Brief Summary
This phase III trial studies how well radiation therapy with protons works compared with photons in treating patients with liver cancer. Radiation therapy, such as photon therapy, uses high energy x-rays to send the radiation inside the body to the tumor while proton therapy uses a beam of proton particles. Proton therapy can stop shortly after penetrating through the tumor and may cause less damage to the surrounding healthy organs and result in better survival in patients with liver cancer.
Brief Title
Radiation Therapy With Protons or Photons in Treating Patients With Liver Cancer
Detailed Description
PRIMARY OBJECTIVE:
I. To determine if overall survival (OS) is different for hepatocellular carcinoma patients treated with protons compared to photons.
SECONDARY OBJECTIVES:
I. To determine the difference in progression-free-survival (PFS) in patients with hepatocellular carcinoma (HCC) treated with protons compared to patients with HCC treated with photons.
II. To determine the difference in local progression (LP) in patients with HCC treated with protons compared to patients with HCC treated with photons.
III. To determine differences in toxicity in patients with HCC treated with protons versus photons.
IV. To determine differences in fatigue, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue in patients with HCC treated with protons, versus photons; as well as quality-adjusted survival, if the primary endpoint is met.
V. To determine if there are correlations between the baseline values of hepatocyte growth factor (HGF) and outcomes (OS/PFS/fatigue).
EXPLORATORY OBJECTIVES:
I. To determine differences in overall quality of life, measured by Functional Assessment of Cancer Therapy-Hepatobiliary Cancer (FACT-Hep) in patients with HCC treated with protons.
II. Biospecimen collection for future correlative science projects.
OUTLINE: Patients are randomized to 1 of 2 arms, photon or proton therapy (see Arms and Interventions).
Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly thereafter.
I. To determine if overall survival (OS) is different for hepatocellular carcinoma patients treated with protons compared to photons.
SECONDARY OBJECTIVES:
I. To determine the difference in progression-free-survival (PFS) in patients with hepatocellular carcinoma (HCC) treated with protons compared to patients with HCC treated with photons.
II. To determine the difference in local progression (LP) in patients with HCC treated with protons compared to patients with HCC treated with photons.
III. To determine differences in toxicity in patients with HCC treated with protons versus photons.
IV. To determine differences in fatigue, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue in patients with HCC treated with protons, versus photons; as well as quality-adjusted survival, if the primary endpoint is met.
V. To determine if there are correlations between the baseline values of hepatocyte growth factor (HGF) and outcomes (OS/PFS/fatigue).
EXPLORATORY OBJECTIVES:
I. To determine differences in overall quality of life, measured by Functional Assessment of Cancer Therapy-Hepatobiliary Cancer (FACT-Hep) in patients with HCC treated with protons.
II. Biospecimen collection for future correlative science projects.
OUTLINE: Patients are randomized to 1 of 2 arms, photon or proton therapy (see Arms and Interventions).
Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly thereafter.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
RECURRENT HEPATOCELLULAR CARCINOMA
STAGE III HEPATOCELLULAR CARCINOMA AJCC V7
UNRESECTABLE HEPATOCELLULAR CARCINOMA
Eligibility Criteria
Inclusion Criteria:
* Pathologically (histologically or cytologically) or radiographically-proven (based on the American Association for the Study of Liver Diseases \[AALSD\] criteria) unresectable or locally recurrent hepatocellular cancer prior to registration
* Appropriate stage for study entry based on the following diagnostic workup:
* All patients must have computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen is permitted
* Participants must have measurable disease at study entry, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 2 cm with conventional techniques or as \> 1 cm with spiral CT scan
* Patient must have 3 or fewer single or multinodular tumors; for patients with a single lesion, lesion must be 15 cm or less in greatest dimension; for patients with two lesions, no lesion may be greater than 10 cm in greatest dimension; for patients with three lesions, no lesion may be greater than 6 cm in greatest dimension; portal vein involvement or thrombosis combined with a single lesion that is \>= 1 cm and =\< 15 cm in greatest dimension is allowed
* Age \>= 18
* Zubrod performance status 0-1 within 30 days prior to registration
* Negative urine or serum pregnancy test for women of childbearing potential within 7 days prior to study entry
* Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3
