REVIEW

CURRENT
OPINION Pancreatic neuroendocrine tumors
Giampaolo Perri, Laura R. Prakash, and Matthew H.G. Katz

Purpose of review
Pancreatic neuroendocrine tumors (pNETs) are a rare, heterogeneous group of pancreatic neoplasms with
a wide range of malignant potential. They may manifest as noninfiltrative, slow-growing tumors, locally
invasive masses, or even swiftly metastasizing cancers.
Recent findings
In recent years, because of the increasing amount of scientific literature available for pNETs, the
classification, prognostic stratification criteria, and available consensus guidelines for diagnosis and
therapy have been revised and updated.
Summary
The vast majority of new pNET diagnoses consist of incidentally discovered lesions on cross-sectional
imaging. The biologic behavior of pNETs is defined by the grade and stage of the tumor. Surgery is the
only curative treatment and it, therefore, represents the first therapeutic choice for any localized pNET;
however, recent evidence suggests that patients with small (<2 cm), nonfunctioning G1 tumors can be
safely observed.
An aggressive surgical approach towards liver metastases is recommended in selected cases, as well as
liver-directed therapies for disease control. In the presence of unresectable progressive disease,
somatostatin analogs, targeted therapies such as everolimus, peptide receptor radionuclide therapy, and
systemic chemotherapy are all useful tools for prolonging survival.
Keywords
neuroendocrine tumor, octreotide, pancreas, pancreatic islet cell tumor, peptide receptor radionuclide therapy

INTRODUCTION, EPIDEMIOLOGY, staining alone is not a defining criterion for tumor

NOMENCLATURE
Pancreatic neuroendocrine tumors (pNETs) are a
heterogeneous group of neoplasms that arise from
the endocrine tissues of the pancreas. Previously
known as islet cell tumors because of their presumed
origin in the islets of Langerhans, they comprise less
than 2% of all pancreatic neoplasms and approxi-
mately 7% of all neuroendocrine tumors (NETs)
across all anatomic sites [1]. These tumors have an
incidence of 1 or less case per 100 000 individuals
per year [2,3] but their incidence has increased
significantly in recent years, along with the wide-
spread use of cross-sectional imaging and the
increased rate of detection of so-called pancreatic
incidentalomas [4–6] (Fig. 1). pNETs may manifest
at any age but are most often diagnosed between the
age of 40 and 65 [1].
pNETs may be classified as either functional
(F-pNET) or nonfunctional (NF-pNET), depending
on their secretion of various peptide hormones,
including insulin, gastrin, glucagon, and vasoactive
intestinal peptide (VIP), resulting in various
clinical syndromes (Table 1). Immunohistochemical
classification, as both F-pNETs and NF-pNETs may
secrete multiple peptides. NF-pNETs account for the
majority (50–75%) of pNETs.
Although the vast majority of pNETs are spo-
radic, approximately 10% of all pNETs can be also
associated with hereditary genetic endocrinopa-
thies. These tumors are found in 80–100% of
patients with multiple endocrine neoplasia type I
(MEN-1), in whom NF-pNET, gastrinomas, and insu-
linomas are most common. NF-pNETs are found in
approximately 20% of patients with von Hippel
Lindau (VHL) syndrome. pNETs are also found,
albeit less commonly, in patients with neurofibro-
matosis type I and tuberous sclerosis [7–9]. Tumors
Department of Surgical Oncology, MD Anderson Cancer Center, The
University of Texas, Houston, Texas, USA
Correspondence to Matthew H.G. Katz, MD, Department of Surgical
Oncology, MD Anderson Cancer Center, The University of Texas, 1400
Pressler Street, FCT 17.6058, Unit 1484, Houston, TX 77030-4009,
USA. E-mail: mhgkatz@mdanderson.org
Curr Opin Gastroenterol 2019, 35:468–477
DOI:10.1097/MOG.0000000000000571

