Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Conditions
Brief 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.
Detailed description
PRIMARY OBJECTIVES: I. To determine if stereotactic body radiation therapy (SBRT) improves overall survival in hepatocellular carcinoma (HCC) patients treated with sorafenib (sorafenib tosylate). SECONDARY OBJECTIVES: I. To determine the difference in time to progression (TTP) and progression-free survival (PFS) in HCC patients treated with sorafenib compared to SBRT followed by sorafenib. II. To measure differences in toxicity in HCC patients treated with sorafenib versus SBRT followed by sorafenib. III. To measure vascular thrombosis response post sorafenib versus SBRT followed by sorafenib. IV. To measure differences in health related quality of life (QOL) and quality-adjusted survival in HCC patients treated with sorafenib compared to SBRT followed by sorafenib. V. Collection of biospecimens for future correlative studies to investigate differences in potential biomarkers in patients treated with sorafenib versus SBRT followed by sorafenib.
Interventions
DRUGSorafenib
By mouth (PO)
RADIATIONstereotactic body radiation therapy
Intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), and proton therapy are allowed.
Sponsors
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years. | An event for overall survival (OS) is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis was to occur after 153 deaths were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years. | Progression (failure) is defined as any of the following events: new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant metastases that were present at study entry, new HCC within the liver including tumor thrombosis, and vascular thrombosis events=progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. Time to progression was measured from the date of randomization to the date of first failure, death (competing risk), or last follow-up (censored). Progression rates are estimated by the cumulative incidence method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions. |
| Progression-free Survival | From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years. | Failure for progression-free survival (PFS) include death, new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant Mets that were present at study entry, new HCC within liver including tumor thrombosis, and vascular thrombosis events =progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. PFS time is defined as the time from randomization to the date of first failure, date of death, or last known follow-up (censored). PFS rates are estimated by the Kaplan-Meier method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions. |
| Number of Participants by Highest Grade Adverse Event Reported | From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years. | Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment | Baseline and 6 months | The FACT-Hep total score measures quality of life in patients with hepatobiliary cancer. Possible scores range from 0 to 180, with higher scores indicating a better outcome. Improvement in FACT-Hep total score is defined as an increase from the baseline to 6-month score of at least 5 points. |
| Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | From randomization to last follow-up. Imaging occurs every 3 months for two years then every six months. Maximum follow-up at time of analysis was 7.6 years. | Complete response: Complete resolution of thrombosis, with recanalization of vessel. Partial response (PR): * Partial recanalization (if prior complete blockage) * Unequivocal reduction in the maximal girth * Unequivocal reduction in the volume, or elimination, of arterial enhancing portion Progressive disease (PD): any unequivocal, unambiguous * New enhancing tumor thrombosis * Increase in the volume of enhancing portion * Unequivocal progression of thrombosis (non-measurable disease), the increase in overall tumor burden (enhancing thrombosis) must be comparable to the increase required for the Response Evaluation Criteria in Solid Tumor 1.1 definition of PD of measurable disease (e.g. ≥ 73% increase in volume, which is similar to 20% increase in diameter, and at least a 5 mm absolute increase). Stable disease: * No/small changes that do not meet the above criteria for PR or PD * Increase in the volume of non-enhancing thrombosis * New bland non-enhancing thrombosis |
| Quality Adjusted Life Years | The EQ-5D-5L is administered at baseline, six months and one year. | Quality adjusted life years is calculated as the weighted sum of the number of years spent in different health states. The weight value is a utility score between 0 (worst health state) and 1 (best health state) derived from the EQ-5D-5L questionnaire, designed to describe and value health based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. |
Countries
Australia, Canada, Hong Kong, South Korea, United States
Contacts
PRINCIPAL_INVESTIGATORLaura Dawson
Radiation Therapy Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Alone 400 mg sorafenib by mouth twice a day for 28-day cycle. Continue up to 5 years in the absence of disease progression or unacceptable toxicity. | 92 |
| SBRT Followed by Sorafenib 27.5 Gy to 50 Gy stereotactic body radiation therapy (SBRT) in 5 fractions 24-72 hours apart over 5-15 days followed within 1-5 days by one cycle of 200 mg sorafenib by mouth twice a day. Starting with second cycle, if tolerable, increase to 400 mg sorafenib by mouth twice a day. Continue up to 5 years in the absence of disease progression or unacceptable toxicity. | 85 |
