NcXHF

THE SPECTRUM OF NEUROENDOCRINE TUMORS
The majority of PanNETs (40% to 91%) are welldifferentiated
and nonfunctional, thus they are not associated
with a clinical syndrome from hormone excess.
Historically diagnosed at a late stage, advances in diagnostic
imaging techniques (including endoscopic ultrasound) have
facilitated detection of incidentally discovered small nonfunctional
tumors, which now comprise up to 40% of newly
diagnosed tumors. 61-63 Interestingly, asymptomatic secretion
of peptides can be documented in 60% to 100% of
nonfunctional tumors (e.g., chromogranin, pancreatic polypeptide,
and others). 64 In contrast, a minority of patients
(22% in a recent series) presents with a clinical syndrome
stemming from hormone excess. 65 Insulin-producing tumors
are the most common (90% of which exhibit benign
behavior), followed by gastrinomas, glucagonomas, and
other rarer syndromes. 64
The initial work-up of a patient suspected to have a Pan-
NET typically involves cross-sectional imaging with multiphasic
CT or MRI to assess the primary tumor site and extent
of disease. Endoscopic ultrasound, radiolabeled somatostatin
receptor scintigraphy, and biochemical evaluations are
recommended as clinically indicated. 64-66 Serum chromogranin
A levels are elevated in 60% or more patients with a
PanNET. 67
Although indolent, PanNETs have malignant potential, as
manifested by local invasion, lymph node involvement, and
distant metastases. Most studies suggest that the risk of malignant
behavior correlates with tumor size, as at least 50% of
PanNETs recur or metastasize. 68 The presence of lymph
node metastases also portends a worse prognosis in resected
PanNETs (5-year survival is 49.4%). 69 Survival also depends
on age, histologic grade, and functional status. 57 In contrast
to other PanNETs, nearly all insulinomas are cured by complete
resection. 64
The etiology of PanNETs is largely unknown. Most tumors
appear to be sporadic, but a small proportion of tumors arise
in the setting of an inherited cancer syndrome (most commonly
MEN1). 64 The potential for an accompanying inherited
syndrome should always be considered, particularly if
the patient has a compelling personal or family history, multifocal
disease, a gastrinoma, or an insulinoma. 64
Treatment
In addition to controlling tumor growth, it is critical to recognize
the need for medical management of the hormoneexcessive
state in PanNETs. Somatostatin analogs (SSTa) are
often employed for symptom control, but medications to
control gastric acid hypersecretion and hypoglycemia are essential
for patients with gastrinomas and insulinomas, respectively.
64,66 Of note, SSTa should generally be avoided in
patients with insulinomas whose tumors test negative by somatostatin
receptor scintigraphy. 66
Patients with localized PanNETs are typically treated with
surgical resection with regional lymph node dissection as
there are no data to support neoadjuvant or adjuvant therapy.
The optimal surgical technique depends on the location
of the tumor. For some patients, enucleation may suffıce
(e.g., patients with insulinomas and incidentally detected
small nonfunctional PanNETs). 70 The resultant lack of
lymphadenectomy is a potential concern, however, as nonfunctional
tumors that measure 10mm to 20 mm have a small
but real risk of lymph node involvement. 66,70 On the other
hand, several studies suggest that nonfunctional tumors that
measure less than 10 mm may be safely observed in some
cases. 66,71 Given the relatively indolent nature of the disease,
patients with PanNET should be followed for recurrence for
up to 10 years postresection. 66
The treatment of advanced PanNETs has evolved dramatically
in the last 5 years. Surgical resection of all known disease
is recommended when feasible, although the data
suggest that such operations are not curative. 66 The risk of
recurrence after resection of NET liver metastases approaches
100% at 10 years in some series. 72,73 The role of cytoreductive
surgery and/or ablation is more controversial,
but is a consideration in select patients.
In patients with an unresectable disease, observation is an
acceptable option in asymptomatic individuals with a low tumor
burden and stable disease. 66 If systemic therapy is required,
several targeted agents have proven cytostatic activity
in PanNETs. Recent data suggest that biologically important
subgroups may exist (e.g., those with MEN1 or DAXX/ATRX
mutations), but studies correlating mutations with a clinical
outcome have been mixed. 74 Additional research is needed to
identify valid biomarkers predictive of response to therapy in
PanNETs. Octreotide delays progression in tumors of a
midgut origin and is presumed to be active in PanNETs. 75
Patients with nonfunctional WD-NETs (including Pan-
NETs) were included in the CLARINET study, in which patients
were randomly selected to receive lanreotide or
placebo. 76 Treatment with lanreotide improved progressionfree
survival (PFS; not reached vs. 18 months for placebo;
hazard ratio 0.47; 95% CI, 0.30 to 0.73; p 0.001), leading to
approval for this indication. Peptide receptor radiotherapy
with Lu 177 -orY 90 -labeled SSTa also holds promise, but remains
investigational for the treatment of PanNETs in the
United States. 77
The biologically targeted agents sunitinib and everolimus
also delay tumor growth in progressive PanNETs and are approved
for this indication. 30,78 Sunitinib is an oral multitargeted
agent that inhibits vascular endothelial growth factor
(VEGF) receptor signaling. In patients with progressive Pan-
NET, treatment with sunitinib delays progression by approximately
6 months (median PFS 11.4 months vs. 5.5 months
with placebo; p 0.001). 78 The mTOR inhibitor everolimus
also delays progression in patients with PanNETs (median
PFS duration 11.0 months vs. 4.6 months with placebo, p
0.001). 30 There are no data to guide the sequence of these
agents, which have distinct side effect profıles and are characterized
by stability, not shrinkage. Of note, although still
considered investigational, preliminary results suggest that
dual targeting of mTOR and VEGF signaling may be a means
of inducing tumor regression, not just stability, in PanNET. 79
The role of chemotherapy in PanNETs is evolving, but remains
an option, particularly in patients with a progressive
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