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Peptide receptor radionuclide therapy
(PRRT)
Prof. Dr. Christophe DerooseNuclear Medicine - University Hospitals Leuven (UZ Leuven)
Department of Imaging & Pathology – KU Leuven
Leuven Cancer Institute (LKI)
Leuven, Belgium
ESMO preceptorship on GI Neuroendocrine tumors
November 28th and 29th
Leuven, Belgium
Diagnostic agents for SSR
DIAGNOSTIC COMBINATIONS:• 111In-DTPA-octreotide (Octreoscan®)• 68Ga-DOTA,Tyr3-octreotide (68Ga-DOTATOC)• 68Ga-DOTA,Tyr3-octreotate (68Ga-DOTATATE)• 68Ga-DOTA, [Phe1-1-Nal3]-octreotide) (68Ga-DOTANOC)
Radionuclide + Chelator + Somatostatin analogue
111Indium99mTechnetium68Gallium18Fluorine
DTPADOTANOTAHYNIC
OctreotideTyr3-octreotide (TOC)Tyr3-octreotate (TATE)Naph-octreotide (NOC)
SPECTPET
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Theranostic concept: Therapeutic agents for Peptide Receptor Radionuclide Therapy (PRRT)
THERAPEUTIC COMBINATIONS:
• 111In-DTPA-octreotide (Octreoscan®)
• 90Y-DOTA, Tyr3-octreotide (90Y-DOTATOC)
• 177Lu-DOTA,Tyr3-octreotate (177Lu-DOTATATE)
• 213Bi-DOTA, Tyr3-octreotide (213Bi-DOTATOC)
Radionuclide + Chelator + Somatostatin analogue
111Indium
90Yttrium
177Lutetium
213Bismuth
DTPA
DOTA
NOTA
Octreotide
Tyr3-octreotide (TOC)
Lanreotide
Tyr3-octreotate (TATE)
mRNAReceptor DNA
RNA
Cytoplasm
Nucleus
SSTR
Dectection of NET with radionuclides
Cell withoutSSTR expression
Receptor DNA
111In-OCTREOTIDE
68Ga-DOTATOC
18F-DOTATOC
Radiopharmacon
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mRNAReceptor DNA
RNA
Cytoplasm
Nucleus
Radiopharmacon
Receptor
Therapy of NET with radionuclides
Cell without receptor expression
Receptor DNA
111In-OCTREOTIDE
90Y-DOTATOC
177Lu-DOTATOC
DNA Damage
Selection for PRRT: target presence Krenning Scale – 111In-Octreotide
Comparison of uptake in tumor versus normal organsValidated as strongest prognostic factor for effect of PRRT
I II III IV
< Liver = Liver > Liver Most intense
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Absence of SSR expression – no candidate for PRRT
Absence of SSR expression – no candidate for PRRT
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High SSR expression: PRRT candidate
Molecular imaging of GEP-NET patient
68Ga-DOTATATE 18F-FDG
MIP (ant) MIP (lat)
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68Ga-DOTATATE
MIP (ant) MIP (lat)
Lutetium-177 PRRT post-therapy imaging
MIP (ant) MIP (lat)
177Lu-DOTATATE(7.4 GBq)
Lutetium-177 PRRT post-therapy imaging
177Lu-DOTATATEWhole body scintigraphy
SPECT/CT
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Therapeutic agents
THERAPEUTIC/DIAGNOSTIC COMBINATIONS:• 111In-DTPA-octreotide (Octreoscan®)• 90Y-DOTA, Tyr3-octreotide (DOTATOC)• 90Y-DOTA-lanreotide (DOTALAN)• 177Lu-DOTA,Tyr3-octreotate (DOTATATE)
Radionuclide + Chelator + Somatostatin analogue
111Indium
90Yttrium
177Lutetium
DTPA
DOTA
NOTA
Octreotide
Tyr3-octreotide (TOC)
Lanreotide
Tyr3-octreotate (TATE)
Specific features: radionuclide
RADIONUCLIDE:• Most documented: 111In - 90Y – 177Lu• Differ in:
– emitted particles
– energy of particles
– tissue penetration
Radionuclides Emitted
particle
Energy of
particles
Max tissue
penetration
Half life
(days)
Indium-111 Auger
elektron
γ-radiation
3 en 19 keV
171 en 245 keV
10 μm 2.8
Yttrium-90 β-radiation 935 keV 11 mm 2.7
Lutetium-177 β-radiation
γ-radiation
130 keV
113 en 208 keV
2 mm 6.7
Large tumors
Small tumors
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NET Therapy: multimodal approach
Surgery
Chemotherapy
PRRT
TACE
LiverTxHormonal therapy
Targeted therapy
Goals of systemic NET treatment
�Control of hormonal symptoms�Control of tumor related symptoms�Control of tumor growth�Improved survival
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90Y-DOTATOC in NET
REMARKS:
