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inside Classification and pathology Clinical features symptoms and signs

Assessment and diagnostic techniques Management

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Neuroendocrinetumours

The authors

DR MICHAEL HOFMAN,

nuclear medicine physician,

centre for cancer imaging, Peter

MacCallum Cancer Centre, and

clinical senior lecturer, University

of Melbourne.

ASSOCIATE PROFESSOR

MICHAEL MICHAEL,

medical oncologist, head of upper

GI tumour stream, Peter


co-chair, neuroendocrine service,

and associate professor of

medicine, University of Melbourne

"4117-1111

MR BENJAMIN THOMSON,

hepatobiliary surgeon, Peter


head of upper GI tumour stream,

Royal Melbourne Hospital.

Media Monitors Client ServiceCentre 1300 880 082

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ID 00137490062 PAGE 1 of 16

BackgroundNEUROENDOCRINE cells arelocated throughout the body. Theyrelease hormones in response to a vari-ety of stimuli to regulate a wide rangeof normal physiological functions. Neu-roendocrine tumours (NETs) arise fromthis diverse group of cells and are mostcommonly found in the gastrointesti-nal tract and pancreas.

Although these tumours sharecommon markers of neuroendocrinedifferentiation, they have differentembryological origins and extremelyvariable biological behaviour, rangingfrom benign to very aggressive tumours.Some NETs secrete hormones that cancause significant morbidity and be life-threatening despite their slow growth.By contrast, some patients with veryslow-growing tumours survive formany years, even in the presence ofmetastatic disease.

In the past decade there have beenmultiple advances in biochemical,histopathological and imaging tech-niques, resulting in improved diagno-sis, classification and accuracy of prog-nosis. These advances are enabling anew era of personalised medicine inwhich a number of new targeted thera-

pies can be selected for an individualpatient, leading to improved patientoutcomes.

EpidemiologyAlthough uncommon, the incidence ofNETs has risen significantly over thepast few decades, and NETs now con-stitute the second most prevalent GItumour after colorectal cancer.Improved awareness combined withadvances and better availability ofimaging, biochemistry and endoscopictechniques has almost certainly con-tributed to this rise. Therefore, it is dif-ficult to discern if there has been a trueincrease in tumour incidence.

Most NETs are sporadic but someare observed in high frequency ininherited familial syndromes, includ-ing multiple endocrine neoplasia(MEN), von HippelLindau diseaseand neurofibromatosis. In sporadiccases we have noted a disproportion-ately high number of patient refer-rals from non-metropolitan areas andfurther research is needed to eluci-date potential carcinogens.

cont'd next page

PROFESSOR RODNEY HICKS,

department of medicine and

radiology, University of Melbourne,

and director, centre for cancer

imaging; co-chair, neuroendocrine

service and translational research

group; and head, molecular

imaging and targeted therapeutics

laboratory, Peter MacCallum

Cancer Centre, Melbourne.

NETs can he classified accordingto the site of origin and the degreeof differentiation and function.

SiteTraditionally, NETs were classifiedby the site of origin as:

Foregut (stomach, duodenum,pancreas, bronchus).Midgut (small bowel to ascend-ing colon, including appendix).Hindgut (transverse colon torectum, genitourinary).The term gastroenteropancre-

atic (GEP-NETs) is now used toencompass the broad range ofNETs arising from the bowel orpancreas. Pancreatic NETs (also

called islet cell tumours) arisefrom the cells of the islets ofLangerhans of the endocrine pan-creas, and are distinct from pan-creatic adenocarcinomas whicharise in the exocrine pancreas.

The term carcinoid (cancerlike') was introduced in 1907 todescribe GI NETs that had slowgrowth as opposed to the malig-nant pattern seen with adenocar-cinoma.

Degree of differentiation andfunctionNETs can be divided into well-differentiated or poorly differenti-ated categories, which charac-

terise disease biology and prog-nosis and enable appropriateselection of treatment (table I).There is, however, a continuum

between the two, and moderatelydifferentiated tumours may havecharacteristics of either group andmuch less predictable behaviour.

oieli-EntterenthiNdThe cells of well-differentiatedNETs closely resemble the normalneuroendocrine cell from whichthey arose, and the tumours tendto have slow growth with an indo-lent natural history. The functionalactivity of the original cells can bepreserved and amplified, resulting





ID 00137490062 PAGE 2 of 16

>"in high and inappropriate levelsof hormone secretion. Thus, theycan be characterised as function-ing (hormone producing) or non-functioning.

Serotonin (5-hydroxytrypta-mine) production is most com-monly seen in carcinoid tumours,but production of more than 50peptides or amines have beendescribed. Some hormone-produc-ing tumours can be clinicallysilent due to the synthesis of hor-mone precursors or inactive hor-mones.

Well-differentiated NETs have ahigh degree of expression ofsomatostatin receptors (SSTRs) ontheir cell surface. Somatostatin is apeptide hormone that exerts aninhibitory effect on a variety ofcellular functions. For example,somatostatin normally inhibits therelease of:

TSH, growth hormone andACTH from the anterior pitu-itary.Insulin and glucagon from thepancreas.Gastrin from the gastric mucosa.Secretin from the intestinalmucosa.It is an important hormone for

the regulation of GI function suchas gastric emptying and of pancre-atic hormone secretion. Thiscommon feature of high levels ofSSTR expression across a range ofdiverse NETs provides a uniqueand specific target for both imagingand treatment.

Poorly chitorentialod NETsThe cells of poorly differentiatedNETs less closely resemble normalneuroendocrine cells and behaveaggressively, with rapid proliferationand clinical course.

Well-differentiated rumours can de-differentiate (or transform) over timeinto the poorly differentiated aggres-sive subtype and, as such, all NETsshould be regarded as having malig-nant potential. Over time, tumourheterogeneity can develop, with well-differentiated and poorly differenti-ated phenotypes coexisting at differ-ent sites in the same patient.

