Biotherapy

1
Biotherapy

• Interferon-a IntronA 35 MUxIIIV/week
• PegInterferon alpha 50100 mgxI/week
• Adjust the dose according to tolerance and
  leukocyte count lt3.0
• Octreotide, Lanreotide
• Sandostatin 100500 mgx23
• Sandostatin LAR 2030 mg/34 weeks i.m.
• Somatuline Autogel 90120 mg/4 weeks s.c.

2
Biotherapy
Carcinoids
Treatment Objective response Stable disease Biochemical/symptomatic
alpha-interferon 1020 33100 50
octreotide/lanreotide lt10 2457 4080
EPT
Treatment Objective response Stable disease Biochemical/symptomatic
alpha-interferon 1015 4060 50
octreotide/lanreotide lt10 3050 6090
3
Treatment
Treatment Disease Disease Objective response Objective response
alpha-interferon alpha-interferon EPT, carcinoids EPT, carcinoids 1215
octreotide/lanreotide octreotide/lanreotide EPT, carcinoids EPT, carcinoids 06
streptozocin 5-FU/doxorubicin streptozocin 5-FU/doxorubicin EPT EPT 669
cisplatin etoposide cisplatin etoposide EPT, foregut EPT, foregut 739
DTIC 5-FU epirubicin DTIC 5-FU epirubicin EPT EPT 27
Paclitaxel Paclitaxel EPT, carcinoids EPT, carcinoids 4
Docetaxel Docetaxel Carcinoids Carcinoids 0
Topotecan Topotecan EPT, carcinoids EPT, carcinoids 0
Gemcitabine Gemcitabine EPT, carcinoids EPT, carcinoids 0
Granberg 2007
4
Treatment
Treatment 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
5
Temozolomide
All patients (n36) EPT (n12) Bronchial carcinoids (n13) Thymic carcinoids (n7) Other (n4)
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
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Temozolomide before and after
Decrease of the endocrine panceatic tumor
7
Temozolomide before and after
Decrease of the liver metastases
8
Temozolomide capecitabine

• Patients
• 17 patients with advanced NET
• Treatment
• Capecitabine 1000 mg b.i.d. day 114
• Temozolomide 150200 mg/m2 day 1014
• Cycle length 28 days
• Results
• CR 1/17 (6)
• PR 9/17 (53)
• Median response duration 9 months
• Biochemical response 6/7 (86)

Isacoff 2006
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Temozolomide bevacizumab

• Patients, n29
• EPT, n17
• Carcinoid, n12
• 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, n17 4 (24) 12 (70) 1 (6)
Carcinoid , n12 0 11 (92) 1 (8)
All, n29 4 (14) 23 (79) 2 (7)
Kulke 2006
10
Temozolomide thalidomide

• Patients, n28 (carcinoid, n14 EPT, n11, pheo,
  n3)
• Treatment Temozolomide 150 mg/m2 for 7 days
  every 2 week
• Thalidomide 50400 mg daily (median 100
  mg)

Results CR PR CRPR SD PD
Carcinoid, n14 1 1 (14)
EPT, n11 1 4 5 (45)
All, n28 7 (25) 19 (68) 2 (7)

• Conclusions
• Temozolomide thalidomide is active in NETs
• Temozolomide thalidomide seems more active in
  EPTs than in carcinoids

Kulke 2006
11
Sunitinib

• Patients
• EPT, n52
• Carcinoid, n41
• Treatment
• Sunitinib 50 mg/day for 4 weeks, followed by a 2
  week break
• Results

PR SD PD
EPT, n52 7 (13.5) 40 (77) 3 (5.5)
Carcinoid , n41 2 (5.1) 36 (92.3) 1 (2.6)
Kulke 2006
12
Treatment
Liver embolization Objective response
Carcinoids 3881
EPT 2560
All 2581
Chemo-embolization
Carcinoids 744
EPT 1150
All 750
13
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
14
Targeted irradiation therapy

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

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Isotopes

• 111Indium
• g-emitter
• T1/2 2.83 days
• 90Yttrium
• b- emitter
• T1/2 2.67 days
• 177Lutetium
• b- emitter( weak g- emitter)
• T1/2 6.71 days
• 131Iodine
• b- emitter g- emitter
• T1/2 8.02 days

16
Isotopes
T1/2 (days) Range in tissue Range in tissue
Average Max
111In 2.83 10 mm
90Y 2.67 4 mm 12 mm
177Lu 6.71 0.5 mm 2 mm
Breeman 2001
17
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
18
177Lu-DOTA-octreotate therapyThe Rotterdam
experience

• Patients, n131
• 70 carcinoid (64 small bowel, 4 lung, 1 thymic, 1
  gastric)
• 33 EPT non-functioning
• 8 gastrinoma
• 2 insulinoma
• 18 unknown
• Treatments
• Dosage 100200 mCi
• Cumulative dose 600800 mCi (22.2 to 29.6 GBq)
• Interval 610 weeks

Kwekkeboom 2005
19
177Lu-DOTA-octreotate therapyThe Rotterdam
experience

• Results

CR 3 (2) PR 32 (26) MR 24 (19) SD 44 (35) PD 2
2 (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
20
177Lu-DOTA-octreotate therapyThe Uppsala
experience