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KEY POINTS
 pNETs are a very heterogeneous group of neoplasms
with a wide range of behavior.
 Surgery is the only curative treatment.
 Observation is a reasonable approach for patients with
small, low-grade NF-pNET.
 Systemic therapies are useful to control unresectable/
progressive disease.
 The role of preoperative therapy for patients with
advanced pNETs is still unclear.
that develop in the context of an inherited syn-
drome tend to share a more indolent course than
sporadic tumors.
In general, NF-pNETs have a wide range of clini-
cal behavior. They may manifest as noninfiltrative,
slow-growing tumors, locally invasive masses, or
even swiftly metastasizing cancers. The biologic
behavior of F-pNETs and NF-pNETs is defined by
their grade and stage.
FIGURE 1. Time trends of the overall pancreatic neuroendocrine tumors caseload from 1990 to 2015 in a high-volume center
for pancreatic surgery (previously published) (from [36 ]).
&
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Pancreatic neuroendocrine tumors Perri et al.
CLASSIFICATION SYSTEMS FOR TUMOR
GRADE AND STAGE
The original WHO criteria for pNETs were first
established in 2000 [10]. The revised 2010 classi-
fication system [11] officially adopted the label
‘neuroendocrine’ and the European Neuroendo-
crine Tumor Society (ENETS) grading system. This
represents a proliferation-based system with stratifi-
cation into three tiers of proliferative activity deter-
mined on the basis of mitotic count and Ki-67 index.
The prognostic value of this system has been vali-
dated by several large studies [12]. The current WHO
&&
classification system was adopted in 2017 [13 ].
It raised the cut-off levels of Ki-67 for G2 tumors
to 3% and now discriminates between two subsets of
G3 tumors on the basis of their degree of histopath-
ologic differentiation (Table 2).
Like other tumors, pNETs are staged using the
tumor/node/metastasis (TNM) classification.
Although the WHO classification grades tumors
on the basis of their anticipated biological behavior,
the TNM classification estimates prognosis on the
basis of tumors’ anatomic extent. Past TNM staging
systems for pNETs included a variant proposed by
the 7th edition of American Joint Committee on
www.co-gastroenterology.com 469
Pancreas

Table 1. Clinical features of functional pancreatic neuroendocrine tumors

Secreted Malignant Clinical Biochemical
Tumor Incidence Location hormone (%) features diagnosis

Insulinoma 40–55% Pancreas (>99%) Insulin <10 Hypoglycemic syndromes Insulin  5 mIU/la
(Whipple’s triad) Glucose 40 mg/dl
C-peptide 0.6 ng/ml
Proinsulin  20 pmol/l
(or >25% of
immunoreactive
insulin)
Gastrinoma 25–50% Duodenum (70%) Gastrin 60–90 Zollinger–Ellison syndrome Serum gastrin level
Pancreas (25%) (abdominal pain, 10 times normal
Others (5%) gastroesophageal reflux, range þ gastric
diarrhea, duodenal pH < 2
ulcers, PUD/GERD)
Glucagonoma Rare Pancreas (100%) Glucagon 50–80 Rash, glucose intolerance, Glucagon > 500 pg/ml
necrolytic migratory
erythema, weight loss
Somatostatinoma Rare Pancreas (55%) Somatostatin >70 Diabetes mellitus, Somatostatin-fasting
Duodenum- cholelithiasis, diarrhea serum level
jejunum (45%)
VIPoma (Verner– Rare Pancreas (90%) Vasoactive 40–70 WHDA VIP fasting serum level
Morrison) Other (10%) intestinal
peptide
ACTHoma Rare Pancreas (4–16% Adreno 95 Cushing’s syndrome
all ectopic Cortico
Cushing’s) Tropic
Hormone
(ACTH)
pNET-causing Rare Pancreas (100%) Serotonin, 60–90 Carcinoid syndrome Urinary 5-HIAA in a
carcinoid tachynins 24-h urine collection
syndrome

GERD, gastroesophageal reflux disease; 5-HIAA, 5-hydroxyindoleacetic acid; PUD, peptic ulcer disease; VIP, vasoactive intestinal peptide; WHDA, watery
diarrhea, hypokalemia, achlorhydria.
a
Should be performed at the time of hypoglycemia during prolonged fasting (up to 72 h).

