Radioembolization of Liver Tumors. Considerations on DOSIMETRY

Radioembolization

of Liver Tumors.

Considerations on DOSIMETRY

Patrick Flamen, MD, PhD Hugo Levillain, Medical Physics, doctoral fellow

Dpt. Nuclear Medicine, Institut Jules Bordet Brussels / BELGIUM

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SIRT with Radiolabeled Microspheres

• 35μ diameter

• Yttrium90

• Beta 0.93 MeV

• Half-life: 64.1 hours

• Penetration

– 2.5 mm mean

– 11 mm maximum

electron micrograph SIR-spheres

SIRT : Selective Internal RadioTherapy

Microsphere specifications TheraSphere® SIR-Spheres® Quiremspheres®

Radionuclide (T½ in hours) 90Y (64.1) 90Y (64.1) 166Ho (26.8)

Eβmaxin MeV 2.28 (99.9%) 2.28 (99.9%) 1.85 (>90%)

Eγ in keV 2x 511 (<0.1%) 2x 511 (<0.1%) 81 keV (6.8%)

Microsphere material Glass Resin Polylactic acid

Relative embolic effect Low High High

Number of particles 5 million 50 million 30 million

Specific activity (Bq/microsphere) 1.250 – 2.500 50 330 – 450

Scout dose 99mTc-MAA 99mTc-MAA 166Ho-MS

Contrast injection during infusion Possible Only alternately Possible

Imaging modality SPECT or PET SPECT or PET SPECT or MRI

Dosing of SIRT

Optimalization of SIRT according

to patient and tumor characteristics

Efficacy

Maximal tolerable dose

Dose-response relationship

Toxicity

Dose limiting toxicity

Functional hepatic reserve

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Therapeutic Window : - SIRT treatment FOV - Tumor targeting (arterial hypervascularization of Tumor) - Functional Hepatic Reserve

How to Dose SIRT ? Clinical Parameters

SIRT Treatment FOV

Whole Liver Treatments

Lobar treatments

Ablative versus non-ablative

Radiation segmentectomy

Oncological ambition

Palliative

Curative (pre-operative)

Tumor downstaging resectability

Contralateral Lobar Hypertrophy

Multidisciplinary Tumor Board

Dosimetry

Predictive dosimetry

SIRT simulation

Tc99m-MAA SPECT-CT

Treatment position

Lung shunting

Extrahepatic deposition

Measuring SIRT FOV

Asssessing T/Normal liver uptake

Controversial

Identical Cath position

Time between SIMUL and SIRT

Post SIRT dosimetry

Y90 PET/CT imaging

Treatment verification

Real dosimetry of Tumors and Liver


Classic (Primitive) SIRT activity prescription methods

Courtesy of Prof. M. Lam / Utrecht

SIR-spheres TheraSphere

The recommended dose to the liver is between 80 Gy to 150 Gy.

Personalized SIRT activity prescription

Partition Model

Personalized voxel-based dosimetry


Lungs Liver Tumor

90Y SIR-Spheres PET/CT 99m Tc-MAA SPECT/CT

Convert to 90Y-MS TIA map

90Y SIR-Spheres isodoses

Dose volume Histogram

Treatment 90Y-MS isodoses

On baseline FDG PET/CT

Lesion Liver TF

Lesion Dmean = 190 Gy

Non-tumoural treated liver Dmean = 40 Gy

47% of the liver is not treated (outside SIRT Treatment Field

Is there a dose-response relationship ?

What is the minimal effective tumor dose ?

Efficacy : dose-response correlation ?

Colorectal Cancer

A. Van Den Hoven et al. 2016, Journal of Nuclear Medicine Strong and statistically significant correlation 40-60 Gy cut-offs

K. Willowson et al. 2017, Eur J Nuc Med Research R2 = 0.61 50Gy cut-off

H. Levillain et al. 2018, Eur J Nuc Med Research

R2=0. 81

9 VPP NPV

40 Gy 86% 92%

60 Gy 96% 63%

SIRT Dose versus Patient Outcome in mCRC

• Dose-cut off : 40 Gy

– N=11 vs N=13

– P=0.012

– OS : 13 vs 5 months

– HR 2.6 (95%CI 0.98-7.00)

H. Levillain et al. 2018, Eur J Nuc Med Research

Primary endpoint: Overall survival

Secondary endpoints: PFS, Progression at any site, Progression in the liver as

the first event, tumour response, disease control, HRQoL, Safety/tolerability

Stratified by

• ECOG

• Vascular invasion

• Prior TACE

• Institution

Randomised

1:1

n = 467

SIR-Spheres

Y-90 resin

microspheres

n = 237 enrolled

n = 222 enrolled

Eligible Patients

• Locally advanced or inoperable

HCC who failed ≤2 TACE

• Child-Pugh class A or B ≤7

• ECOG Performance status 0-1

Sorafenib

The SARAH study design Prospective open-label multi-centre French national RCT

Vilgrain V et al. Lancet Oncol 2017; 18: 1624–36.

ITT population Per Protocol population (22% did not receive SIRT)

HR 1.15 [95% CI 0.94 – 1.41]; p=0.18

mOS: 8.0 vs. 9.9 months HR 0.99 [95% CI 0.79 – 1.24]; p=0.92

mOS: 9.9 vs. 9.9 months


Overall survival

SARAH trial Pre-planned dosimetry analyses

Median Overall Survival

Overall Survival is significantly improved in

patients who received ≥ 100 Gy

55% patients (67/121) received ≥ 100 Gy to the

tumour

Hermann et al. EASL 2018 Vilgrain V et al. Lancet Oncol 2017; 18: 1624–36.

