2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

A Renaissance in Therapeutic Options for
Pancreatic Neuroendocrine Tumors
Overview: The field of pancreatic neuroendocrine tumors
(NETs) has seen a remarkable renaissance in recent years with
exponential increases in published research, clinical trials,
and U.S. Food and Drug Administration (FDA)-approved treatments.
Surgical resection remains the foundation for management
of locoregional disease. However, for patients with
advanced disease, novel therapeutic options have emerged.
NETS ARISE from neuroendocrine cells throughout
the body, most commonly in the lungs, gastrointestinal
tract, and pancreas. The field of pancreatic NETs has seen
a remarkable renaissance in recent years, with exponential
increases in published research, clinical trials, and FDAapproved
treatments (Fig. 1). Pancreatic NETs have an
estimated incidence of 0.32 cases/100,000 people 1 and account
for 1% of all pancreatic cancers by incidence and 10%
of pancreatic cancers by prevalence. 2 The median age at
diagnosis is age 60, with a white male predominance. The
majority of NETs are functionally inactive but some produce
hormones that lead to the clinical syndromes associated
with hormone excess. Though most pancreatic NETs are
indolent, the spectrum of clinical behavior is quite variable
and sometimes difficult to predict. The nomenclature, classification,
and grading systems for NETs have historically
been inconsistent. Through critical evaluations of these
systems, common principles have emerged. 3,4 NETs are
generally divided into two main categories: welldifferentiated
(low and intermediate grade) and poorly differentiated
(high grade). The proliferative rate (mitotic
index and Ki67) is considered a critical component of pathologic
evaluation. Well-differentiated tumors usually have
less than 20 mitoses/high powered field (hpf) and a Ki67
index of less than 20%, and poorly differentiated tumors
more than 20 mitoses/hpf and a Ki67 more than 20%.
This discussion will focus on the management of welldifferentiated
pancreatic NETs.
Approach to Treatment
Locoregional Disease
At the time of diagnosis, approximately 40% of patients
with pancreatic NETs have locoregional disease. 2 Surgical
resection remains the mainstay of treatment for these patients.
There is currently no role for adjuvant treatment
following resection of a primary pancreatic NET, as little is
known about patient and tumor characteristics that predict
for recurrence.
Unresectable and Metastatic Disease
Nonsurgical therapies play a role in the setting of unresectable
and metastatic disease, which account for approximately
50% of newly diagnosed patients. 2 Patient selection
is a critical first step in the treatment algorithm. For
patients with functional tumors, somatostatin analogs
should be considered to alleviate symptoms of peptide release.
For patients with nonfunctional tumors, systemic
treatments are generally indicated for patients with pro-
By Pamela L. Kunz, MD
Two separate randomized placebo-controlled studies have
shown prolonged progression-free survival (PFS) with everolimus
or sunitinib. Future studies are designed to answer
questions about the role of somatostatin analogs as antiproliferative
agents, combinations of biologic therapies, and new
cytotoxic chemotherapy backbones.
gressive, bulky, or symptomatic disease. Otherwise, patients
with low-volume, stable, and asymptomatic disease may be
monitored closely without treatment.
Mediating Symptoms of Hormone Excess
An estimated 40% to 53% of pancreatic NETs are functional.
5,6 Functional tumors are defined as having inappropriate
elevation of serum hormone markers combined with
clinical evidence of hormone oversecretion, including insulinomas,
gastrinomas, VIPomas, glucagonomas, and somatostatinomas.
Somatostatin analogs are the foundation of
symptom management for patients with functional pancreatic
NETs and can both decrease the secretion of such
hormones and inhibit their end-organ effects. Somatostatin
is a naturally occurring polypeptide produced by paracrine
cells that are scattered throughout the gastrointestinal tract
and inhibits gastrointestinal endocrine and exocrine function.
Its effects are mediated through G-coupled protein
somatostatin receptors (SSTR 1–5). Short- and long-acting
octreotide (with high affinity for SSTR 2) is available in the
United States. Lanreotide, available in Europe, is a longacting
analog with similar binding affinity to octreotide.
Pasireotide, a novel somatostatin analog with a different
binding affinity profile compared to octreotide or lanreotide,
is currently in development. Note that somatostatin analogues
should be used with caution for patients with insulinomas,
as it may precipitate or worsen hypoglycemia.
Oncologic Control
Biologic Agents
Recent studies with inhibitors of signaling pathways
that target vascular endothelial growth factor (VEGF) and
the mammalian target of rapamycin (mTOR) have demonstrated
considerable activity in pancreatic NETs.
RADIANT-3 was a randomized phase III study that evaluated
the efficacy of everolimus, an mTOR inhibitor, in
advanced pancreatic NETs. 7 In this international, multisite
study, 410 patients with low- or intermediate-grade progressive
advanced pancreatic NETs were randomly selected to
From the Stanford University School of Medicine, Stanford Cancer Institute, Stanford,
CA.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Pamela L. Kunz, MD, Stanford University School of Medicine,
Stanford Cancer Institute, 875 Blake Wilbur Drive, Stanford, CA 94305; email:
pkunz@stanford.edu.
© 2012 by American Society of Clinical Oncology.
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