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Developed in Japan in the 1980s, TACE became the most frequent treatment for unresectable hepatocellular carcinoma (HCC) in patients with preserved hepatic function after 2002, when two radiochemotherapies (RCTs) showed survival benefits for HCC patients who underwent conventional Lipiodol-based TACE (cTACE). Nowadays, nearly half of HCC patients undergo this procedure during their clinical history. In the last ten years, cTACE has been challenged by an alternative procedure, drug-eluting beads-TACE (DEB-TACE), after the introduction of calibrated embolizing microspheres loaded with a chemotherapeutic agent. DEB-TACE is considered to be less toxic and better standardized than cTACE, with reported no differences in patient survival. Since 2006, DEB-TACE has become the standard in many centers worldwide. Though, the need of adding doxorubicin to small beads embolization alone (TAE) remains unsettled. Though cTACE/DEB-TACE and TAE have been compared in several RCTs, no study demonstrated a clear survival benefit associated with the former.
Our study aims to compare first-line DEB-TACE and TAE on a random sample of HCC with the hypothesis that the addition of drug to embolization with small size beads is not associated with a survival benefit when compared to embolization alone performed with tiny calibrated microspheres. HCC is considered a chemo-resistant tumor and to date there is no clear evidence of benefits in associating anticancer agents to TAE. On the other hand, the optimal size of embolic agents has still to be defined. A comparative evaluation of TACE and TAE is essential for two additional reasons: a) it is still unclear whether side effects following embolization procedures are related to the embolization itself, to drug addition or both; b) DEB-TACE procedure is more expensive than TAE and, given the current attention on cancer-related health care cost control, identification of opportunities for cost savings in HCC treatments of an increasingly common cancer would be valuable.
Full description
Specific Aims
Specific aim 1 Compare time to progression (TTP) treated with TAE and DEB-TACE in a homogeneous hepatocellular carcinoma (HCC) patient population
Specific aim 2 Compare
Study plan
Experimental design This is an interventional with drug, multicenter, prospective, randomized open label study.
Experimental design Aim 1 The study was designed, in relation to the primary endpoint, as an equivalence trial between two intra-arterial HCC treatments, i.e. DEB-TACE and TAE. The TTP considered as the reference value for the DEB-TACE arm is 9 months, on the basis of the results of our previous multicentric experience. The study is designed as an equivalence trial on the primary endpoint. The standard deviation of TTP is expected not to exceed 6 months, through accurate selection criteria of included patients. The equivalence limit is set to no more than 5 months between the two arms. Thus, using appropriate formulae each arm will be formed by 69 patients (alpha:0.05; beta:0.80). Taking into account a 10% of drop-out, the final sample size per each arm will be of 77 patients (154 total).
Experimental design Aim 2
Study population The study involves the enrollment of a total of 154 patients, 77 per randomization arm, with a HCC diagnosis, according to the guidelines of the American Association for the Study of the Liver Disease (AASLD), as in clinical practice. The enrolled patients will have to meet the inclusion criteria and sign the informed consent for the participation in this study. At the time of enrollment, demographic, clinical and radiological data will be collected, as in standard clinical practice.
Treatment
Treatment study In the present study, only patients in the DEB-TACE arm (Arm A) will receive intra-arterial hepatic chemotherapy (Doxorubicin). Both treatment arms, on the other hand, will receive arterial embolization of the branches that vascularize the tumor lesions.
Arm A: DEB-TACE or chemoembolization with microspheres. The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM® (Boston Scientific) microspheres. TANDEM® embozene microspheres are made of non-resorbable, biocompatible, hydrogel microspheres, subjected to precision calibration and coated with an inorganic perfluorate polymer (Polyzene®-F). Thanks to their design, the microspheres can be loaded with drugs, such as doxorubicin, in order to administer a local, controlled and constant dose of the drug to the tumor sites affected after embolization.
TANDEM® embozene microspheres are available in three different sizes, in 2 ml and 3 ml volumes of product and are supplied in preloaded vials and syringes.The maximum loadable amount on the hydrospheres 50 mg of Doxorubicina for ml. The maximum injectable dose of Doxorubicin for each treatment is 150 mg and therefore the maximum amount of microspheres that can be used for each treatment is 3 ml. The size of microspheres that will be used in this study is up to 100 ± 25 μm.
Arm B: TAE or embolization with microspheres. The TAE will be performed with Embozene microspheres (Boston Scientific). Embozene microspheres are spherical particles of hydrogel, precisely calibrated, biocompatible, non-absorbable and coated with a perfluorinated inorganic polymer (Polyzene-F). This medical device is available in various sizes; in this study, to avoid that the particle size exceeds the one used for the treatment of arm A, it will be possible to use microspheres with dimensions up to 100 μm (range 75 ± 125 μm).
Embozene microspheres are offered in vials containing 1 ml of suspended product in physiological saline solution for apyrogenic sterile transport. The total volume of the Embozene microspheres, including the transport solution, is about 7 ml. To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy.
In enrolled patients, regardless of the treatment arm, the possible presence of extra-hepatic shunts, such as gastric and pulmonary arteries arising from the hepatic branches, should be appropriately assessed. As in standard radiological practice in case of intra-arterial hepatic treatments, if these shunts are macroscopically evident, the preventive closure of the same vessels will be evaluated, using the devices that will be more suitable on a case-by-case basis. If these shunts are not treatable by occlusive devices, the enrolled patient will not be treated in the clinical study and the patient will be considered as drop-out. Both treatments will be repeated "on demand" after demonstration to the imaging of the presence of vital tumor ie absence of complete response (complete response, CR) or in case of intrahepatic distal recurrence at follow-up.
Safety assessment The evaluation of the safety of the experimental treatment will consist in the monitoring and recording of AEs and SAEs.
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Inclusion criteria
Second level eligibility criteria include:
The modified hepatoma arterial-embolization prognostic score (m-HAP-II), based on bilirubin, albumin, serum alpha fetoprotein, tumor number and tumor size, divides patients in 4 classes (A, B, C, D) with different survivals and is useful for prognosis stratification. The first selection criteria will be m-HAP-II classes B or C fulfilment.
The UNOS/TNM stage: only patients with T1, T2, T3 and T4 tumors will be included.
These two main criteria will be used for stratification of patients prior to randomization in order to obtain identical prevalence of m-HAP-II classes B/C and of UNOS/TNM stages from T1 to T4a
obtaining of the informed consent.
Exclusion criteria
Primary purpose
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154 participants in 2 patient groups
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Central trial contact
Rita Golfieri, Professor
Data sourced from clinicaltrials.gov
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