Table 1: Spectrum of NETs, from well to poorly differentiated

GRADE (ENETS)Well differentiated Poorly differentiated

Ki-67 index

Anatomical imaging

Functional imaging

Low (GI)

<2

Indolent (slowly growing)

ObservationSomatostatin analoguesRadionuclide therapy

Intermediate (G2) High (G3)

Aggressive

Surgery for localised ± resectable metastatic disease

Chemotherapy

Everolimus, sunitinib, alpha interferonLiver metastases: radiofrequency ablation, hepatic

embolisation, TACE, SIR-Spheres

ENETs = European Neuroendocrine Tumour Society

Ki-67 = cell-cycle-dependent marker

SPECT = single photon emission computerised tomography

SSTR = somatostatin receptor

FDG = fluorodeoxyglucose

TACE = trans-arterial chemoembolisation

tense disease biology and prog-nosis and enable appropriateselection of treatment (table 1).

There is, however, a continuum

2-20 >20

More rapid growth on serial imaging

Prognosis

Treatment options





ID 00137490062 PAGE 3 of 16

Clinical features symptoms and signs

SMALL NETs are usually asymp-tomatic and it is unusual for themto be diagnosed until there islocally advanced or metastatic dis-ease, and even then untreatedpatients can remain asymptomaticor have only vague symptoms formany years. Careful history canidentify symptoms related to excesshormone secretion by NETs, partic-ularly those of carcinoid syndrome.Some early-stage NETs are discov-ered as incidental findings on imag-ing or endoscopy without clinicalsequelae, or due to secretion ofbioactive hormones resulting incharacteristic clinical syndromes.

Carcinoid syndromeCarcinoid syndrome is the clinicalmanifestation of excess serotoninproduction (figure 1, page 36). Inpatients with early-stage carcinoidtumours that secrete serotonin, sys-temic symptoms do not occur, asactive hormone enters the portalcirculation and is rapidly degradedby hepatic enzymes. Carcinoid syn-drome, which occurs in about 10%of carcinoid tumours, manifestsonly when the tumour has metasta-sised to the liver or extra-peritonealabdominal organs such as theovary, allowing hormone to enterthe systemic circulation, therebyescaping hepatic degradation.

Characteristic symptoms of car-cinoid syndrome include:

Intermittent or progressive facialflushing (figure 2, page 36).Secretory diarrhoea (charac-terised by lack of response tofasting).Abdominal cramps.Wheezing.A carcinoid crisis (prolonged

severe flushing, diarrhoea, hypoten-sion, tachycardia, severe dyspnoea,

peripheral cyanosis and sometimeshaemodynamic instability) canoccur if large amounts of hormoneare secreted acutely. This can betriggered by diet, alcohol, surgeryor chemotherapy. In one case ofwhich we are aware, a carcinoidcrisis was precipitated by vigorouspalpation by an enthusiastic groupof medical students.

About 50% of patients with car-cinoid syndrome have cardiacabnormalities caused by chronicexposure of the heart valves toserotonin, which causes fibrosisand thickening of the tricuspid andpulmonary valves, resulting inregurgitation or, less commonly,stenosis. Right heart failure andcongestive cardiac failure can

result. Clinical signs include elevatedjugular venous pressure with large vwaves, right ventricular heave, thepansystolic murmur of tricuspidregurgitation and a large, pulsatileand tender liver. Ascites and oedemacan also occur. The consequenthepatic congestion results in adecreased capacity of the liver todegrade hormones, which furtherexacerbates symptoms and can resultin acute decompensation.

Gastrointestinal NETs

Small-bowel carcinoids are frequentlyasymptomatic or present with vagueabdominal symptoms that can hemistaken for irritable bowel syn-drome. Some patients present withintermittent or acute bowel obstruc-tion. Production of serotonin orother bioactive amines is a typicalfeature of small-bowel carcinoids,and local secretion causes mesentericfibrosis that predisposes to bowelobstruction or can compress mesen-

teric vessels, resulting in bowelischaemia and malabsorption.

Most gastric, appendiceal andrectal carcinoids present as inciden-tal findings. These tumours areusually non-functioning and remainasymptomatic until advanced.

Pancreatic NETsNon-functioning pancreatic NETsmay grow for a long time withoutcausing symptoms. When largeenough, obstruction of bile or pan-creatic ducts may cause obstructivejaundice or symptoms due to pan-creatic enzyme insufficiency, suchas diarrhoea.

About half of pancreatic NETsare functional, producing a rangeof hormones resulting in character-istic syndromes (table 2). Tumours

cont'd page 36

from page 34

can secrete a range of hormonesother than serotonin, includingACTH or corticotrophin-releasinghormone (CRH), resulting in Cush-ing's syndrome, or parathyroid-hor-mone-related peptide (PTHrP),resulting in hypercalcaemia. Co-secretion of multiple hormones is notuncommon, and some apparentlynon-functioning tumours can occurbecause of co-secretion of antagonisthormones, for example, insulin andglucagon.

Bronchial NETsBronchial carcinoid tumours cancause recurrent pneumonia fromairway obstruction, pleurisy,haemoptysis and shortness ofbreath. A small proportion of thesetumours produce serotonin or sim-





ID 00137490062 PAGE 4 of 16

*-

Gastrinoma Gastrin(Zollinger-Ellisonsyndrome)

Glucagonoma Glucagon

VIP-oma Vasoactive

intestinalpeptide (VIP)

Somatostatinoma Somatostatin

ilar bioactive hormones, resultingin carcinoid syndrome, or ACTH,resulting in Cushing's syndrome.

Metastatic diseaseCommon sites of metastatic diseaseinclude local or distant lymph nodes,liver, bone and peritoneum. In femalesthe ovary can he a site of metastaticdisease. Some patients present withsymptoms of fatigue and weight loss.Unlike other malignancies in whichuntreated metastatic disease is usu-ally rapidly progressive, even widelyspread metastatic NETs can be indo-lent, sometimes referred to as 'cancerin slow motion'. It is not uncommonfor it to present initially as a cancer ofunknown primary, as the burden ofmetastatic disease can be large, whilethe primary site remains small anddifficult to locate.

symptoms of hypoglycaemia(eg, blurred vision, sweating,tremor, weakness, confusion,coma)

glucose <2.2mmol/Lrelief of symptoms withadministration of glucose

CgA = chromogranin A

5-HIM = 5 hydroxyindole acetic acid

VIP = vasoactive intestinal peptide

*Secretin test: administration of exogenous secretin; test is positive if serum gastrin levels increase

Investigations (blood)

CgA, urinary 5-HIM

Fasting or random glucose72-hour fast test (requireshospitalisation)

Insulin, C-peptideDrug screen (to excludefactitious hypoglycaemia)

Fasting gastrinGastroscopy/24h pH-metrySecretin test*

Glucagon

VIP

Hypokalaemia

Somatostatin

Figure 1: Careinoid syndrome.

