Diagnostic imaging with Diagnostic imaging with 111In-DTPA-octreotide:111In-DTPA-octreotide:

Clinical impact on the management of Clinical impact on the management of patients with neuroendocrine tumourspatients with neuroendocrine tumours

Ulrike Garske MDUlrike Garske MD

Specialist in oncology, nuclear and internal Specialist in oncology, nuclear and internal medicinemedicine

Kotka May 2010Kotka May 2010

OverviewOverview

Neuroendocrine tumours: clinic and treatmentNeuroendocrine tumours: clinic and treatment Indications for imagingIndications for imaging SomatostatinSomatostatin 111111In-DTPA-octreotide (OctreoScan®)In-DTPA-octreotide (OctreoScan®)

ImagingImaging Normal FindingsNormal Findings Uptake scaleUptake scale Typical and unusual findingsTypical and unusual findings

Some patients, that you have sent to us for treatment Some patients, that you have sent to us for treatment Thank youThank you

Neuroendocrine tumoursNeuroendocrine tumours

A small tumour group, with lots to learn A small tumour group, with lots to learn from!from!

During the last decade, an evolving model for During the last decade, an evolving model for designing and studying tracers in nuclear designing and studying tracers in nuclear imaging and therapyimaging and therapy

Neuroendocrine tumoursNeuroendocrine tumoursGastro-entero-pancreaticoduodenal tumours (GEP-NETs)Gastro-entero-pancreaticoduodenal tumours (GEP-NETs)

””Carcinoids”: derived from embryonal foregut, midgut Carcinoids”: derived from embryonal foregut, midgut and hindgutand hindgut Foregut och midgut carcinoids: Production of Foregut och midgut carcinoids: Production of

5-HIAA (classic carcinoid syndrom: flushing, 5-HIAA (classic carcinoid syndrom: flushing, palpitation, diarrhea)palpitation, diarrhea)

Endocrine pankreaticoduodenal tumours (EPTs): Endocrine pankreaticoduodenal tumours (EPTs): functioning or non-functioningfunctioning or non-functioning Different associated hormonal syndromsDifferent associated hormonal syndroms

Gastrin, insulin, glucagon, VIP, somatostatin, Gastrin, insulin, glucagon, VIP, somatostatin, ACTH….ACTH….

Neuroendocrine tumoursNeuroendocrine tumours

Pheochromocytomas /paragangliomasPheochromocytomas /paragangliomas Medullary thyroid carcinomasMedullary thyroid carcinomas Neuroendocrine cancers/ neuroendocrine Neuroendocrine cancers/ neuroendocrine

tumours of unknown origintumours of unknown origin ……………………..many rare entities..many rare entities

Treatment overviewTreatment overview

SurgerySurgery Local destruction of livermetastasesLocal destruction of livermetastases

LeverembolisationLeverembolisation Radiofrequency ablationRadiofrequency ablation

Biological treatment Biological treatment (alpha-Interferon, (alpha-Interferon, SomatostatinanalogsSomatostatinanalogs))

ChemotherapyChemotherapy RadiationRadiation

External BeamExternal Beam Brachytherapy of livermetastases (SIR-spheres®)Brachytherapy of livermetastases (SIR-spheres®) Peptide receptor radionuclide therapy (PRRT)Peptide receptor radionuclide therapy (PRRT)

Indications for diagnostic imaging Indications for diagnostic imaging

Staging of recently diagnosed patientsStaging of recently diagnosed patients Finding small tumours: important in case of Finding small tumours: important in case of

significant hormone production (pancreas) , or to significant hormone production (pancreas) , or to rule out extrahepatic disease prior to rule out extrahepatic disease prior to livertransplantationlivertransplantation

Receptor status before chosing therapyReceptor status before chosing therapy Follow-up of therapyFollow-up of therapy

If finding small tumours is If finding small tumours is important…..important…..

……Maybe PET/CT is your choiceMaybe PET/CT is your choice

11C-5-HTP(HTP)

11C

11C-5-hydroxytryptophan

If the receptor status is important…..If the receptor status is important…..

Imaging with somatostatin Imaging with somatostatin analogs! analogs!

SomatostatinSomatostatin

SomatostatinSomatostatin

SomatostatinSomatostatin

Regulatory hormone, thatRegulatory hormone, that Inhibits growth hormoneInhibits growth hormone Inhibits/suppresses release of a row of Inhibits/suppresses release of a row of

gastrointestinal hormones (VIP, glucagon, gastrointestinal hormones (VIP, glucagon, cholecystokinin, gastrin, motilin, secretin….)cholecystokinin, gastrin, motilin, secretin….)