| Total | 177 |
Baseline characteristics
| Characteristic | Sorafenib Alone | SBRT Followed by Sorafenib | Total |
|---|---|---|---|
| Age, Continuous | 67 years | 66 years | 66 years |
| Age, Customized ≤ 49 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized 50 - 59 years | 15 Participants | 20 Participants | 35 Participants |
| Age, Customized 60 - 69 years | 39 Participants | 42 Participants | 81 Participants |
| Age, Customized 70 - 79 years | 26 Participants | 18 Participants | 44 Participants |
| Age, Customized ≥ 80 years | 9 Participants | 4 Participants | 13 Participants |
| BCLC Stage Advanced (C) | 77 Participants | 68 Participants | 145 Participants |
| BCLC Stage Intermediate (B) | 15 Participants | 17 Participants | 32 Participants |
| Child Pugh Score 5 (Grade A) | 69 Participants | 64 Participants | 133 Participants |
| Child Pugh Score 6 (Grade A) | 23 Participants | 21 Participants | 44 Participants |
| Enhancing vascular thrombosis No | 26 Participants | 23 Participants | 49 Participants |
| Enhancing vascular thrombosis Yes | 66 Participants | 62 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 47 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 32 Participants | 36 Participants | 68 Participants |
| Hepatitis Status Hepatitis B or B and C | 17 Participants | 16 Participants | 33 Participants |
| Hepatitis Status Hepatitis C | 38 Participants | 35 Participants | 73 Participants |
| Hepatitis Status Other | 37 Participants | 34 Participants | 71 Participants |
| Hepatocellular carcinoma (HCC) tumor volume / liver volume <10% | 40 Participants | 40 Participants | 80 Participants |
| Hepatocellular carcinoma (HCC) tumor volume / liver volume 10-40% | 42 Participants | 39 Participants | 81 Participants |
| Hepatocellular carcinoma (HCC) tumor volume / liver volume >40% | 10 Participants | 6 Participants | 16 Participants |
| M Stage M0 | 88 Participants | 82 Participants | 170 Participants |
| M Stage M1 | 4 Participants | 3 Participants | 7 Participants |
| N Stage N0 | 89 Participants | 80 Participants | 169 Participants |
| N Stage N1 | 3 Participants | 4 Participants | 7 Participants |
| N Stage NX | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 18 Participants | 41 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) White | 58 Participants | 59 Participants | 117 Participants |
| Region of Enrollment North America | 90 Participants | 85 Participants | 175 Participants |
| Region of Enrollment Other | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 10 Participants | 17 Participants | 27 Participants |
| Sex: Female, Male Male | 82 Participants | 68 Participants | 150 Participants |
| T Stage T1 | 9 Participants | 6 Participants | 15 Participants |
| T Stage T2 | 17 Participants | 19 Participants | 36 Participants |
| T Stage T3a | 12 Participants | 16 Participants | 28 Participants |
| T Stage T3b | 49 Participants | 38 Participants | 87 Participants |
| T Stage T4 | 5 Participants | 6 Participants | 11 Participants |
| Zubrod performance status 0 | 41 Participants | 47 Participants | 88 Participants |
| Zubrod performance status 1 | 44 Participants | 33 Participants | 77 Participants |
| Zubrod performance status 2 | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 80 / 92 | 73 / 85 |
| other Total, other adverse events | 88 / 88 | 83 / 83 |
| serious Total, serious adverse events | 20 / 88 | 19 / 83 |
Outcome results
Primary
Overall Survival
An event for overall survival (OS) is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. Analysis was to occur after 153 deaths were reported.
Time frame: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Population: Eligible participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib Alone | Overall Survival | 12.30 months |
| SBRT Followed by Sorafenib | Overall Survival | 15.85 months |
Comparison: Original design: Hypothesized 28% reduction (HR=0.72) with SBRT (corresponds to median OS = 14.5 months). Assuming an exponential distribution and constant hazards, 292 patients were required to reach 238 OS events, with 80% statistical power, a 1-sided α of 0.05. Revised design (see limitations/caveats): For same above hypotheses, at least 155 OS events from 193 randomized patients provided 65% statistical power, with a 1-sided α of 0.05.p-value: 0.055490% CI: [0.59, 1.01]Log Rank
Secondary
Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable)
Complete response: Complete resolution of thrombosis, with recanalization of vessel. Partial response (PR): * Partial recanalization (if prior complete blockage) * Unequivocal reduction in the maximal girth * Unequivocal reduction in the volume, or elimination, of arterial enhancing portion Progressive disease (PD): any unequivocal, unambiguous * New enhancing tumor thrombosis * Increase in the volume of enhancing portion * Unequivocal progression of thrombosis (non-measurable disease), the increase in overall tumor burden (enhancing thrombosis) must be comparable to the increase required for the Response Evaluation Criteria in Solid Tumor 1.1 definition of PD of measurable disease (e.g. ≥ 73% increase in volume, which is similar to 20% increase in diameter, and at least a 5 mm absolute increase). Stable disease: * No/small changes that do not meet the above criteria for PR or PD * Increase in the volume of non-enhancing thrombosis * New bland non-enhancing thrombosis
Time frame: From randomization to last follow-up. Imaging occurs every 3 months for two years then every six months. Maximum follow-up at time of analysis was 7.6 years.
