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Transarterial Chemoembolization (TACE) Versus TACE Plus Stereotactic Body Radiation Therapy (SBRT) in Liver Carcinoma (TACE)

Primary Purpose

Hepatocellular Carcinoma

Status
Recruiting
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Stereotactic Body Radiation
Transarterial Chemoembolization
Sponsored by
Lawson Health Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatocellular Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Primary hepatobiliary cancer confirmed pathologically
  • Non - lymphoma liver metastases confirmed pathologically
  • Radiographic liver lesions most consistent with metastases, in a patient with known pathologically proven non - lymphoma cancer and a previously negative CT or MRI of the liver
  • Hepatocellular carcinoma diagnosed with vascular enhancement of the lesion consistent with hepatocellular carcinoma, and with an elevated AFP, in the setting of cirrhosis or chronic hepatitis.
  • ≤ 5 liver lesions measurable on a contrast - enhanced liver CT or MRI performed within 90 days prior to study entry.
  • Primary liver lesion or liver metastases measuring ≤ 25 cm.
  • Extrahepatic cancer is permitted if liver involvement is judged to be life - limiting.
  • All intrahepatic disease must be encompassed within the radiation fields according to protocol criteria.
  • Patient must be judged medically or surgically unresectable
  • Zubrod Performance Scale = 0 - 3
  • Age > 18
  • All intrahepatic disease must be amenable to TACE
  • Previous liver resection or ablative therapy is permitted.
  • Chemotherapy must be completed at least 2 weeks prior to radiation therapy or TACE, and not planned to be administered for at least 1 week (for anthracyclines at least 4 weeks) after completion of treatment.
  • Life expectancy > 6 months.
  • Women of childbearing potential and male participants must practice adequate contraception.
  • Patient must sign study specific informed consent prior to study entry.

Pretreatment Evaluations Required for Eligibility:

  • A complete history and general physical examination.
  • CBC, INR, Total bilirubin, albumin, alkaline phosphatase, ALT, AST within 4 weeks prior to study entry. Appropriate levels are as follows:
  • Absolute neutrophil count (ANC) ≥ 1,500 cells / mm3
  • Platelets ≥ 70,000 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 < 3 mg / dL
  • Prothrombin time / INR < 2 (if not on anticoagulants)
  • Albumin ≥ 28 g / L
  • AST and ALT < 10 times ULN

Exclusion Criteria:

  • Severe cirrhosis or liver failure defined as Child Pugh > B7
  • Primary liver tumor or liver metastasis > 25 cm in maximal dimension.
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Severe, active co-morbidity, defined as limiting the patients life to less than 6 months
  • Active hepatitis or clinically significant liver failure.
  • Pregnancy, nursing women, or women of childbearing potential, and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be teratogenic.

Sites / Locations

  • London Health Sciences Centre, London Regional Cancer ProgramRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Transarterial Chemoembolization (TACE)

TACE Plus Stereotactic Body Radiation Therapy (SBRT)

Arm Description

Transarterial Chemoembolization (TACE)

Stereotactic Body Radiation Therapy (SBRT)

Outcomes

Primary Outcome Measures

Overall Survival
Overall Survival-number of patients alive censored for deaths by any cause
Time to Intrahepatic Progression
This will be measured using the modified RECIST (Response evaluation criteria in solid tumors) criteria

Secondary Outcome Measures

Measurement of Response Rate
Modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria
Local Failure
Within 1 cm from the original tumor volume
Extrahepatic failure
This will be defined as any lesion found to be new or progressing outside the hepatic organ.
Time to intrahepatic progression
This will be measured using the modified RECIST (Response evaluation criteria in solid tumors) criteria
Radiation Therapy Overall Toxicity Assessment
CTC V4.0 (Common Terminology Criteria version 4.0)
Radiation Therapy Classic Radiation Toxicity Assessment
Classic RILD (Radiation-induced liver disease)
Radiation Therapy Non-Classic Toxicity Assessment
Non-classic RILD (Radiation-induced liver disease)
Radiation Therapy Toxicity Assessment
Measured using Child-Pugh score to indicate the severity of toxicity. Five variables are considered: presence of ascites, encephalopathy, serum levels of albumin, total bilirubin and prolongation of the clotting time. Each of these variables is assigned a score between 1 and 3 according to its severity or degree of abnormality. The sum of the five scores is used to assign a "Child-Pugh grade" of A, B or C to the patient's clinical condition at that point in time. Grade A indicates a well-functioning liver, Grade B indicates significant functional compromise, Grade C indicates decompensation of the liver.
Change in Health related Quality of Life (QOL)
Measured using the EORTC (European Organisation for Research and Treatment of Cancer) QLQ H&N35 (Quality of Life Questionnaire Head & Neck). According to the EORTC scoring guidelines All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Overall Quality of Life (QOL)
QLQC30 (Quality of Life Questionnaire version 3)
Liver Related Quality of Life (QOL)
FACT-L (Functional Assessment of Cancer Therapy-Lung)
Cost-benefit
A cost benefit analysis will be used to evaluate the total anticipated cost of the project and compare it to the total expected benefits.

