Accurate Dosimetry and Biomarkers Improve Survival in HCC Patients Treated With Resin 90 Yttrium (90Y)-Microspheres (DOSEY90)

Accurate Dosimetry and Biomarkers Improve Survival in HCC Patients Treated With Resin 90 Yttrium (90Y)-Microspheres: a Randomized Trial

This trial involves patients with hepatocellular carcinoma (HCC) diagnosis treated with transarterial radioembolization (TARE) with resin microspheres loaded with 90Y. Patients will be divided in two groups based on prescription method to calculate the therapeutic radionuclide activity to be injected. In arm A, standard dosimetric approach such as Body Surface Area (BSA) method and Medical Internal Radiation Dosimetry (MIRD) monocompartmental method will be used. In arm B, novel voxel-based dosimetry, based on pre-treatment simulation with 99m-Technetium (99mTc)-Macro Aggregated Albumin (MAA) injection and SPECT/CT image acquisition, will be used. The primary outcome will be the overall survival of patients included in arm A and arm B. Secondary outcomes will be adverse events, tumor response, biomarkers assessed from blood samples prior and after the treatment and voxel-based dosimetry obtained from post-treatment PET/CT images acquisitions.

Study Overview

• Status: Recruiting
• Conditions: HCC
• Intervention / Treatment: Radiation: Standard dosimetry approach; Radiation: Personalized dosimetry approach

Detailed Description

The hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. For a large number of patients surgery is not feasible, due to disease multifocality or liver impairment. Several techniques have been proposed in the last years to treat inoperable HCC, including transarterial radioembolization (TARE), also known as selective internal radiotherapy (SIRT). The TARE is an interventional procedure in which micron-sized embolic particles (resin or glass microspheres) loaded with beta-emitter radionuclides of 90Y are directly injected in the hepatic arteries. This allows to treat the tumor, which receives most of its blood supply from these arteries, and to spare the liver parenchyma, which is supplied mainly by the portal vein. Microparticles are directly released to the target and remain trapped in it, locally delivering a curative amount of radiation dose. In addition to the dose delivered to the tumor and to the liver parenchyma, which have been showed to be related to the treatment efficacy and to the occurrence of liver toxicity, several studies highlighted the role of biomarkers such as the alpha-fetoprotein or the PIVKA-II to describe the tumor progression or aggressiveness.

The procedure can be simulated with the injection of 99mTc-labeled macroaggregated albumin (MAA), through the acquisition of a SPECT/CT, and verified after the treatment with bremsstrahlung SPECT imaging or PET imaging.

To assess the amount of radionuclide to be injected for a curative purpose (namely, the activity at the injection time), several methods have been proposed. Among them, the Body Surface Area (BSA) method allows to estimate the activity based on patient's height and weight and liver/tumor volumes, while the Medical Internal Radiation Dosimetry (MIRD) monocompartmental method allows to estimate the activity based on the desired dose delivered to the target or liver, assuming that all the activity is deposited inside these volumes. Both methods currently represent the standard dosimetric approach.

In addition, in recent years, voxel based dosimetry has been proposed as a novel dosimetric approach. In voxel based dosimetry, the absorbed dose distribution can be calculated from the SPECT/CT acquisition obtained in the simulation procedure prior to the treatment. This allows to take into account the inhomogeneity of the radionuclide distribution among the liver and the target volumes. Voxel based dosimetry can be used to prescribe the activity at injection time that would allow to deliver the desired absorbed dose to the target without exceeding the radiation dose to the healthy tissues.

In this randomized trial, patients with hepatocellular carcinoma (HCC) diagnosis are equally divided into arm A (activity prescription based on standard dosimetry approach) and arm B (activity prescription based on novel voxel-based dosimetry approach). The primary goal of the study is to show the superiority of the novel dosimetry approach in terms of patients' overall survival. As secondary goal, the following data will be recorded: adverse events, tumor response, biomarkers assessed from blood samples prior and after the treatment and voxel-based dosimetry obtained from post-treatment PET/CT images acquisitions.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lidia Strigari, PhD MSc; Phone Number: 00390512143570 00390512143570; Email: lidia.strigari@aosp.bo.it
• Study Contact Backup: Name: Carmine Troiano; Phone Number: 00390512143575 00390512143575; Email: fissansegr@aosp.bo.it

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna
    • Contact: Lidia Strigari, PhD MSc; Phone Number: 00390512143570 00390512143570; Email: lidia.strigari@aosp.bo.it
    • Contact: Carmine Troiano; Phone Number: 00390512143575 00390512143575; Email: fissansegr@aosp.bo.it
    • Principal Investigator: Lidia Strigari, PhD MSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• hepatocellular carcinoma diagnosis (BCLC stage B or C)
• appropriate liver function (Child-Pugh A or B<8)
• life expectancy > 3 months
• bilirubin < 2.0 ng/ml
• multidisciplinary team consensus to the treatment
• multiphasic CT within 1 month prior to the treatment
• written informed consent

Exclusion Criteria:

• lung shunt fraction > 20%
• Child-Pugh score C
• BCLC stage D
• liver impairment
• relevant ascites
• hepatic encephalopathy
• vascular abnormality not allowing proper catheterization
• significant distant metastasis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard dosimetric approach for 90Y activity calculation; The radionuclide activity to be injected is calculated with standard dosimetric approach such as body surface area (BSA) method or Medical Internal Radiation Dose (MIRD) monocompartmental method.	Radiation: Standard dosimetry approach; The radionuclide activity to administer is calculated using standard (BSA or MIRD) dosimetry approach
Experimental: Personalized voxel-based dosimetric method for 90Y activity calculation; The radionuclide activity to be injected is calculated with voxel-based approach based on pre-treatment simulation with the injection of 99mTc-MAA and the acquisition of SPECT/CT images.	Radiation: Personalized dosimetry approach; The radionuclide activity to administer is calculated using personalized voxel-based dosimetry approach

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Patients overall survival after receiving the treatment will be recorded. Correlation between the patients survival and the assigned Arm will be assessed.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Related adverse events in both arms as assessed by National Cancer Institute criteria (National Cancer Institute Common Terminology Criteria for Adverse Events, CTCAE v.5.0)	Related adverse events will be assessed with CTCAE v.5.0. Only adverse events within 6 months from the treatment will be considered treatment-related and considered in the secondary outcome.	6 months
Tumor response in both arms as assessed by Response Evaluation Criteria in Solid Tumours (RECIST v1.1)	Tumor response after the treatment will be assessed with Response Evaluation Criteria in Solid Tumours (RECIST v1.1).	3 years
Biomarkers prior and after the treatment	Biomarkers (PIVKA-II and Alpha-fetoprotein) values will be measured by blood samples prior the treatment (basal value) and at 1-month and 3-months follow-up after the treatment	3 months
Post-therapeutic dosimetry measured with Positron Emission Tomography - Computed Tomography (PET/CT) acquisition	Voxel-based dosimetry will be performed based on a PET/CT acquisition the day after the treatment. The dose delivered to the whole and healthy liver, the tumor and the lungs will be recorded.	1 day

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Collaborators: Regina Elena Cancer Institute
• Investigators: Principal Investigator: lidia strigari, PhD MSc, IRCCS Azienda Ospedaliero-Universitaria di Bologna

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2018
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: January 10, 2022
• First Submitted That Met QC Criteria: January 26, 2022
• First Posted (Actual): February 7, 2022

Study Record Updates

• Last Update Posted (Actual): February 7, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: randomized trial; radioembolization; voxel dosimetry
• Other Study ID Numbers: 742/2019/Oss/AOUBo

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No