Cancer (AJCC) staging manual [14] and a second

Table 2. 2017 WHO classification and grading of promoted by the ENETS [12,15]. The current 8th
PanNENs edition of the AJCC staging manual is routinely used
Classification/ Ki-67 proliferation Mitotic for anatomic staging in 2019.
Grade indexa (%) indexa As shown in a recent large population-based
Well-differentiated PanNENs: PanNETs study, tumor grade and stage are crucial parameters
PanNET G1 <3 <2 for stratifying patients with pNET by prognosis. The
PanNET G2 3–20 2–20 5-year survival rate ranges from 55% for patients
PanNET G3 >20 >20 with localized, resected pNETs to 15% for patients
Poorly differentiated PanNENs: PanNECs with nonresectable pNETs [14]. Median overall
PanNEC (G3) >20 >20 survival durations range from around 12 years for
Small-cell type patients with G1-grade pNETs to 10 months for
Large-cell type &
patients with G3 pNETs [16 ].
Mixed neuroendocrine-nonneuroendocrine neoplasm

PanNECs, pancreatic neuroendocrine carcinomas; PanNENs, pancreatic

neuroendocrine neoplasms; PanNETs, pancreatic neuroendocrine tumors.
Reproduced with permission from Lloyd RV, Osamura RY, Klöppel G, Rosai J.
World Health Organization Classification of tumours of endocrine organs,
4th ed. Lyon, IARC, 2016; p 211. Copyright ß 2017 International Agency
for Research on Cancer.
a
The Ki-67 proliferation index is based on the evaluation of at least 500 cells
in areas of higher nuclear labeling (so-called hotspots). The mitotic index is
based on the evaluation of mitoses in 50 high-power fields (0.2 mm2 each) in
areas of higher density and is expressed as mitoses per 10 high-power fields
(2.0 mm2). The final grade is determined on the basis of whichever index
(Ki-67 or mitotic) places the tumor in the highest grade category. For
assessing Ki-67, casual visual estimation (eyeballing) is not recommended;
manual counting using printed images is advocated.
CLINICAL PRESENTATION
F-pNETs typically present with specific clinical
syndromes related to hypersecretion of specific
hormones, as described in Table 1. The most
common F-pNETs include insulinomas, which typi-
cally present with Whipple’s triad (hypoglycemia
especially after fasting, low plasma glucose mea-
sured at the time of symptoms and relief of symp-
toms when the glucose is raised to normal), and
gastrinomas, which presents with peptic ulcer