Heartpulmonary andtircaspid fihrosts

Liver

hapatomegaly

GestrolniestaIaldiarrhoeacrampsnauseavomiting

Skin

%dal flushing

Respaahxycoughvrtiwzing

etYsPnoi.

Retro.peritoneadand pelvic

fibrosis

Figure 2: Facial Bustling in carcicaidsyndrome.

Table 2: Features of selected syndromes

Disease Hormoneproduced

Site (mostcommon)

Clinical features

Carcinoid syndrome Serotonin,others

Smallbowel

Flushing, diarrhoea, abdominalpain, carcinoid heart disease

(histamine,substance P)

(tricuspid regurgitation, rightheart failure)

lnsulinoma Insulin Pancreas Whipple's triad:

DuodenumPancreas

Pancreas

Pancreas

Peptic ulcer, gastric reflux,diarrhoea

Rash (necrolytic migratoryerythema), impaired glucoseintolerance or diabetes

Profuse watery diarrhoea andresultant dehydration,hypokalaemia and achlorhydria(pancreatic cholera syndrome)

Pancreas Triad of diabetes mellitus,steatorrhoea and gall stones,also associated withhypochlorhydria





ID 00137490062 PAGE 5 of 16

Assessme and diagnostic techniques

INVESTIGATION should be person-alised for each patient, taking intoaccount the likely natural history andthe general health of the patient.

Biochemical markersIn patients with suspicious symp-toms, measurement of chromo-granin-A (CgA) can be helpful,but other more complex tests arebest co-ordinated by an endocri-nologist, gastroenterologist oroncologist. CgA is a glycoproteinpresent in the secretory granulesof most neuroendocrine cells. It isco-secreted along with other hor-mones but can be elevated ineither functional or non-functionalNETs. Very high levels of CgA arerarely found outside the setting ofNETs. Mild or moderate elevationand consequent false-positiveresults may occur in patientstreated with gastric acid secretoryblockers, especially proton-pumpinhibitors, and also in patientswith impaired renal function,pregnancy, Parkinson's disease oruntreated hypertension.

If there is suspicion of a specificsyndrome, tests for hormoneexcesses are indicated (table 2).

5-Hydroxyindole acetic acid (5-HIAA) is the urinary breakdownproduct of serotonin and can bemeasured using a 24-hour urine col-lection in patients with features ofcarcinoid syndrome. Some foods,including plums, pineapples,bananas, eggplants, tomatoes, avoca-dos and walnuts contain high levelsof serotonin, which can increase uri-nary levels of 5-HIAA, and shouldbe avoided three days before collec-tion. 5-HIAA can also be increasedin patients with untreated malab-sorption such as in coeliac disease. Avariety of medications can alsoincrease or decrease 5-HIAA levels.CgA measurement is more sensitiveand is increasingly replacing use of

urinary 5-HIAA.

ImagingOnce NET is strongly suspected onthe basis of symptoms, biochemicaltesting, or confirmed on biopsy, sys-temic staging is necessary, sincelocalisation of the primary site ofdisease and the presence of metas-tases has both prognostic and thera-peutic implications.

CT of the thorax, abdomen andpelvis is generally the first test butunfortunately has relatively low

sensitivity for the primary tumourand will often significantly underes-timate the extent of metastatic dis-ease. In particular, liver metastasescan be difficult to detect unless atriple-phase protocol involving pre-contrast, arterial and portal venousphase imaging is adopted.

Small hepatic metastases can bemost sensitively identified using 3-Tesla MRI with a hepatocyte-spe-cific contrast agent.

Unless a primary lesion is readilyapparent, specialised imaging tech-niques may be necessary. Theseinclude CT enteroclysis (CT com-bined with intraluminal radiocon-trast) for small-bowel lesions, and

MRI or endoscopic ultrasound forpancreatic lesions. These are bestarranged by specialists experiencedin the management of NETs, espe-cially oncological surgeons.

By virtue of SSTR expression inmost NETs, various radiolabelledsomatostatin analogues have beendeveloped for diagnostic imaging.These have three basic components

a radiometal that emits radiationdetectable outside the body, linkedvia a chelating agent to a peptidethat binds to the SSTR. The onlycommercially available andapproved agent for SSTR-imaging isIndium-111 DTPA-octreotide(Octreoscan). The radiotracer is

injected intravenously followed by

imaging on a nuclear medicinegamma camera over the next 1-2days. In addition to obtaining two-dimensional 'planar' imaging, it isnow routine to obtain three-dimen-sional cross-sectional images byrotating the detectors around thepatient, using a technique calledsingle photon emission tomography(SPECT).

Although widely available, Octre-oscan imaging is an expensive testand quite difficult to interpret. Aninherent drawback is the absence ofanatomical information, precludinglesion characterisation or preciselocalisation, leading to difficulty dis-

tinguishing physiological or benignuptake from pathological uptake.

These limitations can be overcomewith hybrid SPECTCT scanners,which provide both functional(SPECT) and anatomical (CT) infor-mation. Octreoscan imaging is bestperformed on a multi-sliceSPECTCT device and is signifi-cantly more sensitive than conven-tional imaging, with a large impacton patient management.