Population: Eligible participants who had vascular thrombosis at study entry
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Alone | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Unknown | 21 Participants |
| Sorafenib Alone | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Stable Disease | 25 Participants |
| Sorafenib Alone | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Partial Response | 6 Participants |
| Sorafenib Alone | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Progressive Disease | 14 Participants |
| Sorafenib Alone | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Complete Response | 0 Participants |
| SBRT Followed by Sorafenib | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Progressive Disease | 4 Participants |
| SBRT Followed by Sorafenib | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Complete Response | 2 Participants |
| SBRT Followed by Sorafenib | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Unknown | 11 Participants |
| SBRT Followed by Sorafenib | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Partial Response | 22 Participants |
| SBRT Followed by Sorafenib | Best Vascular Thrombosis Response up to the Time of Progressive Disease (if Applicable) | Stable Disease | 23 Participants |
Secondary
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 4.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Population: Eligible, started treatment, and were assessed for adverse events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sorafenib Alone | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 2 Participants |
| Sorafenib Alone | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 10 Participants |
| Sorafenib Alone | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 21 Participants |
| Sorafenib Alone | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 6 Participants |
| Sorafenib Alone | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 49 Participants |
| SBRT Followed by Sorafenib | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 2 Participants |
| SBRT Followed by Sorafenib | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 1 Participants |
| SBRT Followed by Sorafenib | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 51 Participants |
| SBRT Followed by Sorafenib | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 9 Participants |
| SBRT Followed by Sorafenib | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 20 Participants |
Secondary
Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment
The FACT-Hep total score measures quality of life in patients with hepatobiliary cancer. Possible scores range from 0 to 180, with higher scores indicating a better outcome. Improvement in FACT-Hep total score is defined as an increase from the baseline to 6-month score of at least 5 points.
Time frame: Baseline and 6 months
Population: Eligible participants who consented to the quality of life component and had data at baseline and six months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Alone | Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment | 10 percentage of participants |
| SBRT Followed by Sorafenib | Percentage of Participants With Improvement in the Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) Total Score 6 Months After the Start of Treatment | 35 percentage of participants |
Secondary
Progression-free Survival
Failure for progression-free survival (PFS) include death, new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant Mets that were present at study entry, new HCC within liver including tumor thrombosis, and vascular thrombosis events =progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. PFS time is defined as the time from randomization to the date of first failure, date of death, or last known follow-up (censored). PFS rates are estimated by the Kaplan-Meier method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions.
Time frame: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Population: Eligible participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Alone | Progression-free Survival | 5.49 percentage of participants |
| SBRT Followed by Sorafenib | Progression-free Survival | 9.22 percentage of participants |
p-value: 0.000195% CI: [0.4, 0.75]Log Rank
Secondary
Quality Adjusted Life Years
Quality adjusted life years is calculated as the weighted sum of the number of years spent in different health states. The weight value is a utility score between 0 (worst health state) and 1 (best health state) derived from the EQ-5D-5L questionnaire, designed to describe and value health based on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Time frame: The EQ-5D-5L is administered at baseline, six months and one year.
Population: The protocol states that this endpoint would be addressed if and only if the primary endpoint supports the primary hypothesis, therefore data is not reported.
Secondary
Time to Progression
Progression (failure) is defined as any of the following events: new tumor thrombosis, progression of hepatocellular carcinoma (HCC) within liver excluding tumor thrombosis status, progression of distant metastases that were present at study entry, new HCC within the liver including tumor thrombosis, and vascular thrombosis events=progression-new enhancing tumor thrombosis/progression-Increase in the volume of enhancing portion of thrombosis. Time to progression was measured from the date of randomization to the date of first failure, death (competing risk), or last follow-up (censored). Progression rates are estimated by the cumulative incidence method. The protocol specifies only that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided as a summary of the distributions.
Time frame: From randomization to last follow-up: weekly during SBRT, post-SBRT/pre-sorafenib, monthly during sorafenib, and overall, from study entry: every 3 months for 2 years, then every 6 months. Maximum follow-up at time of analysis was 7.6 years.
Population: Eligible participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Alone | Time to Progression | 66.3 percentage of participants |
| SBRT Followed by Sorafenib | Time to Progression | 56.4 percentage of participants |
p-value: 0.03495% CI: [0.48, 0.99]Gray's test