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disease (Zollinger–Ellison syndrome), gastroesoph-
ageal reflux disease, or secretory diarrhea. Less com-
mon F-pNETs include VIPomas, glucagonomas, and
somatostatinomas.
The vast majority of new pNET diagnoses consist
of an NF-pNET incidentally discovered on cross-
sectional imaging performed for another indication.
Indeed, NF-pNETs typically remain asymptomatic
until they reach a significant tumor burden. When
they become symptomatic, they may present with
vague symptoms, such as nonspecific abdominal
pain, early satiety, or weight loss, typically related
to mass effect. Locally advanced lesions can present
with bowel obstruction or obstructive jaundice. NF-
pNETs frequently synthesize peptides, but they do
not produce symptoms or specific syndromes (either
because they produce hormones at a low enough
level to not cause symptoms or hormones that do
not cause symptoms).
When metastases occur, they are typically mul-
tifocal and located in the liver, though other meta-
static sites including lungs, bone, peritoneum,
adrenal, brain, and spleen are also observed [17].
DIAGNOSIS AND STAGING
As mentioned above, NF-pNETs are often discovered
incidentally on cross-sectional imaging, and, in gen-
eral, cross-sectional imaging is indicated in all
patients in whom a pNET is suspected.
Localization and staging
Diagnostic imaging for suspected pNETs should
typically begin with a multiphase abdominal com-
puted tomography (CT) scan with intravenous con-
trast using a pancreatic protocol given its good
sensitivity, specificity, and availability. pNETs
characteristically appear as well-circumscribed
lesions that hyperenhance with contrast in the arte-
rial phase that washes out in the delayed venous
phase. Hypoenhancement in the arterial phase and
the presence of calcifications are associated with
more aggressive tumors and worse prognosis [18,19].
On CT images, the differential diagnosis of
a hyperenhancing pancreatic mass includes solid
pseudopapillary tumors, pancreatic renal cell carci-
noma metastases, and intrapancreatic splenule
(if in the pancreatic tail), because of the solid hyper-
enhancing radiographic appearance of all these enti-
ties. Solid pseudopapillary tumors may be
distinguished from pNETs because of their central
cystic component, owing to hemorrhagic degenera-
tion, causing the enhancing solid areas to be
typically noted only peripherally. For renal cell car-
cinoma metastases, the patient’s past oncological
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Pancreatic neuroendocrine tumors Perri et al.
history plays a major role in the differential
diagnosis.
MRI represents an alternative to CT, with the
advantages of less radiation exposure and possibly a
higher sensitivity than CT for detecting smaller
pancreatic lesions and liver metastases [20,21].
Somatostatin receptor scintigraphy, also known as
an octreotide scan, remains useful for its ability
to detect radiographically occult metastases and
to characterize the presence or absence functional
expression of somatostatin receptors, which may
also guide systemic therapy decisions.
PET with CT 68Gallium-labeled somatostatin
analogs (SSAs) ((68)Ga-DOTATATE) has the highest
sensitivity for localizing pNETs [22,23]. For these
reasons, it is routinely performed in our center for
most patients with a suspected pNET. In contrast,
PET/CT with 18flourodeoxyglucose (FDG) is not
typically useful in the diagnosis of NF-pNETs. It
may remain useful as a prognostic tool, as well-
differentiated tumors are generally positive on
(68)Ga-DOTATATE scan and negative on FDG scan,
whereas the opposite is true for poorly differenti-
ated, grade 3 tumors [24].
Endoscopic ultrasonography (EUS) provides
high-resolution imaging of the pancreas with high
sensitivity [25]. Although limited by the require-
ment of a highly skilled endoscopist, it can detect
lesions as small as 2–3 mm in diameter. It is there-
fore useful in patients who present with a hormonal
syndrome suggestive of a pNET but who lack evi-
dence of disease on conventional imaging. At the
same time, EUS-guided fine needle aspiration (FNA)
aspiration biopsy can secure a nonoperative histo-
logic diagnosis and quantify tumor grade. The eval-
uation of the tumor grade on EUS–FNA material
should be included in the workup of each patient
with an NF-pNET, as proposed by the recently pub-
&&
lished ENETS consensus guidelines update [26 ].
Biochemical evaluation
The assay of hormones or peptides, including insu-
lin, glucagon, gastric, VIP, and somatostatin, is
essential for the diagnosis when signs or symptoms
of an F-pNET are present. For a suspected insulin-
oma, the biochemical assessment of insulin,
glucose, C-peptide, and proinsulin should be per-
formed at the time of hypoglycemia during a pro-
longed, monitored fast. When gastrinoma is
suspected, fasting serum gastrin levels should be
evaluated. A serum gastrin level that is 10 times
greater than the upper limit of the normal range
along with a gastric pH less than 2 is diagnostic of
gastrinoma. The characteristic biochemical findings
of the most common F-pNETs are listed in Table 1.
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Pancreas
Chromogranin A (CgA) and neuron-specific
enolase (NSE) are commonly used markers for func-
tional and nonfunctional pNETs. CgA, a protein
that is stored in the secretory granules of different
NETs, has been correlated with tumor burden and
metastasis of well-differentiated NETs rather than
poorly differentiated NETs and has been used as a
prognostic marker for both progression-free and
overall survival and a clinical tool for monitoring
therapeutic response [27,28]. Unfortunately, CgA is
sensitive but not specific [29,30], and its level may
vary day by day and is influenced by food intake and
other medical conditions, like the use of proton
pump inhibitors, or renal and hepatic insufficiency.
NSE is an enzyme released after neuronal damage
caused by different conditions but is also stored in
the cytoplasm of NET cells. Its sensitivity and speci-
ficity, in two series totaling more than 200 patients
with gastroentero-pancreatic NETs, were only 39–
43 and 65–73%, respectively, for differentiating
NET from nonendocrine tumors [31,32]. At our
center, clinical decisions are rarely made on the
basis of either of these two markers and we find
them of limited utility.
SURGICAL MANAGEMENT
In general, surgery is the only curative treatment for
pNET, and it therefore represents the treatment of
choice for any patient with localized pNET [33]. Nev-
ertheless, the improvement of cross-sectional imag-
ing and its extensive use in the general population
have significantly increased the detection of small,
asymptomatic NF-pNETs, raising interest in the
FIGURE 2. MD Anderson Institutional Algorithm for treating G1–G2 NF-pNETs.
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potential role of observation, especially for tumors
anticipated to have an indolent natural history.
Localized disease
The evidence that small (<2 cm) pNETs often
&&
behave in an indolent manner [34 ] has altered
the historic practice of resecting all pNETs.
Although long-term follow-up data are needed to
guarantee the safety of a conservative, nonsurgical
approach, ENETS guidelines suggest that observa-
tion can be considered for NF-pNETs less than 2 cm,
following a careful analysis of the risks and benefits
&&
of surgery in each patient [26 ]. The potential role
of surgery should take tumor grade, functional sta-
tus, and the presence or absence of symptoms into
&&
account [26 ,35]. In general, in the absence of
symptoms, radical resections are reserved for
patients with a favorable performance status and
either a high-grade (G2þ) or a larger, low-grade
&
tumor [36 ]. At our center, we typically advise obser-
vation for patients with G1 NF-pNETs less than 1 cm,
typically advise resection for patients with G1 NF-
pNETs more than 2 cm, and carefully balance possi-
ble risks and benefits of surgery in patients with G1
tumors between 1 and 2 cm. Surgical resection is
generally recommended for large or G2 pNETs, or
symptomatic (including functional) tumors (Fig. 2).
The role of surgery for patients with G3, well-differ-
entiated NETs, NEC is controversial [37,38]. Cura-
tive surgery may be attempted in localized disease,
although retrospective series indicates that it is
rarely curative as a sole therapeutic modality given
its high relapse rate following radical surgery. At our
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 Pancreatic neuroendocrine tumors Perri et al.