* Platelets \>= 50,000 cells/mm\^3
* Hemoglobin \>= 9.0 g/dl; (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable)
* Total bilirubin \< 4 x institutional upper limit of normal (ULN)
* Transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \< 6 x institutional ULN
* Albumin \>= 2.5 g/dl
* Creatinine \< 2 mg/dl
* Prior chemotherapy, targeted biological therapy (e.g. sorafenib), surgery, transarterial chemoembolization (TACE), ablation for present disease is acceptable
* Must have Child-Turcotte-Pugh (CTP) A or B7
* The patient or a legally authorized representative must provide study-specific informed consent prior to study registration
Exclusion Criteria:
* PRIOR TO STEP ONE REGISTRATION:
* Definitive clinical or radiologic documentation of extrahepatic tumor, defined as 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
* Uncontrolled prior invasive malignancy, excluding the current diagnosis
* Systemic chemotherapy for the study cancer \< 2 weeks prior to registration
* 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
* HIV positive with CD4 count \< 200 cells/microliter; note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 (cluster of differentiation 4)count \>= 200 cells/microliter prior to registration; note also that HIV testing is not required for eligibility for this protocol; this exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields (to include Y90)
* Prior liver transplant
* PRIOR TO STEP TWO RANDOMIZATION:
* Unable to obtain confirmation of payment coverage (insurance or other) for either possible treatment
* Pathologically (histologically or cytologically) or radiographically-proven (based on the American Association for the Study of Liver Diseases \[AALSD\] criteria) unresectable or locally recurrent hepatocellular cancer prior to registration
* Appropriate stage for study entry based on the following diagnostic workup:
* All patients must have computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen is permitted
* Participants must have measurable disease at study entry, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 2 cm with conventional techniques or as \> 1 cm with spiral CT scan
* Patient must have 3 or fewer single or multinodular tumors; for patients with a single lesion, lesion must be 15 cm or less in greatest dimension; for patients with two lesions, no lesion may be greater than 10 cm in greatest dimension; for patients with three lesions, no lesion may be greater than 6 cm in greatest dimension; portal vein involvement or thrombosis combined with a single lesion that is \>= 1 cm and =\< 15 cm in greatest dimension is allowed
* Age \>= 18
* Zubrod performance status 0-1 within 30 days prior to registration
* Negative urine or serum pregnancy test for women of childbearing potential within 7 days prior to study entry
* Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3
* Platelets \>= 50,000 cells/mm\^3
* Hemoglobin \>= 9.0 g/dl; (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable)
* Total bilirubin \< 4 x institutional upper limit of normal (ULN)
* Transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \< 6 x institutional ULN
* Albumin \>= 2.5 g/dl
* Creatinine \< 2 mg/dl
* Prior chemotherapy, targeted biological therapy (e.g. sorafenib), surgery, transarterial chemoembolization (TACE), ablation for present disease is acceptable
* Must have Child-Turcotte-Pugh (CTP) A or B7
* The patient or a legally authorized representative must provide study-specific informed consent prior to study registration
Exclusion Criteria:
* PRIOR TO STEP ONE REGISTRATION:
* Definitive clinical or radiologic documentation of extrahepatic tumor, defined as 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
* Uncontrolled prior invasive malignancy, excluding the current diagnosis
* Systemic chemotherapy for the study cancer \< 2 weeks prior to registration
* 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
* HIV positive with CD4 count \< 200 cells/microliter; note that patients who are human immunodeficiency virus (HIV) positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 (cluster of differentiation 4)count \>= 200 cells/microliter prior to registration; note also that HIV testing is not required for eligibility for this protocol; this exclusion criterion is necessary because the treatments involved in this protocol may be significantly immunosuppressive
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields (to include Y90)
* Prior liver transplant
* PRIOR TO STEP TWO RANDOMIZATION:
* Unable to obtain confirmation of payment coverage (insurance or other) for either possible treatment
Inclusion Criteria
Inclusion Criteria:
* Pathologically (histologically or cytologically) or radiographically-proven (based on the American Association for the Study of Liver Diseases \[AALSD\] criteria) unresectable or locally recurrent hepatocellular cancer prior to registration
* Appropriate stage for study entry based on the following diagnostic workup:
