Biotherapy

• Interferon-: IntronA 3–5 MUxIII–V/week• PegInterferon alpha 50–100 gxI/week

– Adjust the dose according to tolerance and leukocyte count <3.0

• Octreotide, Lanreotide: – Sandostatin 100–500 gx2–3– Sandostatin LAR 20–30 mg/3–4 weeks i.m.– Somatuline Autogel 90–120 mg/4 weeks s.c.

Biotherapy

Treatment Objective response

Stable disease

Biochemical/symptomatic

alpha-interferon 10–15% 40–60% ≤50%

octreotide/lanreotide <10% 30–50% 60–90%

Treatment Objective response

Stable disease

Biochemical/symptomatic

alpha-interferon 10–20% 33–100% ≤50%

octreotide/lanreotide <10% 24–57% 40–80%

EPT

Carcinoids

TreatmentTreatment Disease Objective

response

alpha-interferon EPT, carcinoids 12–15%

octreotide/lanreotide EPT, carcinoids 0–6%

streptozocin + 5-FU/doxorubicin EPT 6–69%

cisplatin + etoposide EPT, foregut 7–39%

DTIC + 5-FU + epirubicin EPT 27%

Paclitaxel EPT, carcinoids 4%

Docetaxel Carcinoids 0

Topotecan EPT, carcinoids 0

Gemcitabine EPT, carcinoids 0

Granberg 2007

TreatmentTreatment Disease Objective

response

Temozolomide EPT, carcinoids 17%

Temozolomide + capecitabine EPT 59%

Temozolomide + thalidomide EPT, carcinoids 45%, 7%

Temozolomide + bevacizumab EPT, carcinoids 14%

Sunitinib EPT, carcinoids 10%

Temsirolimus EPT, carcinoids 5%

Bortezomib EPT, carcinoids 0

Endostatin EPT, carcinoids 0

Granberg 2007

Temozolomide

All patients (n=36)

EPT (n=12)

Bronchial carcinoids

(n=13)

Thymic carcinoids

(n=7)

Other (n=4)

PR 5 (14%) 1 (8%) 4 (31%) 0 0

SD 19 (53%) 8 (67%) 4 (31%) 5 (71%) 2 (50%)

PD 12 (33%) 3 (25%) 5 (38%) 2 (29%) 2 (50%)

Ekeblad 2007

Temozolomide – before and after

Decrease of the endocrine panceatic tumor

Temozolomide – before and after

Decrease of the liver metastases

Temozolomide + capecitabine

Isacoff 2006

Patients:• 17 patients with advanced NET

Treatment: • Capecitabine 1000 mg b.i.d. day 1–14• Temozolomide 150–200 mg/m2 day 10–14• Cycle length 28 days

Results:• CR 1/17 (6%)• PR 9/17 (53%)

– Median response duration 9 months• Biochemical response 6/7 (86%)

Temozolomide + bevacizumab

Kulke 2006

Patients, n=29:• EPT, n=17• Carcinoid, n=12

Treatment: • Temozolomide 150 mg/m2 p.o. for 7 days every other week• Bevacizumab 5 mg/kg i.v. every other week

Results:PR SD PD

EPT, n=17 4 (24%) 12 (70%) 1 (6%)

Carcinoid , n=12 0 11 (92%) 1 (8%)

All, n=29 4 (14%) 23 (79%) 2 (7%)

Temozolomide + thalidomide

Kulke 2006

Patients, n=28 (carcinoid, n=14 EPT, n=11, pheo, n=3)

Treatment: Temozolomide 150 mg/m2 for 7 days every 2 week Thalidomide 50–400 mg daily (median 100 mg)

Results: CR PR CR+PR SD PD

Carcinoid, n=14 1 1 (14%)

EPT, n=11 1 4 5 (45%)

All, n=28 7 (25%) 19 (68%) 2 (7%)

Conclusions: • Temozolomide + thalidomide is active in NETs• Temozolomide + thalidomide seems more active in EPTs

than in carcinoids

Sunitinib

Kulke 2006

Patients:• EPT, n=52• Carcinoid, n=41

Treatment: • Sunitinib 50 mg/day for 4 weeks, followed by a 2 week break

Results: PR SD PD

EPT, n=52 7 (13.5%) 40 (77%) 3 (5.5%)

