Clinical Trial Comparing TACE With TACE + SABR in Stage BCLC B HCC (HepSTAR)

Study Overview
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Brief Summary
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This will be multicentre a phase II randomized controlled and open-label trial. It will compare the 6-months objective response (CR+PR) rates obtained with Drug Eluting Bead Trans-Arterial Chemo-Embolization (DEB-TACE) alone versus DEB-TACE followed by Stereotactic Ablative Radiotherapy (SABR) in patients with hepatocarcinoma stage BCLC B. This trial will also include one substudy. This substudy will confront the immuno-histochemical results collected on tumoral biopsies to the biological and imaging (MRI) results. Every patient participating to the trial can also participate to this substudy.

Detailed Description
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The patients will be randomized in 2 arms determining the treatment they will receive: Arm A: actual standard treatment = TACE Arm B: experimental arm = TACE + SABR

Official Title
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Randomized Controlled Phase II Trial Comparing Trans-Arterial Chemo-Embolization (TACE) With TACE Plus Stereotactic Ablative Radiotherapy (SABR) in Stage BCLC B Hepatocarcinoma (HepSTAR)

Conditions
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Liver Neoplasms, Hepatocellular Cancer

Intervention / Treatment
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* Procedure: Trans-arterial Chemo-Embolization
* Drug: Doxorubicin
* Radiation: Stereotactic Ablative Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatocellular carcinoma larger than 3 cm and non-resectable, with a diagnosis established either by: dynamic imaging (non-invasively), showing a typical contrast enhancement and wash-out histopathology satellite lesions are allowed (at most three lesions) as long as the doses constraints are still achievable Hepatocellular carcinoma belonging to Barcelona Clinic Liver Cancer Stage System class B Tumor must be measurable on a multi-phase MRI according to mRECIST criteria Non-tumoral liver volume ≥ 800 cc Child-Pugh (CP) A to B7 cirrhosis HCC Patients can be included if they require treatment prior to liver transplantation ECOG performance status 0-1 AST/ALT < 5 times ULN Initial platelets ≥ 50 000 x 10E9/l, neutrophils > 1500 x 10E9/l, Hb > 9 g/dl Serum creatinine < 1.5 X normal, or calculated Creatinine clearance rate ≥ 60 mL/min As tumor biopsy can be performed after inclusion, pure hepatocellular carcinoma but also mixed hepatocellular carcinoma will be allowed in this trial. Cholangiocarcinoma cannot be included. Written informed consent form to be signed, Patient willing and able to comply to the follow-up schedule Patients in fertile age should use a contraceptive method during treatment and 4 months after. Exclusion Criteria: Eligibility for resection or ablative treatments Extra hepatic spread of the disease Previous treatment of the same lesion with TACE Previous treatment with selective internal radiotherapy or radiotherapy to the upper abdomen Uncontrolled Ascites Uncontrolled Encephalopathy Any clinical sign of acute viral or non-viral hepatitis (new serological testing are not required) Known current pregnancy Uncontrolled active co-morbidity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Trans-Arterial Chemo-embolization (TACE)<br>Trans-arterial Embolisation will be performed with drug-eluting beads loaded with Doxorubicin. First session will be given within 4 weeks after randomization. 4-phase MRI will be performed every 2 months to assess the response. In case of insufficient response according to the MRI performed at 2 or 4 months, a second or third session of DEB-TACE will be allowed, according to the physician's choice. Once complete response is achieved, the follow-up period will start. The date of the last session of TACE corresponds to the treatment completion date. | Procedure: Trans-arterial Chemo-Embolization<br>* Trans-Arterial Chemo-Embolization will be performed with Doxorubicin-Eluting-Beads (DEB-TACE). It will be performed in each arm of treatment.<br>* Other names: TACE;Drug: Doxorubicin<br>* Drug-eluting Bead for Trans Arterial Chemo-Embolization will be loaded with Doxorubicin.<br>* Other names: DEB-TACE;|