�Better results in tumor response, compared to 111In-octreotide
�Optimal treatment stays unclear:
DIFFERENT PROTOCOLS
Different activities
Different number of cycles Different response criteria
Clinical Results (3)
Overview of 177Lu-DOTATE data (Rotterdam)
• n=504
• 3 to 4 cycles @ 100-200mCi/cycle
• Objective response– CR: 2%– PR: 28%– SD: 51%– PD: 20%
• Median TTP: 40 months
• Toxicity: – Hemato 9.5%– Renal 0.4%– MDS 0.8%– Liver 0.6%
Kwekkeboom, 2009, Nature Rev End
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Overview of 177Lu-DOTATE data (Rotterdam)• N=310, GEP-NETs only
Kwekkeboom, 2008, JCO
Survival with 177Lu-DOTATE
• 4 to 6 year survival benefit
• CAVE: – Comparison with
other studies
– Non-randomised
Kwekkeboom, 2009, Nature Rev End
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90Y-DOTATOC (Basel experience; n=1109)
Disease control vs. progressive disease
Imhof, JCO, 2011
Median survival: 94.6 months
CR: 0.6%PR: 34%SD: 5%Objective response: 39% (PR+SD)
90Y-DOTATOC (Basel experience; n=1109)
Survival as function of 111In-Octreotide binding
Imhof, JCO, 2011
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90Y-DOTATOC (Basel experience; n=1109)
Imhof, JCO, 2011
Side effects
Early effects: • Nausea (amino acids)• Vomiting (amino acids)• Abdominal pain (amino acids)• Fatigue (first week)� symptomatic treatment
Late effects:• Hematologic/Bone marrow• Renal• Liver
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TOXICITY: late effects
HEMATOLOGIC TOXICITY: (177Lu-TATE > 90Y-TOC)
- 15% of the patiënts
- post-chemo
- ”overdose” (e.g. 111In-octreotide: > 100GBq)
Generally low grade, low probability and reversible.
Low risk for leukaemia/MDS if doses arerespected
RENAL TOXICITY: (90Y-TOC > 177Lu-TATE)-total renal radiation dose (37Gy BED)/tissue penetration
-dose volume
-therapy fractionation
-clinical: AHT, DM, age
�AA: reduction of renal uptake (20-47%)
� (individual) Dosimetry
LIVER TOXICITY
-diffuse liver metastasis
-preceding treatments with liver toxicity
Side effects (2)
90Y-DOTATOC (Basel experience; n=1109)
Incidence of grade 4 and 5 renal toxicity
Imhof, JCO, 2011
Death
Death
9.2%Odds ratio
1,52 3 Vs 2
4,60 2 vs 1
3,13 1 vs 0
Incidence
Score 3 11.2%
Score 2 7.7%
Score 1 5.3%
Score 0 1.8%
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90Y-DOTATOC (Basel experience; n=1109)
Incidence of grade 4 and 5 renal toxicity
Imhof, JCO, 2011
Death
Death
9.2%
Combined treatment with 90Y-DOTATE and 177Lu-DOTATATE vs 90Y-DOTATE• N= 50 (25 vs. 25)• Not randomised, 2 consecutive cohorts
OS PFS
Kunikowksa, EJNMI&MI, 2011
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Combined 177Lu and 90Y treatment
Villard L et al. JCO 2012;30:1100-1106
Combined 177Lu and 90Y treatment
[90Y-DOTA]-TOC + [177Lu-DOTA]-TOC was associated with improved overall survival compared with [90Y-DOTA]-TOC alone in patients
completing three or more cycles of treatment.Villard L et al. JCO 2012;30:1100-1106
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ESMO guideline
Öberg, Ann Oncol 2012
Netter-1 trial: phase III RCT 177Lu-PRRT vs. Octreotide LAR 60 mg in midgut NET
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UZ Leuven PRRT experience
• 90Y-DOTATOC therapy• Fixed activity, 4 cycles, 8 week invterval, with treshold (37 Gy
BED kidney) based on pre-therapeutic 111In-Dosimetry• First patient Q3 2009• Dosimetries: 58• Treated patients 49 (>150 administrations)• Tumour types
– Small bowel NET: 30 (61%)– Pancreas NET: 6 (12%)– Other GEP-NET: 1 ( 2%)– Non-GEP-NET: 12 (24%)
• Future: availability of 177Lu-DOTATATE
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PRESTUDY
6 weeks STUDY40 weeks
4 CYCLI
E633, 24u
FOLLOW UPUntil progression
� 111In-octreotide
� MRI
� 68Ga-DOTATOC PET/CT
� 51Cr-EDTA
I II III IV
