway may
reveal predictive markers of benefit. For VEGF inhibitors, recent studies suggest that
functional imaging holds promise for identifying patients likely to respond to treatment
(55). Confirmation of these findings in a prospective study will open the way for a
personalized approach to treatment.
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Table 1. Recent and ongoing phase III studies in advanced NETs
Regimen
N
Median PFS/TTP
(months)
P
Status and reference
Pancreatic NETs
Sunitinib
171
11.4 PFS
.0001* Study completed
Placebo
5.5
Raymond et al, 2011 (29)
Everolimus
410
11 PFS
< .0001 Study completed
Placebo
4.6
Yao et al, 2011 (26)
Carcinoid tumors
Octreotide LAR
90
14.3 TTP
<. 0001 Study completed
Placebo
6.0
Rinke et al, 2009 (34)
Everolimus+octreotide LAR
429
16.4 PFS
.026** Study completed
Placebo+octreotide LAR
11.3
Pavel et al, 2011 (56)
Lanreotide
200
Accrual completed
Placebo
Bevacizumab+octreotide LAR
400
Recruiting
Interferon alpha+octreotide LAR
Carcinoid Syndrome
Octreotide LAR
202
Recruiting
Pasireotide LAR
Lanreotide
100
Recruiting
Placebo
* Not statistically significant due to unplanned analyses and early termination
** Not statistically significant. Pre-specified boundary is P ≤ .0246.
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Figure 1. Targeting critical signaling pathways in neuroendocrine tumors. Recent data
from pivotal phase III studies have demonstrated the importance of somatostatin, mTOR,
and angiogenic pathways in neuroendocrine tumors.
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New Strategies for Advanced Neuroendocrine Tumors in the Era
of Targeted Therapy
Mei Dong, Alexandria T Phan and James C Yao
Clin Cancer Res Published OnlineFirst February 15, 2012.
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