Hepatocellular Cancer, Liver Neoplasms
Conditions
Keywords
Hepatocellular cancer, Stereotactic Body Radiotherapy, Chemoembolization, Therapeutic
Brief summary
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
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
Interventions
PROCEDURETrans-arterial Chemo-Embolization
Trans-Arterial Chemo-Embolization will be performed with Doxorubicin-Eluting-Beads (DEB-TACE). It will be performed in each arm of treatment.
DRUGDoxorubicin
Drug-eluting Bead for Trans Arterial Chemo-Embolization will be loaded with Doxorubicin.
RADIATIONStereotactic Ablative Radiotherapy
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.
Sponsors
Erasme University Hospital
Jules Bordet Institute
University of Liege
Clinique Saint Joseph, Liège
Centre Hospitalier Universitaire UCLouvain Namur
Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate at 6 months | 6 months after the completion of treatment | Objective response rate including complete and partial response based on the MRI evaluation (mRECIST) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1-year overall survival | 1 year after the treatment completion | defined as survival rate of patients at 1 year after the end of treatment |
| Late toxicities | 6 months after treatment completion | Late toxic events will have to be described and recorded in accordance with the CTCAE 4.03 (Common Terminology Criteria for Adverse events). |
| Quality of life assessment by questionnaire at baseline | 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. |
| Quality of life assessment by questionnaire at 2 months | 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 |
| Quality of life assessment by questionnaire at 6 months | 6 months after treatment completion | 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 |
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at baseline | 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. |
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at 2 months | 2 months after treatment completion | 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 |
| Assessment by questionnaires of specific for hepatocarcinoma quality of life at 6 months | 6 months after treatment completion | 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 |
| Overall response rate based on the MRI evaluation in Child Pugh B7 patients | 6 months | 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. |
| Time to progression | 1 year after the treatment completion | 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 |
| Time to untreatable progression | 1 year after the treatment completion | defined as the time between the end of treatment and the occurrence of untreatable intra-hepatic disease |
| 6-months overall survival | 1 year after the treatment completion | defined as survival rate of patients at 6months after the end of treatment |
| Acute toxicities | 6 months after treatment completion | Acute toxic events will have to be described and recorded in accordance with the CTCAE 4.03 (Common Terminology Criteria for Adverse events). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 2 months after treatment | 2 months after treatment completion | 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). |
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 4 months after treatment | 4 months after treatment completion | 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). |
| Biological detection of tumoral marker(s) (AFP +/- DCP) at 6 months after treatment | 6 months after treatment completion | 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). |
| MRI description of tumors at the hepatobiliary phase at baseline | at baseline | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected |
| MRI description of tumors at the hepatobiliary phase at 2 months after treatment | 2 months after treatment completion | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected |
| MRI description of tumors at the hepatobiliary phase at 6 months after treatment | 6 months after treatment completion | immunohistochemical markers and imaging features in hepatobiliary phase will be compared to see if any correlation can be detected |
| Baseline biological detection of tumoral marker(s) : AFP +/- DCP | at baseline | 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). |
| Immuno-histochemical detection of tumoral markers on biopsy (AFP/CK19/DCP) | at time of biopsy | Differents markers will be checked on biopsy (AFP = alpha foetoprotein/ CK19 = cytokeratin 19/ DPC= Des Carboxy prothrombin). |
Countries
Belgium
Outcome results
None listed