Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001444875
Ethics application status
Approved
Date submitted
16/04/2021
Date registered
25/10/2021
Date last updated
7/04/2024
Date data sharing statement initially provided
25/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HCC (The SOCRATES HCC Study)
Scientific title
A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HCC (The SOCRATES HCC Study)
Secondary ID [1] 305226 0
TROG 21.07
Universal Trial Number (UTN)
Nil known
Trial acronym
The SOCRATES HCC Study
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Early Hepatocellular Carcinoma 321593 0
Condition category
Condition code
Cancer 319334 319334 0 0
Liver

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Each participant will be allocated into a cohort based on the following criteria;
- Patients with HCC equal to or less than 3 cm deemed eligible for percutaneous thermal ablation will be allocated to Cohort 1
- Patients with HCC greater than 3cm or (HCC equal to or less than 3 cm) deemed ineligible for percutaneous thermal ablation will be allocated to Cohort 2

Interventions:
Cohort 1: Participants will be randomised (1:1) to receive either percutaneous ablation (PA) (either radiofrequency ablation (RFA) or microwave ablation (MWA) technique) versus Stereotactic Ablative Body Radiotherapy (SABR).
Cohort 2: Participants will be randomised (1:1) to receive SOC therapies versus SABR.
- SOC therapies may include transarterial therapies (such as transarterial chemoembolization (TACE) or transarterial radioembolisation (TARE)) and/or MWA/RFA (alone or in combination)

PA and transarterial therapies will be performed as per local hospital protocols.

SBRT technique will follow a standardised protocol with allowable dose ranges stipulated below. Centres will be required to have completed the Trans Tasman Radiation Oncology Group (TROG) SBRT credentialing process prior to being activated.

Interventions are to be delivered within 42 days of randomisation as follows:
1) SBRT: 36-45Gy in 3 fractions (ie 3 treatment sessions) or 40-50Gy in 5 fractions (ie 5 treatment sessions) delivered on 2-3 non-consecutive days/week.
- Each treatment session will take around 30-60 mins as a day procedure.
2) PA (RFA or MWA): To be given as per local practice.
- Ultrasound or CT guided aiming for ablation margin of >5mm, the prescribed voltage will follow the local prescribed algorithm depending on the lesion size (generally administer 100kW to one lesion for 2-4 mins). Verification with post-ablation contrast enhanced CT.
- Eligible candidate will receive one treatment session, which usually takes around 45-60 mins.
3) Transarterial therapies (TACE or TARE): To be given as per local practice.
- Eligible candidate will receive one treatment session, which usually takes around 60-90 mins.
Intervention code [1] 320286 0
Treatment: Other
Comparator / control treatment
Standard of care treatment (SOC) as per the institution's local practice which may include PA (radiofrequency ablation (RFA) or microwave ablation (MWA) techniques), transarterial chemoembolization (TACE) and/or transarterial radioembolisation (TARE), all performed as per local hospital protocols

1) Either radiofrequency ablation (RFA) or microwave ablation (MWA) techniques may be used which will be ultrasound- or CT-guided aiming for ablation margin of >5mm. Verification with post-ablation contrast enhanced CT.

2) Transarterial chemoembolization (TACE) or transarterial radioembolisation (TARE)
Control group
Active