center, we often offer patients with G3 pNETs sys-
temic therapy prior to consideration for resection.
Small, low-grade pNETs and insulinomas may
often be enucleated from the adjacent parenchyma
safely as long as they are distant from the pancreatic
duct and the integrity of this structure can be guaran-
teed. Endoscopic placement of a pancreatic stent to
protect the main pancreatic duct can be considered
preoperatively. Although enucleation and nonana-
tomic resections (e.g., central pancreatectomy) have
the advantage of a decreased long-term endocrine/
exocrine impairment when compared with standard
resections, they are associated with a relatively high
rate of pancreatic fistulae and postoperative acute
pancreatitis [39]. Furthermore, a lymphadenectomy
is not typically performed concurrently with these
limited operations. Therefore, we typically favor for-
mal pancreatectomy with lymphadenectomy and
reserve nonanatomic operations for patients with
insulinomas and small G1 NF-pNETs, where a stan-
dard lymphadenectomy may not be required.
Several reports have stressed the prognostic
importance of lymph node involvement in resected
pNETs, confirming that the finding of positive
lymph nodes was associated with a shorter time
interval to metastatic liver recurrence, shorter
median disease free-survival, and shorter survival
& &
in long-term follow-up [36 ,40,41,42 ]. A positive
nodal status can be observed in the case of G1 and
G2 tumors, with a range in the literature between 17
&
and 53% [36 ]. However, as recently observed by
&
Marchegiani et al. [42 ] nonfunctioning G1 pNETs
20 mm or less without nodal metastasis or vascular
invasion have a negligible risk of developing recur-
rence and may be considered cured by surgery
(Fig. 3). Other commonly recognized prognostic

FIGURE 3. Kaplan–Maier curves for predicted cumulative disease-free survival comparing: (a) pancreatic neuroendocrine
tumors (pNET) less than 20 mm (1) versus pNET more than 21 mm (2); (b) N0 (1) and N1 (2); (c) G1 (1), G2 (2), and G3 (3);
(d) absence (1) and presence of vascular infiltration (2) (previously published) (from [42 ]).
&