Carcinoid , n=41 2 (5.1%) 36 (92.3%) 1 (2.6%)

Treatment

Liver embolization Objective response

Carcinoids 38–81%

EPT 25–60%

All 25–81%

Chemo-embolization

Carcinoids 7–44%

EPT 11–50%

All 7–50%

Treatment

Liver embolization Objective response

% no

Carcinoids 81% 34/42

EPT 25% 8/32

Chemo-embolization Objective response

% no

Carcinoids 44% 12/27

EPT 50% 11/22

Gupta 2005

Targeted irradiation therapy

• 111In-DTPA0 -octreotide• 90Y-DOTA0 ,Tyr3 -octreotide• 177Lu-DOTA0,Tyr3-octreotate• 131I-MIBG• 90Y-SIR-Spheres

Isotopes• 111Indium

– -emitter

– T1/2 2.83 days

• 90Yttrium– - emitter

– T1/2 2.67 days

• 177Lutetium– - emitter(+ weak - emitter)

– T1/2 6.71 days

• 131Iodine– - emitter + - emitter

– T1/2 8.02 days

Isotopes

T1/2 (days) Range in tissue

Average Max

111In 2.83 10 m

90Y 2.67 4 mm 12 mm

177Lu 6.71 0.5 mm 2 mm

Breeman 2001

Grading of radionuclide uptake at somatostatin receptor scintigraphy

Grade Appearance of somatostatin receptor scintigraphy

0 No radionuclide accumulation in known tumor lesions 1 Suspected but not certain uptake in known tumor lesions 2 Accumulation in known tumor lesions, intensity less or equal to normal liver uptake 3 Clear uptake in known tumor lesions, higher than liver uptake 4 Intense uptake in known metastases

177Lu-DOTA-octreotate therapyThe Rotterdam experience

• Patients, n=131– 70 carcinoid (64 small bowel, 4 lung, 1 thymic, 1 gastric)– 33 EPT non-functioning– 8 gastrinoma– 2 insulinoma– 18 unknown

• Treatments:– Dosage 100–200 mCi– Cumulative dose 600–800 mCi (22.2 to 29.6 GBq)– Interval 6–10 weeks

Kwekkeboom 2005

177Lu-DOTA-octreotate therapyThe Rotterdam experience

CR 3 (2%)

PR 32 (26%)

MR 24 (19%)

SD 44 (35%)

PD 22 (18%)

• Higher remission rates: – higher uptake– limited no. of liver metastases– gastrinomas

• PD: low performance status extensive disease

Median time to progression: 36 mo

Serious adverse events:

• renal insufficiency (1 patient)

• liver failure (1 patient)Kwekkeboom et al, JCO, 2005

Results:Results:

177Lu-DOTA-octreotate therapyThe Uppsala experience

• 56 patients, (27 MGC, 11 EPT non-functioning, 5 gastrinoma)

• 152 treatments (1–6): Dose 200 mCi (7.4 GBq), interval 6–12 weeks

• Results, n=34, mean follow-up 7.6 months (2,8–22,6):

– 1 CR, 6 PR (21% CR+PR), 1 MR, 25 SD, 1 PD, 3 dead

• Toxicity: 26 hematological grade 3–4 (24 lymfopenia, 5 neutropenia, 3 leucopenia, 1 thrombopenia), 9 renal grade 1

Before After 15 months

Tumor responses in patients with GEP tumors, treated with different radiolabelled somatostatin analogs

Tumor Response

Center Ligand Pats. CR+PR SD PD

Rotterdam (111In-DTPA0)octr 26 0(0%) 16(62%) 10(38%)

New Orleans (111In-DTPA0)octr 26 2(8%) 21(81%) 3(12%)

Milan (90Y-DOTA0,Tyr3)octr 21 6(29%) 11(52%) 4(19%)

Basel (90Y-DOTA0,Tyr3)octr 74 18(24%) 48(65%) 8(11%)

Basel (90Y-DOTA0,Tyr3)octr 33 11(33%) 19(57%) 3(9%)

Rotterdam (90Y-DOTA0,Tyr3)octr 54 4(7%) 40(74%) 10(19%)

Rotterdam (177Lu-DOTA0,Tyr3)octr 76 23(30%) 39(51%) 14(18%)