* All patients must have computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen is permitted
* Participants must have measurable disease at study entry, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 2 cm with conventional techniques or as \> 1 cm with spiral CT scan
* Patient must have 3 or fewer single or multinodular tumors; for patients with a single lesion, lesion must be 15 cm or less in greatest dimension; for patients with two lesions, no lesion may be greater than 10 cm in greatest dimension; for patients with three lesions, no lesion may be greater than 6 cm in greatest dimension; portal vein involvement or thrombosis combined with a single lesion that is \>= 1 cm and =\< 15 cm in greatest dimension is allowed
* Age \>= 18
* Zubrod performance status 0-1 within 30 days prior to registration
* Negative urine or serum pregnancy test for women of childbearing potential within 7 days prior to study entry
* Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3
* Platelets \>= 50,000 cells/mm\^3
* Hemoglobin \>= 9.0 g/dl; (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable)
* Total bilirubin \< 4 x institutional upper limit of normal (ULN)
* Transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \< 6 x institutional ULN
* Albumin \>= 2.5 g/dl
* Creatinine \< 2 mg/dl
* Prior chemotherapy, targeted biological therapy (e.g. sorafenib), surgery, transarterial chemoembolization (TACE), ablation for present disease is acceptable
* Must have Child-Turcotte-Pugh (CTP) A or B7
* The patient or a legally authorized representative must provide study-specific informed consent prior to study registration
* Pathologically (histologically or cytologically) or radiographically-proven (based on the American Association for the Study of Liver Diseases \[AALSD\] criteria) unresectable or locally recurrent hepatocellular cancer prior to registration
* Appropriate stage for study entry based on the following diagnostic workup:
* All patients must have computed tomography (CT) scan chest/abdomen/pelvis with multiphasic liver CT scan prior to registration; if CT contrast is contraindicated, CT chest without contrast and magnetic resonance imaging (MRI) of abdomen is permitted
* Participants must have measurable disease at study entry, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 2 cm with conventional techniques or as \> 1 cm with spiral CT scan
* Patient must have 3 or fewer single or multinodular tumors; for patients with a single lesion, lesion must be 15 cm or less in greatest dimension; for patients with two lesions, no lesion may be greater than 10 cm in greatest dimension; for patients with three lesions, no lesion may be greater than 6 cm in greatest dimension; portal vein involvement or thrombosis combined with a single lesion that is \>= 1 cm and =\< 15 cm in greatest dimension is allowed
* Age \>= 18
* Zubrod performance status 0-1 within 30 days prior to registration
* Negative urine or serum pregnancy test for women of childbearing potential within 7 days prior to study entry
* Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3
* Platelets \>= 50,000 cells/mm\^3
* Hemoglobin \>= 9.0 g/dl; (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 9.0 g/dl is acceptable)
* Total bilirubin \< 4 x institutional upper limit of normal (ULN)
* Transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \< 6 x institutional ULN
* Albumin \>= 2.5 g/dl
* Creatinine \< 2 mg/dl
* Prior chemotherapy, targeted biological therapy (e.g. sorafenib), surgery, transarterial chemoembolization (TACE), ablation for present disease is acceptable
* Must have Child-Turcotte-Pugh (CTP) A or B7
* The patient or a legally authorized representative must provide study-specific informed consent prior to study registration
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03186898
Org Class
Other
Org Full Name
NRG Oncology
Org Study Id
NRG-GI003
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase III Randomized Trial of Protons Versus Photons for Hepatocellular Carcinoma
Primary Outcomes
Outcome Description
Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at last known follow-up.
Outcome Measure
Percentage of Participants Alive (Overall Survival)
Outcome Time Frame
From randomization to death or last follow-up. Median follow-up time for all patients at time of analysis was 20.4 months. One- and two-year estimates are reported.
Secondary Ids
Secondary Id
NCI-2016-02009
Secondary Id
NRG-GI003
Secondary Id
NRG-GI003
Secondary Id
U10CA180868
Secondary Outcomes
Outcome Description
Progression is defined as local, regional, or distant progression. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive without progression at time of last follow-up.
Outcome Time Frame
From randomization to progression, death, or last follow-up, whichever occurs first. Median follow-up time for all patients at time of analysis was 20.4 months. One- and two-year estimates are reported.
