REVIEW - Carcinoid Cancer Foundation · 2016-12-29 · Sandler,4 in seeking to provide a logical framework to ... introduction of more generic terminology that embraces all neuroendocrine

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:526–547

EVIEW

herapeutic Options for Gastrointestinal Carcinoids

RVIN M. MODLIN, IGOR LATICH, MARK KIDD, MICHELLE ZIKUSOKA, and GEETA EICK
epartment of Surgery, Yale University School of Medicine, New Haven, Connecticut
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lthough wide surgical resection is the optimal curativeherapy for carcinoid tumors, in most patients the pres-nce of metastatic disease at diagnosis usually rendersxcision a palliative procedure. This nevertheless de-reases tumor burden, facilitates symptom control, andrevents complications caused by bleeding, perforation,r bowel obstruction resulting from fibrosis. In the stom-ch (types I and II) and rectum endoscopic excision maye adequate provided the lesion(s) are local. Long-termherapy is focused on symptom alleviation and improve-ent of quality of life using somatostatin analogues,

articularly in a subcutaneous depot formulation. Inome instances interferons may have a role but theirsage often is associated with substantial adversevents. Conventional chemotherapy and external radio-herapy either alone or in a variety of permutations aref minimal efficacy and should be balanced against theecrease in quality of life often engendered by suchgents. Hepatic metastases may be amenable to sur-ery, radiofrequency ablation, or embolization eitherlone or in combination with chemotherapeutic agentsr isotopically loaded microspheres. Rarely hepaticransplantation may be of benefit although controversyxists as to its actual use. Peptide-receptor–targetedadiotherapy for advanced disease using radiolabeledctapeptide analogs (111In/90Yt/177Lu-octreotide) ap-ear promising but data are limited and its status re-ains investigational. A variety of antiangiogenesis and

rowth factor–targeted agents have been evaluated, buts yet have shown little promise. The keystone of cur-ent therapy remains the long-acting somatostatin ana-ogues that alleviate symptomatology and substantiallymprove quality of life with minimal adverse effects.

his review article provides a comprehensive assess-ment of progress that has been made in the man-

gement of carcinoid tumors over the past 3 decades.lthough the disease was described in morphologic

erms early in the 20th century, it has only been in theast 50 years that the clinical and biochemical basis ofarcinoid neoplasia has been defined. In 1888, Lubarsch1

nitially noted the microscopic features of ileal carcinoids
ut considered them to be carcinomas. Thereafter, Ran-
om2 described the first observation of the classic pre-entation of carcinoid syndrome in a patient with a lesionf the ileum. However, it was Oberndorfer3 in 1907 whooined the term karzinoid (carcinoma-like) to describehese tumors, which showed a more benign behaviorhan adenocarcinomas. Little more than sporadic reportsere available thereafter until 1963 when Williams andandler,4 in seeking to provide a logical framework toescribe what appeared to be a ubiquitous collection ofesions, classified carcinoids by their embryologic site ofrigin as follows: (1) foregut (respiratory tract, stomach,uodenum, biliary system, and pancreas), (2) midgutsmall bowel, appendix, cecum, and proximal colon), and3) hindgut (distal colon and rectum). Although useful inhe context of contemporary biological knowledge of thatime, current considerations of the morphologic andiological heterogeneity of these lesions has led to thentroduction of more generic terminology that embracesll neuroendocrine tumors (NET) including carcinoidumors. Thus, carcinoid tumors of the gastrointestinalract currently are regarded as gastroenteropancreaticETs (GEP-NETs) because it is apparent that the term

arcinoid fails to define adequately the spectra of tumorshat are derived from different neuroendocrine cell types,ecrete a diverse spectrum of hormones, and have vastlyiffering clinical presentations.5

The incidence of gastrointestinal carcinoids has in-reased over the past 20 years, most likely as a result ofncreased awareness and detection.6,7 The tumors can beither sporadic or occur as part of familial syndromes,ainly multiple endocrine neoplasia I and II, von Hip-

el–Lindau disease, and neurofibromatosis. Overall, theyccur most frequently (74%) in the gastrointestinal tract,

Abbreviations used in this paper: CTGF, connective tissue growthactor; 5-FU, 5-fluorouracil; GEP, gastroenteropancreatic; HDAC, his-one deacetylase; 5-HIIA, 5-hydroxyindoleacetic acid; IFN, interferon;AR, long-acting repeatable; 131I-MIBG, Iodine-131-Meta-Iodobenzyl-uanidine; NET, neuroendocrine tumors; NP, neuropilin; SST, soma-ostatin; VEGF, vascular endothelial growth factor.© 2006 by the American Gastroenterological Association Institute

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May 2006 CARCINOID THERAPEUTIC OPTIONS 527

f which 38% are in the small intestine, 18% are in theppendix, 21% are in the rectum, 12% are in the colon,nd 6% are in the stomach.7 Clinically, their local man-festations include bleeding, obstruction, or perforationaused by either direct tumor invasion or fibrosis inducedy the tumor. Indeed, in many instances, carcinoids areetected incidentally at surgery performed for anotherastrointestinal disorder or during emergency surgery forppendicitis or obstruction, bleeding, or perforation. Sys-emic manifestations (flushing, sweating, diarrhea, bron-hospasm) often are paroxysmal and the result of theecretion of biological mediators by either the primaryesion or metastases, or the consequences of cardiac fail-re engendered by tricuspid or pulmonary valvular fi-rosis.Although in general the understanding of gastrointes-

inal carcinoids has improved, they usually are misdiag-osed and their treatment often is delayed. Fortunately,heir growth rate usually is relatively indolent (althoughome are aggressive) compared with most adenocarcino-as and appropriate treatment can be associated with

uite reasonable outcomes in some circumstances.This review provides an overview of the modalities

hat have been used in the treatment of these diverseumors in the past and assesses current therapy androvides information regarding options currently undernvestigation.

MethodsA retrospective survey of the world’s literature over the

igure 1. Therapeutic algorithm: management algorithm for gastrointeU, lutetium.

ast 26 years (1979-2005) was undertaken to evaluate the devel- r

pment of therapeutic approaches to gastrointestinal carcinoidumors. The key words used for this PubMed (www.pubmed.gov)earch included “carcinoid,” “therapy,” and more specific termsncluding but not limited to: “biochemical markers,” “tumorize,” “disease stability,” and “symptom improvement.” Whenossible, only data that pertain to patients with gastrointestinalarcinoids were extracted from series of GEP-NET studies. Dataere pooled and median values were calculated for each therapeu-

ic modality reviewed.

ResultsPrimary Surgical Resection

Resection of the primary tumor and local lymphodes is the only potentially curative therapy for gastro-ntestinal carcinoid tumors and usually is possible in upo 20% of patients (Figure 1).8 –10 Moreover, resection ofonhepatic tumor primaries has been associated with anncreased median survival duration from 69 to 139onths.11,12 The extent of resection, however, depends

n the identity of a given tumor (presently defined byite of origin, which in the future likely will be replacedy more precise molecular definition), its location, andhe involvement of surrounding structures and the extentf metastases. Overall, tumors of the appendix and rec-um have the best prognosis (largely owing to earlierresentation) and therefore a local excision is the mostppropriate treatment for most patients with lesionsmaller than 1 cm and with no lymph node involve-ent.13 In the case of rectal lesions this may be accom-

lished endoscopically provided endoscopic ultrasonog-

l carcinoids. RF, radiofrequency; PL, plasma; YT, yttrium; IND, indium;
stina
aphy confirms that disease is localized. For appendiceal

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528 MODLIN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 5

umors larger than 2 cm, a right hemicolectomy withesenteric excision should be performed but factors in-

luding location of the lesion (base of the appendix),istologic evidence of atypia, presence of mucin, andvidence of invasion override the arbitrary 2-cm sizeelineation.14 Colonic and small intestinal lesions showhe worst prognosis among gastrointestinal carcinoidsnd warrant a classic en bloc resection. Bowel resectionhould ensure extensive lymphadenectomy and wide re-oval of the mesentery, and should include a careful

xploration for multicentric disease.15 Surgical manage-ent of gastric carcinoids depends mainly on the type of

he lesion and the extent of the lesion. Sporadic carci-oids (type III) may be regarded as akin to neuroendo-rine carcinoma and usually behave aggressively andhould be managed as for gastric adenocarcinoma. Le-ions larger than 2 cm associated with local invasionequire subtotal gastrectomy or extended local resec-ion.16 However, types I and II gastric carcinoids (asso-iated with hypergastrinemia) may be managed by re-eated endoscopic or local wedge excisions, unless theesions are excessive in number or evidence of invasion ishown. Large lesions that ulcerate or bleed may requireore extensive surgical resection, particularly if the pa-

ient is young and evidence of diffuse gastric microcar-inoidosis is evident. Although initially proposed as ahysiologic solution to resolve the hypergastrinemia andhereby resolve enterochromaffin-like cell proliferation,he effect of an antrectomy may be unpredictable if thenterochromaffin-like cell lesions have become gastrinutonomous.17

In patients with metastatic carcinoids (hepatic, mes-nteric, and peritoneal), conservative resections of thentestine, mesenteric tumors, and fibrotic areas may im-rove symptoms and quality of life considerably. How-ver, the definitive role of surgery in metastatic disease isot established clearly. In principle, however, if theondition of the patient is such that surgery is not areater risk than the disease, the primary tumor shoulde resected to obviate the inherent dangers of an unpre-ictable emergency presentation with obstruction, per-oration, or bleeding.18

Although it is commonly accepted that resection of ateast 90% of the tumor burden is required to achievealliation, approximately 60% of patients will experi-nce symptom recurrence (surgery alone), and the 5-yearurvival rate is between 35% and 80%, depending on thexperience of the center.10,11 The benefits of surgicalreatment of gastrointestinal carcinoid tumors thereforehould be weighed carefully in each patient against the
otential risks inherent in an open exploration, especially 1
ecause treatment with somatostatin analogues canchieve similar rates of symptom relief with fewer ad-erse effects. Tumor debulking, however, may renderharmacologic therapy more effective by decreasing theecretion of bioactive substances.