Recently, a few specialised cen-tres have introduced SSTR-imag-ing on combined positron-emissiontomographyCT (PETCT)devices, using gallium-68 DOTA-octreotate (DOTATATE, GaTate)instead of indium-111 in the radio-labelled somatostatin analogues.PET provides vastly superior imag-ing (accurately identifying diseaseas small as 2-3mm [figure 3]) andspeed (the scan can be completed in60-90 minutes) compared withconventional gamma cameraSPECT imaging. Patients in whomthere is a strong clinical suspicionof NETs but who test negative onconventional imaging and Octreo-scan, or patients who have Octreo-scan findings suggesting limited dis-ease amenable to curative resection,should be considered for this form





ID 00137490062 PAGE 6 of 16

)10-

As well as more accurately defin-ing the presence and extent of NETs,SSTR-imaging also characterises thebiology of disease. As a marker ofnormal cellular differentiation, highuptake of Octreoscan or the PETanalogues indicates that the diseaseis well differentiated and generallyhas an indolent natural history andtherefore tends to be resistant to con-

ventional oncology treatments, suchas chemotherapy.

As the disease becomes de-differ-entiated and aggressive, there tendsto be a loss of SSTR. This is anadverse prognostic indicator butdoes indicate a higher likelihood ofbenefit from chemotherapy, asdetailed below. As with mostaggressive tumour types, PETCT

Authors' case study 1A MIDDLE-aged woman presentedwith intermittent severe epigastric painand secretory diarrhoea. These wereinitially thought to be due topancreatic duct strictures secondaryto chronic pancreatitis and weretreated with stenting of the proximalpancreatic duct via endoscopicretrograde cholangiopancreatography(ERCP).

Symptoms persisted despite distalpancreatectomy and splenectomy, anda further ERCP-guided stent procedure.At re-operation two years later severalsub-cm hepatic metastases werediscovered, with histologydemonstrating well-differentiated NETof low proliferative index (Ki-67 < 1%).

Triple-phase CT of the chest,abdomen and pelvis demonstrated noabnormality apart from multiplesclerotic bone lesions considered tobe benign bony islands(osteopoikilosis) with prior 'negative'bone biopsy. 111-In-octreotide(Octreoscan) scan (figure 3B) anteriorplanar and SPECT-CT (not shown)demonstrated a solitary leftsupraclavicular nodal abnormality(blue arrow). GaTate PET-CT scan(figure 3A: anterior maximum imageprojection [MIP], figure 3C)demonstrated widespread smallvolume nodal and osseous metastaticdisease, and also identified apancreatic primary and further sub-cmliver metastases (red arrows).Elevation of vasoactive intestinal peptide (VIP) level confirmed the diagnosis of a VIP-oma.

On the basis of the high somatostatin-receptor cell-surface expression demonstrated on this functional imaging,the patient was treated with a long-acting somatostatin analogue. Despite this there were progressive symptomsresulting in an ICU admission. The patient had a trial of alpha interferon without significant response andsubsequently underwent radionuclide therapy with 111-In- and 177-lutetium-octreotate with marked reduction insymptoms.

imaging with fluorodeoxyglucose(FDG), a glucose analogue, is asensitive means to detect and stagedisease, as rapidly proliferatingcells use glucose as a substrate forenergy. In some patients, the com-bination of SSTR imaging andFDG PETCT is indicated to char-acterise sites of well and poorly dif-

cont'd page 38

Figure 3: Extensive metastatic disease demonstrated with GaTate PET/CT.A: GaTate PET/CT scan. B: 111-In-octreotide (Octreoscan) scan, anteriorplanar. C: selected axial PET/CT fusion slices.

AMIN&A





ID 00137490062 PAGE 7 of 16

Authors' case study 2THIS patient presented with symptoms of tremor, sweats and mild confusion associated with exercise and prevented byeating small and frequent meals. A 72-hour fast produced symptomatic hypoglycaemia with elevated insulin and Cpeptide levels, consistent with an insulinoma.

CT and MRI demonstrated a large left upper-quadrant mass arising from the pancreatic tail, with multiple hepaticmetastases. 18F-FDG and 68Ga-Octreotate (GaTate) PET-CT demonstrated significantly different patterns of uptake, asdemonstrated by the maximum intensity projection (MIP) images on the left and right in figure 4.

An axial slice through the liver (colour panel 1) demonstrates a GaTate-positive but FDG-negative hepatic metastasis,indicative of a well-differentiated lesion with high-somatostatin cell surface expression. An axial slice through the leftupper-quadrant mass (colour panel 2) demonstrates a largely GaTate-negative but FDG-positive lesion, indicative ofmore poorly-differentiated (aggressive) phenotype.

Without the knowledge of the PET findings, core biopsy on the basis of CT or MRI could reveal either subtype, whichmight misinform decision-making. The PET studies demonstrate tumour heterogeneity suggesting both well- and poorlydifferentiated disease at different sites. (Note: Sites of physiological activity including renaVbladder activity on bothstudies, myocardial activity on the FDG PET, and splenic activity on the GaTate PET).

Anal F/DG PEPET GaTalei PE7CT

EV) GiaTaie -Eve; vetil-clifgefentiateuiflleeill

FDG +vs, GaTate ve: paorly ditferwilaied gQressiveIGaTato PET

from page 34

ferentiated disease (figure 4). Nei-ther test is currently funded andavailability is limited to centres withspecialist interest and expertise inthese tumours. These tests are partic-ularly valuable in selecting and mon-itoring the response to treatment.

EchocardiographyCarcinoid heart disease is seen in ahigh proportion of patients withlongstanding carcinoid syndrome,and echocardiography is needed to

assess this. Specific features arethickening of valvular cusps andchordae, which results in regurgita-tion or stenosis (usually of the tri-cuspid valve) leading to right ven-tricular dilation and reducedfunction, as well as right atrial dila-tion.

HistopathologyTissue from either biopsy of a pri-mary tumour or metastases isneeded to confirm the diagnosisand characterise disease biology:

Immunostaining for neuroen-docrine cell markers, includingsynaptophysin and chromo-granin-A (CgA), is used to con-firm the diagnosis.Aggressiveness of tumour isdetermined by counting thenumber of mitoses per high-power field or, more accurately,by immunostaining for the Ki-67antigen, a cell-cycle-dependentmarker. The Ki-67 index servesas the basis for grading tumoursinto grades 1-3 (see table 1).