Rotterdam (177Lu-DOTA0,Tyr3)octr 125 35(28%) 68(54%) 22(18%)

Kwekkeboom 2005

Tumor responses according to tumor type in patients with GEP tumors, treated with different radiolabelled

somatostatin analogs

Tumor Response (CR + PR)

EPT Carcinoid Unknown

Center Ligand Funct Total G-I Bronch origin Total

Basel (90Y-DOTA0,Tyr3)octr NA 37% 5% 20% 29% 24%

Basel (90Y-DOTA0,Tyr3)octr NA 33% 25% 0% 36% 33%

Milan (90Y-DOTA0,Tyr3)octr 63% 51% 35% 14% 21% 38%

Rotterdam (177Lu-DOTA0,Tyr3)octr 71% 36% 20% 100% 42% 30%

Kwekkeboom 2005

Side effects in patients with GEP tumors, treated with different radiolabelled somatostatin analogs

Grade 3/4 hematologic

Center Ligand Pats. Platelets Hb WBC Other

Rotterdam (111In-DTPA0)octr 50 10% 15% 2% 3 AML or MDS

New Orleans (111In-DTPA0)octr 27 7% 11% 7% 3 liver, 1 renal

Milan (90Y-DOTA0,Tyr3)octr 40 7% 3% 7%

Basel (90Y-DOTA0,Tyr3)octr 29 3% 7% 0% 4 renal

Basel (90Y-DOTA0,Tyr3)octr 39 0% 3% 0% 1 renal

Rotterdam (90Y-DOTA0,Tyr3)octr 60 12% 8% 13% 1 liver, 1 renal

Rotterdam (177Lu-DOTA0,Tyr3)octr 200 3% 1% 2% 1 MDS, 1 renal

Kwekkeboom 2005

Conclusion

• Somatostatin receptor mediated treatment provides a feasible, widely well tolerated therapeutic option for patients with neuroendocrine tumors

• beta emitters are promising

• Treatment with combination of 90Y and 177Lu seem to provide even better tumor control

• Best time for radioisotopes in the treatment of these patients is still to be established

131I-MIBG-treatment

Carcinoid Pheochromocytoma/paraganglioma

Response: No % No %

Radiologic 10/75 13 8/21 38

Biochemical 19/52 37 12/20 60

Symptomatic 35/72 49 19/22 86

Toxicity:

Hematologic 13/98 13 4/33 12

Nausea/vomiting 4/98 4 2/33 6

Deaths 2/98 2 3/33 9

Safford 2003–2004

Results:

Treatment

SIRT = Selective Internal Radiation Therapy

• Liver embolization with SIR-Spheres®

• SIR-Spheres® = 90Yttrium-labelled resin

microspheres

• Size ≈ 30–35 m

Selective Internal Radiation Therapy

• High dose of radioactivity delivered selectively to liver metastases

• Pre-treatment angiography to clarify the vascular anatomy

• Pre-treatment scintigraphy with 99Tc macroalbumin to assess lung shunt (≤20%)

Diagnostic scan before SIRT

Selective Internal Radiation Therapy

Patients, n=34:• 15 carcinoids (10 small bowel, 2 cecum, 1 bonchial, 1

gastric, 1 rectum)• 8 endocrine pancreatic tumor• 2 medullary thyroid carcinoima• 9 unknown

Treatment:• Single injection of SIR-Spheres® in the hepatic artery• Concomitant single 7 day systemic infusion of 5-FU 225

mg/m2

Median follow-up 9.8 monthsKing 2005

Selective Internal Radiation Therapy

Results: PR PR SD SD

No % No %

1 month (n=34) 8 24% 23 68%

3 months (n=29) 6 21% 19 66%

12 months (n=10) 2 20% 6 60%

18 months (n=7) 1 14% 5 71%

King 2005

4 patients died from progresssive disease

Complications: 3 duodenal ulcers, 1 pancreatitis, 2 jaundiceAll patients experienced abdominal pain, nausea and lethargy

Selective Internal Radiation Therapy

Conclusion:

SIRT appears to have efficacy in treating unresectable neuroendocrine liver metastases