Biotherapy

The development of long-acting somatostatin an-logues and depot formulations has proven instrumentaln the amelioration of the carcinoid syndrome and haveed to a substantial improvement in quality of life withelatively mild adverse effects.19,20 There have been spo-adic reports of cytostatic effects of such agents althoughigorous data are lacking. Indeed it has been proposedhat such agents have been responsible for an overallncrease in life expectancy in symptomatic patients.21

ntravenous somatostatin analogues are effective in theanagement of carcinoid crises, usually precipitated by

nesthesia or surgical or radiologic interventions.22 Re-ombinant leukocyte interferon (IFN)-� alone or in com-ination with somatostatin analogues has been used inisseminated carcinoid disease to alleviate diarrhea,ushing, and in some patients has been noted to induceome degree of tumor regression.23 Its use, however, alsoan be associated with significant toxic side effects.19,24

Somatostatin analogues. Although somatostatinrst was isolated by Brazeau et al25 in 1973 from theheep hypothalamus, it subsequently has been recognizeds a major neurotransmitter expressed throughout theentral nervous system, thyroid and adrenal glands, kid-eys, peripheral tissues, endocrine pancreas, and gastro-ntestinal tract. Most of the inhibitory effects of soma-ostatin on neurotransmission, motor and cognitiveunctions, smooth muscle contractility, glandular andxocrine secretions, intestinal motility, and absorption ofutrients and ions are mediated by cAMP inhibi-ion.26,27 Particularly appealing has been the experimen-al observations of its cytostatic effect on tumorells.28,29 Mechanistically this involves hyperphosphory-ation of the retinoblastoma gene product and G1 cell-ycle arrest, but also can result from somatostatin recep-or subtype 3–mediated (and to a lesser extent, subtype–mediated) apoptosis.28,30 Somatostatin itself also ap-ears to show some antiangiogenic properties.31,32

By the early 1980s a number of short synthetic ana-ogues of somatostatin including SMS201-995 (oc-reotide), RC-160 (vapreotide), BIM 23014 (lanreotide),nd MK 678 (Seglitide) were developed.26 These cyclicctapeptides are more resistant to peptidases and theiralf-lives and hence their biological activities are sub-tantially longer than native somatostatin (1.5–2 h vs
–2 min).33 In the 1990s, 5 somatostatin receptor sub-

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ypes were cloned and their distribution in various typesf normal and tumor tissues was described.34 Fifty per-ent of the amino acids in these receptors are identicalmong the 5 subtypes. In addition to being expressed ineuroendocrine tumors of the GEP axis, somatostatineceptors also are expressed at high densities in menin-iomas; medulloblastomas; medullary thyroid carcino-as; adenocarcinomas of the breast, ovary, and colon; and

n inflammatory and immune cells.35 Undifferentiatedumors tend to express somatostatin receptors less oftennd at a lower density than well-differentiated (less-alignant) neoplasias. The currently available soma-

ostatin analogues display high-affinity binding for typeand type 5 receptors, low affinity for type 1 and type 4,

nd medium affinity for type 3.26 The more recentlyescribed analogue (SOM230) shows nanomolar potencyor types 1, 2, 3, and 5, with no agonist activity at theype 4 receptor.26,36 In contrast to octreotide, this novelnalogue (currently in phase II clinical trials for midgutarcinoids) shows a high affinity for type 5 receptors,hich may prove therapeutically advantageous.36 –38

Octreotide. The somatostatin analogue octreotideSandostatin; Novartis, East Hanover, NJ) was the firstiotherapeutic agent used in the management of carci-oid tumors. Pooled data from 14 trials spanning theast 2 decades and including close to 400 patients re-ected a median biochemical response rate of 37%

able 1. Effects of Octreotide in Gastrointestinal Carcinoids

Study YearNumber ofpatients

Biochemicalresponse %

vols et al32 1986 25 72vols et al39 1987 19 63inik and Moattari40 1989 14 75berg et al41 1991 23 27altz et al42 1993 20anson et al43 1992 24 45anson and Oberg44 1993 55 37rnold et al21 1996 64 33i Bartolomeo et al45 1996 31 77ilsson et al34 1998 10 33’Toole et al46 2000 28 50arland et al47 2003 27 25olby et al19 2003 35 0elin et al20 2004 12 17edian 24 37ange 10–64 0–77

OTE. Pooled data of 14 trials spanning the past 2 decades reflectecreased urinary 5-HIAA levels in more than half of the patients studianging between 3% and 9%), with the cumulative tumor response ratf carcinoid disease, with 28% and 55% of patients manifesting bioco symptom relief, with 71% of patients experiencing resolution of di

, not reported/no data available.

range, 0%–7%), with only 4 trials showing decreased i

rinary 5-hydroxyindoleacetic acid (5-HIAA) levels inore than half of the patients studied (Table

).19,20,32,34,39 – 48 Objective tumor responses werehown in only 3 trials (range, 3%–9%), with the cumu-ative tumor response rate at 0%. In contrast, octreotideherapy appears better at slowing the progression ofarcinoid disease, with a median of 28% and 55% ofatients manifesting biochemical or tumor stability inhese studies, respectively. In general, the beneficial ef-ects of octreotide are limited to symptom relief, with1% of patients experiencing resolution of diarrhea orushing. There are no rigorous clinical data to support annhibitory effect on tumor growth and to date only about0 patients experienced partial tumor regression withomatostatin analogue therapy.10

Lanreotide. Lanreotide (Somatuline; Ipsen, Slough,K), a long-acting somatostatin analogue administered

very 10–14 days, has a similar efficacy to octreotide in thereatment of carcinoid tumors, but its formulation is easiernd more comfortable for patients to use. 49 The therapeuticffects of lanreotide have been studied in 11 groups, totalingbout 300 patients over the past decade, with little overallmprovement in responses over shorter-acting octreotide,lthough the decreased need for injection is advantageousTable 2).46,50 – 60 The median biochemical response rate ofhe entire patient population treated with lanreotide is 42%vs 37% with octreotide), with 3 trials reporting objective

Tumoresponse

%

No disease progression%

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0 28 62 88 920 — — — —0 25 50 75 1009 36 — 500 50 710 17 62 — —2 49 — 69 700 — 55 64 753 23 — 40 50

77 — — —— — 79 48

0 25 48 810 46 — —0 75 75 — —0 28 55 71 71

0–9 17–77 48–75 40–88 48–100

dian biochemical response rate of 37%, with only 4 trials showingbjective tumor responses were shown in only 3 trials (individual rates%. Octreotide therapy has a better effect on slowing the progression

cal or tumor stability. The beneficial effects of octreotide are limiteda or flushing.

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ared with octreotide, lanreotide has somewhat better ef-ects on tumor stability, with 46% and 81% of patientsaintaining biochemical and tumor size status quo, respec-

ively. The effects of lanreotide on symptom relief areomparable with those of octreotide, with 75%–80% ofatients reporting decreased diarrhea and flushing, respec-ively.

Depot formulations. The development of a depotormulation of octreotide, Sandostatin LAR (Novartis)long-acting repeatable), administered up to 30–60 mgnce every 4 weeks has to a large extent eliminated theeed for daily injections. However, symptom break-hrough in the weeks before a steady state is achieved orn the last week of the cycle sometimes necessitatesescue with an additional 50 or 100 �g (up to 1000 �g)oses of a short-acting analogue such as Sandostatin, ory increasing the dose and/or frequency of the depotnjection. A new slow-release depot preparation of lan-eotide, Lanreotide Autogel (Ipsen), administered subcu-aneously up to 120 mg once a month has been intro-uced in Europe. Ruszniewski et al60 evaluated thefficacy and safety of this 28-day aqueous prolongedelease formulation of lanreotide in 75 patients in a-month dose-titration study. Thirty percent of patientshowed a biochemical response and 75% and 80% ofatients reported resolution of diarrhea and flushing,espectively, which is comparable with the reported ef-

able 2. Effects of Lanreotide on Gastrointestinal Carcinoids

Study YearNumber ofpatients

Biochemicalresponse %

anobbio et al57 1994 8 62cherubl et al50 1994 12 —riksson et al51 1996 19 54uszniewski et al52 1996 33 42ymenga et al53 1999 48 27

aiss et al58 1999 19 —omasetti et al54 2000 10 —ucreux et al59a 2000 38 40’Toole et al46 2000 28 50icci et al55 2000 12 42ohaizak and Farndon56 2002 10 0uszniewski et al60 2005 55 30edian 19 42ange 8–55 0–62

OTE. The median biochemical response rate of the entire patient potrials reporting objective improvements in tumor size. Compared wit5% of patients maintaining biochemical and tumor size status qu

anreotide on symptom relief, particularly diarrhea, are less pronouanreotide reported decreased flushing, only 42% reported resolutioedian rate of symptom relief of both was 71%., not reported/no data available.