ID 00137490062 PAGE 8 of 16

Key points on diagnosis andstaging

Chromogranin-A (CgA) is the mostpractical and useful general serumtumour marker in patients withNETs.

Elevated CgA levels occur inpatients on proton-pump inhibitors,but very high levels are rarely seenoutside the setting of NETs.

Somatostatin receptor (SSTR)

IN patients with advanced-stagedisease, early referral to a centrewith multidisciplinary expertiseincorporating surgical oncology,medical oncology, nuclear medi-cine, interventional radiology,endocrinology, gastroenterologyand radiation oncology is advised.Given the complexity and hetero-geneity of this disease, therapy isindividualised based on several fac-tors, including:

Disease extent.Rate of growth determined bytemporal change on imaging andhistological grade/proliferativeindex.Level of SSTR expression andFDG avidity (ie, positivity) onnuclear medicine imaging.Disease-related symptoms withregard to the primary lesion ormetastatic deposits.Patient comorbidities.

SurgeryComplete surgical resectionremains the only curative treatmentfor NETs. Unfortunately mostpatients present late with metasta-tic disease. While some pancreatichormone-secreting tumours may beidentified early due to symptoms,the more common pancreatic neu-roendocrine tumours are usuallysilent. Metastatic disease does not,however, necessarily preclude con-sideration for curative or palliativesurgery.

Most published data for surgical

Management

imaging with OctreoscanSPECTCT is more sensitive thanconventional imaging forlocalisation and staging NETs.

SSTR PETCT imaging is availablein a few specialised centres butcan have a high managementimpact in patients with anunknown primary site of disease(by directing to curative surgery) orin patients with limited-stagedisease on conventional workup

resection of NE Is reports onpatients who have only had con-ventional CT or Octreoscan scan-ning preoperatively, which, asexplained above, may have under-

estimated the extent of disease inthose patients. The development of3-Tesla MRI and SSTR PETCThas significantly improved theaccuracy of preoperative stagingand detection of metastatic disease.Although not widely available,these should now be consideredessential preoperative staging inves-tigations when resection is beingconsidered. Cure will only be possi-ble in patients in whom all sites ofdisease can be resected.

Guidelines exist to aid in deci-sion making about surgical treat-ment for the broad range of poten-tial sites involved with tumour.'Gastric tumours are usuallyresected by partial gastrectomy,which can be performed laparo-scopically. Small mucosal tumoursof the stomach and duodenum canbe managed with cndoscopic resec-tion. Distal pancreatectomy or pan-creaticoduodenectomy are appro-priate for pancreatic tumours.Small-bowel resection along withresection of the draining lymphnodes is appropriate for carcinoidtumours. Standard colorectal resec-tions are appropriate for colonictumours. However, small peduncu-lated tumours are occasionallyremoved endoscopically.

before major surgical intervention(by detecting distant metastaticdisease and directing away fromfutile surgery).

In patients with carcinoidsyndrome, echocardiography isimportant to detect carcinoid heartdisease.

Tumour grading plays a key role indefining prognosis and therapeuticoptions.

Surgery in the setting of metastaticor urpresectable diseaseSmall-bowel NETs (carcinoidtumours) present particular prob-lems related to the local effects ofhormones produced by the tumour.This often leads to a scleroticresponse within the mesentery ofthe small bowel, producingischaemic symptoms as well asobstruction. Simple bypass of theobstruction will not resolve theischaemic symptoms, so resectionof the associated lymphadenopa-thy within the mesentery isrequired. Even in the setting ofunresectable metastatic disease, pal-liative resection of carcinoidtumours may be warranted forcontrol of the ischaemic andobstructive symptoms.

For patients with carcinoid syn-drome secondary to hepaticmetastatic disease, surgical cure isstill possible if complete resectionof hepatic metastatic deposits canbe performed. For patients inwhom not all of the liver diseaseis resectable, symptom control isstill possible if 90% of the diseasecan be removed or ablated. In bothsurgical situations (with curative orpalliative intent), resection with orwithout ablative techniques (eg,microwave or radiofrequency abla-tion) can be used.





ID 00137490062 PAGE 9 of 16

For patients with extensivehepatic replacement by tumour,surgical resection is not possible.Hepatic transplantation has beenused in this context but Australianguidelines do not recommend itsuse.

For locally advanced pancreatictumours or pancreatic tumours withunresectable metastatic disease,there is little evidence to support thebenefit of debulking surgery. If pres-ent, jaundice and gastric outletobstruction can be controlled withendoscopic techniques without theneed for open surgery. In contrastto pancreatic adenocarcinomas, theobstructive symptoms are less fre-quent and worsen more slowly.

Anaesthetic considerationsPreoperative anaesthetic prepara-tion is an important part of surgicalmanagement. Historically the mor-tality following resection of carci-noid tumours has been as high as50%. This is due to the haemody-namic consequences of hormonerelease, as well as the presence ofcarcinoid heart disease. Cardiacechocardiography is required forpatients with a raised CgA orsymptoms of carcinoid heart dis-ease. Preoperative blockade withlong-acting somatostatin analogues(described below) is beneficial andshould be co-ordinated with anaes-thetic review.

MedicalThe aim of medical therapy forpatients with advanced NETs isto relieve symptoms related to thetumour (due to hormone secre-tion or directly related to the pri-mary tumour or its metastasis)and to slow down tumourgrowth. There is a broad range ofmedical treatments available, asoutlined below.

Somatostatin analoguesSomatostatin analogues (SSAs) areindicated in patients with low- tointermediate-grade NETs whosedisease is avid (strongly positive)

on SSTR imaging and whose dis-ease is progressing on regularradiological review, whether theyhave functional or non-functionaltumours.

SSA therapy is associated with40-70% biochemical response,that is, a reduction in serum CgAand urinary 5-HIAA. Up to 70%

of patients experience resolutionof symptoms related to their car-cinoid syndrome, including diar-rhoea and flushing. There is someevidence that the response ratesmay increase with higher doses ofthe SSAs.