Outcomes
Primary outcome [1] 327202 0
To evaluate 2 year freedom from local progression (FFLP) based on MRI or CT scans for SABR versus thermal ablation in Cohort 1 and SABR versus standard of care (transarterial therapies and/or thermal ablation) in Cohort 2.
Timepoint [1] 327202 0
2 years post commencement of treatment
Secondary outcome [1] 394187 0
2-year overall survival (OS)
Timepoint [1] 394187 0
At 2 years post-commencement of treatment
Secondary outcome [2] 396472 0
2-year progression-free survival (PFS)
- Clinical assessment, blood tests and radiological assessment (contrast-enhanced abdominal CT or MRI) will be performed at 2 years.
- Local progression will be indicated by progressive disease (greater than or equal to 20% increase in diameter with an absolute increase of =5 mm).
Timepoint [2] 396472 0
At 2 years post-commencement of treatment
Secondary outcome [3] 396475 0
Safety and adverse events (Grade greater than or equal to 3 using CTCAE v5.0)
- Clinical assessments, blood tests and/ or radiological assessment (contract-enhanced abdominal CT or MRI) will be performed at week 6, week 12, and every 3 months thereafter until 2 years.
- Toxicity will be graded according to CTCAE V5.0 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50) and grouped into early toxicities (less than or equal to 3 months) or late toxicities (greater than 3months)
- Common toxicities include liver dysfunction, bone marrow suppression (anaemia, neutropenia, thrombocytopenia), nausea/ vomiting, diarrhoea, and abdominal pain.
Timepoint [3] 396475 0
During follow up period performed at week 6, week 12, and every 3 months thereafter until 2 years post-commencement of treatment
Secondary outcome [4] 396481 0
Cost-effectiveness analysis; Incremental cost per outcome (additional patient with FFLP assessed by MRI or CT scan at 2 years; and quality adjusted life years) for SABR compared with SOC.
Timepoint [4] 396481 0
During follow up periods up to 2 years
Secondary outcome [5] 396482 0
To compare patient reported outcomes between SABR and SOC therapies using EORTC QLQ-C30 and QLQ-HCC18 - mean scores over time. Time to =10 point decrease in the combined GHS/QoL score.
Timepoint [5] 396482 0
Assessed at recruitment, four weeks post primary therapy and 6-monthly thereafter until end of study.

Eligibility
Key inclusion criteria
Inclusion Criteria:
1) Histological or radiological diagnosis of single, new HCC with largest diameter =8 cm (BCLC stage 0 or A).
a) If prior history of HCC, the prior HCC must have been:
- Early stage, solitary HCC, =5 cm in size and,
- Have arisen within a different liver segment to the current HCC and,
- Treated with curative intent therapy >2 years prior with no evidence of activedisease at the site.
2) As per local multidisciplinary HCC meeting consensus patient is suitable for percutaneous thermal ablation and/or transarterial therapies and not suitable for or declined liver resection and not planned for liver transplantation.
3) Child-Pugh score =B7* with no or diuretic-controlled ascites
4) ECOG performance status =2
5) Platelets =50x109/L, Haemoglobin =80 g/L, Neutrophils =1.0x109/L, INR <1.8 (except if on therapeutic anticoagulation)
6) 18 years of age or older and able to provide written consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Presence of multifocal HCC, macrovascular invasion or extrahepatic disease
2) Prior treatment for any HCC within last 2 years.
3) Clinically evident ascites or hepatic encephalopathy
4) Prior abdominal radiation therapy that would preclude the delivery of protocol defined SABR to the tumour.
5) Untreated Hepatitis B or C
6) Known additional invasive malignancy (excluding non-melanoma skin cancer) that is progressing or required treatment within the last 2 years.
7) Pregnancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation for both patient groups will be performed using block sizes of 6 and 4 to help ensure minimal imbalance in the size of treatment groups for each patient group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified block randomization using two factors: Child-Pugh classification (A vs. B7) and BCLC stage (very early/0 vs. early stage/A) will be used for SBRT vs SOC cohorts.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Participant and treating clinicians will not be blinded to the treatment assignment after the randomisation process. Given the distinct post-treatment imaging appearances of the different therapies it is also not feasible to reliably blind the local radiologists or central independent radiological review to treatment assignment.
Data collectors and analysers will be blinded to treatment assignment
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
All analyses will be performed according to an intention-to-treat protocol, with a per-protocol analysis performed as a sensitivity analysis. For the FFLP, PFS, TTP, ORR and OS endpoints, analysis will be performed comparing 2-year estimates from cumulative incidence (FFLP) and Kaplan-Meier survival curves (PFS and OS). The two comparisons between groups (SABR vs. MWA/RFA and SABR vs. SOC) will be analysed separately. Secondary analysis using Gray and log-rank tests will be performed to evaluate differences in overall time to event distributions. Fine and Gray, Cox proportional hazards regression will used to estimate hazard ratios with 95% confidence intervals. Secondary outcomes including the EORTC QLQ-C30 and QLQ-HCC18 (presented as mean scores over time) will be assessed using linear mixed-effects models to account for repeated measures. Additionally, time to deterioration (TTD) of combined GHS/QoL will be analysed. TTD will be defined as the time to first onset of a =10 point decrease from baseline. A 2-sided type-1 error rate of alpha=0.05 will be used for all hypothesis testing. All analysis will be performed using Stata software (version 17).

