Chemoembolization Versus Radioembolization in Treating Patients With Liver Cancer That Cannot Be Treated With Radiofrequency Ablation Or Surgery

Study Overview
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Brief Summary
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RATIONALE: Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping chemotherapy drugs near the tumor. Radioembolization kills tumor cells by blocking the blood flow to the tumor and keeping radioactive substances near the tumor. It is not yet known which treatment regimen is more effective in treating patients with liver cancer. PURPOSE: This randomized phase II trial is studying radioembolization to see how well it works compared with chemoembolization in treating patients with liver cancer that cannot be treated with Radiofrequency Ablation or removed by surgery.

Detailed Description
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OBJECTIVES: Primary Compare and contrast TACE and Y90 in order to determine either equivalence or superiority as measured by time-to-progression. Secondary Characterize the safety and toxicity profile of these regimens. Determine the need for subsequent treatment in these patients. Determine tumor response in these patients Characterize change in quality of life and functional status in these patients. Determine time to progression in these patients. OUTLINE: Patients are randomized to receive either TACE or Y90 Arm I (radioembolization): Patients undergo radioembolization with yttrium Y 90 glass microspheres by hepatic artery infusion for approximately 1-3 courses. Arm II (transarterial chemoembolization [TACE]): Patients undergo TACE with mitomycin C, doxorubicin hydrochloride, and cisplatin by hepatic artery infusion for approximately 1-3 courses. In both arms, treatment modifications may apply according to response. After completion of study treatment, patients are followed every 3 months.

Official Title
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An Investigator Initiated Multicenter Prospective Randomized Study of Chemoembolization Versus Radioembolization for the Treatment of Hepatocellular Carcinoma (PREMIERE Trial)

Conditions
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Liver Cancer

Intervention / Treatment
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* Radiation: yttrium Y 90 glass microspheres
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Hepatocellular Carcinoma confined to the liver that is unresectable with surgery or unable to be treated with radiofrequency ablation diagnosed by biopsy or imaging criteria (CT/MRI) No segmental, lobar, or main portal vein thrombosis as evidenced by CT or MRI imaging Inclusion Criteria Adults > 18 years old of either gender Diagnosis of liver confined HCC confirmed by histology or American Association for the Study of Liver Diseases (AASLD) guidelines [59,60] [appendix A]. Lesions < 1 cm in diameter have a low likelihood of being malignant and should be followed. Lack of growth over 1-2 years suggests it is not HCC. AFP >200 and radiological evidence (arterial hypervascularity) of lesion > 2 cm does not require biopsy. Two imaging modalities (triphasic CT, MRI, ultrasound, angiography) demonstrating arterial hypervascularity in the background of cirrhosis does not require biopsy One imaging modality with a lesion with arterial hypervascularity with wash out in early or delayed venous phase, does not require a biopsy Atypical appearances on imaging requires a biopsy. Non-conclusive biopsy requires closer monitoring For non-cirrhotics (by biopsy or imaging findings), diagnosis of HCC requires biopsy Patients with <50% liver involvement Measurable liver confined disease with bi-dimensional measurements, required within 4 weeks of screening. Lesions reported on imaging as too small to characterize, abdominal lymph nodes < 2.0 cm or ascites in the setting of cirrhosis are not considered metastatic disease unless cytology proven. No segmental, lobar or main portal vein thrombosis as evidence by cross sectional imaging Prior resection permitted, no prior systemic, ablative or infusion therapy permitted Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 [appendix B] Childs score of A or B [appendix C] Required lab parameters within 28 days of screening Serum bilirubin ≤ 2.0 mg/dl (unless segmental infusion can be performed AST and ALT ≤ 5 times upper limit of normal (ULN) Creatinine ≤ 1.5 times ULN Prothrombin time (PT)/ International normalized ratio (INR) ≤ 2.3 or PT ≤ 6 seconds above control. If subjects are being anticoagulated they can participate if proof of no coagulation abnormality existed prior to use of anticoagulants Negative serum or urine pregnancy test for females of child bearing potential Ability to understand and sign the informed consent; patient must have signed informed consent prior to registration on study Women of childbearing potential and sexually active males must use contraception while on study Lesions must be treatable angiographically by either radioembolization or chemoembolization. Exclusion criteria Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (angina symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Patients with infiltrative HCC are not eligible. Patients with bulk disease (≥70% tumor replacement of liver) are not eligible. Patients with ≥50% tumor replacement of liver, with an albumin < 3.0 g/dl are not eligible. Major surgery within 4 weeks prior to the screening visit Active clinically serious infection > Common Toxicity Criteria for Adverse Events (CTCAE v 4.0) Grade 2 Any condition (psychological, physical or use/abuse of substances) which, in the opinion of the principal investigator (PI) or a sub-investigator (sub-I), would possibly endanger the subject during their participation in the study, or allow for non-compliance with the investigational drug and treatment under study. Due to the experimental nature of the therapy and the unknown risk to a fetus, pregnant and/or lactating women are not eligible to participate in this study. In the opinion of the investigator, patient is not a candidate/lesion not amenable for RFA (e.g. lesion location, shape, abnormal coagulation parameters, multi-focality).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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 |
| --- | --- |
| Experimental: Arm I (radioembolization)<br>Patients undergo radioembolization with yttrium Y 90 glass microspheres by hepatic artery infusion for approximately 1-3 courses. | Radiation: yttrium Y 90 glass microspheres<br>* Patients undergo radioembolization.<br>* Other names: Radioembolization;|
| Experimental: Arm II (transarterial chemoembolization [TACE])<br>Patients undergo TACE with mitomycin C, doxorubicin hydrochloride, and cisplatin by hepatic artery infusion for approximately 1-3 courses. | Drug: Doxorubicin<br>* 75mg fixed dose<br>* Other names: Chemoembolization (TACE);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) in Patients Treated With TACE and Y90 | Compare and contrast TACE and Y90 in order to determine either equivalence or superiority as measured by time-to-progression. Patients have repeat imaging done (MRI or CT) at 1-month post procedure and then every 3 months after that. TTP and overall survival (OS) analyses were calculated from day of randomization by Kaplan-Meier analysis on intention-to-treat (ITT) basis. Progression (which is detected on follow-up imaging scans) was defined as: Progression by World Health Organization (WHO) response criteria 25% increase in bidimensional cross product. Progression by European Assosciation for the Study of the Liver (EASL): 25% increase in arterial enhancement Malignant portal vein tumor thrombus development Index lesion: lesions requiring re-treatment because of worsening circumferential enhancement Development of new lesions or extra-hepatic metastases. | Up to 6 yrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Achieved Complete or Partial Radiologic Response After Treatment | Repeat imaging (CT/MRI) and lab work including tumor markers will be assessed 1 month post-treatment then every 3 months after that. Both EASL & WHO criteria are used. By EASL criteria Complete response is 100% Decrease in amount of enhancing tissue in index lesion, Partial response is ≥50% deecrease in amount of enhancing tissue in index lesion, Stable disease is <50% Decrease in to ≤ 25% increase in amount of enhancing tissue in index lesion, Progressive disease <25% Increase in amount of enhancing tissue in index lesion and/or new enhancement in previously treated index lesion. | up to 6 years | 
| Overall Survival | Comparing overall survival of both treatment arms. | From day of randomization until date of death, or liver transplant or 7/15/2016, whichever came first, assessed up to 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced adult primary liver cancer, localized unresectable adult primary liver cancer, recurrent adult primary liver cancer, adult primary hepatocellular carcinoma