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KEYWORDS
Everolimus Medical treatment Surgery Peptide receptor radionuclide therapy
Somatostatin receptor ligands Sunitinib Telotristat etiprate Theranostics
KEY POINTS
There is consensus that an individualized patient pathway agreed to by a multidisciplinary
team is the optimal planning approach to treatment.
Use of somatostatin receptor ligands as first-line therapy has been the paradigm for some
time but this may now be challenged with newer trial data on mammalian target of rapa-
mycin inhibitor and after peptide receptor radionuclide therapy (PRRT).
It is anticipated that as PRRT becomes more widely available it may become second-line
or first-line therapy.
BACKGROUND
The first multiple distal ileal neuroendocrine tumors (NETs) were found at autopsy in
1888 by Lubarsch and the name karzinoide or carcinoma-like tumor was later coined
by Oberndorfer in 1907.1–3 Carcinoid tumors are derived from enterochromaffin or Kul-
chitsky cells.4,5 A variety of biochemical syndromes are associated with carcinoid tu-
mors with foregut tumors (lungs, thymus, duodenum, and pancreas), which cause
angioedema, a hive-like pink flushing or rash due to histamine, 5-hydroxytryptophan
(5-HTP), and other vasoactive substances, and with serotonin-secreting midgut tu-
mors (small intestine, appendix, and proximal colon),6,7 which is the cause the classic
carcinoid syndrome (CS) with nondiaphoretic flushing, diarrhea, and occasional
wheezing due to right-sided cardiac failure following cardiac valve stenosis or
thickening5 (Fig. 1). Hindgut tumors (transverse colon, sigmoid colon, and rectum)
infrequently secrete hormones and typically are either incidentally discovered on lower
gastrointestinal (GI) endoscopy or present with obstructive symptoms.
Fig. 1. Main features of midgut CS and carcinoid crisis, with treatment options. CS is usually
caused by primary well-differentiated midgut NET with hepatic metastatic lesions that
release vasoactive compounds. Carcinoid crisis is characterized by profound flushing, bron-
chospasm, tachycardia, and hypotension, and is usually precipitated by tumor cytoreductive
surgery, embolization, or radio ablation. Serotonin antagonists and somatostatin receptor
ligands are the major treatment options. TGF, transforming growth factor; 5HT2a, serotonin
receptor 2a; 5TH2b, serotonin receptor 2b; 5TH4, serotonin receptor 4. (Adapted from Mota
JM, Sousa LG, Riechelmann RP. Complications from carcinoid syndrome: review of the cur-
rent evidence. Ecancermedicalscience 2016;10:662; with permission.)
New Treatments for the Carcinoid Syndrome 3
TREATMENTS
Established Therapies
Surgery
In the setting of an isolated primary tumor, surgical resection offers the possibility of
cure but even in the setting of high tumor burden, surgical cytoreduction plays an impor-
tant role in alleviation of carcinoid symptoms16 and can significantly improve survival.17
However, surgery in midgut carcinoid tumors may present several challenges. First,
the primary tumor may be small and difficult to locate and is often encased in fibrotic
tissue, causing bowel stricture, lymphatic obstruction, and mesenteric ischemia.9
Second, in cases in which right-sided carcinoid heart disease has affected tricuspid
and pulmonary valve function, elevated central venous pressure increases bleeding
from the hepatic veins, complicating resection of hepatic metastases.16
Locoregional therapies
Because NET liver metastases receive 80% to 90% of their blood supply from the he-
patic artery, whereas normal liver tissue is supplied by the portal vein,18–20 therapies
such as bland embolization, chemoembolization, selective internal radiotherapy, and/