Health economics analysis
This study uses a cost-effectiveness analysis to investigate whether the use of SABR represents value for money relative to SOC. The assessment of costs will reflect the use of SABR and its associated comparators, as well as ongoing patient management costs for HCC care (including physician visits, diagnostic and monitoring services, and the management of treatment relative toxicities). Primary hospital service use for the delivery of SABR and conduct of SOC treatments will be recorded through case report form reporting, noting the mode of delivery for SABR, the form of SOC undertaken and whether or not patients received TACE prior to MWA/RFA. Ongoing treatment costs will be assessed using administrative data (Medicare data) for outpatient medical service use (MBS) and pharmaceutical services (PBS). Patient specific costs associated with accessing care, particularly those associated with travel time for attending clinics for care, will also be assessed based on a patient completed questionnaire. In addition, out-of-pocket costs for MBS and PBS use will be estimated based on Medicare data reporting. For each patient, the costs of care will be assessed at the end of follow-up.
Outcomes for the cost-effectiveness analysis include the difference in the proportion of patients with FFLP at two years, and the difference in quality adjusted life years (QALYS) observed over the study period. In the first instance, outcomes will be expressed based on the primary outcome, the two-year FFLP rate, and the cost-effectiveness expressed as the cost per additional patient with local control at two years. QALYs, the combined impact of the impact of HCC and its treatment on survival and quality of life, will be assessed using patient completed information from the EORTC QLQ-C30. Thus, responses to that questionnaire, will be converted to values on a preference scale – 0 to 1 and applied to survival time to estimate QALYs, allowing the cost per QALY gained for SABR compared with SOC at two years to be estimated.
The base case analysis will adjust for the effect on OS of crossover post-progression. The potential for costs and outcomes to extend beyond the duration of the trial, and the resulting impact on the cost per QALY, will be explored in a modelled analysis. Cost-effectiveness will be estimated for each of the patient cohorts separately (PA eligible and stage migration patients, respectively) and for an overall weighted analysis based on the proportion of early inoperable HCC patients in Australia anticipated to fall into these two groups.



Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
29/11/2022
Date of last participant enrolment
Anticipated
29/10/2025
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
218
Accrual to date
39
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 26196 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 26197 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 26198 0
Nepean Hospital - Kingswood
Recruitment hospital [4] 26199 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [5] 26200 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [6] 26201 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [7] 26202 0
Eastern Health - Box Hill
Recruitment hospital [8] 26203 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [9] 26204 0
Gold Coast University Hospital - Southport
Recruitment hospital [10] 26205 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [11] 26206 0
Westmead Hospital - Westmead
Recruitment hospital [12] 26207 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [13] 26208 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 42072 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 42073 0
5042 - Bedford Park
Recruitment postcode(s) [3] 42074 0
2747 - Kingswood
Recruitment postcode(s) [4] 42075 0
5000 - Adelaide
Recruitment postcode(s) [5] 42076 0
6150 - Murdoch
Recruitment postcode(s) [6] 42077 0
4029 - Herston
Recruitment postcode(s) [7] 42078 0
3128 - Box Hill
Recruitment postcode(s) [8] 42079 0
3050 - Parkville
Recruitment postcode(s) [9] 42080 0
4215 - Southport
Recruitment postcode(s) [10] 42081 0
6009 - Nedlands
Recruitment postcode(s) [11] 42082 0
2145 - Westmead
Recruitment postcode(s) [12] 42083 0
2050 - Camperdown
Recruitment postcode(s) [13] 42084 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 308359 0
Government body
Name [1] 308359 0
Medical Research Future Fund (MRFF)
Country [1] 308359 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Trans Tasman Radiation Oncology Group (T/A TROG Cancer Research)
Address
Trans Tasman Radiation Oncology GroupPO Box 88Waratah, NSW, 2298Australia
Country
Australia
Secondary sponsor category [1] 318029 0
None
Name [1] 318029 0
NA
Address [1] 318029 0
NA
Country [1] 318029 0
Other collaborator category [1] 282960 0
Other Collaborative groups
Name [1] 282960 0
Australasian Gastro-Intestinal Trials Group (AGITG)
Address [1] 282960 0
GI Cancer Institute @LifehouseLevel 6, 119-143 Missenden RdCamperdown NSW 2050
Country [1] 282960 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308330 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 308330 0
Peter MacCallum Cancer Centre
Locked Bag 1, A’Beckett Street
Victoria 8006
Ethics committee country [1] 308330 0
Australia
Date submitted for ethics approval [1] 308330 0
09/05/2022
Approval date [1] 308330 0
03/08/2022
Ethics approval number [1] 308330 0

Summary
Brief summary
The SOCRATES HCC study aims to investigate whether a radiotherapy technique (called Stereotactic Ablative Body Radiotherapy or SABR) can improve outcomes for people with early stage liver cancer compared to other current treatments.