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Pancreas
factors include tumor size, presence of metastases,
the status of the surgical margins, and microscopic
vascular involvement.
In selected patients, aggressive, extended resec-
tion of locally advanced tumors including en bloc
removal of adjacent vascular structures and viscera,
and even simultaneous surgical resection of the
primary tumor and synchronous liver metastases
have been described to be associated with acceptable
morbidity, low mortality, and survival benefit in
several studies [43–47]. However, such resections
should be offered only to well-selected patients in
high-volume, experienced hepatopancreatobiliary
centers following standard oncologic principles
and a multidisciplinary approach.
Enucleation and distal pancreatectomy (with or
without splenic preservation) may be performed
using a laparoscopic or robotic fashion, with some
possible advantages such as reduced length of hos-
pitalization [48,49]. Robotic pancreaticoduodenec-
tomy appears to provide similar perioperative
and oncologic outcomes in selected patients when
performed at experienced, high-volume centers
[50,51].
Nonsporadic pancreatic neuroendocrine
tumors
In the context of VHL patients, given their better
long-term outcome, lesions 15 mm or less can be
safely observed.
In MEN-1 patients with pNETs less than 2 or
3 cm, routine surgical resection is not recom-
mended, whereas in MEN-1 patients with pNETs
more than 2 cm surgical excision may improve sur-
vival, preventing or delaying distant metastases
&&
[26 ]. Parenchymal-preserving operations are gen-
erally recommended, whereas formal pancreatec-
&&
tomy is reserved for specific selected cases [26 ].
Typically in our center, we offer resection only for
3 cm or larger tumors, symptomatic tumors, and/or
rapidly growing tumors. We always attempt to
perform parenchymal sparing operations when
possible, even in the setting of multifocal disease.
Liver metastases
According to ENETS guidelines, an aggressive
approach toward liver metastases is recommended
whenever a radical resection (>90% of tumor
removal) is possible, in the absence of extraabdomi-
nal disease, and in the presence of a low Ki-67 (G1–
G2 at cytology) and somatostatin receptors (to
deliver radiolabeled therapies after cytoreductive
surgery). Even in selected cases, the rate of tumor
recurrence is high, up to 76% [52,53]. But, the 5-year
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survival of patients treated with hepatic resection
may be as long as 60% [54].
At the time of presentation, around 80% of
patients with metastatic disease have unresectable
liver metastases. For most other malignancies, there
is little rationale to resect the primary site when
widespread, unresectable metastases are present.
However, because a prolonged life expectancy
may be associated with slow-growing pNETs, resec-
tion of the primary tumor for local control may be
beneficial if the primary site is causing symptoms or
to avoid local complications.
When patients are not a candidate for liver
resection, alternative methods such as radiofre-
quency ablation, hepatic artery embolization, or
radioembolization can be considered as an alterna-
tive to systemic therapy to improve local control
and palliate symptoms [55].
Liver transplantation may represent an option
for well-selected patients with unresectable liver
metastases and a low proliferation rate, who are
not responsive to medical therapy and are free from
extrahepatic metastases. However, the experience is
limited and liver transplantation for pNETs metas-
tases has been associated with worse overall out-
comes and early recurrence, possibly because of
postoperative immunosuppressive treatment and/
or undiagnosed extrahepatic metastases [56].
SYSTEMIC THERAPIES
Somatostatin analogs
SSAs are used for syndrome control in nonresectable
F-pNETs (such as in carcinoid syndrome, VIPoma,
and somatostatinoma). Given their antiproliferative
effects, they are also an established first-line therapy
to control the growth of nonresectable, well-
differentiated NF-pNETs, as many of them express
somatostatin receptors. Two placebo-controlled tri-
als (PROMID and CLARINET) have found signifi-
cantly prolonged progression-free survival with
long-acting release octreotide and long-acting lan-
reotide (14 versus 6 months and 32 versus 18
months, respectively) [57,58].
Targeted therapies
pNETs have been found to be responsive to the
targeted agents everolimus (an oral mTOR inhibitor)
and sunitinib (an oral tyrosine-kinase inhibitor).
Therefore, based on the result of two different pla-
cebo-controlled trials attesting their efficacy [59,60],
they are recommended for progressive G1–G2 pNET
as a second line after the failure of SSA or systemic
chemotherapy, irrespective of Ki-67 or tumor
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 Pancreatic neuroendocrine tumors Perri et al.