Overlapping patient population with Ruszniewski et al, 1996.52 Res

ects of other lanreotide preparations. The median de- e

rease in levels of urinary 5-HIAA and serum chromo-ranin A was 24% and 38%, respectively. The responseas higher in patients who had not been treated previ-usly with somatostatin analogs (46% vs 34%).

Although studies have indicated comparable efficaciesf the immediate-release octreotide, the 28-day LARctreotide, and the lanreotide 30-mg microparticle for-ulation at steady-state levels, there have been no re-

orts directly comparing the 28-day prolonged releaseormulations of lanreotide and octreotide.46,61 A recenteport comparing subcutaneous immediate-release oc-reotide with monthly octreotide LAR reported an in-reased median survival from the time of metastaticisease diagnosis (143 vs 229 months in favor of the LARorm).62 This represents a 66% lower risk for deathmong patients treated with the long-acting formula-ion. In addition, most recent data from a study withltra-high dose octreotide (Onco-LAR; Novartis) at 160g intramuscularly every 2 weeks for 2 months followed

y the same dose once monthly, appear to show someromise.33 The preliminary results in 12 patients showedumor size stabilization in 9 and biochemical responsesnd/or stability in 11. No significant tumor reductionas noted. At 6 months, the median plasma concentra-

ions of octreotide were 25–100 times higher than thosebtained by using octreotide LAR at regular doses. Therotocol also showed significant inhibition of angiogen-

Tumoresponse %

No Disease progression%

Symptomaticresponse %

Biochemical Tumor Diarrhea Flushing

0 38 90 100 870 — 58 42 860 — 90 — —0 46 — 38 538 52 81 389 — 52 —0 — 90 90 805 24 54 — 40— — — 89 418 — — 36 1000 83 — 90— — — 75 810 46 81 75 80

0–9 46–83 58–90 36–100 38–100

ion treated with lanreotide is 42% (vs 37% with octreotide), with onlyeotide, lanreotide has better effects on tumor stability, with 52% and28% and 55% of patients treated with octreotide). The effects ofcompared with octreotide. Although 80% of patients treated withecrease of diarrhea. In the population treated with octreotide, the

defined as �30% decrease in biochemical markers.

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uch as vascular endothelial growth factor (VEGF) andbroblast growth factor.33 In general, the highest re-ponse rates were reported using octreotide in dosesreater than 30 mg/day or lanreotide in doses greaterhan 5 mg/day (and up to 15 mg/day).58

An interim analysis of a phase II trial of SOM230 in1 patients with metastatic carcinoid tumors whoseymptoms (diarrhea and flushing) were refractory/resis-ant to octreotide LAR showed symptom relief in 33%.63

Although the biochemical and tumor responses toomatostatin analogues vary with the frequency and typef analogue used, the typical length of treatment withhese compounds is approximately 12 months as a resultf the development of tachyphylaxis (reported less fre-uently with longer-acting formulations) and/or in-reased tumor burden.19,64,65 Nevertheless, treatmentith somatostatin analogues generally is well-tolerated

nd their efficacy in symptom relief is unparalleled.dverse effects such as nausea, cramping, loose stools,

teatorrhea, cardiac conduction abnormalities and ar-hythmias, endocrine disturbances (hypothyroidism, hy-oglycemia, or, more commonly, hyperglycemia), andnfrequently gastric atony may occur.33,66 Cholelithiasisnd biliary sludge occur in up to 50% of patients, butew (1%–3%) develop acute symptoms requiring chole-ystectomy.67

Interferons. IFN-�, IFN-�, and human leuko-yte IFN all have been used in the pharmacologic man-gement of carcinoid tumors.24,67 Although the exactechanism of their action is understood poorly, it vari-

usly may include immune cell–mediated cytotoxicitynd delayed progression of the cell cycle from S to G2hase as a result of a reduction in cellular cyclin B andnhibition of Cdc2 kinase activity.68 Recent reports alsoave suggested a direct antiproliferative effect and inhi-ition of tumor angiogenesis mediated by suppression ofEGF gene expression, although a serum analysis of 29atients with carcinoid tumors found no correlation be-ween IFN treatment and serum VEGF levels.68,69 IFNsend to have substantial adverse effects including alope-ia, anorexia, fatigue, weight loss, fever, a flu-like syn-rome, and myelosuppression, but may show greaterntitumor activity (sic) than somatostatin analogues.49

Interferon-�. In addition to somatostatin ana-ogues, IFN-� is the most well-researched biothera-eutic agent in the treatment of carcinoid disease. Itsherapeutic effects are largely identical to those ofomatostatin analogues, with marginally better tumoresponses.23,24,70 – 81 Pooled data from 14 groups thatotalled more than 350 patients showed a median
iochemical response rate of 42% (range, 17%–75%), r
hich is comparable with octreotide (37%) and lan-eotide (42%), with 6 centers reporting reductions iniochemical markers (�50%) in half or more of theatients treated. Although the median tumor responseate of patients treated with somatostatin analoguesas 0%, treatment with IFN-� resulted in approxi-ately 10% of patients experiencing objective tumor

egression. The median time to progression from thetart of therapy is 12 months, whereas median survivalanged from 44 to 80 months.10 Biochemical andumor stability were achieved in 40% and 66% ofatients, respectively. Similar to somatostatin ana-ogues, the most pronounced effects of IFN-� arenhibition of disease progression and symptom relief,ith approximately 75% of patients reporting resolu-

ion of diarrhea or flushing.Human leukocyte interferon. The effects of human

eukocyte interferon are somewhat comparable with theeported outcomes of IFN-� trials.67,82– 85 Pooled datarom more than 70 patients treated at 3 Scandinavianenters in the mid- and late 1980s showed medianiochemical and tumor responses in 29% and 14% ofatients, respectively (vs 42% and 11% of patientsreated with IFN-�, respectively). Approximately 50%f patients treated with human leukocyte IFN main-ained disease stability at the time of follow-up evalua-ion. However, human leukocyte IFN seems to have lessronounced effects on carcinoid symptoms, with only6% and 36% of patients reporting resolution and/orecrease in diarrhea and flushing, respectively.

Interferon-� � interferon-�. A recent phase II trialith IFN-� in 51 patients with carcinoid tumors failed

o produce significant antitumor effects and the medianime to progression in the 3 patients (6%) who had aartial response was 5.5 months.86 The combination ofnterferon-� and interferon-� appears to be no moreffective, with 1 trial of 12 patients showing no bio-hemical or tumor responses but achieving disease sta-ility in 58% and 92% of patients, respectively, withalf of the patient population reporting symptom re-ief.87

Interferon-� � octreotide. It is debatable whetheromatostatin analogues and IFNs show a synergistic effectn carcinoid syndrome symptom management. Dual ther-py with octreotide and interferon-� is limited by the smallumber of trials, but the median biochemical response ratef 75% for the cumulative population of more than 80atients is far higher than the rates for each of the individualgents.19,43,44,88 Although biochemical responses were re -orted in 77%, 72%, and 75% of patients, none of the trials
eported any improvement in tumor size, and a median of

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5% of patients achieved biochemical stability. The mostecent study reported no significant difference in survivaletween patients treated with octreotide alone comparedith a group managed with combination therapy. 19 Theedian 5-year survival rates were 36.6% and 56.8%, re-

pectively. Symptom response data were available for 1roup of 19 patients; 47% reported improvement.

Tamoxifen. Tamoxifen initially was reported torovide symptom relief in 2 patients with carcinoidyndrome.89,90 In a subsequent study in the early 1980shat included 16 patients, tamoxifen therapy showed noiochemical or tumor responses.91

Chemotherapy

The majority of single-agent chemotherapeuticrotocols (5-fluorouracil, streptozocin, doxorubicin, acti-omycin D, dacarbazine) show little beneficial effect.ubsequent combination trials have not resulted in ad-itional increases in response rates.

Single-agent therapy. Numerous trials of single-gent chemotherapy with 5-fluorouracil (5-FU), dacarba-ine, doxorubicin, streptozocin, and dactinomycin,mong others, were conducted in the 1980s. No modal-ty showed response rates greater than 31% (Table).92–104 The most thoroughly researched chemothera-

able 3. Effects of Single-Agent Cytotoxic Therapies onGastrointestinal Carcinoids

Agent (study) YearsNumber ofpatients

Response,%

luorouracil92,101 1979–1983 49 20oxyrubicin92,94,101 1983–1984 114 21acarbazine92,95,96,101,103 1983–1995 95 16treptozocin92,97,101 1983–1987 13 15actinomycin95 1983 17 6isplatin98 1986 15 7arboplatin99,100 1990–1993 20 0yclophosphamide101 1979 — 0toposide102 1987 17 12elphalan92,101 1983 7 0ocetaxel104 2004 21 31a

edian (range) 17 (7–114) 12 (0–31)

OTE. The most thoroughly researched chemotherapeutic modality isacarbazine, with 4 trials achieving a trial-defined response rate of6%. Approximately 1 in 5 patients treated with 5-FU and doxyrubicinchieved therapeutic responses, whereas only 15% of patientsreated with streptozocin, 12% of patients treated with etoposide, 7%f patients treated with cisplatin, and 6% of patients treated withactinomycin were reported to have successful therapeutic out-omes. Trials with cyclophosphamide, carboplatin, and melphalaneported no clinically significant improvements. The median responseate of the entire patient population treated with single-agent chemo-herapy was 12%.

