Internal view of patient's torso demonstrating targeted accuracy of TheraSphere Y-90 Glass Microspheres in liver.

THERASPHERETM CLINICAL EVIDENCE

DOSISPHERE-01 trial

DOSISPHERE-01 trial summary

This Level 1 clinical trial demonstrated that personalised TheraSphere dosimetry, using multicompartamental dose administration, achieved a 26.6 month median OS for large tumour HCC patients and a 16-month survival improvement compared to the control arm on standard dosimetry.

Garin E, Tselikas L, Guiu B, Chalaye J et al. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol 2020; Published Online: November 06, 2020 https://doi.org/10.1016/S2468-1253(20)30290-9

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“Personalized dosimetry is safe and leads to a meaningful improvement in the objective response rate and overall survival of patients with locally advanced hepatocellular carcinoma [...] when compared with standard dosimetry.”

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Study objectives and design

A randomised, multicentre, investigator sponsored phase 2 trial comparing the clinical outcomes of SIRT with TheraSphere in patients with advanced HCC using two pre-treatment dosimetry determination methods: (1) Standard, single-compartment dosimetry (STD); defined as a uniform distribution of absorbed dose within the perfused volume – both tumour and normal liver or (2) Personalised dosimetry (PERSO); defined as multi-compartment Y90 distribution of absorbed dose within the perfused volume that accounts for preferential blood flow into the tumor compared with normal parenchyma.

Study design

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Key results

Personalised dosimetry improved survival

Median overall survival in the intention-to-treat (ITT) population

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  • 26.6 months median OS with personalised dosimetry
    (95% CI: 11.7–not reached)
  •  10.7 months median OS in the standard dosimetry group
    (95% CI: 6.0–16.8)


HR: 0.421 (95% CI: 0.215–0.826, P=0.0096)

23 months median OS for PVT patients in personalized arm vs 9.5 months in standard arm
16-month survival improvement

Personalised dosimetry improved response

Index lesion response rate at 3 months using EASL in mITT population

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  • Doubled response rates in patients with unresectable locally advanced HCC following personalised TheraSphere Y90 Therapy vs standard dosimetry2

Personalised dosimetry allowed more patients to be downstaged to surgery

Overall patient population downstaged

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  • 36% of patients with unresectable locally advanced HCC accessed liver resection following personalised TheraSphere Y90 Therapy vs standard dosimetry2

PVT patient population downstaged

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  • 44% of PVT patients with unresectable locally advanced HCC accessed liver resection following personalised TheraSphere Y90 Therapy vs standard dosimetry2
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DOSISPHERE-01 editorial

The DOSISPHERE-01 Study challenges the evolving narrative that patients with advanced hepatocellular carcinoma should have systemic therapy at the expense of locoregional therapy. This notion is particularly true for patients with large tumors and local vascular invasion.”1

Robert J Lewandowski, MD, Riad Salem, MD, DOSISPHERE Editorial, Lancet Gastroenterology & Hepatology


Patient demographics (mITT population)

ParameterPDA (n = 28)SDA (n = 28)
Male (%)92.992.9
Child-Pugh Status (%)CP A5: 786     CP A6/B7: 21.4CP A5: 786     CP A6/B7: 21.4
BCLC (%)BCLC B = 11  BCLC C = 89BCLC B = 7  BCLC C = 93
Bilobar (%)4357
Mean Total Biliburin (μM/L±S/D)14.0±6.414.3±6.4
PVT* Present (%)64.375.0
PVT° Location (%)Segmental 29.6  Main/Lobar 30/33Segmental 32.1  Main/Lobar 32/43
Index lesion (mean, cm)10.5±2.410.9±2.57

*TheraSphere not indicated for patients with PVT
Data in parenthesis are 95% CIs.


Treatment characteristics and dosimetry (mITT population)

Investigator Assessments PDA (n = 28)SDA (n = 28)P value
Number of Y-90 glass microspheres treatmentsOne treatment, n=26                       Two treatments, n=2              One treatment, n=23                       Two treatments, n=5             no (not significant)
Activity administered GBq (mean, min-max)3.6 (2.4-4.8)2.6 (2.2-3.0)0.0049
AD* to perfused liver (Gy) Mean (±SD)178.4±59.9120.3±15.20.0001
% of patients with AD to perfused liver > 150 Gy684<0.0001
AD to index lesion (Gy) Mean (±SD)331.1±131.5221.3±139.40.0007
% of patients with AD to index lesion > 205 Gy8838<0.0008
AD to perfused normal tissue (Gy) Mean  (±SD)92.8±30.164.5±36.60.007

*AD=absorbed dose


Liver adverse events (Grade ≥3) related to TheraSphere Y90 Therapy*

 

Liver adverse events (Grade ≥3) related to TheraSphere Y90 Therapy*
 Personalised (n=35)Standard (n=21)
Patients with ≥ 1 AE3 (8.6%)3 (14.3%)
Death1 (2.9%)1 (4.8%)
Liver AEs4 (11.4%)5 (23.8%)
   • Ascites1 (2.9%)2 (9.5%)
   • Encephalopathy00
   • GI haemorrhage02 (9.5%)
   • Bilirubin increase/jaundice1 (2.9%)2 (9.5%)
   • Hepatic failure2 (5.7%)0

*Adverse events occurring in >5% of patients

DOSISPHERE-01 conclusion

After a long-term follow-up period, a meaningful improvement in OS was sustained after personalised dosimetry. OS was dramatically improved for patients who were downstaged toward resection and then resected, including most PVT* patients. Because the 5 year survival rates for patients without resection remain low, randomised trials comparing SIRT with personalised dosimetry plus immunotherapy versus immunotherapy alone are now warranted in this specific patient population.
 

References

1.Gabr A, al. Liver Transplantation Following Yttrium‐90 Radioembolization: 15‐year Experience in 207‐Patient Cohort. Hepatology 2021;73(3):998-1010.

2.DOSISPHERE-01: Garin E, et al. Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2021 Jan;6(1):17-29.

Abbreviations

AE, adverse event; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; GI, gastrointestinal; HCC, hepatocellular carcinoma; HR, hazard ratio; mITT, modified intention-to-treat; ORR, objective response rate; PVT, portal vein thrombosis; Y90, yttrium-90.

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TheraSphere is a registered trademark of Theragenics Corporation, used under license by Boston Scientific Medical Device Limited, a wholly owned indirect subsidiary of Boston Scientific Corporation. Simplicit90Y is a registered trademark of Boston Scientific Medical Device Limited. Simplict90Y is developed by Mirada Medical Ltd. and used under license by Boston Scientific Corporation, the sales agent for Simplicit90Y. All rights reserved.