Full Information

First Posted
March 21, 2019
Last Updated
November 10, 2021
Sponsor
Lawson Health Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03895359
Brief Title
Transarterial Chemoembolization (TACE) Versus TACE Plus Stereotactic Body Radiation Therapy (SBRT) in Liver Carcinoma
Acronym
TACE
Official Title
A Phase III Randomized Trial of Transarterial Chemoembolization (TACE) Versus TACE Plus Stereotactic Body Radiation Therapy (SBRT) in Primary or Secondary Liver Carcinoma
Study Type
Interventional

2. Study Status

Record Verification Date
November 2021
Overall Recruitment Status
Recruiting
Study Start Date
May 27, 2019 (Actual)
Primary Completion Date
June 1, 2027 (Anticipated)
Study Completion Date
June 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
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
Data Monitoring Committee
No

5. Study Description

Brief Summary
Trans-arterial chemoembolization (TACE) is a standard treatment for patients with hepatocellular carcinoma (also called liver cancer). This is where chemotherapy is injected into the arteries of the liver and liver cancer. Unfortunately, the tumour grows after TACE in many patients. A new treatment using a specialized radiation procedure called Stereotactic ablative body radiotherapy (SBRT) may increase the chance to control liver cancer. SBRT allows radiation treatments to be focused more precisely, and be delivered more accurately than with older treatments. The purpose of this study is to find out if TACE alone versus TACE plus SBRT is better for you and your liver cancer.
Detailed Description
HCC tends to remain within the liver and, therefore, cure with preserved liver function is possible.4 Treatments with relatively high success rates include surgical resection and liver transplantation. Surgical resection results in 5-year survival rates of approximately 60%-70%.4 Liver transplantation can cure both the cancer and underlying liver disease with 4-year survival for HCC within the Milan criteria (single HCC <5 cm or ≤3 HCC <3 cm) at 70%-85% after transplantation.5 Unfortunately, most patients are not resectable due to the extent of disease. Transarterial chemoembolization (TACE) has become the mainstay of treatment for unresectable HCC. 5,6 TACE is relatively safe due to the liver's unique vascular supply from the portal vein. HCC on the other hand, is supplied almost entirely by branches of the hepatic artery.7 In a randomized controlled trial for unresectable HCC not suitable for a curative intent, transarterial chemoembolisation or TACE were compared to conservative treatment.8 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 to TACE decline rapidly with increasing size.9 TACE alone resulted 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 resulted in 2 year overall survivals of 63%, 50% and 17% for lesions 5-7cm, 8-10cm, and >10cm, respectively.9 External beam radiotherapy has long been considered to have a very limited role in the treatment of liver tumors. This has historically been because minimum dose required for local ablation exceeded the dose that would result in liver toxicity.10,11 The technical development of stereotactic body radiation therapy (SBRT), alone or in combination with TACE, renewed interest in radiation for HCC.12,13 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. This research in HCC 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.14,15 SBRT is offered as an ablative radical local treatment. In total as of 2015, 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 (Table A). 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. 16-19 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 (Table B), 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.

