Transarterial Chemoembolization (TACE) With or Without Stereotactic Body Radiotherapy (SBRT) in Hepatocellular Carinoma (TACERT)
Primary Purpose
Hepatocellular Carcinoma
Status
Withdrawn
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
transarterial chemoembolization
TACE plus RT
Sponsored by

About this trial
This is an interventional treatment trial for Hepatocellular Carcinoma
Eligibility Criteria
Inclusion Criteria:
- HCC (diagnosed through biopsy or radiological criteria)
- Age >18 years of age
- Number of lesions: not more than 3 lesions
- Lesion size: up to 10 cm (and up to 10 cm cumulative diameter)
- Unilobar +/- segment 4
- Child-Pugh A within 6 weeks prior to study entry
- Barcelona Clinic (BCLC) Stage A/B
- Absence of comorbidities
- ECOG Performance Status 0-2
- Must be fit (eligible) for RT and TACE
- Unsuitable/unwilling for resection or transplant or radiofrequency ablation (RFA) or if these options are not available
- All blood work obtained within 6 weeks prior to study entry with adequate organ marrow function defined as follows:
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets ≥ 50,000 cells/mm3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.) Total bilirubin < 2 mg/dL Prothrombin time/INR < 1.7 (unless on Coumadin/Warfarin) Albumin ≥ 28 g/L AST and ALT < 5 times ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min
- May have had previous surgery, ethanol injection and RFA to the liver
- No evidence of metastatic disease including nodal or distant metastases (clinically defined by each institution).
- Distance between GTV (lesion) and luminal structures (including esophagus, stomach, duodenum, small or large bowel) is >5 mm
Exclusion Criteria:
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 2 years (Note that carcinoma in situ of the breast, oral cavity, or cervix are all permissible). No active cancer therapy.
- Major vascular invasion/thrombus
- Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) Raoul et al (2011)
- Previous TACE and radiation to the liver (including SIRT )
- Life-threatening condition including untreated HIV and active hepatitis B/C
- Pregnancy or women of childbearing potential require a negative pregnancy test within 28 days
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Experimental
Arm Label
TACE alone
TACE plus RT
Arm Description
Transarterial chemoembolization (TACE)
Combination of transarterial chemoembolization and radiation (TACERT)
Outcomes
Primary Outcome Measures
Intrahepatic progression
Lesion growth as characterized by RECIST criteria
Secondary Outcome Measures
Response rate - Modified RECIST criteria
Response of treated lesions using modified RECIST criteria
Local failure - within 1 cm from the original tumor volume
evidence of disease within 1cm of the tumor
Overall survival
overall survival percentage
Toxicity
Measured by NCI - CTC V4.0 at year 2
QoL-quality of life
EORTC QLQC30 at year 2
Full Information
NCT ID
NCT03079778
First Posted
March 11, 2016
Last Updated
February 20, 2020
Sponsor
Lawson Health Research Institute
1. Study Identification
Unique Protocol Identification Number
NCT03079778
Brief Title
Transarterial Chemoembolization (TACE) With or Without Stereotactic Body Radiotherapy (SBRT) in Hepatocellular Carinoma
Acronym
TACERT
Official Title
Transarterial Chemoembolization (TACE) With or Without Stereotactic Body Radiotherapy (SBRT) in Hepatocellular Carinoma
Study Type
Interventional
2. Study Status
Record Verification Date
April 2019
Overall Recruitment Status
Withdrawn
Why Stopped
Opened up a separate Clinicaltrials.gov trial form, study ID TACE
Study Start Date
July 31, 2019 (Anticipated)
Primary Completion Date
August 2022 (Anticipated)
Study Completion Date
August 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Lawson Health Research Institute
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Hypothesis: Patients with hepatocellular carcinoma (HCC) have few options if they fail or are unable to undertake surgery, transarterial chemoembolization (TACE) and/or chemotherapy. Radiation (RT) in a range of doses has been combined with TACE in several case cohort studies demonstrating safety and a dramatic improvement in survival. Clearly these trials are subject to bias due to non-randomized selection, possible lack of generalizability to Canadian patients, and heterogeneous patient populations.
Objective: Therefore, there is a high priority need to investigate the addition of RT to TACE in a randomized fashion to determine if we can improve survival in this rapidly growing poor prognosis patient population that have no other options.
Methodology: TACE eligible patients with HCC will be randomized to TACE alone or TACE plus radiation (TACERT). They cannot be eligible for standard treatments such as transplant and resection. Primary endpoint will be time-to-intrahepatic-progression. Secondary endpoints will be response rate (Modified RECIST criteria), overall survival, local failure, extrahepatic failure, toxicity, quality of life and economic feasibility.