• 56 patients, (27 MGC, 11 EPT non-functioning, 5
  gastrinoma)
• 152 treatments (16) Dose 200 mCi (7.4 GBq),
  interval 612 weeks
• Results, n34, mean follow-up 7.6 months
  (2,822,6)
• 1 CR, 6 PR (21 CRPR), 1 MR, 25 SD, 1 PD, 3 dead
  
• Toxicity 26 hematological grade 34 (24
  lymfopenia, 5 neutropenia, 3
  leucopenia, 1 thrombopenia), 9 renal grade 1

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After 15 months
Before
23
Tumor responses in patients with GEP tumors,
treated with different radiolabelled somatostatin
analogs

• Tumor Response
• Center Ligand Pats.
  CRPR 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
24
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
25
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
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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

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131I-MIBG-treatment
Results
Carcinoid Carcinoid Carcinoid Pheochromocytoma/paraganglioma Pheochromocytoma/paraganglioma
Response Response No No
Radiologic Radiologic 10/75 13 8/21 38
Biochemical Biochemical 19/52 37 12/20 60
Symptomatic Symptomatic 35/72 49 19/22 86
Toxicity Toxicity
Hematologic Hematologic 13/98 13 4/33 12
Nausea/vomiting Nausea/vomiting 4/98 4 2/33 6
Deaths Deaths 2/98 2 3/33 9
Safford 20032004
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Treatment

• SIRT Selective Internal Radiation Therapy

• Liver embolization with SIR-Spheres
• SIR-Spheres 90Yttrium-labelled resin
• microspheres
• Size 3035 mm

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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)

30
Diagnostic scan before SIRT
31
Selective Internal Radiation Therapy

• Patients, n34
• 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 months

King 2005
32
Selective Internal Radiation Therapy
Results PR PR SD SD
No No
1 month (n34) 8 24 23 68
3 months (n29) 6 21 19 66
12 months (n10) 2 20 6 60
18 months (n7) 1 14 5 71
4 patients died from progresssive disease
Complications 3 duodenal ulcers, 1 pancreatitis,
2 jaundice All patients experienced abdominal
pain, nausea and lethargy
King 2005
33
Selective Internal Radiation Therapy

• Conclusion
• SIRT appears to have efficacy in treating
  unresectable neuroendocrine liver metastases

King 2005
34
SIRT in NET Pilot Study
Patient 2
Morphological Response
El-Sheik, Barcelona 2006
35
SIRT before and after
36
Diagnosis of midgut carcinoids

• Biochemistry
• Plasma chromogranin A
• U-5HIAA
• Radiology
• CT
• Ultrasonography biopsy
• Octreoscan
• PET
• Echocardiography

37
Treatment of midgut carcinoids

• Cytoreductive procedures
• Surgery Primary tumour, lymph nodes, liver
  metastases
• Radiofrequency ablation
• Liver embolisation Particles, SIRT
• Biotherapy interferon-a, somatostatin analogs
• Surgery of carcinoid heart disease
• Progression
• Liver embolisation Particles, SIRT
• 177Lu-octreotate, 90Y-octreotide
• Experimental RAD001, antiangiogenesis

38
Diagnosis of lung carcinoids

• Biochemistry
• Plasma chromogranin A
• Radiology
• CT
• Octreoscan
• Bronchoscopy biopsy (Ki67, CD44)
• PET

39
Treatment of lung carcinoids

• Radical surgery
• Primary tumour
• Lymph node metastases
• Frozen sections
• Long-term follow-up, at least 10 years

40
Treatment of lung carcinoids

• Low proliferative rate (Ki67lt23)
• Biotherapy interferon-a, somatostatin analogs
• Chemotherapy temozolomide, STZ 5-FU
• 177Lu-octreotate, 90Y-octreotide
• Intermediate proliferative rate (Ki67 510)
• Chemotherapy temozolomide, STZ dox
• 177Lu-octreotate, 90Y-octreotide
• High proliferative rate (Ki67 gt1520)
• cisplatin/carboplatin etoposide
• temozolomide capecitabine/bevacizumab
• taxanes dox
• Experimental RAD001, tyrosine kinase/angiogenesis
  inhibitors

41
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

42
Treatment of EPT

• Low proliferative rate (Ki67lt23)
• Chemotherapy STZ 5-FU
• Biotherapy interferon-a, somatostatin analogs
• 177Lu-octreotate, 90Y-octreotide
• Intermediate proliferative rate (Ki67 510)
• Chemotherapy , STZ 5-FU/dox, temozolomide
• 177Lu-octreotate, 90Y-octreotide
• High proliferative rate (Ki67 gt1520)
• cisplatin/carboplatin etoposide
• taxanes dox
• temozolomide capecitabine/bevacizumab
• Experimental RAD001, tyrosine kinase/angiogenesis
  inhibitors

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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-a
• Ketoconazole
• Metyrapone

44
Malignant neuroendocrine GEP-tumours
Diagnosis Histopathology,tumour biology,
localisation and staging
Cytoreductive procedures Surgery, RF
Low proliferating tumours (Ki-67 lt3) 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,
Temozolomide Tumour targeted therapy 90Y,
177Lu Cisplatin Etoposide (Ki-67 gt20)
Progression
Tumour targeted therapy 90Y-DOTA-Octreotide,
177Lu-DOTA-Octreotate Embolisation,
chemoembolisation, SIRT Experimental RAD001,
taxanes, tyrosine kinase/angiogenesis inhibitors
45
Acknowledgements

• Dept 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

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