, not reported/no data available.Biochemical response.

eutic modality is dacarbazine. Trial-defined response r

ates of 16% were noted in approximately 100 patientstudied.92,93,95,96,103 Approximately 20% of patientsreated with 5-FU or doxorubicin achieved therapeuticesponses, whereas only 15% of patients treated withtreptozocin, 12% of patients on etoposide, 7% of pa-ients on cisplatinum, and 6% of patients treated withactinomycin were reported to have successful therapeu-ic outcomes.92,95,97,98,101,102 Trials with cyclophospha-ide, carboplatin, and melphalan reported no clinically

ignificant improvements.93,99 –101 The most recentlyublished data on the effects of docetaxel in 21 patientsith metastatic carcinoid disease reported biochemical

esponses in 31% of evaluable patients and tumor sizetabilization in 81% of patients, albeit without signifi-ant tumor regression.104 The median progression-freeurvival time was 10 months and the median overallurvival time was 24 months. The median response ratef the entire patient population treated with single-agenthemotherapy was approximately 10%.

Multiple-agent therapy. Of the numerous permu-ations of chemotherapeutic agents, the combination of-FU and streptozocin with or without cyclophospha-ide is the most extensively studied.101 Pooled data

rom 5 trials that included a total of 165 patients treatedith 5-FU and streptozocin reflected a median response

ate of 39%.84,94,97,101,105 Triple therapy with 5-FU,yclophosphamide, and doxorubicin achieved a similaresponse rate (38%), but the addition of streptozocin tohis combination did not result in an improved out-ome.106 –108 The only 2 trials that reported improvedutcomes in a more significant proportion of patients80% and 50%) were double-agent studies of 5-FU withomustine and cisplatin with doxorubicin. These studies,owever, were limited by the relatively small populationizes of 5 and 6 patients, respectively.109,110 The medianesponse rate of the entire patient population treatedith these combination chemotherapies was 22%, which

eflects little improvement over the efficacy of singlegents (0%–21%).

Overall there is little robust evidence available todvocate the use of single-agent or multiagent chemo-herapeutics in this essentially chemoresistant diseaseecause no protocol has shown objective tumor responseates greater than 15%. The only 2 groups of tumors forhich chemotherapy has shown some results, albeit tran-

ient, are pancreatic and undifferentiated NETs.111

Biochemotherapy

The addition of chemotherapeutics to biotherapyith interferon-� has been studied in 2 small trials.riple therapy with interferon-�, streptozocin, and doxo-

ubicin resulted in no measurable biochemical or objec-

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ive tumor responses in 11 patients.76 The addition ofuorouracil to interferon-� in 14 patients resulted in 2 ofpatients experiencing a biochemical response and 1 of

4 patients experiencing a reduction in tumor size.112

he addition of chemotherapeutic agents to biotherapyrotocols does not appear to improve on results of indi-idual modalities.

Management of Hepatic Metastases

Overview. The presently available pharmacologicnterventions usually have not addressed hepatic carci-oid metastases specifically, but as noted earlier areomewhat ineffective overall and often show severe ad-erse effects. Similarly, an invasive surgical approachften is risky, sometimes has serious associated adversevents, or may be unfeasible technically. Interventionepends on the extent of hepatic disease and its anatomicsegment) localization. This may range from wedge re-ection to hemihepatectomy or the use of local ablativeechniques (cryofrequency or radiofrequency ablation) ifultiple metastases precluding segmental resection are

resent. In instances of diffuse metastasis or multipleetastases with dominant lesions, selective angiography-

uided occlusion or embolization of the hepatic arterialree has been developed as an alternative modality foratients in whom safe or effective surgical excision isnattainable. This relatively minimally invasive ap-roach is based on the premise that most of the vascularupply to metastases originates from branches of theepatic artery. Normal hepatic parenchyma, on the otherand, receives additional blood supply from the portalenous system.

Initially, the devascularization and necrosis of hepaticetastases was achieved through open surgical ligation

f the common hepatic artery. However, the outcomesere inconsistent, short-lasting (development of collat-

rals), and frequently unacceptably costly because of bothhe need to repeat the procedure and high perioperativeortality rates of up to 20%.113 The subsequent devel-

pment of interventional radiologic approaches that in-olve highly selective embolization of tumor vasculatureas led to a significant reduction of reactive angiogenesisnd collateral formation, and most importantly hashown much less morbidity, thus obviating the need forpen surgical ligation.15,114

Currently, most vascular occlusion protocols involveranscatheter arterial chemoembolization by injection ofn emulsion of a cytotoxic drug (usually streptozocin oroxorubicin) into the branches of the hepatic artery,ollowed by embolization with gelatin sponge particlesr microspheres until a significant decrease in blood flow
s achieved. The therapeutic injection is preceded by w
uperior mesenteric and celiac trunk arteriography tossess the arterial distribution and portal vein patencynd to evaluate tumor blood flow.113,115 The underlyingrinciple behind the combination of intra-arterial chemo-herapy and hepatic artery embolization is based on theotion that a combination of reduced vascularization andnoxia will increase local drug concentrations and decreaseash-out time in the metastasis. 116,117 In situ cryofre-uency or radiofrequency ablations usually are reserved foratients with localized or residual disease, and often are useds adjuncts to primary resective surgery. Hepatic emboliza-ion with concurrent local irradiation with radiolabeledicrospheres (brachyradiotherapy) and alcohol injection di-

ectly into liver foci also have been used for metastases ofarious tumors, but the experience with gastrointestinalarcinoids is limited.118,119

Surgical resection. There have been more than aozen trials or reports over the past decade on the effectsf surgical resection on hepatic metastases. Most series,owever, do not discriminate carcinoid tumors fromETs and GEPs and very few report biochemical/objec-

ive response rates. This notwithstanding, the medianesponse rate of the entire pool (�400 patients) is morehan 90%, with about 60% of patients experiencingecreased urinary 5-HIAA levels after surgery. Symp-omatic improvement is reported in 90% of patients andhe median duration is between 19 and 45 months.120

he median time to progression varies between 16 and0 months, depending on whether the surgical resectionas palliative or complete.121 McEntee et al11 retrospec-

ively reviewed the Mayo Clinic experience of hepaticesection for patients with metastatic NETs who under-ent resection between 1970 and 1989 (37 patients; 24atients had a carcinoid). Of the 10 patients with carci-oid who underwent resection with curative intent, 9chieved complete clinical response; similarly, of the 13atients who underwent palliative resections, 6 of 786%) showed biochemical responses.11 In a 1996 seriesf 64 patients with disseminated midgut carcinoids, 14atients (22%) who underwent hepatic resectionschieved anatomic and biochemical cure by surgerylone, with a mean reduction of urine 5-HIAA secretionf 78% and a 5-year survival rate of 100%. Forty patientsith bilobar hepatic disease underwent embolization in

ombination with octreotide. In this group, 5-HIAAevels were reduced by 55%, 17 patients (43%) showedbjective tumor response, and the 5-year survival rateas 56%.122 The largest review to date that included20 carcinoid patients reported a biochemical responseate of 96% among patients whose hepatic metastases
ere resected surgically.121 This was associated with a

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-year survival rate of 61%, which is slightly less thanhe median rate of 72% for the entire patient populationreated surgically for hepatic metastases surveyed in thiseview. In contrast, the 5-year survival rate withouturgical therapy is approximately 30%.10

Hepatic artery embolization. The use of occlusivegents with or without concurrent chemoembolization isssociated with biochemical responses in 5%–75% andumor responses in 8%– 60% of patients.70,79,123–136

he most frequently used single-agent modality is gel-tin powder, and in more than 60 patients with carcinoidumors the use of gelatin powder resulted in 34% and2% of patients achieving biochemical and tumor-dim-nution responses, respectively.123–125 In a separate seriesf 23 patients, embolization with either gelatin powder,olyvinyl alcohol, or coils resulted in effective biochem-cal responses in 52% of patients.126

Trials using transcatheter arterial occlusion with che-oembolization have reported biochemical responses in

2%–75% of patients, with a median response rate ofpproximately 60%.70,79,127–136 Reported tumor re-ponse rates are 8%–60%, with a median of 50% ofatients showing objective tumor regression (Figure 2).n a group of 42 patients treated with hepatic-arterycclusion followed by systemic chemotherapy, the me-ian overall decrease in 5-HIAA levels among respondersas 75% with hepatic artery occlusion alone and 89%ith added chemotherapy.132 The most thoroughly re-

earched combination occlusion modality, hepatic arteryigation with Gelfoam (Pharmacia, Peapack, NJ) andoxorubicin (4 trials and 66 patients), resulted in bio-hemical responses in 71% of patients and tumor regres-ion in approximately 50% of patients.127–130 Otherombination modalities of chemotherapeutic agents (5-U/cisplatin/mitomycin) with occlusive agents (gelfoam,

igure 2. Hepatic metastasis prehepatic and posthepatic artery em-olization. (A) Computed tomography (preembolization): axial sectioneveals large metastatic focus involving the left hepatic lobe with amall area of central necrosis. Note para-aortic/mesenteric adenop-thy. (B) Positron emission tomography–computed tomographypostembolization): large attenuated mass in the left hepatic lobeonsistent with necrosis with recent known embolization of the met-static carcinoid tumor.

olyvinyl alcohol, coils) have not been associated with l

ny increased therapeutic advantage.79,131,133,134,136 Athis time it is unclear whether combinations of chemo-herapeutic agents and vascular occlusive material such aselfoam, starch particles, lipiodol, or radioisotope-loadedpheres result in any significant survival benefits.