Apart from the inhibitoryeffects of SSAs on hormone secre-tion, these agents also have anantiproliferative effect in slowingtumour growth, stabilising themradiologically in about two-thirdsof patients, and inducing tumourregression in up to 10% ofpatients.' The introduction ofSSAs may be responsible for theincreased survival of patients withNETs observed over the last twodecades.

The two currently availableSSAs are octreotide (Sandostatin100-500pg [a short-acting prepa-ration] and Sandostatin LAR 10-30mg [a long-acting repeatabledepot preparation]) and lan-reotide (Lanreotide Autogel 60,90, 120mg [a depot preparationl).The short-acting preparation isgiven by subcutaneous injection,has a half-life of 1.5-2 hours andis used for the treatment of break-through secretory symptoms. Thedepot preparations are given onceevery four weeks by deep SC orIM injections and are used forlong-term control.

These agents do have adverseeffects, including:

Nausea.Cramping.Diarrhoea.Steatorrhoea.Cardiac conduction abnormalities.Endocrine dysfunction (hypo-

thyroidism, hypo- andhyperglycaemia).Cholelithiasis in up to 50% ofpatients (although cholecystitisdevelops in fewer than 5%).Patients undergoing surgicalresection of NETs should beconsidered for prophylacticcholecystectomy to facilitatelater use of SSAs.There is still debate on the util-

ity of SSAs in patients withsomatostatin-receptor-expressingbut non-functional tumourswhose disease is radiologicallystable over a prolonged period oftime. One option is continuedobservation; the other is to startSSA therapy for its antiprolifera-rive effects. However, patientsmust be fully aware of theiradverse effects and the need forprolonged therapy.

Symaiomalle therapyAs stated above, SSAs are gener-ally successful in controlling typicalcarcinoid syndrome symptoms suchas diarrhoea and flushing. In somepatients additional control can beachieved with use of over-the-counter antidiarrhoeal agents suchas loperamide and or cholestyra-mine. The latter may be particu-larly helpful in patients who haveundergone an deal or extensivesmall-bowel resection to counter-act defective bile acid reabsorption.

Histamine oversecretion in gas-tric and thoracic NETs can induceskin rashes that can be treatedwith antihistamine type-1 block-ade. Bronchospasm can be treatedwith the usual antiasthmaticpreparations.

Management of cardiac failuresecondary to carcinoid cardiac dis-ease requires input by a cardiolo-gist and an assessment of the needof valvular surgery.

Oiruel treat:mud of Islet call hceTh0110

Insulinomas can cause episodic andoften symptomatic hypoglycaemia.Such patients can be treated withdiazoxide (which decreases islet cellfunction), prednisolone (which





ID 00137490062 PAGE 10 of 16

raises blood glucose by mobilisingcarbohydrate stores) or SSAs. Gas-trinomas can be associated withZollingerEllison syndrome, withsevere peptic ulceration, and canhe controlled with aggressive PPItherapy.

eh .,,therapyIn the case of well-differentiatedNETs, chemotherapy may be indi-cated when a patient's disease hasprogressed despite SSA therapy,although increasingly radionuclidetherapy is used in these patients, asdiscussed below. In general, classicmidgut carcinoids tend to be lesschemosensitive than pancreatic isletcell tumours. Regimens generallyare based upon streptozocin ortemozolomide, with response ratesin up to 30-70%, depending on thetype of regimen, with higherresponse rates seen in tumours ofintermediate grade.

In patients with poorly differenti-ated NETs (Ki-67 >20%), or dis-ease that is avid on FDG PET (ie,very metabolically active),chemotherapy consisting of carbo-platin plus etoposide is generallyused, with response rates of 50-60%. However, the duration ofresponse is often short-lived.

I tver-direcfrd itprapomThe liver receives its blood supplymainly from the portal vein butalso the hepatic artery. Livermetastases, however, receive theirblood supply principally from thehepatic artery. Trans-arterialchemoembolisation (TACE)involves injecting slow-releasechemotherapy-eluting beads intothe hepatic artery via a catheterplaced in the groin, with the aimof maximising the dose ofchemotherapy to the metastaseswhile minimising systemic sideeffects.

Another form of liver-directedtherapy is intra-arterial adminis-tration of SIR-Spheres, which aremicrospheres impregnated withyttrium-90 (Y-90), a beta-radia-tion-emitting isotope. These treat-ments can have significant mor-

bidity and should only beadministered in specialist centresafter careful consideration of risksvs benefits.

IoIoqlcaI thq.raple,,These include the immunomodu-lator, alpha interferon, and thetyrosine kinase inhibitor, sunitinib(Sutent), and the m-TORinhibitor, everolimus (Afinitor).These can be considered for thetreatment of patients with low- tointermediate-grade pancreaticNETs who progress after priortherapies. All these agents can beassociated with significant toxicityand so require careful monitoringby experienced oncologists. Qual-ity-of-life considerations areimportant in the decision to usethese agents and they are gener-ally only indicated in patientswith significant disease progres-sion or uncontrolled symptoms.

Alpha interferon. This is a cytokinethat increases the expression of thesomatostatin receptors in NET cellsand, therefore, has been used incombination with SSAs in patientsin whom there is disease progres-sion on SSA monotherapy. Thecombination is associated with a40% biochemical and 10% radio-logical response rate.

Sunitinib (Sutent). This is a tyro-sine kinase inhibitor that acts onseveral pathways involved in thegrowth and spread of NETs. Arecent randomised study has shownthat sunitinib provides greater pro-longation of tumour control andradiological response comparedwith placebo.'

Everolimus (Afinitor). This is anoral drug that inhibits m-TOR, aprotein that plays a central role inthe growth of NET cells. Tworecent randomised trials havedemonstrated that everolimus com-bined with octreotide LAN. (long-acting repeatable) provides greaterprolongation of tumour controland radiological response com-pared with octreotide FAR alone.'