Outcome Measure
Percentage of Participants Alive Without Progression (Progression-free Survival)
Outcome Description
Local progression rates are estimated using the cumulative incidence method in which death is treated as competing risk and participants alive without local failure are censored at last known follow-up.
Outcome Time Frame
From randomization to local progression, death, or last follow-up, whichever occurs first. Median follow-up time for all patients at time of analysis was 20.4 months. One- and two-year estimates are reported.
Outcome Measure
Percentage of Participants With Local Progression
Outcome Description
Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Adverse events reported as possibly, probably, or definitely related to treatment are considered to be treatment-related adverse events.
Outcome Time Frame
From randomization to death or last follow-up. Median follow-up time for all patients at time of analysis was 20.4 months.
Outcome Measure
Percentage of Participants With Grade 3+ Treatment-Related Adverse Events
Outcome Description
The PROMIS Fatigue Short Form v1.0 8a contains 8 items that assess self-reported fatigue symptoms over the past 7 days. Item responses are summed to obtain a raw score ranging from 8 to 40, which is then converted to a standardized T-score (mean = 50, standard deviation = 10). Higher T-scores indicate greater fatigue. Change from baseline is calculated as the post-baseline T-score minus the baseline T-score, with positive change scores indicating increased fatigue and negative change scores indicating decreased fatigue.
Outcome Time Frame
Baseline and one month
Outcome Measure
Change From Baseline to One Month in the Patient Reported Outcomes Measurement Information System - Fatigue Short Form version1.0 8a [PROMIS Fatigue Score]
Outcome Description
Was to be calculated using the EuroQol 5-Dimension Three Level Questionnaire (EQ-5D-3L).
Outcome Time Frame
Baseline up to 12 months
Outcome Measure
Quality-adjusted LIfe Years
Outcome Description
Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at last known follow-up. HGF will be dichotomized at 2311 pg/mL.
Outcome Time Frame
From randomization to death or last follow-up. One- and two-year estimates will be reported.
Outcome Measure
Percentage of Participants Alive (Overall Survival) by Plasma Hepatocyte Growth Factor (HGF) Level
Outcome Description
Progression is defined as local, regional, or distant progression. Progression-free survival rates are estimated using the Kaplan-Meier method, censoring participants alive without progression at time of last follow-up. HGF will be dichotomized at 2311 pg/mL.
Outcome Time Frame
From randomization to progression, death, or last follow-up, whichever occurs first. One- and two-year estimates will be reported.
Outcome Measure
Percentage of Participants Alive Without Progression (Progression-free Survival) by HGF Level
Outcome Description
The PROMIS Fatigue Short Form v1.0 8a contains 8 items that assess self-reported fatigue symptoms over the past 7 days. Item responses are summed to obtain a raw score ranging from 8 to 40, which is then converted to a standardized T-score (mean = 50, standard deviation = 10). Higher T-scores indicate greater fatigue. Change from baseline is calculated as the post-baseline T-score minus the baseline T-score, with positive change scores indicating increased fatigue and negative change scores indicating decreased fatigue. HGF will be dichotomized at 2311 pg/mL.
Outcome Time Frame
Baseline and one month
Outcome Measure
Change From Baseline to One Month in PROMIS Fatigue Score by HGF Level
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Nitin Ohri
Investigator Email
nitin.ohri@einsteinmed.org
Investigator Phone
Categories Mesh Debug
Cancer --- CARCINOMA
Cancer --- NEOPLASMS
Gastrointestinal (GI) Cancers --- DIGESTIVE SYSTEM NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Digestive System --- DIGESTIVE SYSTEM DISEASES
Liver --- DIGESTIVE SYSTEM DISEASES
Digestive System --- LIVER DISEASES
Liver --- LIVER DISEASES
MeSH Terms
CARCINOMA, HEPATOCELLULAR
ADENOCARCINOMA
CARCINOMA
NEOPLASMS, GLANDULAR AND EPITHELIAL
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
LIVER NEOPLASMS
DIGESTIVE SYSTEM NEOPLASMS
NEOPLASMS BY SITE
DIGESTIVE SYSTEM DISEASES
LIVER DISEASES
PROTON THERAPY
RADIATION
RADIOTHERAPY
HEAVY ION RADIOTHERAPY
THERAPEUTICS
PHYSICAL PHENOMENA