or radiofrequency ablation can be very effective to not only debulk hepatic disease but
also to rapidly (within 24 hours) improve CS symptoms8,19–27 and improve sur-
vival.21,28,29 Liver-directed radiation is also a safe procedure29–31 and has been shown
to improve symptoms, decrease tumor markers,24 and offer excellent response
rates23,30 in neuroendocrine liver metastases.23,30 Female gender, well-differentiated
NETs, and a low number of metastases limited to the liver portend a better response
to 90yttrium (90Y) therapy.32,33
Liver-directed therapies are generally well-tolerated with low mortality rates,23,29,30
although some patients experience a postembolization syndrome with fever and fa-
tigue being the most common (80%–90%).19 Other complications include bile duct
injury with radiofrequency ablation. Lung shunting of beads,21,30 liver fibrosis, and
radiation gastritis can be seen in selective internal radiotherapy.21 Sepsis can compli-
cate all liver-directed procedures but particularly bland embolization and chemoem-
bolization. Bowel or liver ischemia with liver abscess and hepatorenal failure can be
serious complications.19 Despite these risks, liver-directed therapies can be very
effective treatments for CS control.20
4 Loughrey et al
Medical
For many years before the availability of somatostatin receptor ligands (SRLs), simple
medical therapies, such as the antidiarrheal agents loperamide,6 diphenoxylate, atro-
pine, and opium tincture,9 histamine 1 and 2 receptor blockers were the mainstay of
symptom control.34,35
First-generation somatostatin receptor ligands Due to its short half-life, naturally
occurring somatostatin has no clinical utility as a therapeutic agent. The first-
generation subcutaneously administered SRL octreotide (150 mg 3 times a day) was
demonstrated in 1986 to improve CS symptoms12,36–39 in 88% of treated subjects.38
Monthly administered octreotide long-acting release (LAR) and lanreotide Autogel
have equivalent affinity for somatostatin receptors (SSTRs) subtypes 2, 3, and 5,6,12
and exhibit multiple antitumor effects via inhibition of angiogenesis,40–42 interaction
with the immune system,12,42,43 inhibition of growth factors,44 and blockade of tumor
cell proliferation.42 Well-tolerated, even at high doses, their most common side effects
are nausea, abdominal discomfort, loose stools, and gallbladder dysfunction with gall-
stones or biliary sludge.45
One drawback to treatment with SRLs is that, over time, patients can become less
responsive to the drug (so-called tachyphylaxis). The mechanism of this phenomenon
is not fully understood but internalization or downregulation of SSTR2,6,46 upregulation
of other SSTRs not targeted by octreotide and lanreotide,12,47,48 variable SSTR phos-
phorylation, heterodimerization of the SSTRs with other receptors, and the effects of
b-arrestins on SSTR signaling, have all been proposed.49 However, despite tachyphy-
laxis, SRLs remain a mainstay of medical treatment for CS6,37,50 and have significantly
improved survival in NETs.51
New Therapies
Next-generation somatostatin receptor ligands
Unlike the first-generation SRLs sandostatin and lanreotide, which primarily target the
SSTR2, pasireotide has higher affinity to SSTRs 1, 3, and 5 (40 times)9,37,46,74 but 2.5
times lower affinity for SSTR2.9,37,75 Approved for the treatment of acromegaly and
Cushing disease,76,77 it has demonstrated lower rates of tachyphylaxis for growth
6 Loughrey et al
New Treatments for the Carcinoid Syndrome 7
hormone and insulin-like growth factor 1 inhibition in animal studies. This benefit may
extend to human subjects with carcinoid tumors.46,78,79
An open-label, single-arm, phase II prospective trial in 29 NET subjects, 5 of whom
had CS, examined treatment with 60 mg of intramuscular pasireotide every 4 weeks.80