Detailed Description
DETAILED OUTLINE OF RESEARCH PROPOSAL
Current State of Knowledge Primary liver cancer, hepatocellular carcinoma (HCC), is a major health problem worldwide. It is the 5th most common cancer and the 3rd most common cause of cancer death in the world. Eighty-five percent of cases occur in developing countries, while in the United States and Canada, it is the fastest growing cancer.
General Treatment Overview: HCC tends to remain within the liver and, therefore, cure with preserved liver function is possible. Surgical resection results in 5-year survival rates of 60%-70%. Liver transplantation can cure both the cancer and underlying liver disease. Four-year survival for HCC within the Milan criteria (single HCC <5 cm or ≤3 HCC <3 cm) is 70%-85% after transplantation. Unfortunately, most patients are not resectable. Transarterial chemoembolization (TACE) has become the mainstay of treatment for unresectable HCC. What makes TACE relatively safe is the liver-unique vascular supply from the portal vein, whereas HCC is supplied almost entirely by branches of the hepatic artery. In a randomized controlled trial for unresectable HCC not suitable for a curative intent, transarterial chemoembolisation or TACE were compared to conservative treatment. TACE induced objective responses (complete and partial response) that were sustained for at least 6 months in 35% of cases. Survival probabilities at 1 year and 2 years were 82% and 63% for TACE, significantly better than 63% and 27% obtained with conservative treatment. Overall survival at 1 and 2 years was also significantly better for the chemoembolization group 57% and 31% vs. 32% and 11%. However, many patients have large tumours and response rates decline rapidly with increasing size. TACE alone results in 2 year overall survivals of 42%, 0 and 0 for lesions 5-7cm, 8-10cm, and >10cm, respectively. Therefore, additional locally ablative treatments are being sought. In the same report, TACE plus radiation results in 2 year overall survivals of 63%, 50% and 17% for lesions 5-7cm, 8-10cm, and >10cm, respectively.
External beam radiotherapy has long been considered to have a very limited role in the treatment of liver tumors. This is due to the fact that the minimum dose required for local ablation exceeded the dose that would result in liver toxicity. The technical development of stereotactic body radiation therapy (SBRT), alone or in combination with TACE, renewed interest in radiation for HCC. This work was done mainly by two groups, in Michigan and Stockholm, who demonstrated that the delivery of high doses of radiation to limited volumes of the liver had promising results in terms of local control and survival with acceptable toxicity. Dr. Lock and his team are one of the first centres to initiate this type of work and currently have one of the largest databases outside of asia. In addition, he leads one of only two groups in Canada able to dose escalate based on radiobiological parameters thereby providing the highest possible doses within known toxicity constraints. For SBRT, advanced techniques are used to very accurately deliver a high total dose to the target in a small number of daily fractions while avoiding dose delivery to surrounding healthy structures. SBRT is offered as an ablative radical local treatment. In total, eleven primary series reported on tumor response and survival of around 300 patients who have been treated with stereotactic body radiation therapy as primary therapy for HCC. The reported percentage of objective responses defined as complete and partial was ≥64% in 7 of 8 series. Median survival between 11.7 and 32 months has been observed. Toxicity, based on multiple case series trials, indicate that the treatment is considered safe. The most common CTC grade 3-4 toxicity was elevation of liver enzymes.
For unresectable cases, both TACE and SBRT have been used safely and with good efficacy as separate treatments. Particularly for larger lesions that are more commonly seen in London, the outcome remains suboptimal compared to surgery. Combined treatment case series have shown dramatic results, but there has not been any randomized trial to compare the value of combining the two modalities. Therefore a clinical study comparing SBRT and SBRT+TACE will be significant as it addresses a common problem in one of the two most deadly cancers.
Combined Modality Treatment RT in a range of doses has been combined with TACE in several case cohort studies. One example is a phase 1 dose escalation study that demonstrated that 62 Gy and 52 Gy were safe doses for HCC <10 cm and >10 cm, respectively, in conjunction with TACE. Koo et al prospectively studied 42 patients who received TACE followed by RT. Survival in this cohort was improved compared with a historical control group of 29 patients who received TACE alone (median survival 11.7 vs. 4.7 months). Four studies specifically compared cohorts of patients that received TACE alone versus TACE+SBRT. All demonstrated significant improvement in response rates and overall survival. Clearly these trials are subject to bias due to non-randomized selection, possible lack of generalizability to Canadian patients, and heterogeneous patient populations. Therefore, there is an important clinical need to investigate combined RT+TACE to improve outcomes in this rapidly growing poor prognosis patient population that has few options.
