Sorafenib Tosylate With or Without Stereotactic Body Radiation Therapy in Treating Patients With Liver Cancer
Condition: Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer
MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms
Intervention: Sorafenib; stereotactic body radiation therapy
Intervention description: By mouth (PO); Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.
Intervention MeSH terms: Sorafenib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 193.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial studies sorafenib tosylate and stereotactic body radiation
      therapy to see how well they work compared to sorafenib tosylate alone in treating patients
      with liver cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of
      the enzymes needed for cell growth. Stereotactic body radiation therapy may be able to send
      the radiation dose directly to the tumor and cause less damage to normal tissue. Giving
      sorafenib tosylate together with stereotactic body radiation therapy may kill more tumor
      cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have a diagnosis of HCC by at least one criterion listed below within
             360 days prior to study entry:

               -  Pathologically (histologically or cytologically) proven diagnosis of
                  HCC,(biopsies are recommended, and are to be submitted for research evaluation if
                  patients consent)

               -  At least one solid liver lesion or vascular tumor thrombosis (involving portal
                  vein, inferior vena cava (IVC) and/or hepatic vein) > 1 cm with arterial
                  enhancement and delayed washout on multi-phasic computerized tomography (CT) or
                  magnetic resonance imaging (MRI) in the setting of cirrhosis or chronic hepatitis
                  B or C without cirrhosis.

               -  For patients whose CURRENT disease is vascular only: enhancing vascular
                  thrombosis (involving portal vein, IVC and/or hepatic vein) demonstrating early
                  arterial enhancement and delayed washout on multi-phasic CT or MRI in a patient
                  with known HCC (diagnosed previously <720 days) using the above criteria.

          -  Measureable hepatic disease and/or presence of vascular tumor thrombosis (involving
             portal vein, IVC and/or hepatic vein) which may not be measureable as per Response
             Evaluation Criteria in Solid Tumors (RECIST) on liver CT or MRI, within 28 days of
             registration

          -  Appropriate for protocol entry based upon the following minimum diagnostic workup:

               -  History/physical examination including examination for encephalopathy, ascites,
                  weight, height, and blood pressure within 14 days prior to study entry

               -  Assessment by radiation oncologist and medical oncologist or hepatologist who
                  specializes in treatment of HCC within 28 days prior to study entry

               -  Pre-randomization Scan (REQUIRED for All Patients): Within 28 days prior to study
                  entry, multiphasic liver CT or multiphasic liver MR scan.

               -  Within 28 days prior to study entry CT chest with CT or MR abdomen and CT or MR
                  pelvis, or positron emission tomography (PET) CT chest/abdomen/pelvis.

          -  Zubrod performance status 0-2 within 28 days prior to study entry

          -  All blood work obtained within 14 days prior to study entry with adequate organ marrow
             function defined as follows:

               -  Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

               -  Platelets >= 60,000 cells/mm^3

               -  Hemoglobin >= 8.0 g/dl (note: the use of transfusion or other intervention to
                  achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable)

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 6 times
                  upper limit of normal (ULN)

               -  Serum creatinine =< 2 x ULN or creatinine clearance >= 60 mL/min

          -  Barcelona Clinic Liver Cancer (BCLC) stage: intermediate (B) or advanced (C) within 28
             days prior to study entry

          -  Child-Pugh score A within 14 days prior to study entry

          -  Women of childbearing potential and male participants must agree to practice adequate
             contraception while on study and for at least 6 months following the last dose of
             radiation therapy (RT) and for at least 28 days following the last dose of sorafenib
             (whichever is later)

          -  Unsuitable for resection or transplant or radiofrequency ablation (RFA)

          -  Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or
             drug eluting beads (DEB) for any of the following reasons, as described by Raoul et al
             (2011):

               -  Technical contraindications: arteriovenous fistula, including, surgical
                  portosystemic shunt or spontaneous portosystemic shunt

               -  Severe reduction in portal vein flow: due to tumor portal vein, IVC or atrial
                  invasion or bland portal vein occlusion

               -  Medical contraindications including congestive heart failure, angina, severe
                  peripheral vascular disease

               -  Presence of extrahepatic disease

               -  No response post TACE (or DEB) or progressive HCC despite TACE; prior TACE or DEB
                  is allowed but must be > 28 days from study entry

               -  Serious toxicity following prior TACE (or DEB); prior TACE or DEB must be > 28
                  days from study entry

               -  Other medical comorbidities making TACE (or DEB) unsafe and/or risky (e.g.
                  combination of relative contraindications including age > 80 years, tumor > 10
                  cm, > 50% replacement of the liver by HCC, extensive multinodular bilobar HCC,
                  biliary drainage)

          -  Patients treated with prior surgery are eligible for this study if they otherwise meet
             eligibility criteria

          -  Patient must be able to provide study-specific informed consent prior to study entry

        Exclusion Criteria:

          -  Prior invasive malignancy (except non-melanomatous skin cancer and T1 renal cell
             carcinoma) unless disease free for a minimum of 2 years (note that carcinoma in situ
             of the breast, oral cavity, or cervix are all permissible)

          -  Prior sorafenib use > 60 days and/or grade 3 or 4 sorafenib related toxicity. Note
             that prior chemotherapy for HCC or a different cancer is allowable

          -  Prior radiotherapy to the region of the liver that would result in overlap of
             radiation therapy fields

          -  Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time

          -  Severe, active co-morbidity, defined as follows:

               -  Unstable angina and/or congestive heart failure requiring hospitalization within
                  the last 6 months PRIOR TO registration

               -  Transmural myocardial infarction within the last 6 months prior to study entry

               -  Unstable ventricular arrhythmia within the last 6 months prior to study entry

               -  Acute bacterial or fungal infection requiring intravenous antibiotics within 28
                  days prior to study entry

               -  Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or
                  variceal bleed within 28 days prior to study entry

               -  Bleeding within 28 days prior to study entry due to any cause, requiring
                  transfusion

               -  Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is
                  permitted.

               -  Known bleeding or clotting disorder

               -  Uncontrolled psychotic disorder

          -  Pregnancy or women of childbearing potential and men who are sexually active and not
             willing/able to use medically acceptable forms of contraception; this exclusion is
             necessary because the treatment involved in this study may be significantly
             teratogenic

          -  Maximal diameter of any one hepatocellular carcinoma > 15 cm

          -  Total sum of maximum diameters of each definite parenchymal hepatocellular carcinoma
             within the liver or maximum diameter of a single conglomerate HCC > 20 cm

          -  More than 5 discrete intrahepatic parenchymal foci of HCC

          -  Direct tumor extension into the stomach, duodenum, small bowel or large bowel

          -  Measureable common or main branch biliary duct involvement with HCC

          -  Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC)
             > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph
             node or two 2 cm lung lesions); note that benign non-enhancing periportal
             lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if
             the sum of enlarged nodes is > 2.0 cm

          -  Prior liver transplant

          -  HIV positive with CD4 (T-cell count) count < (350) cells/microliter. Note that
             patients who are HIV positive are eligible, provided they are under treatment with
             highly active antiretroviral therapy (HAART) and have a CD4 count ≥ (350)
             cells/microliter, and no known detectable viral load, at the time of study entry. Note
             also that HIV testing is not required for eligibility for this protocol