The primary end point of the study was PFS assessed with computerized tomography
(CT) and MRI using RECIST.80 The median PFS was 11 months and subjects with
low hepatic disease burden, normal chromogranin A (CgA), and high SSTR5 seemed
to receive most benefit; 4 of the 5 subjects with CS-derived symptomatic
improvement.80 The most common side effect of the drug was hyperglycemia
(65%), which required management with oral hypoglycemic agents or insulin in 13
of 22 subjects.80 Only 1 subject had a medical history of diabetes at commencement
of the study.80
In a phase II open-label multicenter trial in subjects with CS whose symptoms were
inadequately controlled by octreotide-LAR, pasireotide was trialed with dosage esca-
lation from 150 mg twice a day to maximum 1200 mg twice a day until a clinical
improvement was observed.74 In this study, pasireotide at a dosage of 600 to
900 mg twice a day achieved complete or partial symptom control of diarrhea and
flushing in 27% of these subjects who were inadequately controlled by first-
generation SRL therapy.74 Tumor response as assessed by RECIST found 43% had
stable disease, whereas 57% exhibited disease progression.74
However, a subsequent randomized double-blind phase III study compared pasir-
eotide LAR 60 mg every 28 days with octreotide LAR 40 mg every 28 days in subjects
with carcinoid symptoms refractory to first-generation SRLs. The study was
concluded early due to low probability of the study meeting its primary endpoint.50
No significant difference in symptom control or PFS was reported at study close.50
Again, the major side effect of pasireotide was hyperglycemia; 9.4% for pasireotide-
treated and 1.6% in octreotide-treated subjects, respectively.50 The lack of clear su-
periority of pasireotide versus octreotide for symptom control in combination with its
frequent induction and/or worsening of hyperglycemia has tempered its use in CS in
most patients.81
=
Fig. 2. The mechanisms for the antiproliferation and antiangiogenesis effects of sunitinib
and everolimus. Vascular endothelial growth factor (VEGF) and platelet-derived growth fac-
tor (PDGF) are the potent growth factors involved in tumor invasion and metastasis that
drive downstream secondary messengers, including phosphatidylinositol 3-kinase (PI3K)-
AKT–activated mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Sunitinib is
an oral small molecule multitargeted receptor tyrosine kinase inhibitor that inhibits the ac-
tion of VEGF to induce angiogenesis. mTOR is a serine-threonine kinase and functions as a
key component of 2 multifunctional signal-transducing enzymes, downstream of the
growth factor–regulated PI3K-AKT pathway, influencing the translation, cell cycle progres-
sion, survival, and angiogenesis during cancer development and progression. When mTOR is
associated with raptor and mLST8 to form a complex mTORC1, it regulates cap-dependent
translation by phosphorylation and activation of ribosomal S6 kinase-1 (p70S6K), and phos-
phorylation and inactivation of 4E-BP1, initiating the classic translation process for many
proteins known to be important in cancer, such as hypoxia-inducible factor (HIF)-1. Everoli-
mus binds mTOR and inhibits signaling downstream of mTORC1. Prolonged or high dosage
of everolimus treatment can also inhibit mTORC2 formed by mTOR, rictor, sin1, and mLST8,
and it blocks AKT pathway activation, inhibiting downstream cell survival and proliferation
signal. (Data from Kutmon M, van Iersel MP, Bohler A, et al. PathVisio 3: an extendable
pathway analysis toolbox. PLoS Comput Biol 2015;11(2):e1004085; and van Iersel MP, Kelder
T, Pico AR, et al. Presenting and exploring biological pathways with PathVisio. BMC Bioinfor-
matics 2008;25(9):399.)
