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| Name | Class |
|---|---|
| Erasme University Hospital | OTHER |
| Jules Bordet Institute | OTHER |
| University of Liege | OTHER |
| Clinique Saint Joseph, Liège |
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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Trans-Arterial Chemo-embolization (TACE) | Active Comparator | 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. |
|
| TACE+Stereotactic Ablative Radiotherapy | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trans-arterial Chemo-Embolization | Procedure | Trans-Arterial Chemo-Embolization will be performed with Doxorubicin-Eluting-Beads (DEB-TACE). It will be performed in each arm of treatment. |
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Immuno-histochemical detection of tumoral markers on biopsy (AFP/CK19/DCP) | Differents markers will be checked on biopsy (AFP = alpha foetoprotein/ CK19 = cytokeratin 19/ DPC= Des Carboxy prothrombin). | at time of biopsy |
| Baseline biological detection of tumoral marker(s) : AFP +/- DCP |
Inclusion Criteria:
Hepatocellular carcinoma larger than 3 cm and non-resectable, with a diagnosis established either by:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Xavier GEETS | Cliniques Universitaires Saint Luc/MIRO | Principal Investigator |
| Ivan BORBATH | Cliniques universitaires Saint-Luc- Université Catholique de Louvain | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hôpital de JOLIMONT | Jolimont | Hainaut | 7100 | Belgium | ||
| Centre Hospitalier Universitaire/CHC Saint Joseph |
Every participant data will be anonymized for the trial purpose.
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| OTHER |
| Centre Hospitalier Universitaire UCLouvain Namur | OTHER |
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| Doxorubicin | Drug | Drug-eluting Bead for Trans Arterial Chemo-Embolization will be loaded with Doxorubicin. |
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| Stereotactic Ablative Radiotherapy | Radiation | 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. |
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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 |
Biological detection of tumoral marker(s) will be done for every patient included in this trial (at least for AFP = alpha fetoprotein) at baseline then repeated every 2 months after treatment, up to 6 months. Measurement of DCP (Des-Carboxy-prothrombin will not be mandatory). |
| at baseline |
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 2 months after treatment | Biological detection of tumoral marker(s) will be done for every patient included in this trial (at least for AFP = alpha fetoprotein) at baseline then repeated every 2 months after treatment, up to 6 months. Measurement of DCP (Des-Carboxy-prothrombin will not be mandatory). | 2 months after treatment completion |
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 4 months after treatment | Biological detection of tumoral marker(s) will be done for every patient included in this trial (at least for AFP = alpha fetoprotein) at baseline then repeated every 2 months after treatment, up to 6 months. Measurement of DCP (Des-Carboxy-prothrombin will not be mandatory). | 4 months after treatment completion |
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 6 months after treatment | Biological detection of tumoral marker(s) will be done for every patient included in this trial (at least for AFP = alpha fetoprotein) at baseline then repeated every 2 months after treatment, up to 6 months. Measurement of DCP (Des-Carboxy-prothrombin will not be mandatory). | 6 months after treatment completion |
| MRI description of tumors at the hepatobiliary phase at baseline | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected | at baseline |
| MRI description of tumors at the hepatobiliary phase at 2 months after treatment | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected | 2 months after treatment completion |
| MRI description of tumors at the hepatobiliary phase at 6 months after treatment | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected | 6 months after treatment completion |
| Liège |
| Liège |
| 4000 |
| Belgium |
| Cliniques Universitaires Saint Luc | Brussels | Woluwé Saint Lambert | 1200 | Belgium |
| Institut Jules Bordet/Hôpital Erasme | Brussels | 1000 | Belgium |
| Clinique et Maternité Sainte Elisabeth/CHU Mont Godinne | Namur | 5000 | Belgium |
| ID | Term |
|---|---|
| D008113 | Liver Neoplasms |
| ID | Term |
|---|---|
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D008107 | Liver Diseases |
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| ID | Term |
|---|---|
| D004317 | Doxorubicin |
| ID | Term |
|---|---|
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
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