Neuroendocrine Tumors of the Pancreas

Anastasios T Dimou
1
, Konstantinos N Syrigos
2
, Muhammad Wasif Saif
2
1
Yale Pathology Department and
2
Yale Cancer Center, Yale University School of Medicine.
New Haven, CT, USA
Summary
Surgical excision has been the mainstay of treatment for neuroendocrine tumors of the pancreas (PNET). Compounds like
streptozocin and dacarbazin have been traditionally used in inoperable cases and somatostatin to treat syndromes deriving from
functional tumors. However, a lot of progress has taken place in the area of molecular characterization of these tumors, revealing
activation of mammalian target of rapamycin (mTOR) and VEGF pathways. Recent data from the 2010 ASCO Gastrointestinal
Cancers Symposium demonstrate antitumor activity of everolimus, an mTOR inhibitor in combination with temozolomide in a phase
I/II trial and of sunitinib versus placebo in a randomized double blinded phase III trial. The role of modern biologic compounds in
the treatment of PNET is not clear yet. In addition, combination of resection and transarterial chemoembolization (TACE) has been
proven effective over either modality alone in the treatment of PNET metastatic to the liver in a retrospective analysis. This comes to
address the problem of selecting local intervention in a metastatic disease, which has been a reasonable choice for this group of
tumors in the past. Last but not least the role of Ki-67 in decision-making in PNET is being discussed.
Introduction
Pancreatic neuroendocrine tumors (PNET) are a rare
subgroup of tumors found in the pancreas and can be
either functional or non-functional [1, 2, 3]. Their
appearance in histology sections has little to contribute
to their malignant potential since this traditionally
depends on the extent of their spread. However, recent
WHO classification classifies PNET into well
differentiated tumors, well differentiated carcinomas
and poorly differentiated carcinomas in an attempt to
predict natural history from the pathology report [1].
They are usually sporadic but they may also appear
among other features of genetic syndromes like
multiple endocrine neoplasia type I or von Hippel-
Lindau disease. Patients usually present with
syndromes induced by hormones secreted from
functional tumors, or with mass effects from non-
functional tumors. Functional PNET can secrete
biologically active peptides like insulin, gastrin,
glucagon, somatostatin, vasoactive intestinal
polypeptide (VIP), whereas non-functional tumors also
express and secrete peptides like neurotensin or
chromogranin A, which are not active [1].
Most of the PNET are already metastatic by the time
they are diagnosed and liver is the most common site
of metastasis. Regional lymph node spread is also
common. PNET are non-functional in their majority
and the absence of a distinct functional syndrome as
well as their indolent course and subsequent delay in
diagnosis is mainly responsible for the advanced stage
at the time of diagnosis [2, 3]. PNET have a 5-year
survival that can range from 97% in benign
insulinomas to as low as 30% in non-functional
metastatic PNET [2, 3]. In addition, more recent data
demonstrate that poorly differentiated PNET can have
similar prognosis with adenocarcinomas of the
gastrointestinal tract [2].
Surgery with curative intent is the mainstay of
treatment for localized or loco-regional disease [1, 2].
Surgery as well as other forms of local treatment like
transarterial chemoembolization or radiofrequency
ablation can also improve prognosis in patients with
liver metastases [2, 4, 5]. For the inoperable cases,
cytotoxic therapy with compounds like streptozotocin,
5-fluorouracil or doxorubicin can achieve modest
outcome [6, 7, 8, 9]. Treatment with somatostatin
Key words Chemoembolization, Therapeutic; everolimus; Ki-67
Antigen; mTOR protein; Neuroendocrine Tumors; sunitinib
Abbreviations mTOR: mammalian target of rapamycin; NET:
neuroendocrine tumor; PTEN: phosphatase and tensin homolog;
TSCII: tuberous sclerosis complex II
Correspondence Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine, 333
Cedar Street, FMP 116, New Haven, CT,USA
Phone: +1-203.737.1569; Fax: +1-203.785.3788
E-mail: wasif.saif@yale.edu
Document URL http://www.joplink.net/prev/201003/12.html

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analogues like octreotide has been proven to prolong
progression-free survival in patients with metastatic
neuroendocrine tumors of midgut origin [9].
This is a review of the recent advances in PNET as
they were reported in four abstracts presented at the
2010 ASCO Gastrointestinal Cancers Symposium
(Table 1).
A Randomized Double Blinded Trial of Sunitinib
versus Placebo in Patients with Advanced PNET
Abstract #127: Updated results of the phase III trial of
sunitinib (SU) versus placebo (PBO) for treatment of
advanced pancreatic neuroendocrine tumors (NET)
[10]
Sunitinib, which is a multi-tyrosine kinase inhibitor,
was compared in this randomized, double-blinded
phase III study to placebo as salvage treatment in
patients with well differentiated tumors of the pancreas
after documented progression. The trial, initially
intended to recruit 340 patients, but was ended after
171 patients enrolled (86 in the sunitinib group and 85
in the placebo group) due to profound benefit in the
sunitinib arm. Primary endpoint was the progression-
free survival. Patients who received sunitinib had a
median progression-free survival of 11.4 months
versus 5.5 months for the patients who received
placebo (P=0.0001; HR=0.418, 95% CI: 0.263-0.662).