8 Loughrey et al
Bevacizumab
Bevacizumab is a monoclonal antibody to the VEGF-A ligand and is well-established
in the treatment of malignancy. Trials in NETs have generally focused on combination
therapies, including with everolimus, to enable dual inhibition of the mTOR and VEGF
pathways. Data have been slightly more promising in PNETs. In 56 subjects with well-
differentiated or moderately differentiated PNETs treated with weekly temsirolimus
25 mg IV in combination with 2 weekly 10 mg bevacizumab IV, there was confirmed
response rate in 23 (41%) subjects and PFS at 6 months in 44 subjects (79%).90 Initial
evidence suggested that bevacizumab may be more effective than interferon91 but a
subsequent study of 427 subjects assessed combination therapy for octreotide LAR
20 mg with bevacizumab 15 mg/kg 3 times weekly (n 5 214) or interferon 5 million
units 3 times weekly (n 5 213) and showed no superiority in advanced NETs.92
11
12 Loughrey et al
(HR 0.45, 95% CI 0.29–0.69, P<.001) and, likewise, pretreatment renal uptake pre-
dicted renal toxicity (HR 1.59, 95% CI 1.17–2.17, P 5 .003).110 Overall, these studies
indicate 90Y is a safe treatment with good CS symptom improvement.107,108
177
Lu is a low-energy beta-emitter and gamma-emitter with a half-life of 6.7 days
and tissue penetration of 2 mm, potentially making it more suitable for treatment of
smaller tumors.100 In the recent large Neuroendocrine Tumors Therapy (NETTER)
phase III randomized trial, 229 subjects with well-differentiated midgut NETs treated
with sandostatin-LAR 30 mg every 28 days were randomly assigned to receive 4
177
Lu-dototate treatments at a dosage of 7.4 GBq every 8 weeks (n 5 116) compared
with octreotide LAR 60 mg intramuscular alone (n 5 113).111 At 20 weeks PFS in the
177
Lu-dototate group was 65.2% (CI 50–76.8) versus 10.8% (CI 3.5–23) in the group
treated with high-dose cold octreotide alone.111 Grade 3 or 4 neutropenia, thrombo-
cytopenia, and leukopenia occurred at rates of 3%, 4%, and 9%, respectively, in
the group treated with 177Lu-dototate.111
Renal function is the dose-limiting factor in PRRT because radiation is reabsorbed
by the proximal tubules and can induce inflammation and fibrosis.98,112 Concomitant
infusion of the positively charged amino acids lysine and arginine were administered in
the radiopharmaceutical group, which reduced the reabsorption of the radiopeptide,
and renal function was stable at interim analysis.111 Age, impaired baseline renal func-
tion, hypertension, diabetes mellitus, and renal morphologic abnormalities are risk fac-
tors for renal dysfunction in PRRT and more caution may be prudent in these
patients.98,113 Overall, PRRT is a relatively safe112,114,115 and well-tolerated treat-
ment98–100,105 with generally mild side effects.100,102 90Y side effects include liver
toxicity, myelodysplastic syndrome (MDS), leukemia,116 cytopenia, male infertility,
and acute renal insult with possible progression to endstage renal failure.105–107 The
shorter tissue penetration of 90Y may result in less myelotoxicity.117 Response rates
to 90Yttrium-labeled-tetra-azacyclododecane tetraacetic acid (DOTA)-Phe1-Tyr3
-octreotide (TOC) (90Y-DOTATOC) and 177Lutetium-labeled-tetra-azacyclododecane
tetraacetic acid (DOTA)-Tyr3-octreotate (TATE) (177Lu-DOTATATE) range from 15%
to 35%.103–105
Other side effects of 177Lu include liver toxicity, hematological toxicity, renal
failure,98 MDS, hair loss,100 male infertility, and a tumor lysis presentation with
hormone-related crises (rare).99,103,118 Acute side effects of nausea, vomiting, and
abdominal pain around the time of PRRT administration are due to the administration
of amino acids rather than the PRRT itself.100,103
Higher baseline performance score, high uptake on pretreatment octreoscan, and
low hepatic disease load,103 suggest favorable responses to 90Y and treatment
response may also be predicted by 68Ga-DOTATOC uptake.119
FUTURE DIRECTIONS
SUMMARY
The other aspect of managing CS in the setting of NETs that is presently unclear is the
utilization or sequence of the now several different treatment options available. There
is general consensus that an individualized patient pathway agreed to by a multidisci-
plinary team is the optimal planning approach to treatment. In settings in which poten-
tial cure is attainable, such as surgery for an isolated primary tumor, the best treatment
option is clear cut. In other instances in which widespread functional NET is present,
use of SRL as first-line therapy has been the paradigm for some time but this may now
be challenged with newer trial data on mTOR inhibition and PRRT. The authors antic-
ipate that, as PRRT with individualized dosimetric analysis becomes more widely
available, in the United States at least, it may become second-line or first-line therapy
in unresectable disease, either alone or in various combinations.
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