The most beneficial aspect of vascular occlusion ther-py is symptom control, with approximately 90% and00% of patients experiencing relief from diarrhea andushing, respectively. Nevertheless, despite the short-erm efficacy the duration of the response after hepatic-rtery occlusion or embolization can be short-lived. Theuration of symptom relief is between 14 and 22onths, with mean survival times of 24 –32 months.127–

30 In 1 study of 23 patients treated with hepatic-arterycclusion without chemoembolization, 20 patients87%) responded to embolization with a median responseuration of 11 months.126

Although surgery is a more formidable procedure, em-olization can be associated with a series of adverse effectshat may range from transient symptoms (pain, nausea,ever, fatigue), which occur in 30%–70% of patients, toiver enzyme abnormalities, which occur in up to 100% ofatients (transaminitis, postembolization syndrome), toorid and potentially lethal carcinoid crisis with massiveelease of vasoactive substances. 10 The latter scenario can bebviated by the prophylactic use of somatostatin analoguesefore embolization.137 Other unwanted effects include gas-rointestinal bleeding, acute pancreatitis, ischemic necrosisf the gallbladder and small bowel, liver abscesses, gastricnd duodenal ulceration, sepsis, renal failure, hepatorenalyndrome, portal vein thrombosis, sclerosing cholangitis,rterial thrombosis, and arrhythmias. 134 These usually re-ect erroneous embolization of nonhepatic vessels or bacte-ial infection of necrosed tumor.

Cryoablation and radio frequency ablation. Ra-iofrequency ablation induces cellular destruction by theonversion of high-frequency alternating current into heat,chieving temperatures in excess of 60°C. Cryotherapy in-olves cycles of freezing and thawing by means of a cryo-robe placed within the tumor foci.138 In 1 series of patientsho underwent cryotherapy, close to 90% experienced

omplete relief of symptoms for a median interval of 11onths and approximately 60% showed decreased 5-HIAA

ecretion.139 Interestingly, during the follow-up period ofpproximately 2 years, about 90% of patients experiencedecurrence. Approximately 50% of recurrences were ob-erved in the previously ablated foci. Another study of 13atients treated with cryoablation for neuroendocrine liveretastases reported a 92% survival rate at a median fol-

ow-up time of 13.5 months.140

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One series of 32 patients who underwent laparoscopicadiofrequency ablation for hepatic metastases from neu-oendocrine tumors, including 13 gastrointestinal carci-oids, showed a partial or significant decrease in tumorarkers in 65% of patients at a mean follow-up period of

.6 years.141 Forty-one percent of patients showed novidence of disease. Local recurrence in the liver occurredn 13%, existing lesions progressed in 13%, new lesionseveloped in 28%, and new extrahepatic disease devel-ped in 25% of patients. The symptomatic response toadiofrequency ablation lasted for a mean of 10.1 monthsrange, 6–24 mo). The study reported no perioperativeortality and the mean hospital stay was 1.1 days.

ikewise, 3 patients with unresectable hepatic carcinoidetastases treated with radiofrequency ablation showed

ecreased symptoms in the first 3 months after treat-ent.142 All 3 patients had decreased octreotide require-ents postprocedure, including 1 patient who discon-

inued octreotide treatment for symptom control. All 3atients showed objective tumor shrinkage on computedomography. In general, cryotherapy and radiofrequencyblation are of limited use in tumors larger than 35 mmnd in patients with multifocal (�5) hepatic metasta-es.113

Orthotopic liver transplantation. At present, thendications for hepatic transplantation are to achieveymptom relief from unresectable neuroendocrine liveretastases in the presence of no other evidence ofetastases.143 However, the benefit of this procedure

n the treatment of metastatic carcinoids has yet to bestablished rigorously because there are few centershat offer the procedure and experience is limited tomall series. Overall, approximately 50 liver trans-lantations have been described, with symptomaticelief occurring in 90%–100% of patients. Given theelatively short follow-up times available, the 5-yearurvival rates of 36%–73% represent for the most partctuarial calculations.144 One of the first case reportsn this subject included a patient with a small-bowelarcinoid who maintained biochemical response forlose to 10 months after surgery and showed no ra-iologic evidence of recurrence at 20 months post-ransplant.145 The first prospective series included 9atients with carcinoid tumors but only 3 patientsere followed-up for longer than 3 years. The reported-year survival rate was 81%.146 A number of earlyeries reported high perioperative mortality rates andrequent tumor recurrence. Thus, in the series by Langt al148 of 12 patients, there was 1 intraoperativeortality and 2 patients died in the postoperative

eriod as a result of sepsis and/or tumor recurrence. c

imilarly, in a series of 6 hepatic transplantations forarcinoid the median survival was 20 months, withisease recurrence occurring in 5 patients at a medianollow-up period of 11 months.148 In a separate seriesf 4 liver transplants for carcinoids, 3 patients werelive at 15– 62 months.149 The largest series to date15 patients with carcinoids in a group of 31 patientsith metastatic NETs) undergoing orthotopic liver

ransplantation reported a 5-year survival rate of 73%,ith only 47% of patients disease-free at follow-up

valuation.150 Of note, however, was the overall post-perative mortality rate of 19%, with 50% of thearcinoid transplant patients suffering at least 1 majoromplication (peritoneal bleeding, acute/chronic re-ection, or acute pancreatitis). Studies that excludedatients with noncarcinoid tumors or extrahepatic dis-ase reported significantly higher success rates. Oneuch series reported actuarial 5-year and disease-freeurvivals of 70% and 53%, respectively.151 Overall,he outcome of liver transplantation for carcinoid he-atic metastases remains less than satisfactory, reflect-ng both morbidity of transplantation and the intrin-ic nature of the disease, and the recrudescence basedn the use of immunosuppressive agents in the pres-nce of undetected or minimal metastatic disease. Inhis respect a recent cumulative review of 103 patientseported that up to 40% manifested extrahepatic dis-ase spread before transplant.152

Radionuclides

The response rate of carcinoid tumors to exter-al beam radiation therapy is very limited.153 Pallia-ive therapy, however, has some efficacy for bone andrain metastases and in the management of spinal cordompression.154 The more recent introduction of sys-emic receptor–targeted (a variety of radiolabeled so-atostatin analogues) or metabolically directed radio-

herapy using a variety of isotopes for the treatment ofnoperable or metastatic GEP tumors has engenderedarly optimism.155 This technique involves targetingf a molecule-radionuclide conjugate to specific sur-ace receptors on tumor cells. On binding to theeceptor, the radioisotope-molecule complex is endo-ytosed. Thus, a very focal and effective dose of radi-tion theoretically can be administered to tumor oreritumoral cells only, leaving the majority of sur-ounding nonneoplastic tissue intact. In addition, bysing isotopes with different emission wavelengthshe extent of local irradiation to a certain extent can beailored to the size range of the lesions. Although renalxposure is of concern, kidney irradiation can be de-
reased substantially by pretherapy amino-acid infusion

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nd adequate hydration.156 The 4 radionuclides mostommonly used in the treatment of carcinoid disease are31I-MIBG (Iodine-131-Meta-Iodobenzylguanidine), in-ium-111, yttrium-90, and lutetium-177 (Table).157–171

� electrons (from isotopes such as iodine-131 andttrium-90) are able to penetrate about 1 cm of tissue.172

radiation (generated from the decay of iodine-131 andndium-111 isotopes) is the most penetrating of all typesf radiation and the photons released engender damagey ionizing molecules they strike. In addition to �adiation, indium-111 also emits Auger electrons by arocess in which an ionized atom emits a second electronather than a photon. Because such electrons typicallyenerate only a few thousand electron-volts in energy,heir effective radius of travel is less than 100 nm andhey are effective only if internalized within a cell.163

nitially iodine and then indium-tagged somatostatinnalogues were used but more recently lutetium-177,173

n emitter of � particles and � rays, has proved moreffective. Lu-177 bound to DOTA0-Tyr3-octreotate haseen reported to result in 3- to 4-fold higher uptake in

majority of somatostatin receptor–positive tumorshen compared with indium-111.174 Because Lu-177

able 4. Effects of Peptide Receptor Radionuclide Therapy in

Investigator YearNumber ofpatients

tte et al158 1999 9 9

aldherr et al159 2001 12 9

irgolini et al160 2002 34 9

cCarthy et al161 1998 10 1

e Jong et al162 1999 10 1

alkema et al163 2002 9 1

nthony et al164 2002 17 1

uscombe et al165 2003 10 1

odlin et al166 2005 29 1

oefnagel et al178,a 1994 52 1

aal et al167 1996 30 1

aal et al167 1996 20 1

ukherjee et al168 2001 18 1

afford et al172 2004 98 1

wekkeboom et al169 2003 12 1

eunissen et al170 2004 26 1

wekkeboom et al171,b 2005 65 1

edian (range) 17 (9–98)