Variable HR 95%CI p

Tumour burden (%) (> 25% vs. ≤ 25%) 1.85 1.15 to 2.97 0.0108

ALBI grade (A2 vs. A1) 1.91 1.15 to 3.20 0.0133

Tumour-absorbed dose (<100 Gy vs. ≥ 100 Gy) 2.70 1.72 to 4.25 < 0.0001

Up to 33.9 months median overall survival

A multivariate analysis determined three independent predictors for prolonged mOS

5.8 months [95%CI 4.47–6.67] with 0 predictor

33.9 months [95%CI 9.46–NA] with 3 predictors

Pre-planned dosimetry analyses

Hermann et al. EASL 2018


SIRT in intra-hepatic Cholangiocarcinoma

Retrospective multicenter study

Non resectable and chemoresistant CCa

4 European SIRT reference centers

N = 58 patients

Median OS = 10.3 months

Belgium Germany Netherlands

Institut Jules Bordet

UZ Gasthuisberg Leuven

Universität Klinikum Bonn

University Medical Center Utrecht

H. Levillain et al. EJNMMI 2018

H Levillain et al. EJNMMI 2018

SIRT in intra-hepatic Cholangiocarcinoma

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P-value = 0.008 14.9 vs. 7.1 months HR = 2.35 (95%CI 1.08-5.11)



FDG positive lymph nodes

MAA Uptake ratio

BSA vs Personalized Method

Standard versus Personalized Activity Prescription

Prospective Randomized Trial

in Hepatocellular Carcinoma using TheraSphere

ASCO GI meeting 2020



in Hepatocellular Carcinoma using TheraSphere





Prospective Randomized Controll Trial


Conclusion: SIRT efficacy is related to dose

Colorectal cancer (SIR-Spheres >60 Gy)

Cholangiocarcinoma (SIR-Spheres >80 Gy)

Hepatocellular carcinoma (SIR-Spheres >100 Gy)

(Therasphere > 200 Gy)

Question : To what degree can we increase the dose ?

What are the SAFETY limits ?

How to measure functional liver reserve

Future liver remnant function (post Surgery / post-SIRT)

Blood parameters (Bolirubine / albumine / PTT)

Volumetry (CT-scan)

> 30 % of TLV in healthy livers

> 40% of TLV in compromised livers

Liver scintigraphy (Tc99m-mebrofenin)

Assessing functional hepatic reserve pre-SIRT

99mTc-Mebrofenin

Planar Dual head dynamic scintigraphy

36 frames 10 sec/frame

Liver, heart, geometric mean dataset

Liver uptake %/min

Ekman algorithm*

SPECT-CT

150 350 sec

%/min

Prediction of liver failure post surgery

Volume vs Functional Reserve ?

Tc99m-mebrofenin

de Graaf et al. J Gastroenterology 2010

Functional liver reserve assessment is most indicated in case of compromised liver function: Suspicion of liver cirrhosis / prior surgery or liver toxic treatment (chemo / SIRT / PRRT / …)

Global and regional liver function: Tc99m-Mebrofenin

Ekman M et al., Nuclear Medicine Communication, 1996

Cieslack KP et al., HPB, 2016

Planar (dynamic) SPECT-CT

Whole liver function Distribution of Liver function

HFBSA=4.4%/min/m²

Lower limit = 2.7 %/min/m²

Hepatic function reserve = 38%

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FDG PET/CT

Simulation isodoses

99mTc-mebrofenin SPECT/CT

Integrating (predictive) dosimetry,

metabolic target imaging and liver function.

Predictive Isodoses (MAA SPECT/CT) Isodoses (Y90 PET/CT)

Bilobar approach 1st SIRT ablative left % volume left lobe: 40 % function liver lobe: 20 Global function BRIDA : 10 Residual global function : 7,5 2nd SIRT right Safe SIRT 40 Gr mean absorbed dose

LEFT

LEFT

Impact of liver scintigraphy on treatment planning

• Superposing predictive MAA-isodoses on BRIDA SPECT/CT

– Appreciate the off-target SIRT risk

– Enables to predict dose (= collateral dammage) to functional liver

• Assessment of residual liver function after ablative SIRT

– Cut-off residual function set at 2,7

• Indirectly provides the functional liver volume that can be « sacrified »

– Assess the loss of liver function after abalative SIRT

• Radiation segmentectomy / lobectomy

Personalized SIRT is now recommended

Multicompartimental dosimetry models

Balance between efficacy and safety

Tumor specific efficacy thresholds

Dose is related to outcome

Assessing functional hepatic reserve

in pats with compromized liver function

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CONCLUSIONS

Cholangiocarcinoma SIRT

mBSA vs Personalized methodology

mBSA : Left = 666 MBq, Personalised SIRT : Left = 2191 MBq Right = 962 MBq, Right = 1965 MBq Total = 1628 MBq Total = 4156 MBq

Baseline pre-SIRT

Cholangiocarcinoma SIRT 99mTc-MAA SPECT/CT

Tumor load is vascularized via left and rigfht artery Two steps approach

Case report

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Hepatobiliary scintigraphy before SIRT

3D visualisation

18FDG PET/CT HBS SPECT/CT

Personalized SIRT in Cholangiocarcinoma

Baseline pre-SIRT 6 weeks post 2nd SIRT

Ablative SIRT left lobe

Safe SIRT right lobe

Documents

Radioembolization of Liver Tumors. Considerations on DOSIMETRY