EARLY RESPONSE
90Y-DOTATOC68Ga-DOTATOC PET/CT
Perfusion-diffusion MRI
W9 D1W1 D1
W7
W2
W7
W17 D1 W25 D1
W40D1
W40D1
68Ga-DOTATOC PET/CT
Every 6 months
90Y-DOTATOC study protocolUZ Leuven Study design
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Dosimetry: Refined estimate leads to clinically useful results
Barone et al. , JNM 2005
•All patients treated to ≈ 28 Gy•Dose calculated with standard kidney volume, without dose rate and biological repair effects•Huge difference in kidney function decline, despite “similar dose” – no dose effect relationship
•Dose calculated with calculated kidney volume, without dose rate and biological repair effects•Dose ranges from 20 to 40 Gy!!!•Dose effect relationship, although still a lot of remaining variance
•Dose calculated with calculated kidney volume, with dose rate and biological repair effects•Dose ranges from 27 to 55 Gy!!•Tight dose effect relationship (R2=0.87), where administered dose is main determinant of decrease in kidney function
<5% decline/year
<37Gy
Results kidney toxicity UZ Leuven
(A)
Van Binnebeek et al. , EJNM&MI 2014
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Results kidney toxicity UZ Leuven: no severe and rapid kidney function deterioration
Van Binnebeek et al. , EJNM&MI 2014
Pro
gres
sion
free
sur
viva
l (%
)
0
10
20
30
40
50
60
70
80
90
100
Time to Progression since baseline [weeks]
0 10 20 30 40 50 60 70 80 90 100 110
Number at risk<= 12.4 11 9 8 6 4 3 3 1 1 1 1>12.4 33 29 27 23 23 21 19 17 14 9 4
Estimated PFS rate (95% CI)
<= 12.4
40 weeks 36.4% (11.2%, 62.7%)
Estimated PFS rate (95% CI)
<= 12.4
52 weeks 27.3% (6.5%, 53.9%)
Estimated PFS rate (95% CI)
<= 12.4
104 weeks 9.1% (0.5%, 33.3%)
Estimated PFS rate (95% CI)
>12.4
40 weeks 69.0% (50.1%, 82.0%)
Estimated PFS rate (95% CI)
>12.4
52 weeks 65.9% (46.9%, 79.5%)
Estimated PFS rate (95% CI)
>12.4
104 weeks 25.3% (10.8%, 42.8%)
p=0.023Q1
Q2 - Q4
Van Binnebeek et al. , in submission
Low baseline 68Ga-DOTATOC uptake predicts worse prognosis
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Pitfalls in SSRT PRRT (1) – Changes in kidney function
1. Change in kidney function between dosimetry and therapy.
2. E.g.1. Acute renal failure
2. Drug toxicity (NSAID’s for painful metastases)
3. Transiently low kidney function during dosimetry will lead to withdrawal of potentially beneficial therapy.
4. Transient decrease in kidney function during therapy will lead to delayed clearance and higher kidney doses.
Pitfalls in SSRT PRRT (1) – Changes in kidney function
Vanbinnebeek, …. & Deroose, 2012, Ann Nuc Med,
1. Persisting high kidney activityinstead of decrease
2. Creatinine (mg/dl)Baseline: 0.97 -> 2.05 @ time scan3. D: acute renal insufficiency
caused by NSAID’s4. Calculated kidney dose after 4
cycles: 153 Gy!!One course = 38Gy!
5. Return normal (eGFR 67, before 77).
6. New dosimetry: kidney doseafter 4 cycles: 28 Gy (5.5times less!)
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Pitfalls in SSRT PRRT (1) – Changes in kidney function
1. Persisting high kidney activityinstead of decrease
2. Creatinine (mg/dl)Baseline: 0.97 -> 2.05 @ time scan3. D: acute renal insufficiency
caused by NSAID’s4. Calculated kidney dose after 4
cycles: 153 Gy!!One course = 38Gy!
5. Return normal (eGFR 67, before77).
6. New dosimetry: kidney dose after4 cycles: 28 Gy (5.5 times less!)
Vanbinnebeek, …. & Deroose, 2012, Ann Nuc Med, epub
Blue: first dosimetry (eGFR~30ml/min/1,73m²)Red: second dosimetry (eGFR 78ml/min/1,73m²)
Pitfalls in SSRT PRRT (1) – Changes in kidney function
1. Persisting high kidney activityinstead of decrease
2. Creatinine (mg/dl)Baseline: 0.97 -> 2.05 @ time scan3. D: acute renal insufficiency
caused by NSAID’s4. Calculated kidney dose after 4
cycles: 153 Gy!!One course = 38Gy!