Suppresses the exocrine function of the Suppresses the exocrine function of the pancreaspancreas

Inhibits TSHInhibits TSH

Octreotide (Sandostatin®)Octreotide (Sandostatin®)

Somatostatin receptorsSomatostatin receptors

5 subtypes (sstr1- sstr5)5 subtypes (sstr1- sstr5) Sstr2 predominant in neuroendocrine tumours, Sstr2 predominant in neuroendocrine tumours,

followed by sst5followed by sst5 Octreotide somatostatin analog predominantly Octreotide somatostatin analog predominantly

used in the clinic (Sandostatin®, Sandostatin used in the clinic (Sandostatin®, Sandostatin LAR®), predominant affinity for sstr2 and 5LAR®), predominant affinity for sstr2 and 5

Golden standard för sstr- diagnostic in nuclear Golden standard för sstr- diagnostic in nuclear medicine: OctreoScan® (medicine: OctreoScan® (111111In-DTPA-octreotide)In-DTPA-octreotide)

Normal distributionNormal distribution

Anterior Posterior

Physiological uptake in:

PituitaryThyroidLiverSpleenKidneysAdrenalsGut

OctreoScan® imagingOctreoScan® imaging

Whole body scan: Scanning time (at least 30min)Whole body scan: Scanning time (at least 30min) SPECT/CT: so much better informationSPECT/CT: so much better information Activity 200MBq for adults; one kit per patientActivity 200MBq for adults; one kit per patient Imaging after 24 hrs sufficient , SPECT/CT and patient Imaging after 24 hrs sufficient , SPECT/CT and patient

preparation importantpreparation important Laxation:Laxation: Toilax® (Bisacodyl) Toilax® (Bisacodyl)

2 tabl. à 5mg noon and evening on day of injection2 tabl. à 5mg noon and evening on day of injection

klysma Toilax® morning of examination dayklysma Toilax® morning of examination day Liquid food 12.00 noon inj. day until examination is Liquid food 12.00 noon inj. day until examination is

finishedfinished

Intensity of uptakeIntensity of uptake

Arbitrary scale (according to Krenning): uptake in Arbitrary scale (according to Krenning): uptake in relation to liver uptakerelation to liver uptake

0: no uptake0: no uptake 1: weak uptake, less than liver1: weak uptake, less than liver 2: moderate uptake equivalent to liver2: moderate uptake equivalent to liver 3: intense uptake, higher than liver3: intense uptake, higher than liver 4:very intense uptake, much higher than liver, more 4:very intense uptake, much higher than liver, more

intense than spleen/kidneysintense than spleen/kidneys

OctreoScan® 1996: both diagnostics and OctreoScan® 1996: both diagnostics and therapytherapy

Normal uptakeNormal uptake

Grade 1

Grade 3-4

Grade 3

Grade 4: Patient with hindgut Grade 4: Patient with hindgut carcinoidcarcinoid

Imaging: Midgut carcinoidImaging: Midgut carcinoid

ant post

Staticposterior

Staticanterior

?

Tornado signTornado sign

Massive mesenterial dissemination Massive mesenterial dissemination

…………and one thoracic lymph nodeand one thoracic lymph node

Midgut High proliferationMidgut High proliferation

Ant post ant post

Cardiac metastasesCardiac metastases

Right liver lobe previously treated Right liver lobe previously treated with embolizationwith embolization

Left liver lobe: untreated metastasesLeft liver lobe: untreated metastases

Imaging: InsulinomaImaging: Insulinoma

Insulinomas: predominant pancreatic endocrine Insulinomas: predominant pancreatic endocrine tumour grouptumour group

Better prognosis than other GEP NETsBetter prognosis than other GEP NETs Excellent surgical curation rate, Excellent surgical curation rate, if localizedif localized express in only 50% sstr2express in only 50% sstr2 Malignant insulinomas may have higher expression Malignant insulinomas may have higher expression

of sstr2of sstr2

73yr-old lady with hypoglycemic fits73yr-old lady with hypoglycemic fits

Isolated insulinoma in ectopic Isolated insulinoma in ectopic pancreatic tissuepancreatic tissue

Patient alive and well……..Patient alive and well……..

Symptom free now 7 years after surgerySymptom free now 7 years after surgery Celebrating her 80th birthday this yearCelebrating her 80th birthday this year

Malignant InsulinomaMalignant Insulinoma

Malignant InsulinomaMalignant Insulinoma

Malignant InsulinomaMalignant Insulinoma

Follow up of therapyFollow up of therapy

Somatostatin receptor densitySomatostatin receptor density may vary in different metastases in the same may vary in different metastases in the same

patientpatient May change over timeMay change over time Somatostatin receptor scintigraphy should Somatostatin receptor scintigraphy should

only be interpreted together with radiological only be interpreted together with radiological informationinformation

56y-old lady, atypical bronchial 56y-old lady, atypical bronchial carcinoidcarcinoid

Previously pulmectomyPreviously pulmectomy 3 years later pain in the back3 years later pain in the back Treatment with temozolomide (Temodal®)Treatment with temozolomide (Temodal®)

Follow-up with OctreoScan®: not a Follow-up with OctreoScan®: not a given indication….given indication….