King 2005

pre 6 month9 month

SIRT in NET – Pilot Study

Patient 2: Morphological Response

El-Sheik, Barcelona 2006

SIRT – before and after

Diagnosis of midgut carcinoids

• Biochemistry– Plasma chromogranin A– U-5’HIAA

• Radiology– CT– Ultrasonography + biopsy

• Octreoscan• PET• Echocardiography

Treatment of midgut carcinoids• Cytoreductive procedures

– Surgery: Primary tumour, lymph nodes, liver metastases– Radiofrequency ablation– Liver embolisation: Particles, SIRT

• Biotherapy: interferon-, somatostatin analogs• Surgery of carcinoid heart disease

• Progression– Liver embolisation: Particles, SIRT– 177Lu-octreotate, 90Y-octreotide– Experimental: RAD001, antiangiogenesis

Diagnosis of lung carcinoids• Biochemistry

– Plasma chromogranin A• Radiology

– CT• Octreoscan• Bronchoscopy + biopsy (Ki67, CD44)• PET

Treatment of lung carcinoids

Radical surgery• Primary tumour• Lymph node metastases• Frozen sections

Long-term follow-up, at least 10 years

Treatment of lung carcinoidsLow proliferative rate (Ki67<2–3%):• Biotherapy –interferon-, somatostatin analogs• Chemotherapy – temozolomide, STZ + 5-FU• 177Lu-octreotate, 90Y-octreotide

Intermediate proliferative rate (Ki67 5–10%):• Chemotherapy – temozolomide, STZ + dox• 177Lu-octreotate, 90Y-octreotide

High proliferative rate (Ki67 >15–20%):• cisplatin/carboplatin + etoposide • temozolomide + capecitabine/bevacizumab• taxanes + dox

Experimental: RAD001, tyrosine kinase/angiogenesis inhibitors

Diagnosis of EPT

• Biochemistry– Chromogranin A– PP, glucagon, insulin, proinsulin, gastrin, calcitonin, VIP– Sectetin test– 72-hour gasting– Meal stimulation test

• Radiology– CT– Ultrasonography– Endoscopic ultrasonography

• Octreoscan• PET

Treatment of EPTLow proliferative rate (Ki67<2–3%):• Chemotherapy – STZ + 5-FU• Biotherapy –interferon-, somatostatin analogs• 177Lu-octreotate, 90Y-octreotide

Intermediate proliferative rate (Ki67 5–10%):• Chemotherapy –, STZ + 5-FU/dox, temozolomide• 177Lu-octreotate, 90Y-octreotide

High proliferative rate (Ki67 >15–20%):• cisplatin/carboplatin + etoposide • taxanes + dox • temozolomide + capecitabine/bevacizumab

Experimental: RAD001, tyrosine kinase/angiogenesis inhibitors

Treatment of EPT• Cytoreductive procedures

– Surgery: Primary tumour, lymph nodes, liver metastases– Radiofrequency ablation– Liver embolisation: Particles, chemoembolisation, SIRT

• Symptomatic– Proton pump inhibitors– Somatostatin analogs– Interferon-– Ketoconazole– Metyrapone

Malignant neuroendocrine GEP-tumours

DiagnosisHistopathology,tumour biology, localisation and staging

Cytoreductive proceduresSurgery, RF

Low proliferating tumours (Ki-67 <3%)Biotherapy: SMS ± IFN

STZ + 5 FU (EPT)Tumour targeted therapy: 90Y, 177Lu

High proliferating tumours (Ki-67 5-10%)Cytotoxic therapy:

STZ + 5 FU/doxorubicin, TemozolomideTumour targeted therapy: 90Y, 177LuCisplatin + Etoposide (Ki-67 >20%)

Progression

Tumour targeted therapy: 90Y-DOTA-Octreotide, 177Lu-DOTA-OctreotateEmbolisation, chemoembolisation, SIRT

Experimental: RAD001, taxanes, tyrosine kinase/angiogenesis inhibitors

AcknowledgementsDept of Endocrine Oncology, Uppsala

• Barbro Eriksson

• Kjell Öberg

• Britt Skogseid

Dept of Nuclear Medicine, Uppsala

• Ulrike Garske

• Lars-Göran Andersson

Dept of Radiology, Uppsala

• Anders Sundin

• Rickard Nyman

SIRTEX Medical, Bonn

• Ralph Peters