OTE. Four radiolabeled somatostatin analogues have been studied inumors (90Yt, 111In, 131MIBG,177Lu). Two of the 3 yttrium trials showedith 131MIBG showed no effect on tumor size. Four of the 6 trials of 11

rial (Teunissen et al, 2004170) showed better tumor responses (48%t 2%. The effects of radionuclide therapy are better at maintaining theize stability, respectively.Collective review of 5 centers.Partial patient population overlaps with Kwekkeboom et al, 2003169

as a lower tissue penetration range compared with A

ttrium-90, it has been proposed that it may be benefi-ial for the treatment of small neuroendocrine tumorsecause the therapeutic-dose exposure of cells distantrom the bound and internalized somatostatin receptorss minimized.172

Although radiopeptide-receptor targeting has beensed for only a relatively limited period of time in thereatment of carcinoid disease, overall this strategy haseen associated with a reasonable degree of disease sta-ilization and, of particular importance, shows relativelyild toxic effects.163

Iodine-131–MIBG. Iodine isotopes (� emitters)ave been used as therapeutic agents since 1942 and ini-ially were used for scintigraphy and thyrotoxicosis. 175

ore recently, 123I and 131I have been used in the treatmentf neuroendocrine tumors.176 In 1994 an initial review ofhe cumulative therapeutic data of 131I-MIBG summarizedhe experience from 5 European centers that included 52atients.177 A tumor response rate of 15% was noted withumor stability achieved in close to 70% of the pooledopulations. Subsequently, Taal et al 167 treated 30 carci-oid patients with 131I-MIBG and 20 patients with unla -eled MIBG, and reported a biochemical response rate ofess than 10% with no objective remission in either group.

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past decade for their potential therapeutic effects on neuroendocrinelete absence of objective tumor regression. Similarly, 2 of the 4 trialsowed response rates between 13% and 20%. The most recent 177Luthe median response rate of the entire patient population remained

us quo, with 53% and 79% of patients achieving biochemical or tumor

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bjective response in 11%.167 The largest retrospectiveeries that analyzed the use of 131I-MIBG in the manage-ent of metastatic midgut carcinoids (n � 58) reported 3-

nd 5-year survival rates of 77% and 63%, respectively, asompared with 56% and 47%, respectively, for controls. 178

he largest prospective series to date (n � 98) of patientsith metastatic carcinoid tumors reported biochemical re-

ponses in 37% of treated patients; however, this was notssociated with increased survival rates. 171

Overall the median tumor response rate for the pa-ients treated with 131I-MIBG is low (�5%), althoughhe modality appears somewhat more effective in achiev-ng biochemical (50%) or tumor stability (70%).

Indium-111. More recently, iodine usage haseen superseded by the use of indium-111 (half-life, 2.83ays, and both a � ray and Auger electron emitter) boundo a variety of somatostatin analogues, including oc-reotide and octreotate.172 111In-labeled somatostatin an-logues are the most commonly studied radiopeptides toate in the treatment of carcinoid disease, largely reflect-ng their availability. Overall tumor response rates areetween 13% and 20%.160 –165 Similar to 131I-MIBG,he benefits of therapeutic protocol mostly were limitedo disease stabilization, with a median of 65% in theverall pool of 85 patients experiencing no progression inumor size and 54% of patients in 1 series experiencingeveling of urinary 5-HIAA levels.163

Yttrium-90. After the evaluation of indium-labeledomatostatin analogues, the �-emitting yttrium-90 (half-ife, 2.67 days) has been assessed as a therapeutic agent foromatostatin-receptor–positive tumors. 172 The use of theomatostatin ligand, DOTA-d-Phe1-Tyr3-octreotide, haseen reported to facilitate administration based on its en-anced stability and easy yttrium-90 labeling. The thera-eutic effects of 90Y-octreotide on tumor stabilization ap-ear to be more effective compared with 111In-labelednalogues. Thus, a median of 92% of patients in a poolf 55 patients maintained stable tumor size.157–159 How-ver, 2 out of 3 trials were unable to show objectiveumor regression whereas 1 trial achieved tumor regres-ion in only 8% of patients. The median time to pro-ression and median overall survival were 30 and 60onths, respectively.

Lu-177. The most promising advance in the fieldf radiopeptide therapy has been the recent developmentf 177Lu-octreotate, which emits both � and � radiation.he 177Lu-octreotate combination has a half-life of 6.64ays and shows a higher affinity for somatostatin-recep-or subtype 2.179 In 76 patients with GEP tumors,iochemical responses were reported in 30% of patients,
hereas stable disease was identified in 40%. Tumor p
esponses were reported in 35% of patients with gastro-ntestinal carcinoids and between 80% and 90% of pa-ients experienced tumor stabilization.168,169,180 Theata on the largest patient series treated to date withutetium-labeled somatostatin analogues (n � 131, ofhich 65 were gastrointestinal carcinoids) found that

emission rates were correlated positively with high pre-herapy octreotide scintigraphy uptake and limited he-atic tumor load.170 Median time to progression (�36o) was significantly shorter in patients with extensive

iver involvement (26 mo).

Management of Carcinoid-Related Fibrosis

Given the increased longevity of carcinoid pa-ients, the sequelae of tumor-induced fibrosis (both localnd systemic) represent a more frequent therapeutic chal-enge.181 Thus, bowel obstruction secondary to perito-eal fibrosis is the most common presenting symptom ofmall intestinal carcinoids, and heart failure secondary toight-sided valvular fibrosis has emerged as one of theost serious extraintestinal manifestations of carcinoid,

ccurring in 20%–70% of patients with metastatic dis-ase and resulting in as much as 50% of carcinoidortality.182,183 As of yet, there is no effective pharma-

ologic therapy for either clinical problem. In the in-tance of bowel obstruction, surgical lysis of the adhe-ions often is demanding technically because of theocoon effect of extensive fibrosis engendered by thebrosis-promoting growth factors produced by the tu-or cells.184 Similarly, bowel anastomosis has a high risk

or ischemic necrosis given the associated mesentericascular fibrosis. Indeed, this biological event may inde-endently culminate in mesenteric ischemia, bowel is-hemia, and perforation.181–183

There is currently no medical therapy that appearsffective in ameliorating carcinoid-induced fibrosis. As aonsequence, valvular replacement usually is required toanage carcinoid heart disease, although temporary

melioration can be provided by palliative balloon pul-onary valvuloplasty.185 Overall, adequate therapy for

ight-sided valve disease is associated with improvementf symptoms and an increased quality of life despite theelatively high morbidity and mortality rates of cardiacntervention.186

Symptomatic Therapy

Although the long-acting depot formulations ofomatostatin antagonists (Somatuline Autogel and San-ostatin LAR) are the principal agents in the alleviationf carcinoid symptoms, other modalities bear some con-ideration.184 Nonspecific supportive care of carcinoid
atients includes advising the patient to avoid factors

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hat induce flushing or bronchospastic episodes such aslcohol ingestion, certain cheeses, nuts, stressful situa-ions, or some kinds of physical activity. Intake of agentshat exacerbate symptoms (flushing, sweating, and diar-hea) such as capsaicin-containing foods (curry, peppers)hould be diminished. Moderate diarrhea generally re-ponds to conventional antidiarrheal agents such as lo-eramide or diphenoxylate; cholestyramine (bile-saltinder) may be useful if the patient has undergone aistal ileal resection to remove the primary tumor (Fig-re 3). More pronounced diarrhea can be treated with the-HT receptor subtype 2 antagonist cyproheptadine,hich is effective in up to 50% of patients, and also maye of benefit in alleviating anorexia or cachexia in thoseith a malignant carcinoid syndrome.187,188

Short-term treatment with the selective 5-HT recep-or subtype 3 antagonist ondansetron has been shown tomeliorate carcinoid diarrhea and improve gastric emp-ying. Flushing, however, was not affected.189 In addi-ion, ondansetron reduces the postprandial colonic hy-ertonic response in carcinoid diarrhea to normal

igure 3. Symptom management: management of gastrointestinalarcinoids symptoms. Carcinoid patients often show a constellationf symptoms that may vary in intensity of both duration and expres-ion. Some symptoms may be abrogated by avoiding inciting or pro-ocative agents, and most can be ameliorated by pharmacologicgents that specifically address a specific symptom. This usuallyesults in polypharmacotherapy, which is difficult for patients to man-ge and has variable efficacy. Overall, somatostatin analogues havehe broadest and most effective coverage for all symptoms, particu-arly when used in a long-acting depot formulation. No effective phar-acologic therapy is available for fibrosis and this currently can beanaged only by surgical intervention.

