Randomized Phase II Trial of Chemoembolization and Sorafenib

Inclusion Criteria: * Unresectable hepatocellular carcinoma with liver-predominant disease, or patients with hepatocellular carcinoma who refuse surgery. No more than 30% of the cohort should have macrovascular invasion and/or asymptomatic extrahepatic disease. Multifocal HCC is acceptable, no diffuse HCC with greater than 70% tumor burden. * Patient is at least 18 years of age. * ECOG performance status of 0-1. * Child-Pugh class of A or B (up to 7). * Adequate end-organ function as manifested by: * Absolute neutrophil count of ≥ 1500/mm3 and platelets ≥ 50,000/mm3 * Creatinine ≤ 2.0 mg/dL * AST, ALT \< 8X ULN * Total bilirubin of ≤ 3 mg/dL * Albumin \> 2.0 g/dL * INR \< 2.0 * Leukocyte count \> 3000 cells/mm3 * Patients who have been treated with previous hepatic surgery, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or cryoablation are eligible if target lesion(s) have not been treated and local therapy is completed at least 6 weeks prior to entry. * Patients with HBV are eligible if controlled with medication. Patients with HCV must have completed treatment with sustained viral response before being eligible for study. * Patients with asymptomatic HIV infection are not eligible. * Willingness of male and female subjects, who are not surgically sterile or post-menopausal, to use reliable methods of birth control for the duration of the study and for 30 days after the last dose of study medication. * Patient must have signed informed consent prior to registration on study. * Resolution of all acute toxic effects of any prior local treatment to CTC adverse event Grade 1 or 0. * At least one tumor lesion can be accurately measured in at least one dimension according to RECIST (Appendix D). The lesion has not been previously treated with local therapy (such as surgery, radiation therapy, RFA, PEI, or cryoablation) unless it has shown progression in the interim. Exclusion Criteria: * Patients unable to swallow oral medications. * Prior embolization, systemic, or radiation therapy for HCC (liver), or patients who have taken sorafenib for greater than 2 weeks. Patients randomized to the sequential arm who started taking sorafenib within 2 weeks of the planned TACE procedure will have to stop sorafenib for 2 weeks before undergoing TACE. This will prevent a possible confounding effect of sorafenib on patients randomized to the sequential arm. * Tumor burden in the liver exceeding 70%. * Complete occlusion of the main portal venous system. Partial or branch portal vein occlusion allowed if without reversal of flow. * Ascites refractory to diuretic therapy (minimal or trace ascites on imaging is acceptable). * Previous or concurrent cancer that is distinct in primary site or histology from HCC, except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1). Any cancer curatively treated more than 3 years prior to entry is permitted. * Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry. * History of bleeding within the past 4 weeks (unless deemed by PI as clinically insignificant, as for example, a brief episode of epistaxis). * Any contraindication to doxorubicin or mitomycin-C administration. * Evidence of severe or uncontrolled systemic diseases. * Congestive cardiac failure greater than NYHA class 2 (Appendix E), myocardial infarction within 6 months, active coronary artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, unstable angina, or laboratory or clinical finding that in the view of the principal investigator makes it undesirable for the patient to participate in the study. * Any prior history of hypertensive crisis or hypertensive encephalopathy. * History of stroke or transient ischemic attack within 6 months prior to study enrollment. * Inadequately controlled hypertension (defined as systolic blood pressure of \> 150/100 mmHg on antihypertensive medications). Patients with treated hypertension are eligible. Patients noted to be hypertensive in our clinic, but with documented normal blood pressure in the office of their referring physician, close follow-up with their referring providers, and a plan for coordination between the referring physician and our team for management of blood pressure while on therapy, are eligible. * Significant vascular disease (e.g. aortic aneurysm, aortic dissection, peripheral vascular disease). * History of organ allograft * Presence of grade 2 or higher hepatic encephalopathy. * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an additional experimental drug. * Evidence of bleeding diathesis or coagulopathy or on warfarin. Note: if a patient has been on Coumadin for a period of 1 month and has been stable, they may be accepted into the protocol. * Presence of clinically evident central nervous system or brain metastases. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1, or anticipation of need for major surgical procedure during the course of the study. * Pregnant (positive pregnancy test) or lactating. * Inability to comply with the study and/or follow-up procedures. * Life expectancy of less than 12 weeks. * Patients with concomitant HIV infection or AIDS-related serious acute or chronic illness. * Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of study results. * Active clinically serious infections (greater than Grade 2) * Patients with obvious and/or symptomatic extrahepatic disease. Findings of uncertain significance, such as lung lesions less than 10 mm in diameter or enlarged periportal lymph nodes will not exclude patients. * Any contraindication to an arterial procedure such as impaired clotting tests (platelet count \< 50,000/mm3 or prothrombin activity \< 50%). * Any contraindication to sorafenib administration