Research Design and Methodology The objective is to demonstrate superiority of SBRT in addition to TACE in terms of intrahepatic disease progression versus TACE alone using a randomized Phase III design. Phase I/II data has been published with recent data providing accurate event rates for statistical estimation of a small sample size requirement for this endpoint.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatocellular Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
randomized to radiation (RT) or TACE plus RT (TACERT)
Masking
None (Open Label)
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TACE alone
Arm Type
Active Comparator
Arm Description
Transarterial chemoembolization (TACE)
Arm Title
TACE plus RT
Arm Type
Experimental
Arm Description
Combination of transarterial chemoembolization and radiation (TACERT)
Intervention Type
Procedure
Intervention Name(s)
transarterial chemoembolization
Intervention Description
Transcatheter arterial chemoembolization (also called transarterial chemoembolization or TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply
Intervention Type
Radiation
Intervention Name(s)
TACE plus RT
Other Intervention Name(s)
radiobiological guided radiation
Intervention Description
radiobiologically guided radiation
Primary Outcome Measure Information:
Title
Intrahepatic progression
Description
Lesion growth as characterized by RECIST criteria
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Response rate - Modified RECIST criteria
Description
Response of treated lesions using modified RECIST criteria
Time Frame
2 years
Title
Local failure - within 1 cm from the original tumor volume
Description
evidence of disease within 1cm of the tumor
Time Frame
2 years
Title
Overall survival
Description
overall survival percentage
Time Frame
2 years
Title
Toxicity
Description
Measured by NCI - CTC V4.0 at year 2
Time Frame
2 years
Title
QoL-quality of life
Description
EORTC QLQC30 at year 2
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
Cost-benefit
Description
costs of performing both treatments versus TACE alone
Time Frame
2 years
Title
Extrahepatic failure
Description
enumeration of number of cancers outside the liver
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
95 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
HCC (diagnosed through biopsy or radiological criteria)
Age >18 years of age
Number of lesions: not more than 3 lesions
Lesion size: up to 10 cm (and up to 10 cm cumulative diameter)
Unilobar +/- segment 4
Child-Pugh A within 6 weeks prior to study entry
Barcelona Clinic (BCLC) Stage A/B
Absence of comorbidities
ECOG Performance Status 0-2
Must be fit (eligible) for RT and TACE
Unsuitable/unwilling for resection or transplant or radiofrequency ablation (RFA) or if these options are not available
All blood work obtained within 6 weeks prior to study entry with adequate organ marrow function defined as follows:
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 Platelets ≥ 50,000 cells/mm3 Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable.) Total bilirubin < 2 mg/dL Prothrombin time/INR < 1.7 (unless on Coumadin/Warfarin) Albumin ≥ 28 g/L AST and ALT < 5 times ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 mL/min
May have had previous surgery, ethanol injection and RFA to the liver
No evidence of metastatic disease including nodal or distant metastases (clinically defined by each institution).
Distance between GTV (lesion) and luminal structures (including esophagus, stomach, duodenum, small or large bowel) is >5 mm
Exclusion Criteria:
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 2 years (Note that carcinoma in situ of the breast, oral cavity, or cervix are all permissible). No active cancer therapy.
Major vascular invasion/thrombus
Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) Raoul et al (2011)
Previous TACE and radiation to the liver (including SIRT )
Life-threatening condition including untreated HIV and active hepatitis B/C
Pregnancy or women of childbearing potential require a negative pregnancy test within 28 days
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Lock, MD
Organizational Affiliation
University of Western Ontario, Canada
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Will be centrally registered data, freely shareable under contract as per ICMJE
IPD Sharing Time Frame
available January 2018
IPD Sharing Access Criteria
No access limitations
Citations:
PubMed Identifier
25186290
Citation
Jacob R, Turley F, Redden DT, Saddekni S, Aal AK, Keene K, Yang E, Zarzour J, Bolus D, Smith JK, Gray S, White J, Eckhoff DE, DuBay DA. Adjuvant stereotactic body radiotherapy following transarterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of >/= 3 cm. HPB (Oxford). 2015 Feb;17(2):140-9. doi: 10.1111/hpb.12331. Epub 2014 Sep 4.
Results Reference
background
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Transarterial Chemoembolization (TACE) With or Without Stereotactic Body Radiotherapy (SBRT) in Hepatocellular Carinoma
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