Radionuclide therapyRadionuclide therapy relies on thespecific uptake and retention of aradioactive chemical within cancercells, then the release of radiationthat induces DNA damage in thatcell or nearby cells. For almost 60years radionuclide therapy has beenused in the treatment of differenti-ated thyroid cancer. In this situa-tion the ability of thyroid cells totake up iodine, used in the synthe-sis of thyroid hormone, is leveragedto concentrate iodine-131 (I-131)within the tumour. The radioactivedecay of this radioisotope leads tothe emission of beta particles,which deposit all their energywithin a millimetre or so, produc-ing damage to DNA. It is particu-larly the formation of double-strand breaks in DNA thatprovides the therapeutic effect,since a relatively small number ofdouble-strand breaks leads to celldeath. Patients with quite dissemi-nated thyroid cancer can be curedwith low toxicity because of theeffective targeting of radiationinternal to the tumour and the rela-tive lack of uptake in other tissues.

Recognition of the importance

of the SSTR to the biology of neu-roendocrine tumours and the abil-ity to radiolabel and image SSTRswith indium-111 octreotide (Octre-oscan) led to the hypothesis thatthis disease might be amenable toradionuclide therapy (figure 5).This treatment, called peptidereceptor radionuclide therapy(PRRT), was first pioneered in theearly 1990s by administering a highdose of Octreoscan. In addition togamma radiation emission used forimaging, In-111 emits Auger (pro-nounced oh-zhay) electrons. Thisproduces damage within a veryshort range of approximately 10microns (a single-cell diameter).While having a low toxicity pro-file, the low energy of the Augerelectron limits the effectiveness ofthis therapy, especially in patientswith a large disease burden.





ID 00137490062 PAGE 11 of 16

The use of beta particle emittersY-90 and lutetium-177 (Lu-177) inthe form of Y-90 and Lu-177DOTATATE (LuTate) are now pre-ferred and have demonstratedexcellent objective response rates(about 70%) with low toxicity.High-energy beta particles from Y-90 can travel up to a centimetre intissue whereas lower-energy parti-cles from Lu-177 travel 1-2mm.Both result in 'crossfire', wherebyeach cell irradiates its neighbours,resulting in efficient radiation deliv-ery to aggregations of cancer cells.

These agents are generallyadministered as a series of 2-5cycles at 6-12-weekly intervals.Subsequent consolidation or main-tenance therapies are feasible inresponders (figure 6, page 40).There is accumulating evidence thatthe effectiveness of these agents isenhanced hy combining them withlow-dose chemotherapy, whichinhibits DNA repair, thereby sensi-tising cells to radiation damage,without significantly increasingtoxicity. Due to its lower toxicity tothe kidneys, LuTate is the preferredagent in most patients and has beenadministered to more than 200patients in Australia since it was

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from previous page

introduced at the Peter MacCallumCancer Centre in 2005.

The objectives of treatment areprimarily to alleviate symptomsrelated to excess hormone secre-tion or due to direct mass effects ofongoing tumour growth. PRRT ishighly effective in achieving theseobjectives with minor side effectsin most patients. Tumour shrink-age tends to be most marked inpatients with tumours with morerapid growth before treatment.Unlike most therapies, ongoingreduction in lesion size can occurfor many months after completionof radionuclide therapy.

PrognosisThe survival rates for patients withadvanced NETs are highly variable,reflecting the wide range of differenttumour subtypes. Patients with pri-mary small-bowel carcinoidtumours had a median survival of12.5 years in one institutional series,with a shorter survival for other car-cinoid tumours of 4.6 years. Patientswith advanced metastatic disease,particularly those that are poorlydifferentiated, have a poor progno-sis, with survival measured inmonths rather than years, althoughthere is increasing evidence that thiscan he improved by care in centresproviding multidisciplinary manage-ment that is personalised to the dis-parate biological characteristics ofthese tumours.

ReferencesClinical Oncological Society ofAustralia, in partnership withAustralia and New ZealandSociety of Nuclear Medicine,Australia New Zealand Hepatic,Pancreatic and Biliary Association,Australian Castro-Intestinal TrialsGroup: Guidelines for theDiagnosis and Management ofGastroentero pancreatic

Neuroendocrine Tununirs (GEPNETs): wiki.cancer.org.au/australia/COSA:NETs_guidelinesRinke A, et al. Placebo-controlled, double-blind,prospective, randomized studyon the effect of octreotide LARin the control of tumor growthin patients with metastaticneuroendocrine midgut tumors: areport from the PROMID studygroup. Journal of Clinical

Oncology 2009; 27:4656-62.Raymond E, et al. Sunitinibmalate for the treatment ofpancreatic neuroendocrinetumors. New England Journal ofMedicine 2011; 364:501-13.Yao JC, et al. Everolimus foradvanced pancreaticneuroendocrine tumors. NetvEngland Journal of Medicine2011; 364:514-23.

Online resourcesEuropean Neuroendocrine TumorSociety (ENETS): www.enets.orgUnicorn Foundation (Australiancharity focused on NETs):www.unicornfoundation.org.auHicks RJ. Use of molecular targetedagents for the diagnosis, stagingand therapy of neuroendocrinemalignancy. Cancer Imaging 2010;10:S83-S91: www.cancerimaging.org/I 0/A19007

Key points managementand prognosis

Symptoms and disease biology arethe most important determinants ofboth prognosis and treatment.

Surgery should be considered asa curative option in patients withlimited disease extent and canalso provide palliative benefiteven when all disease cannot beresected.

Chemotherapy is generallyineffective in patients with well-

differentiated NETs but mayprovide benefit in poorlydifferentiated disease.

New biological therapies showpromise for delaying diseaseprogression in some patients.

Liver-directed therapies are anoption in selected patients butbecause of significant morbidity,these need to be performed incentres with expertise in NETmanagement.

Peptide receptor radionuclidetherapy (PRRT) is a very effectiveand well-tolerated treatment inselected patients but availabilityis currently limited.





ID 00137490062 PAGE 12 of 16

Figure S: Peptkle receptRr radionuclide therapy ,(Pf1Filn,

Dc: octreolaterndium-111

Yttrium-90L Lutetium-177

3. Radiation is depositedintracellularly resutting in double-stranded DNA breaks

1 Radiolabelledpeptide binds tosomatostatin receptor-present on tumourcell surface

2. Radidabelledpeptide isinternalised

Authors' case study 3THIS middle-aged woman initially presented with a history of sacral and sciatic pain and was found to havemetastatic neuroendocrine tumour involving liver, bone and peritoneum. Her pain progressed despite palliativeradiotherapy and she subsequent presented with worsening lower-limb weakness and paraesthesia.