evels.190 l

Histamine 1 receptor blockade (fexofenadine, lorata-ine, terfenadine, diphenhydramine) is also sometimes ofenefit in suppressing skin rashes, particularly in hista-ine-secreting gastric carcinoid tumors. Bronchospasm

an be managed with theophylline or �-2 adrenergiceceptor agonists such as albuterol. Cardiac failure mayecessitate diuretics or valvular surgery.191 Some briefelief can be provided by prednisone in the event of acutexacerbations, particularly in hepatic transplant patients,ut its toxicity warrants cautions.48

Carcinoid crisis manifested by profound flushing, ex-reme blood pressure fluctuations, bronchoconstriction,rrhythmias, and confusion or stupor lasting hours orven days may occur, especially during anesthetic induc-ion or an invasive radiologic procedure.22,192 This po-entially fatal syndrome can occur after manipulation ofumor masses (including bedside palpation), after admin-stration of chemotherapy, or after hepatic arterial em-olization, especially in patients with extensive dis-ase.193 The treatment of carcinoid crises differs fromther causes of acute hypotension because calcium andatecholamines should be avoided because these agentsrovoke the release of bioactive tumor mediators thatay perpetuate or worsen the syndrome. Blood pressure

upport usually is achieved by infusion of plasma andctreotide. In general, somatostatin receptor analoguesave replaced other pharmacologic interventions in thereatment of crises, and their use has been associated withncreased survival rates.194 Indeed, prophylactic use ofubcutaneous octreotide or the administration of a depotnjection in a timely fashion before any procedures arettempted is mandatory to prevent the development of arisis.

Therapies in Development

Symptom relief. The recent development of aeptidomimetic with broader somatostatin-receptor ac-ivity may amplify the efficacy of somatostatin-receptorigand therapy. By using alanine scanning, Bruns et al37

ynthesized SOM230, a compound with high affinity foromatostatin (SST)1-, SST2-, SST3-, and SST5-receptorubtypes, and a lower affinity for SST4. This semi-niversal ligand manifests a 30- to 40-fold higher affinityor SST1 and SST5 than octreotide or lanreotide, witharticularly potent inhibitory effects on growth hormonend insulin-like growth factor-1 release. Animal studiesave indicated that SOM230 can dose-dependently de-rease insulin-like growth factor-1 levels for up to 120ays, with a half-life of nearly 24 hours, compared withhours for octreotide. In contrast to octreotide, there is

o reversal of the suppressive effect on human insulin-
ike growth factor-1 levels and no obvious adverse side

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ffects were noted, including changes in plasma glucoseevels.37,195 Although there are no data to support anntiproliferative effect, SOM230 might be effective innfluencing somatostatin receptor 1– and 3–mediatedntiproliferative effects (cell-cycle inhibition, inductionf apoptosis). This theoretically would confer additionallinical benefit in metastatic carcinoids; islet cell tumors;omatostatin-receptor–positive breast, prostate, and co-onic cancers; and malignant lymphomas. This analogueurrently is under evaluation in phase II clinical trials forcromegaly and midgut carcinoid therapy.37

Antineoplastic. The growth and development ofetastatic lesions to some extent reflects alterations in

ocal regulatory factors that favor angiogenesis. A criticalgent and rate-limiting step in this process is VEGFignaling.196 Angiogenesis and VEGF expression haveeen studied in both gastrointestinal and pulmonaryarcinoids.197–199 In 28 gastrointestinal carcinoids eval-ated, midgut lesions showed strong VEGF expressionut there was no correlation between VEGF expressionnd tumor stage.200 Conversely, an evaluation of angio-enesis in rectal carcinoids indicated that microvesselensity was correlated with the tumor size, lymphatic orenous invasion, and existence of metastasis.201 In addi-ion, strong expression of neuropilin (NP)-2, a receptoror angiogenic factors belonging to the VEGF family, haseen noted in neuroendocrine cells throughout the di-estive tract.202 NP-2– expressing neuroendocrine cellsn the colon were almost identical to the serotonin-roducing subpopulation; however, the majority of colonnd appendiceal carcinoids did not contain NP-2–secret-ng cells. Conversely, small intestinal and gastric carci-oids expressed low levels of NP-2 in isolated foci ofells, suggesting that loss of NP-2 expression may ac-ompany tumor progression in carcinoid tumors.

Despite promising preclinical data, phase I trials tar-eting VEGF with single-agent therapy have not pro-uced substantial clinical benefit. However, recent dataoting anti-VEGF therapy enhancement of chemother-py effects suggests that there may be some use inargeting angiogenic factors.203 The VEGF-A monoclonalntibody, bevacizumab, has been evaluated in a variety ofolid and hematologic malignancies, including renal cellarcinoma, colorectal, breast, prostate, non–small-cell lung,ancreatic, liver, head and neck, and cervical cancers. 204

An early animal study of VEGF-neutralizing mono-lonal antibody in xenotransplanted human duodenalarcinoid lesions reported the development of liver me-astases in 16 of 17 control mice compared with only 2f 19 mice treated with VEGF antibody.205 Similarly,
tudies in patients with carcinoid disease reported a p
ecrease in tumor perfusion within 48 hours of treatmentith bevacizumab.206 A phase II trial in patients withetastatic or unresectable carcinoid tumors reported a

ustained decrease in tumor perfusion and progression-ree survival rate of 95% at 18 weeks.81 Biochemicalesponses of 50% or greater were observed in 21% ofatients. After at least 9 weeks of treatment, 15% ofatients were reported to have responded to therapy,hereas in 80% the disease had stabilized (Table 5).Carcinoid tumors also have been shown to co-express

latelet-derived growth factor and platelet-derivedrowth factor receptor, a receptor/ligand system impor-ant in cell growth and survival.15 A phase II trial of thelatelet-derived growth factor receptor inhibitor, Ima-inib (Gleevec; Novartis), in advanced carcinoid tumorschieved tumor stabilization in 63% of patients after a6-week median follow-up evaluation.207 A biochemicalesponse of greater than 50% was reported in 15% of

able 5. Novel Antineoplastics Currently Under Evaluation

AgentMechanism of

action Evaluated effects Assessment

evacizumab VEGF-A antibody PFS 95% at 18 wk ModeratelyPR (biochem) 21% effectiveSD 80% at 9 wk

ortezomib Proteasomeinhibitor

SD 69% at 3 mo Ineffective

pothilone Microtubulestabilizer

SD 71% at 3 mo Minimallyeffective

emcitabine Pyrimidineantimetabolite

Median PFS 8.3mo

Ineffective

matinib PDGFR inhibitor Median PFS 24wk

Moderatelyeffective

PR (biochem) 15%SD 63% at 4 mo

rinotecan TopoisomeraseI inhibitor

Median PFS 50wk

Minimallyeffective

SD 64% at 6 moB-1091 CD56

recognitionandcytotoxicity

Trial in progress -

CI-779 mTOR kinaseinhibitor

Trial in progress -

efitinib Tyrosine kinaseinhibitor

Trial in progress -

AD001 mTOR kinaseinhibitor

Trial in progress -

OTE. Some trials are still in progress but it currently appears thatost novel antineoplastic therapy can at best be regarded asaving achieved temporary tumor stabilization, with median pro-ression-free survival durations of less than 12 months. PFS,rogression-free survival; PR, partial response (�50% reduction inumor markers); SD, stable disease; mTOR, mammalian target ofapamycin.

atients and the median progression-free survival dura-

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ion was 24 weeks. The study found no correlationetween plasma VEGF and basic fibroblast growth fac-or, computed tomography flow studies, and patientutcome.

A phase II trial investigated the safety and antitumorctivity of epothilone EPO906, a novel microtubule sta-ilizer, in 26 carcinoid patients and other NETs.208

table disease was reported in 71% of patients after 3onths of therapy.A small study (n � 11) of topoisomerase I inhibitor

rinotecan in patients with advanced carcinoid diseasebserved no responses, but disease stabilization was re-orted in 64% of patients at 24 weeks.209 The medianrogression-free survival was 50 weeks.A recent study of the proteasome inhibitor bort-

zomib (PS-341) in 16 patients with metastatic NETs12 carcinoids) failed to produce any measurable tu-or responses, although 11 patients (69%) experi-

nced disease stabilization at 12 weeks.210 Of theatients with stable disease, 3 experienced an 11%–4% reduction in serum pancreastatin levels, althougherum marker levels were not found to correlate withbjective tumor responses.