| Experimental: TACE+Stereotactic Ablative Radiotherapy<br>The first part of the treatment, which is the DEB-TACE delivery, will be exactly the same than in arm A. The radiotherapy (SABR) will then start within 4 to 6 weeks after. Afterwards, 4-phase MRI will be performed every 2 months to assess the response. In case of insufficient response according to the MRI performed at 2 or 4 months, a second or third session of DEB-TACE will be allowed, according to the physician's choice. Once complete response is achieved, the follow-up period will start. The date of the last SABR fraction or the last session of TACE corresponds to the treatment completion date. | Procedure: Trans-arterial Chemo-Embolization<br>* Trans-Arterial Chemo-Embolization will be performed with Doxorubicin-Eluting-Beads (DEB-TACE). It will be performed in each arm of treatment.<br>* Other names: TACE;Drug: Doxorubicin<br>* Drug-eluting Bead for Trans Arterial Chemo-Embolization will be loaded with Doxorubicin.<br>* Other names: DEB-TACE;Radiation: Stereotactic Ablative Radiotherapy<br>* SABR schemes will be adapted according to the CP score and the vicinity of surrounding organs at risk. These are the different schemes proposed in this trial: 48Gy = 3x16Gy BED 124.8Gy ( α/β=10) 50Gy = 5x10Gy BED 100Gy ( α/β=10) 48Gy = 6x8Gy BED 86.4Gy ( α/β=10) 40Gy = 5x8Gy BED 72Gy ( α/β=10) For patients with Child-Pugh (CP) A cirrhosis : the choice of the scheme will be left to each physician. The highest BED should be favored if dose constraints to the organs at risk are respected. For patients with CP B cirrhosis : only the latter scheme will be allowed: 40Gy = 5x8Gy.<br>* Other names: SABR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate at 6 months | Objective response rate including complete and partial response based on the MRI evaluation (mRECIST) | 6 months after the completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression | defined as the time between the end of treatment and the occurrence of a local recurrence. The diagnoses of another intra- or extra-hepatic lesion of HCC will not be considered as progression | 1 year after the treatment completion | 
| Time to untreatable progression | defined as the time between the end of treatment and the occurrence of untreatable intra-hepatic disease | 1 year after the treatment completion | 
| 6-months overall survival | defined as survival rate of patients at 6months after the end of treatment | 1 year after the treatment completion | 
| 1-year overall survival | defined as survival rate of patients at 1 year after the end of treatment | 1 year after the treatment completion | 
| Acute toxicities | Acute toxic events will have to be described and recorded in accordance with the CTCAE 4.03 (Common Terminology Criteria for Adverse events). | 6 months after treatment completion | 
| Late toxicities | Late toxic events will have to be described and recorded in accordance with the CTCAE 4.03 (Common Terminology Criteria for Adverse events). | 6 months after treatment completion | 
| Quality of life assessment by questionnaire at baseline | Quality of life will be assessed by questionnaires: EORTC QLQC30. The investigators will ask each patient to answer to these questionnaires once at randomization. | baseline | 
| Quality of life assessment by questionnaire at 2 months | Quality of life will be assessed by questionnaires: EORTC QLQC30. The investigators will ask each patient to answer to these questionnaires 2 months after treatment completion | 2 months | 
| Quality of life assessment by questionnaire at 6 months | Quality of life will be assessed by questionnaires: EORTC QLQC30. The investigators will ask each patient to answer to these questionnaires 6 months after treatment completion | 6 months after treatment completion | 
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at baseline | Quality of life will be assessed by questionnaires specific for patients with hepatocarcinoma:EORTC QLQH18. The investigators will ask each patient to answer to these questionnaires once at randomization. | baseline | 
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at 2 months | Quality of life will be assessed by questionnaires specific for patients with hepatocarcinoma:EORTC QLQH18. The investigators will ask each patient to answer to these questionnaires 2 months after treatment completion | 2 months after treatment completion | 
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at 6 months | Quality of life will be assessed by questionnaires specific for patients with hepatocarcinoma:EORTC QLQH18. The investigators will ask each patient to answer to these questionnaires 6 months after treatment completion | 6 months after treatment completion | 
| Overall response rate based on the MRI evaluation in Child Pugh B7 patients | As the choice of the irradiation scheme will be influenced by the severity of the underlying cirrhosis with a Child Pugh score B7, the overall response rate in this specific kind of patients will be separately measured besides the overall response rate of the whole cohort. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular cancer, Stereotactic Body Radiotherapy, Chemoembolization, Therapeutic