MRI demonstrated multi-level cord compression due to widespread osseous metastases and she underwentfurther radiotherapy without significant improvement in mobility. She remained confined to a wheelchair withongoing severe bone pain requiring high-dose opiate analgesia.

The patient underwent four induction cycles of lutetium-177 octreotate (LuTate) therapy with rapid improvementof bone pain. Quality of life improved and she regained normal mobility. She remains well and asymptomatic threeyears later, with several maintenance LuTate treatments over this time resulting in further imaging response andreduction of disease burden.





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021200B

LuTite 4Consolidation kJTate 3

How to Treat QuizNeuroendocrine tumours

16 March 2012

INSTRUCTIONSComplete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes

by post or fax.

The mart required to obtain points is 80%. Please note that some questions have more than one conect answer.

ONUNE ONLYwww.australiandoctor.com.au/cpd/ for immediate feedback





ID 00137490062 PAGE 14 of 16

1. Which TWO statements are correct?Neuroendocrine tumours (NETs) can occur atany gastrointestinal site from the stomach tothe rectumPancreatic NETs arise from the exocrinecells of the pancreasThe term 'carcinoid describes GI NETs thathave rapid growthWell-differentiated NETs tend to have slowgrowth with an indolent natural history

2. Which TWO statements are correct?Well-differentiated NETs always secrete highand inappropriate levels of hormonesSerotonin is the hormone most commonlyproduced by carcinoid tumoursWell-differentiated NETs rarely expresssomatostatin receptors (SSTR) on their cellsurfacePoorly differentiated NETs behaveaggressively, with rapid cell proliferation andclinical course

3. Which TWO statements are correct?Locally advanced or metastatic well-differentiated NETs are usually associatedwith significant symptomsNETs that secrete serotonin are usuallysymptomatic well before there is metastaticspread

Characteristic symptoms of carcinoidsyndrome include facial flushing, diarrhoea,abdominal cramps and wheezingChronic exposure to serotonin causesfibrosis and thickening of the tricuspid andpulmonary valves

4. Which THREE statements are correct?Local secretion of serotonin can causefibrosis leading to bowel obstruction, bowelischaemia and malabsorptionPancreatic NETs can cause diarrhoea as aresult of pancreatic enzyme deficiencyCushing's syndrome, hypercalcaemia andhypoglycaemia can all be associated with

functioning pancreatic NETsWidespread metastatic NETs are usuallyaggressive and fast growing

5. Which TWO statements are correct?Chromogranin-A (Cg-A) is a useful blood testfor suspected NETsCg-A is only elevated in hormone-secretingNETs

Patients taking proton-pump inhibitors mayhave mild or moderate elevation in Cg-Alevels

Urinary 5-hydroxyindole acetic acid (5-HIM)measurement is more sensitive for NETsthan Cg-A

6. Which TWO statements are correct?CT is highly sensitive for detecting the primary

NETs mass and the presence of metastasesRadiolabelled somatostatin analogues areuseful for imaging most NETs

Single photon emission computerisedtomography (SPECT) using Octreoscanprovides 3-D cross-sectional imaging of NETsSPECT alone provides highly accurateanatomical localisation of the NET deposits

7. Which TWO statements are correct?High uptake of Octreoscan indicates that theNET is likely to have a rapid and aggressivenatural history

Poorly differentiated NETs are metabolicallyvery active and are identified well by

fluorodeoxyglucose-PET scanningThe presence of metastatic disease means thatcurative or palliative surgery is not appropriateSurgery for NETs can be combined with

ablating techniques such as those usingmicrowave or radio-frequency radiation

8. Which TWO statements are correct?Preoperative use of long-acting somatostatinanalogues (SSAs) decreases the risks of NETs

surgery by reducing the secretory function ofthe tumourSSAs are only used in patients with functioning





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(ie, secretory) NETs

SSA therapy reduces the symptoms ofcarcinoid syndromeSSAs are for symptomatic treatment only anddo not slow tumour growth

9. Which THREE statements are correct?SSAs may cause GI side effects, cardiacconduction abnormalities, and cholelithiasisLoperamide or cholestyramine can be used in

combination with SSAs for control of diarrhoeaHypoglycaemia associated with insulinoma canbe treated with diazoxide, prednisolone orSSAs

Chemotherapy is usually effective in patients

Dideton,Education'

HOW TO TREAT Editor: Dr Giovanna ZingarelliCo-ordinator: Julian McAllanQuiz: Dr Giovanna Zingarelli

with slowly growing well-differentiated NETs

10. Which THREE statements are correct?Treatment can be targeted against liver

metastases by injecting chemotherapy-elutingbeads into the hepatic artery

Radionuclide therapy uses the specific uptakeof a radioactive chemical into cancer cells, theradiation emitted then damaging DNA in thosecells or in nearby cellsIn NETs, radionuclide therapy uses radioactivesomatostatin analogues

With radionuclide therapy, any reduction inlesion size is only maintained for the durationof therapy

CPD QUIZ UPDATEThe RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPDor PDP points for the 2011-13 triennium. You cancomplete this online along with the quiz at www.australiwidoctoccom.au. Because this is a requirement, we are no longer able to accept the quiz by post orfax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

NEXT WEEK The next How to Treat looks at knee disorders in adults, ranging from traumatic and sporting injuries mostly in younger adults, to degenerativeconditions in older patients. The author isAssociate Professor Peter Papantoniou, orthopaedic and lumbar spine surgeon, St George Private Hospital, Kogarah; St Luke's Private Hospital, Elizabeth Bay; Da!cross Adventist Hospital, Killara; andassociate professor, Sydney Adventist Hospital Clinical School, University of Sydney.





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Media Monitors Client Service Copyright Agency Ltd (CAL) 1 of 16 …€¦ · hormone secretion by NETs, partic-ularly those of carcinoid syndrome. Some early-stage NETs are discov-ered