burden. The median progression-free survival was
around 11 months with either of the drugs, whereas
tumor remission was superior for sunitinib versus
placebo. Targeted agents should be used with the
intent of controlling disease, not to downsize or
downstage it in anticipation for surgical resection.
Peptide receptor radionuclide therapy
Peptide receptor radionuclide therapy (PRRT) is a
tumor-targeted strategy that uses radiation to
induce tumor cell death by coupling radionuclides
to somatostatin analogs. Typical radionuclides
include 90yttrium and 177lutetium. PRRT represents
a therapeutic option as a second or third line in
progressive pNETs with somatostatin receptor posi-
tivity and homogenous expression [61]. To date, no
phase 3 trial of PRRT has been conducted in patients
with NET with a pancreatic primary site, and the
optimal sequencing with targeted drugs and/or che-
motherapy needs to be defined in pNETs.
Chemotherapy
Systemic chemotherapy is currently indicated for
patients’ locally advanced or progressive G1-G2
pNETs, next to SSA and targeted drugs therapy, or
as a first-line therapy in case of G3 pNETs and small
or large-cell pancreatic neuroendocrine carcinomas
(pNECs). The most widely used regimens include
combinations of temozolomide with capecitabine,
and streptozocin (STZ), doxorubicin, and 5-fluoro-
uracil (FAS) [62–65].
A cooperative group trial (ECOG 2211) recently
randomized 144 patients with progressive pNETs to
received temozolomide monotherapy versus temo-
zolomide and capecitabine, with progression-free
survival (PFS) as the primary endpoint [66]. The
temozolomide and capecitabine regimen was asso-
ciated with one of the longest PFS durations
reported for pNET-directed therapy (median PFS
22.7 months for temozolomide and capecitabine
versus 14.4 months). Our institution has previously
shown how a combination regimen FAS (5-florour-
acil, STZ and doxorubicin) is associated with a
response rate as high as 55% among patients with
primarily metastatic disease [67,68]. Based on these
data, temozolomide and capecitabine can be con-
sidered a standard of care regimen in advanced, well-
differentiated pNETs, although intravenous strepto-
zocin-based regimens remain a valid option. In G3
pNECs, cisplatin-based chemotherapy is the stan-
dard first-line therapy, followed by second-line
folinic acid, fluorouracil and oxaliplatin (FOLFOX)
or folinic acid, fluorouracil and irinotecan [69].
Preoperative therapy
Based on its cytotoxic activity, systemic chemother-
apy has recently been explored as preoperative ther-
apy for patients with locoregionally advanced or
borderline-resectable pNET, alone or in association

FIGURE 4. Percentage change in size of target lesion(s) for each patient treated with FAS (n ¼ 29). Patients that underwent
noncurative pancreatectomy for palliation years after therapy; # patients that developed pulmonary metastases while on
chemotherapy (previously published) (from [74]).

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Pancreas
with PRRT [70–72]. In a recent study, we hypothe-
sized that FAS may be used to reduce the size or
anatomic extent of locoregionally advanced pNET
prior to anticipated pancreatectomy. However,
using objective measures of radiographic response
(Modified Response Evaluation Criteria in Solid
Tumors, RECIST version 1.1) [73], we showed that
a clinically significant change in either the size of
the primary tumor or its relationship with adjacent
mesenteric vasculature is uncommon in response to
FAS therapy (Fig. 4) [74]. The role of preoperative
therapy for patients with advanced pNETs
remains experimental.
CONCLUSION
pNETs are a very heterogeneous group of neoplasms
that have increased in incidence in recent years.
They are often slow growing, but they harbor a wide
range of behavior and may present at an incurable
stage. Therapeutic management is mainly guided by
symptoms, tumor grade, and tumor stage. Surgery is
the only curative treatment, whereas systemic ther-
apies can only control disease progression. Observa-
tion may represent a reasonable approach for
patients with small, low-grade NF-pNET. In the
presence of unresectable progressive disease,
somatostatin analogs, targeted therapies such as
everolimus, PRRT, and systemic chemotherapy are
all useful. The role of preoperative therapy for
patients with advanced pNETs is still unclear.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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