Baseline after 3 6 9 courses

……but it may help to interprete your but it may help to interprete your CT-findingsCT-findings

Cave: Receptor up-regulationCave: Receptor up-regulation

Treatment can change receptor expressionTreatment can change receptor expression New uptake does not necessarily need to represent New uptake does not necessarily need to represent

new lesions.new lesions.

Example of a patient with malignant Example of a patient with malignant pheochromocytomapheochromocytoma

OctreoScan®OctreoScan®

OctreoScan®OctreoScan® 123123I MIBGI MIBG

Malignant PheochromocytomaMalignant Pheochromocytoma

Diagnostic imaging Therapy123I-MIBG 111In-Oscan 131I-MIBG 177Lu-DOTA-tate October 08 October 08 April 09

TreatmentTreatment

Treatment with radiolabelled Treatment with radiolabelled somatostatin analogssomatostatin analogs

A renaissance for imaging with A renaissance for imaging with 111111In-DTPA-In-DTPA-octreotide?!!octreotide?!!

OctreotideOctreotide

LutetiumLutetium

177177Lu-DOTA-TyrLu-DOTA-Tyr33-Octreotate-Octreotate

111111In-DTPA-octreotide In-DTPA-octreotide 177177Lu-DOTA-octreotate Lu-DOTA-octreotate 24h24h

ant post ant post antant post post

Diagnostic images and therapy control: Diagnostic images and therapy control: tumour-to-backgroundtumour-to-background

Oscan 24h Lu 0h 24h 96h 168h

Treatments with 177Lu-DOTA-octreotateTreatments with 177Lu-DOTA-octreotate

0

50

100

150

200

250

Antal behandlingar

2005 2006 2007 2008 2009

Hindgut carcinoid: therapy 1-4Hindgut carcinoid: therapy 1-4

Effect of therapy over timeEffect of therapy over time

Feb 09 April 09 July 09 Aug 09 Jan 10

Ther 1Ther 1 Ther 6Ther 6

Glomerular filtration rate before therapyGlomerular filtration rate before therapy

Before ther1 ther2 ther3 ther4 ther5 ther6

Therapy effects 2: Therapy effects 2: Patient with hindgut carcinoidPatient with hindgut carcinoid

ther 1 ther 2 ther 3 ther 4 ther 5 ther 6

Anterior view , 177Lu-DOTA-octreotate 24 h pi

Therapy 1Therapy 1 Therapy 3Therapy 3

CT-interpretation: take advantage of CT-interpretation: take advantage of your scintigraphy!your scintigraphy!

Therapy 1Therapy 1 Therapy 6Therapy 6

Therapy 1Therapy 1 Therapy 6Therapy 6

177Lu-DOTA-octreotate therapyResults from Rotterdam

Kwekkeboom et al, JCO, 2008

Result 3 months after completed therapy(n=310):Result 3 months after completed therapy(n=310):

CRCR 55 (2%)(2%)

PRPR 8686 (28%)(28%) 46%46%

MRMR 5151 (16%)(16%)

SDSD 107107 (35%)(35%)

PDPD 6161 (20%)(20%)

4% with SD or MR improved further after 6 months

5% with SD or MR improved further after 12 months

Thank you toThank you to

Mattias Sandström and collegue hospital physicistsMattias Sandström and collegue hospital physicists Prof emeritus Hans Lundqvist (Radiophysics) Prof emeritus Hans Lundqvist (Radiophysics) Prof Barbro Eriksson och Prof Kjell Öberg, endocrine oncologyProf Barbro Eriksson och Prof Kjell Öberg, endocrine oncology Doc Dan GranbergDoc Dan Granberg Prof Anders SundinProf Anders Sundin Collegues an staff at the department of nuclear medicine, Collegues an staff at the department of nuclear medicine,

Uppsala Academical HospitalUppsala Academical Hospital Research collegues and friends at RudbecklaboratorietResearch collegues and friends at Rudbecklaboratoriet Med kand Daniel LindholmMed kand Daniel Lindholm Our patients, and……….Our patients, and……….

… … Thank You for inviting me to Thank You for inviting me to beautiful Finland !beautiful Finland !