Radiation Therapy With Protons or Photons in Treating Patients With Liver Cancer

Recruitment Status
ACTIVE, NOT RECRUITING
(See Contacts and Locations)Verified March 2026 by NRG Oncology
Sponsor
NRG Oncology
Information Provided by (Responsible Party)
NRG Oncology
Clinicaltrials.gov Identifier
NCT03186898
Other Study ID Numbers:
NRG-GI003
First Submitted
June 11, 2017
First Posted
June 13, 2017
Last Update Posted
May 6, 2026
Last Verified
March 2026

ClinicalTrials.gov processed this data on May 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study 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.

ARM I: Patients undergo proton therapy over 15-24 days for 5 or 15 fractions.

ARM II: Patients undergo photon therapy over 15-24 days for 5 or 15 fractions.

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 for up to 5 years.

Condition or DiseaseIntervention/Treatment
Recurrent Hepatocellular CarcinomaStage III Hepatocellular Carcinoma AJCC v7Unresectable Hepatocellular Carcinoma
Procedure: Biospecimen CollectionProcedure: Biospecimen Collection

Study Design

Study TypeInterventional
Actual Enrollment186 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingNone (Open Label)
Primary PurposeTreatment
Official TitleA Phase III Randomized Trial of Protons Versus Photons for Hepatocellular Carcinoma
Study Start DateJanuary 25, 2018
Actual Primary Completion Date1yr 1mo from now
Actual Study Completion Date1yr 1mo from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Arm I (proton therapy)
Patients undergo proton therapy over 15-24 days for 5 or 15 fractions. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Procedure: Biospecimen Collection
Undergo blood sample collection
Arm II (photon therapy)
Patients undergo photon therapy over 15-24 days for 5 or 15 fractions. Patients undergo CT scan, MRI and blood sample collection throughout the study.
Procedure: Biospecimen Collection
Undergo blood sample collection

Outcome Measures

Primary Outcome Measures
  1. Overall survival (OS)
    Will be estimated by the Kaplan-Meier method. The distributions of OS between treatment arms will be compared using the log rank test. The final analysis will occur after at least 125 deaths have occurred and will include: tabulation of all cases entered and those excluded from the analyses with the reasons for exclusion, distributions of important prognostic baseline variables, the frequencies and severity of adverse events by treatment arm, treatment delivery compliance, observed results with respect to the primary endpoint of OS. Will be tested with a 2-sided significance level of 0.049.
  2. Treatment effect
    Will be performed using the Cox proportional hazard regression model.
Secondary Outcome Measures
  1. Progression-free survival (PFS)
    Will be estimated by the Kaplan-Meier method and compared using the log rank test. The Cox proportional hazard regression model will be used.
  2. Local progression (LP)
    Will be estimated by the cumulative incidence method and compared using Gray's test. The Fine-Gray regression model will be used to analyze.
  3. Incidence of adverse events
    Will be assessed by Common Terminology Criteria for Adverse Events version 4. A Chi-square test will be used to compare the number of patients with at least 1 grade 3 or higher adverse events between the treatment arms.
  4. Fatigue
    Will be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue short form version 1.0 8a.
  5. Change in fatigue
    Will be compared between treatment arms using a t-test. If the data do not satisfy the normality assumption, a Wilcoxon test may be used instead.
  6. Quality-adjusted survival
    Will be evaluated and compared using European Quality of Life Five Dimension Three Level Questionnaire (EuroQol 5D).
  7. Plasma hepatocyte growth factor (HGF) levels
    Will be dichotomized at the median value and evaluated for prognostic significance using Cox regression model at a 2-sided significance level of 0.05. Additionally, predictive analyses will be done by treatment arm and an exploratory test of HGF by treatment interaction, with the understanding that there will be reduced power for the predictive analyses under the same effect size assumptions. However, there may be sufficient power if there is large interaction.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
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 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

Contacts and Locations

Sponsors and CollaboratorsNRG Oncology
Locations
Emory Proton Therapy Center | Atlanta Georgia, United States, 30308Emory University Hospital Midtown | Atlanta Georgia, United States, 30308Emory University Hospital/Winship Cancer Institute | Atlanta Georgia, United States, 30322Emory Saint Joseph's Hospital | Atlanta Georgia, United States, 30342Northwestern Medicine Cancer Center Warrenville | Warrenville Illinois, United States, 60555Maryland Proton Treatment Center | Baltimore Maryland, United States, 21201University of Maryland/Greenebaum Cancer Center | Baltimore Maryland, United States, 21201Massachusetts General Hospital Cancer Center | Boston Massachusetts, United States, 02114Corewell Health Dearborn Hospital | Dearborn Michigan, United States, 48124Corewell Health William Beaumont University Hospital | Royal Oak Michigan, United States, 48073Corewell Health Beaumont Troy Hospital | Troy Michigan, United States, 48085Washington University School of Medicine | St Louis Missouri, United States, 63110Memorial Sloan Kettering Basking Ridge | Basking Ridge New Jersey, United States, 07920Memorial Sloan Kettering Monmouth | Middletown New Jersey, United States, 07748Memorial Sloan Kettering Bergen | Montvale New Jersey, United States, 07645Memorial Sloan Kettering Commack | Commack New York, United States, 11725Memorial Sloan Kettering Westchester | East White Plains New York, United States, 10604New York Proton Center | New York New York, United States, 10035Memorial Sloan Kettering Cancer Center | New York New York, United States, 10065Memorial Sloan Kettering Nassau | Uniondale New York, United States, 11553University of Cincinnati Cancer Center-UC Medical Center | Cincinnati Ohio, United States, 45219Case Western Reserve University | Cleveland Ohio, United States, 44106Ohio State University Comprehensive Cancer Center | Columbus Ohio, United States, 43210University of Cincinnati Cancer Center-West Chester | West Chester Ohio, United States, 45069M D Anderson Cancer Center | Houston Texas, United States, 77030Fred Hutchinson Cancer Center | Seattle Washington, United States, 98109University of Washington Medical Center - Montlake | Seattle Washington, United States, 98195
Investigators
Principal Investigator: Theodore S Hong, NRG Oncology