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
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
128 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Transarterial Chemoembolization (TACE)
Arm Type
Active Comparator
Arm Description
Transarterial Chemoembolization (TACE)
Arm Title
TACE Plus Stereotactic Body Radiation Therapy (SBRT)
Arm Type
Active Comparator
Arm Description
Stereotactic Body Radiation Therapy (SBRT)
Intervention Type
Radiation
Intervention Name(s)
Stereotactic Body Radiation
Intervention Description
For patients randomized to the SMRT arm, SBRT is to be delivered over 5 fractions delivered over 5 to 15 days.
Intervention Type
Drug
Intervention Name(s)
Transarterial Chemoembolization
Other Intervention Name(s)
TACE
Intervention Description
Transarterial chemoembolization is a standard treatment for patients with hepatocellular carcinoma (liver cancer). Chemotherapy is injected into the arteries of the liver and liver cancer.
Primary Outcome Measure Information:
Title
Overall Survival
Description
Overall Survival-number of patients alive censored for deaths by any cause
Time Frame
At 2 years from start of treatment
Title
Time to Intrahepatic Progression
Description
This will be measured using the modified RECIST (Response evaluation criteria in solid tumors) criteria
Time Frame
Pre-treatment, at 1 month and 3 month follow-up, and at follow-up every 3 months up to 2 years
Secondary Outcome Measure Information:
Title
Measurement of Response Rate
Description
Modified RECIST (Response Evaluation Criteria in Solid Tumors) criteria
Time Frame
The sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor.
Title
Local Failure
Description
Within 1 cm from the original tumor volume
Time Frame
5 years
Title
Extrahepatic failure
Description
This will be defined as any lesion found to be new or progressing outside the hepatic organ.
Time Frame
Pre-treatment, at 1 month and 3 month follow-up, and at follow-up every 3 months up to 2 years
Title
Time to intrahepatic progression
Description
This will be measured using the modified RECIST (Response evaluation criteria in solid tumors) criteria
Time Frame
Pre-treatment, at 1 month and 3 month follow-up, and at follow-up every 3 months up to 2 years
Title
Radiation Therapy Overall Toxicity Assessment
Description
CTC V4.0 (Common Terminology Criteria version 4.0)
Time Frame
Weekly during treatment, 1 and 3 month follow-up, and every 3 months thereafter up to 2 years
Title
Radiation Therapy Classic Radiation Toxicity Assessment
Description
Classic RILD (Radiation-induced liver disease)
Time Frame
Weekly during treatment , 1 and 3 month follow-up, and every 3 months thereafter up to 2 years
Title
Radiation Therapy Non-Classic Toxicity Assessment
Description
Non-classic RILD (Radiation-induced liver disease)
Time Frame
Weekly during treatment, 1 and 3 month follow-up, and every 3 months thereafter up to 2 years
Title
Radiation Therapy Toxicity Assessment
Description
Measured using Child-Pugh score to indicate the severity of toxicity. Five variables are considered: presence of ascites, encephalopathy, serum levels of albumin, total bilirubin and prolongation of the clotting time. Each of these variables is assigned a score between 1 and 3 according to its severity or degree of abnormality. The sum of the five scores is used to assign a "Child-Pugh grade" of A, B or C to the patient's clinical condition at that point in time. Grade A indicates a well-functioning liver, Grade B indicates significant functional compromise, Grade C indicates decompensation of the liver.
Time Frame
Patients will be assessed at least once during radiation therapy for toxicity
Title
Change in Health related Quality of Life (QOL)
Description
Measured using the EORTC (European Organisation for Research and Treatment of Cancer) QLQ H&N35 (Quality of Life Questionnaire Head & Neck). According to the EORTC scoring guidelines All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time Frame
Pre-Treatment, weekly during treatment, 1 and 3 month follow-up, and every 3 months thereafter
Title
Overall Quality of Life (QOL)
Description
QLQC30 (Quality of Life Questionnaire version 3)
Time Frame
Pre-Treatment, weekly during treatment, 1 and 3 month follow-up, and every 3 months thereafter up to 2 years
Title
Liver Related Quality of Life (QOL)
Description
FACT-L (Functional Assessment of Cancer Therapy-Lung)
Time Frame
Pre-Treatment, weekly during treatment, 1 and 3 month follow-up, and every 3 months thereafter up to 2 years
Title
Cost-benefit
Description
A cost benefit analysis will be used to evaluate the total anticipated cost of the project and compare it to the total expected benefits.
Time Frame
Through study completion, an average of 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Primary hepatobiliary cancer confirmed pathologically Non - lymphoma liver metastases confirmed pathologically Radiographic liver lesions most consistent with metastases, in a patient with known pathologically proven non - lymphoma cancer and a previously negative CT or MRI of the liver Hepatocellular carcinoma diagnosed with vascular enhancement of the lesion consistent with hepatocellular carcinoma, and with an elevated AFP, in the setting of cirrhosis or chronic hepatitis. ≤ 5 liver lesions measurable on a contrast - enhanced liver CT or MRI performed within 90 days prior to study entry. Primary liver lesion or liver metastases measuring ≤ 25 cm. Extrahepatic cancer is permitted if liver involvement is judged to be life - limiting. All intrahepatic disease must be encompassed within the radiation fields according to protocol criteria. Patient must be judged medically or surgically unresectable Zubrod Performance Scale = 0 - 3 Age > 18 All intrahepatic disease must be amenable to TACE Previous liver resection or ablative therapy is permitted. Chemotherapy must be completed at least 2 weeks prior to radiation therapy or TACE, and not planned to be administered for at least 1 week (for anthracyclines at least 4 weeks) after completion of treatment. Life expectancy > 6 months. Women of childbearing potential and male participants must practice adequate contraception. Patient must sign study specific informed consent prior to study entry. Pretreatment Evaluations Required for Eligibility: A complete history and general physical examination. CBC, INR, Total bilirubin, albumin, alkaline phosphatase, ALT, AST within 4 weeks prior to study entry. Appropriate levels are as follows: Absolute neutrophil count (ANC) ≥ 1,500 cells / mm3 Platelets ≥ 70,000 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 < 3 mg / dL Prothrombin time / INR < 2 (if not on anticoagulants) Albumin ≥ 28 g / L AST and ALT < 10 times ULN Exclusion Criteria: Severe cirrhosis or liver failure defined as Child Pugh > B7 Primary liver tumor or liver metastasis > 25 cm in maximal dimension. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Severe, active co-morbidity, defined as limiting the patients life to less than 6 months Active hepatitis or clinically significant liver failure. Pregnancy, nursing women, or women of childbearing potential, and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be teratogenic.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Lock, M.D.
Phone
519-685-8650
Email
michael.lock@lhsc.on.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Lock, M.D.
Organizational Affiliation
Lawson Health Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
London Health Sciences Centre, London Regional Cancer Program
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5W9
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael Lock, M.D.
Phone
519-685-8650
Email
michael.lock@lhsc.on.ca

12. IPD Sharing Statement

Learn more about this trial

Transarterial Chemoembolization (TACE) Versus TACE Plus Stereotactic Body Radiation Therapy (SBRT) in Liver Carcinoma

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