5. Return normal (eGFR 67, before77).
6. New dosimetry: kidney dose after4 cycles: 28 Gy (5.5 times less!)
Vanbinnebeek, …. & Deroose, 2012, Ann Nuc Med, epub
Blue: first dosimetry (eGFR~30ml/min/1,73m²)Red: second dosimetry (eGFR 78ml/min/1,73m²)
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Pitfalls in SSRT PRRT (2) – Changes in biodistribution of radiopharmaceutical
MIP images – Evolution in Time
19/02/2008 30/04/2009 12/11/200911/08/2009
7 w after 1st Cycle90Y-DOTATOCVanbinnebeek, … Deroose et al., JCO 2011
Pitfalls in SSRT PRRT (2) – Changes in biodistribution of radiopharmaceutical
0,0001
0,0010
0,0100
0,1000
1,0000
10,0000
0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00
(mic
roC
i/ml)
(hrs)
Blood
apr/09apr/09sep/09sep/09YD16YD15YD14YD13YD11YD08
•Delayed blood clearance•Increase AUC•Mean residence time red marrow0.093 h ->0.416h•Increase in red marrow doseafter 4 cycli from 0.8Gy to 2.1Gy(limit: 2.0)•=> Treatment stopped
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Pitfalls in SSRT PRRT (3) – diffuse bone marrow invasion
68GA-DOTATOC PET -CTOncological history:-2/2007: bone and liver metastases of low grade
carcinoma. Liverbiopsy: NET with Ki67 2-3%R/ Cisplatinum en Etoposide
-9/2008: progression, switch to Platinol en 5FU.-9/2009: Start Sandostatin 3 x 0.5-11/2009: Antalgic RT (D3-D5 en D9-D11): 20 Gy (5 x 4
Gy)Current therapy:- Intron A 5 000000 3/week
- Sandostatin 0.5 mg sc 3x per day
- Zometa 1x/month
- Analgetics
Indication for 90Y-DOTATOC therapy: • Extreme fatigue
• Current therapy too difficult (loss of autonomy)
PROBLEM: Diffuse bone metastases, with bone marrow invasion and possible extramedullar hematopoiesis in liver
and spleen with potential dramatic hematologic radiotoxicity after 90Y-DOTATOC
Pitfalls in SSRT PRRT (3) – diffuse bone marrow invasion
• Hematology:– Light anemia– Neutropenia Grade II– Normal tot borderline normal platelets
• Intrepretation: – Intron therapy– Bone marrow insufficiency?– Combination of both
• Bone Marrow Scintigraphy– Little bone marrow activity in central
skeleton, much less than liver > spleen
– No incread marrow activity in peripheral bones
• No therapy was given
Bone marrow scintigraphy
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Pitfalls in SSRT PRRT (4) dosimetry –hepatomegaly and liver dose
MIP 68Ga-DOTATOC PET 68Ga-DOTATOC PET/CT
•67 yr old women•0: Breast carcinoma, M+ liver, lung, bone (ER+, PR+, c-erb2 -)
•R/ 5 anti-hormonal•R/ 5 chemo•R/ LAR•R/ intrahepatic chemo
•9: progression ++ liver
•Standard dosimetry: •Liver dose: 45 Gy•Limit EBRT: ~35 Gy•But liver volume 5.5L•Standard female liver: 1600g•Corrected dose: 13.1 Gy
•Therapy safe, no increase livertest, partial metabolic response
PreTx PostTx
Pitfalls in SSRT PRRT (4) dosimetry –activity superimposed on kidneys
1. Superimposed organs withrelatively high tracer uptake orexcretion will cause anOVERESTIMATION of the kidneyactivity and lead to OVERESTIMATION of the kidneydose
2. Examples1. Metastatic foci2. Liver3. Bowel
Liver metastasis with intense uptake projecting on leftkidney
Right kidney in ectopicposition pushed byenlarged liver
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Pitfalls in SSRT PRRT (5) dosimetry –activity superimposed on kidneys
1. Superimposed organs withrelatively high tracer uptake orexcretion will cause anOVERESTIMATION of the kidneyactivity and lead to OVERESTIMATION of the kidneydose
2. Examples1. Metastatic foci2. Liver3. Bowel
Increased activity in colon transversum
Take Home messages - PRRT
• PRRT with SSR ligands is a promising treatment modality for patients with SSR-expressing NET.
• Two molecules of choice, no direct comparison: – 90Y-DOTATOC– 177Lu-DOTATE
• Response rate: • CR: few %• PR: ≈ 25%• SD: ≈ 50%• PD: ≤20%
• Response can last for several months• Limited toxicity, can be predicted and managed
– Kidney: 177Lu-DOTATE better than 90Y-DOTATOC
• No fase III data, trials eagerly awaited
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Questions?
Leuven City Hall
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