Currently, what treatment patients with early stage liver cancer are offered vary in individual circumstances but include;
• Radiofrequency ablation (RFA) or microwave ablation (MWA) that use heating probes directly inserted into the tumour to kill the cancer cells.
• Transarterial chemoembolisation (TACE) or transarterial radioembolisation (TARE) that uses chemotherapy or radioactive particles injected into the blood supply of the tumour to kill the cancer cells.
• SABR is a highly precise radiation therapy technique that uses high energy x-rays focused on the tumour to kill the cancer cells.

Who is it for?
People who are 18 years of age or over AND have been diagnosed with primary hepatocellular carcinoma (single lesion with the largest diameter equal to or less than 5 cm), AND have not received any prior treatment for this.

Study details:
Participants in this study are randomly allocated (by chance) to one of two groups.
- Patients in Group 1 will receive radiation therapy using a technique called Stereotactic Ablative Body Radiotherapy (SABR) that will be delivered in 3 or 5 outpatient treatment sessions (each 20 to 45 minutes in duration) spaced out over 1 to 2 weeks. The exact number of treatment sessions received, and the duration of each session depends on the size and location of the liver cancer.
- Patients in Group 2 will receive standard of care treatment (SOC) as per their institution's local practice that will be administered by a doctor called an Interventional Radiologist.
The therapies offered will depend on the size and location of the liver cancer and may include one or a combination of radiofrequency ablation (RFA) / microwave ablation (MWA) and/or transarterial chemoembolization (TACE) / transarterial radioembolisation (TARE). This may require an anaesthetic and an overnight admission to the hospital.

Regular follow-up visits will be scheduled at 4 weeks post-treatment and then 3 monthly intervals for 2 years and then 6 monthly until completion of the trial. The same procedures will be repeated but also include imaging; CT or MRI of the liver, blood tests, clinical assessments and a questionnaire on the patient's health status (collected 6 monthly until completion of the trial).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110330 0
Prof Alan Wigg
Address 110330 0
Hepatology and Liver Transplant Medicine Unit,
Southern Adelaide Local Health Network,
Flinders Dr,
Bedford Park.
SA 5042
Australia
Country 110330 0
Australia
Phone 110330 0
+61882044964
Fax 110330 0
Email 110330 0
[email protected]
Contact person for public queries
Name 110331 0
Prof SOCRATES HCC Clinical Research Associate
Address 110331 0
MHA Building, Edith St, Waratah NSW 2298
Country 110331 0
Australia
Phone 110331 0
+61240143911
Fax 110331 0
Email 110331 0
[email protected],au
Contact person for scientific queries
Name 110332 0
Prof Alan Wigg
Address 110332 0
Hepatology and Liver Transplant Medicine Unit,
Southern Adelaide Local Health Network,
Flinders Dr,
Bedford Park.
SA 5042
Australia
Country 110332 0
Australia
Phone 110332 0
+61882044964
Fax 110332 0
Email 110332 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
An interim analysis of the primary (and relevant secondary) outcomes will be performed at the trial's midpoint (1-year follow up post treatment). The analysis will be independently reviewed by a data and safety monitoring board. The trial will be terminated if significance differences for the primary endpoint have already been achieved, or are considered unlikely with ongoing follow up, or if significant safety concerns are identified.
When will data be available (start and end dates)?
Beginning 6 months and ending 5 years following main results publication
Available to whom?
Both interim and final study results will be reported at both national and international conferences and in peer-reviewed journal as they become available.
Dissemination of findings to local HCC multidisciplinary meetings will be a priority of the study steering group.
Available for what types of analyses?
All primary and secondary endpoints as stated in the protocol.
How or where can data be obtained?
Principal investigators email address: [email protected];
Co-Principal investigators email address: [email protected]
Sub-investigator email address: [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11393Study protocol  [email protected] Await provisional trial registration number from A... [More Details]



Results publications and other study-related documents

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