Two current clinical trials examined the therapeuticole of mammalian target of rapamycin kinase inhibitors,hich is involved in the regulation of cell proliferation,

urvival, motility, and angiogenesis through initiation ofene translation in response to nutrients such as aminocids.211,212 The first is a phase II study211 of CCI-779 inatients with progressive metastatic NETs. The second is phase II study212 of RAD001, another mammalianarget of rapamycin kinase inhibitor, plus depot oc-reotide in patients with metastatic or unresectable neu-oendocrine tumors. Preclinical studies reported dose-ependent inhibition of tumor growth and reducedumor vascularity.213

A separate study examining the role of the tyrosineinase inhibitor gefitinib (IRESSA; AstraZeneca, Wil-ington, DE), currently used as second-line treatment of

on–small-cell lung cancer, in patients with metastaticarcinoids and other NETs is underway.212 Similarly, ahase I/II trial of BB-1091, an immunoconjugate thatinds with high affinity to CD56, often expressed on aariety of solid tumors, has been established to examinets therapeutic efficacy in carcinoid tumors.212

Recently published data of a phase II trial of gemcit-bine, a pyrimidine antimetabolite used in the treatmentf patients with advanced pancreatic adenocarcinoma,howed no radiologic or biochemical responses in 18
atients (9 carcinoids) with metastatic neuroendocrine i
umors.214,215 Although 65% of patients achieved dis-ase stabilization as their best response, the median pro-ression-free survival duration was only 8.3 months.Another novel strategy involves the targeting of his-

one deacetylases (HDACs), which are key regulators ofistone deacetylation, which plays a vital role in theegulation of gene expression.216 HDACs also may reg-late gene expression by deacetylating transcription fac-ors, such as p53, and may participate in cell-cycleegulation.217 A number of HDAC inhibitors (MS-27–75, oxamflatin, and the hydroxamic acid–based hybridolar compounds such as pyroxamide and suberoylanilideydroxamic acid) have been identified that induce tumorell cultures (neuroblastoma, melanoma, leukemia,reast, prostate, lung, ovarian, colon) to undergo growthrrest, differentiation, and/or apoptotic cell death.218 Inddition, recent studies have shown increased HDACmmunoreactivity in NETs, including carcinoid tumors,uggesting that HDACs may be markers of neuroendo-rine differentiation.219,220 HDAC inhibitors includinguberoylanilide hydroxamic acid and MS-275 increasehe expression of the cyclin-dependent kinase inhibitor21WAF1/CIP1, which in turn leads to growth arrest inhe G1 phase of the cell cycle and ultimately toifferentiation.221

Goke et al222 investigated the effect of the peroxisomeroliferator-activated receptor-� agonist pioglitazone onrowth and tumor necrosis factor–related apoptosis-in-ucing ligand–induced apoptosis in carcinoid cells. Pio-litazone suppressed growth and induced apoptosis ofarcinoid cells. Importantly, the enhancement of tumorecrosis factor–related apoptosis-inducing ligand–in-uced apoptosis was associated with the up-regulation ofhe cyclin-dependent kinase inhibitor p21waf1/cip1 inioglitazone-treated carcinoid cells.Clinical data on the use of HDAC inhibitors in car-

inoid disease are very limited. In a dose-titration studyhat included 1 carcinoid patient, the therapy with theovel oral HDAC inhibitor, CI-994, did not result inbjective improvement of disease.223

Antifibrotic. Connective tissue growth factorCTGF), a profibrotic cytokine, and transforming growthactor-� are activators of the process that initiates the pro-uction of collagen and fibronectin. A recent study showedTGF overexpression in ileal carcinoids and noted thatrotein expression was correlated with fibrosis in a tissueicroarray.181 Furthermore, CTGF was secreted by ileal

umor cells and was detectable in the serum of patients withleal carcinoids.219 Iloprost is a synthetic prostacyclin ana -ogue that blocks the induction of CTGF and hence the
ncrease in collagen synthesis in fibroblasts exposed to trans-

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orming growth factor-�. Its usage in scleroderma resultedn a decrease in dermal interstitial fluid CTGF levels and aarked decrease in dermal skin tightness, suggesting that it

nhibits skin fibrosis.224 Although the use of this agent inreating carcinoid fibrosis is unknown, is appears attractiveiven the recent identification of a role for CTGF in thevolution of carcinoid fibrosis. 181

Other agents that may be useful in inhibiting theevelopment of fibrosis include FG-3019, a humanonoclonal antibody against CTGF. Phase I clinical

rials using this agent in the treatment of idiopathiculmonary fibrosis and in animal models of lung, kidney,nd systemic fibrosis have shown a reduction of scarissue formation and preservation of organ structure andunction.225 Similarly CAT-192, a monoclonal antibodygainst transforming growth factor-� currently is undervaluation in phase I/II clinical trials in patients withiffuse systemic sclerosis. Preliminary results have pro-ided no definitive conclusions regarding efficacy.

ConclusionsThe clinical management of carcinoid tumors has

volved though a number of phases in the century sincehe lesion first was described. Despite the developmentnd implementation of a number of chemotherapeutic,iotherapeutic, radiologic, and surgical strategies, theverall clinical results are disappointing. Indeed, were itot for the development of the somatostatin analoguelass of drugs that have been so effective in amelioratingymptoms and improving the quality of life, carcinoidumor management would have advanced little.

The somatostatin analogues lanreotide and octreotideemain the main symptomatic therapeutic modalities forhe management of carcinoid tumors. Generally, theirffects are limited to symptom control and stabilizationf the disease progress. Although a decrease in tumor sizes almost nonexistent, they show marginally better ef-ects on biochemical tumor markers. The effects of otheriotherapeutics, such as interferon-�, on tumor cell pro-iferation are indistinguishable from those of somatosta-in analogues, but are associated in many instances withevere adverse effects.

The introduction of longer-acting somatostatin ana-ogues (Somatuline Autogel and Sandostatin LAR) hasncreased dramatically the duration of therapeutic con-rol from days to weeks, and even may extend therapeuticontrol to months with the introduction of novel formu-ations. Thus, advances in drug-delivery systems in con-unction with the development of more stable formula-ions and slow-release depot formulations have facilitated
ymptom management and quality of life further. Nev- t
rtheless, although the number of injections needed toontrol symptoms has decreased, instances of break-hroughs requiring rescue treatment still occur.

There is little evidence that any permutation of che-otherapeutics offers increased efficacy over biotherapy,

nd the frequently severe side effects render chemother-py much less appealing. Although intellectually prom-sing, the therapeutic effects of radiolabeled somatostatinnalogues remain somewhat disappointing. In general,hey may be considered to at best maintain the status quoy stabilizing disease progression. Nevertheless, theyemain the currently most exciting therapeutic develop-ent in the treatment of neuroendocrine tumor disease.verall, �-emitting radionuclides (eg, 131I) have greater

herapeutic potential because the particles they emit haveufficient energy to cause tumor cell damage withoutenetrating far into surrounding tissue.226 –228 Thoseadionuclides emitting primarily �-radiation (eg, 111In)r Auger electrons show antiproliferative effects only ifellular DNA is within the particle range. Such com-ounds therefore may be most effective when given inombination with �-emitters or when used to eradicateicrometastases.229 As an emitter of both � particles

nd � radiation, 177Lu has been shown to induce signif-cant tumor regression and may be of particular benefit inhe treatment of small tumors by minimizing the radi-tion exposure of cells distant from the bound somatosta-in receptors.172

Radionuclides decaying by the emission of �-particles213Bi, 225Ac, and 211At), which because of their shortange have high linear energy transfer (100 keV/�m),ffer the possibility of irradiating tissues in the range ofnly a few cell diameters.230 In comparison, the meaninear energy transfer for the high-energy � particlesmitted by 90Y is only about .22 keV/�m.230 In addi-ion, the effectiveness of high linear energy transfer ra-iation is nearly independent of oxygen concentration,ose rate, and cell-cycle position. Considerable evidenceas shown that radiation-induced biological bystanderffects can result in the killing of cells that have not beenit directly by radiation.230 –232

The issue of receptor heterogeneity, which may beesponsible for some tumor resistance, theoretically coulde overcome by using cocktails of radiolabeled ligands inombination with one another or with other biothera-eutics or chemotherapeutics. One potentially promisingpproach in patients with micrometastases or tumors ofifferent sizes is treatment with a combination of radio-uclides shown to be optimal for treating larger tumors

90Yt) and radionuclides shown to be optimal for smaller
umors (177Lu).229,233 Because the side effects of this type

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f therapy are infrequent, the duration of response ofore than 2 years suggests that such combination cock-

ail isotope therapy may offer a potentially attractiveherapeutic path in the future.

Although primary surgical resection remains the onlyotentially curative modality currently available, theritical issue remains the need to diagnose the lesionefore the development of metastases. At this time noarly biomarkers of the disease exist. Therefore, rationalurgical management needs to be based on the predictionf the likelihood of aggressive local or metastatic behav-or. This requires the identification of tumor-specificolecular signatures that will define the malignant andetastatic potential of an individual lesion and identify

overt metastatic disease undetectable by conventionalicroscopy or immunohistochemistry. Although theanagement of hepatic metastases initially focused on

arieties of hepatic vascular occlusion, embolization oftens associated with morbid events. Alternatively, the sur-ical excision or radiofrequency ablation of hepatic me-astases, especially if undertaken by laparoscopic tech-iques, has a comparable morbidity and mortality withossibly higher rates of perioperative and postoperativeomplications. The results of liver transplantation foretastatic disease are disappointing, and reflect the usu-

lly advanced disease states of transplant recipients.

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Address requests for reprints to: I. M. Modlin, MD, PhD, FACS, Yaleniversity School of Medicine, 333 Cedar Street, PO Box 208062, Newaven, Connecticut 06520-8062. e-mail: [email protected]; fax:

203) 737-4067.Supported by National Institutes of Health grant R01-CA-097050 (to

.M.M.) and by the Bruggeman Medical Foundation (to M.K.).

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REVIEW - Carcinoid Cancer Foundation · 2016-12-29 · Sandler,4 in seeking to provide a logical framework to ... introduction of more generic terminology that embraces all neuroendocrine