Objective response rate was 9.3% in the sunitinib arm
and 0% in the placebo arm (P=0.0066). Sunitinib
caused 3/4 neutropenia in 12% of the patients versus
0% in the placebo arm, grade 3/4 hypertension in 9.6%
versus 1.2% and palmar-plantar erythrodysesthesia in
6.0% versus 0 %. However, the population was not
representative of the general population of PNET,
because it included only well differentiated tumors and
the proportion of non-functional tumors was 50%,
which is less than what it has been historically
considered to be [2, 3]. Furthermore, it would be
interesting to test the control rate that sunitinib can
achieve for the syndromes that accompany the
functional tumors.
Safety and Efficiency Profile of Everolimus plus
Temozolomide in Patients with Advanced PNET: A
Phase I/II Study
Abstract #223: Phase I/II study of everolimus
(RAD001) in combination with temozolomide (TMZ) in
patients (pts) with advanced pancreatic
neuroendocrine tumors (NET) [11]
Everolimus is a compound that inhibits the mammalian
target of rapamycin (mTOR) and temozolomide is an
oral alkylating agent, while both of them have been
suggested as treatment options in the metastatic setting
of neuroendocrine tumors. This group performed a
phase I/II trial that tests the tolerability and efficacy of
the combination of those two agents in patients with
advanced PNET. Two dose levels of everolimus, 5 and
10 mg per os qd were combined with the fixed dose
150 mg/mper os qd of temozolomide for seven
consecutive days every other week. After six four-
week cycles temozolomide was stopped and the patient
would keep on with everolimus only. At the first dose
level except for 1 out of 6 evaluable patients no other
dose-limiting toxicity (DLT) was reported (Table 2).
The group of patients that received treatment at the
second dose level was also used as the phase II
population and consisted of 17 patients with
performance status (PS) 0 or 1 that received a median
of 6 cycles. Sixteen of those were evaluable for
toxicity and grade 3/4 hematologic toxicity was
reported in 11 patients, whereas grade 3/4 non-
hematologic toxicity was reported in 4 patients (Table
2). All 17 patients were evaluable for efficacy. Overall
control rate of the disease was 88% (Table 2). Forty-
five percent of the patients experienced a decrease in
their chromogranin A levels of more than 50%. No
data is provided concerning any previous treatments
the patients received, the metastatic sites and the tumor
burden as well as the grade and other histology aspects
of the tumors that would bear a possible association
with treatment efficacy.
Table 1. Abstracts from 2010 ASCO Gastrointestinal Cancers Symposium concerning pancreatic neuroendocrine tumors.
Abstract
Description
Comments
#127 Raymond E, et al. [10]
Sunitinib vs placebo in metastatic PNET
Phase III
#223 Kulke M, et al. [11]
Everolimus plus temozolomide in patients with advanced PNET
Phase I/II
#234 Celinsky SA, et al. [12] Resection vs. transarterial chemoemblization in metastatic PNET to the liver
Retrospective analysis
#266 Singh S, et al. [13]
Ki-67 in the evaluation of neuroendocrine tumors
Retrospective chart review
PNET: pancreatic neuroendocrine tumors
Table 2. Safety data of everolimous and temozolomide in pancreatic neuroendocrine tumors.
Safety-phase I (grade 3/4 reactions)
Efficacy-phase II
Everolimus
dose level
No. of cases
Hematologic
Non-hematologic
5 mg/m2
6
Thrombocytopenia: 1 (16.7%)
None
None
10 mg/m2
17
Thrombocytopenia: 4 (23.5%)
Lymphopenia: 5 (29.4%)
Neutropenia: 2 (11.8%)
Triglyceride elevation: 1 (5.9%)
Transaminases elevation: 1 (5.9%)
Hyperglycemia: 1 (5.9%)
Rash: 1 (5.9%)
Objective response rate: 6 (35%)
Disease stabilization rate: 9 (53%)
Progression rate: 2 (12%)

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Transarterial Chemoembolization (TACE) versus
Resection of Liver Metastases from a NET Primary
Abstract #234: Multimodality management of
neuroendocrine tumors metastatic to the liver [12]
TACE was compared to resection and to the
combination of the two in a retrospective analysis of
124 patients with neuroendocrine tumors (NET) that
had metastasized to the liver. The different treatment
groups were balanced in terms of gender, age, site of
primary tumor and presence of symptoms. Treatment
with the combination of resection and TACE was the
more efficacious followed by resection alone and
TACE alone (mean survivals: 148 months versus 131
months versus 42 months, respectively; P=0.001).
Patients who had their liver metastases resected were
more likely to have their primary tumor resected as
well than patients who underwent TACE (83% versus
17%). Younger age was associated with better
outcome. Multivariate analysis including age, resection
of the primary tumor and treatment type, showed that
age and treatment type were independent predictors of
overall survival (P=0.009 and P=0.010, respectively).
