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
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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
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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
Vilgrain V et al. Lancet Oncol 2017; 18: 1624–36.
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
Vilgrain V et al. Lancet Oncol 2017; 18: 1624–36.
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)
P-value = 0.0099 16.4 vs. 9.4 months HR = 2.92 (95%CI 1.01-8.43)
P-value = 0.0009 5.5 vs. 14.9 months HR = 2.52 (95%CI 1.23-5.16)
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
Standard versus Personalized Activity Prescription
Prospective Randomized Trial
in Hepatocellular Carcinoma using TheraSphere
ASCO GI meeting 2020
Standard versus Personalized Activity Prescription
Prospective Randomized Trial
ASCO GI meeting 2020
Prospective Randomized Controll Trial
ASCO GI meeting 2020
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
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