peptide receptor radionuclide therapy (prrt) -...

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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)


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)


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)


Survival as function of 111In-Octreotide binding

Imhof, JCO, 2011

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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)


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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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%)


<= 12.4

52 weeks 27.3% (6.5%, 53.9%)


<= 12.4

104 weeks 9.1% (0.5%, 33.3%)


>12.4

40 weeks 69.0% (50.1%, 82.0%)


>12.4

52 weeks 65.9% (46.9%, 79.5%)


>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.


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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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)






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

peptide receptor radionuclide therapy (prrt) -...

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