It is not clear from the abstract the number of patients
that were included in each group. In addition, data
concerning the performance status of the patients and
the differentiation of the tumors and whether those
characteristics were balanced between the groups
would be useful as they could influence the prognosis
of the patients. This analysis refers to neuroendocrine
tumors in general without specification for pancreatic
origin. In addition patients with better performance
status are expected to have undergone resection rather
than TACE, which would introduce some bias in the
analysis. Last but not least, the conclusion is drawn on
the basis of the mean overall survivals in each group
whereas the median would be more appropriate as the
distribution of overall survival is not known (Table 3).
Ki-67: How Often Is It Used in the Workup of
Patients with NET?
Abstract #266: The role of Ki-67 in the prognosis and
management of neuroendocrine (NET) patients in a
multidisciplinary cancer center [13]
In this retrospective analysis from a multi-disciplinary
cancer center, 82 patients with neuroendocrine tumors
were studied for Ki-67 expression. Ki-67 was
categorized into four levels and patients were assigned
to four groups according to the level of Ki-67
expression. Patients with metastatic disease were found
to have higher levels of Ki-67 and patients that
received chemotherapy and/or hormonal therapy were
more likely to have higher Ki-67 levels. However,
symptom control was found to be similar in all the Ki-
67 groups. The investigators do not mention the origin
of the neuroendocrine tumors. In addition, the
conclusion that Ki-67 levels influence treatment
decisions for those tumors is not fully supported by the
data, as it is indicated that there is an association rather
than an influence. Furthermore, no statistical
considerations are taken into account to demonstrate
this association.
Discussion
Neuroendocrine tumors are a rare subset of pancreatic
tumors, but their incidence is rising during the last two
decades [2]. They are traditionally considered to have
indolent course. However, the majority of them is
metastatic at the time of diagnosis and if poorly
differentiated, their prognosis can be dismal. Surgery
has been suggested for the resectable cases. For those
that cannot be resected, old chemotherapy regimens
have been used in the past. Data concerning the newer
biologic compounds is lacking. In addition, it is not
clear, whether TACE can be comparable to resection of
liver metastases.
Activation of the mTOR pathway has been found to be
common in the neuroendocrine tumors of the pancreas
through the inactivation and loss of the mTOR
inhibitors tuberous sclerosis complex II (TSCII) and
phosphatase and tensin homolog (PTEN) [14]. Briefly,
mTOR is integrating signals coming from receptors in
the cell membrane and is implicated in cell
proliferation and anti-apoptotic pathways via pS6k and
4EBP1 which are the main molecules downstream of
mTOR. Akt is the major activator whereas TSCII and
PTEN are the major inhibitors of mTOR.
Downregulation of TSCII and PTEN were significantly
associated with worse differentiation, worse prognosis
and liver metastases in patients with PNET [14].
Furthermore, mTOR inhibitors like everolimus
(RAD001) and everolimus have demonstrated
antiproliferative effects in pancreatic neuroendocrine
cell lines [15, 16, 17]. Everolimus, alone or in
combination with octreotide have been moderatively
effective in pancreatic neuroendocrine tumors in a
phase II trial [18, 19]. Temozolomide and decarbonizes
have been proposed in the past as chemotherapy
options in the metastatic setting of PNET [8, 20].
Kulke et al. [11] are the first to test the safety of the
combination of temozolomide with everolimus in
patients with advanced PNET and to provide some
insight into the possible antitumor effect of the
combination of traditional chemotherapy with the
newer biologic agents in those tumors. More phase II
trials will clarify whether a phase III trial of this
combination is feasible.
Vascular endothelial growth factor (VEGF) has been
implicated in the pathogenesis of neuroendocrine
tumors [21, 22] and makes anti-angiogenesis therapy a
reasonable choice for clinical trials. Sunitinib is a
Table 3. Efficacy data from transarterial chemoembolization and/or
resection in liver metastases from pancreatic neuroendocrine tumors.
Treatment modality
Mean survival
Transarterial chemoembolization (TACE)
42 months
Resection
131 months
Transarterial chemoembolization (TACE) + resection 148 months
P=0.001

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138
multi-target tyrosine kinase inhibitor that has
demonstrated anti-tumor activity in phase II clinical
trials in PNET with an acceptable toxicity profile [23].
Raymond et al. [10] presented the first phase III trial of
sunitinib in patients with advanced PNET. Their study
demonstrated clear clinical benefit of sunitinib over
placebo and had to close early because the primary
endpoint was shown after 171 patients were
randomized. However, results should be interpreted
with caution, as the population did not include poorly
differentiated tumors.
TACE has been a minimally invasive procedure that
has been proposed for the treatment of liver metastases
instead of resection and it has been debatable whether
it can substitute surgery. Celinsky et al. [12] showed
that resection should be preferred when possible and
even combined with TACE for better outcomes.
Overall, PNET can be of dismal prognosis for a large
proportion of patients with this disease. Recent
advances reported in the 2010 ASCO Gastrointestinal
Cancers Symposium were based on advances
concerning the molecular characterization of those
tumors and underscore the priority of understanding
their biologic behavior that will provide rationale for
the clinical trials to come.
Disclosure of interest None
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