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NCT03186898 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-07-02

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part
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 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
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    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.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Computed Tomography
    3. Other: Laboratory Biomarker Analysis
    4. Procedure: Magnetic Resonance Imaging
    5. Other: Quality-of-Life Assessment
    6. Radiation: Radiation Therapy
    label
    Arm I (proton therapy)
    type
    EXPERIMENTAL
  2. description
    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.
    intervention Names
    1. Procedure: Biospecimen Collection
    2. Procedure: Computed Tomography
    3. Other: Laboratory Biomarker Analysis
    4. Procedure: Magnetic Resonance Imaging
    5. Other: Quality-of-Life Assessment
    6. Radiation: Radiation Therapy
    label
    Arm II (photon therapy)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Arm I (proton therapy)
    2. Arm II (photon therapy)
    description
    Undergo blood sample collection
    name
    Biospecimen Collection
    other Names
    1. Biological Sample Collection
    2. Biospecimen Collected
    3. Sample Collection
    4. Specimen Collection
    type
    PROCEDURE
  2. arm Group Labels
    1. Arm I (proton therapy)
    2. Arm II (photon therapy)
    description
    Undergo CT scan
    name
    Computed Tomography
    other Names
    1. CAT
    2. CAT Scan
    3. Computed Axial Tomography
    4. Computerized Axial Tomography
    5. Computerized axial tomography (procedure)
    6. Computerized Tomography
    7. Computerized Tomography (CT) scan
    8. CT
    9. CT Scan
    10. Diagnostic CAT Scan
    11. Diagnostic CAT Scan Service Type
    12. tomography
    type
    PROCEDURE
  3. arm Group Labels
    1. Arm I (proton therapy)
    2. Arm II (photon therapy)
    description
    Correlative studies
    name
    Laboratory Biomarker Analysis
    type
    OTHER
  4. arm Group Labels
    1. Arm I (proton therapy)
    2. Arm II (photon therapy)
    description
    Undergo MRI
    name
    Magnetic Resonance Imaging
    other Names
    1. Magnetic Resonance
    2. Magnetic Resonance Imaging (MRI)
    3. Magnetic resonance imaging (procedure)
    4. Magnetic Resonance Imaging Scan
    5. Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
    6. MR
    7. MR Imaging
    8. MRI
    9. MRI Scan
    10. MRIs
    11. NMR Imaging
    12. NMRI
    type
    PROCEDURE
  5. arm Group Labels
    1. Arm I (proton therapy)
    2. Arm II (photon therapy)
    description
    Ancillary studies
    name
    Quality-of-Life Assessment
    other Names
    1. Quality of Life Assessment
    type
    OTHER
  6. arm Group Labels
    1. Arm I (proton therapy)
    description
    Undergo proton therapy
    name
    Radiation Therapy
    other Names
    1. Cancer Radiotherapy
    2. Energy Type
    3. ENERGY_TYPE
    4. Irradiate
    5. Irradiated
    6. Irradiation
    7. Radiation
    8. Radiation Therapy, NOS
    9. Radiotherapeutics
    10. Radiotherapy
    11. RT
    12. Therapy, Radiation
    type
    RADIATION
  7. arm Group Labels
    1. Arm II (photon therapy)
    description
    Undergo photon therapy
    name
    Radiation Therapy
    other Names
    1. Cancer Radiotherapy
    2. Energy Type
    3. ENERGY_TYPE
    4. Irradiate
    5. Irradiated
    6. Irradiation
    7. Radiation
    8. Radiation Therapy, NOS
    9. Radiotherapeutics
    10. Radiotherapy
    11. RT
    12. Therapy, Radiation
    type
    RADIATION
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
115
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    Differences between treatment arms in the overall score, the four domains (physical, social, emotional, and functional well-being), and the additional concerns subscale will also be analyzed.
    measure
    Overall quality of life by Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) version 4
    time Frame
    Baseline up to 12 months
  2. description
    Estimates of the primary outcome treatment effect and the corresponding 95% confidence intervals (CIs) will be provided by sex.
    measure
    Overall survival by sex
    time Frame
    Up to 48 months after accrual closure
  3. description
    Estimates of the primary outcome treatment effect and the corresponding 95% CIs will be provided by race.
    measure
    Overall survival by race
    time Frame
    Up to 48 months after accrual closure
  4. description
    Estimates of the primary outcome treatment effect and the corresponding 95% CIs will be provided by ethnicity.
    measure
    Overall survival by ethnicity
    time Frame
    Up to 48 months after accrual closure
primary Outcomes
  1. description
    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 88 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 1-sided significance level of 0.039.
    measure
    Overall survival (OS)
    time Frame
    From the date of randomization to the date of death due to any cause assessed up to 48 months after accrual closure
  2. description
    Will be performed using the Cox proportional hazard regression model.
    measure
    Treatment effect
    time Frame
    Up to 48 months after accrual closure
secondary Outcomes
  1. description
    Will be estimated by the Kaplan-Meier method and compared using the log rank test. The Cox proportional hazard regression model will be used.
    measure
    Progression-free survival (PFS)
    time Frame
    From the date of randomization to the date of first PFS failure or last follow-up for patients without a reported PFS event assessed up to 9 years
  2. description
    Will be estimated by the cumulative incidence method and compared using Gray's test. The Fine-Gray regression model will be used to analyze.
    measure
    Local progression (LP)
    time Frame
    From the date of randomization to the date of first LP or date of last follow-up for patients without an LP event reported assessed up to 9 years
  3. description
    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.
    measure
    Incidence of adverse events
    time Frame
    Up to 9 years
  4. description
    Will be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue short form version 1.0 8a.
    measure
    Fatigue
    time Frame
    Baseline up to 6 months
  5. description
    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.
    measure
    Change in fatigue
    time Frame
    Baseline up to 1 month
  6. description
    Will be evaluated and compared using European Quality of Life Five Dimension Three Level Questionnaire (EuroQol 5D).
    measure
    Quality-adjusted survival
    time Frame
    Baseline up to 12 months
  7. description
    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.
    measure
    Plasma hepatocyte growth factor (HGF) levels
    time Frame
    At baseline
Full study description
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.
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. 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 thereafter.
Source references
references
  1. citation
    Duda DG. Targeting Tumor Microenvironment in Liver Cancers: Rationale, Current Progress, and Future Perspective. Keio J Med. 2022;71(3):71. doi: 10.2302/kjm.71-004-ABST.
    pmid
    36155490
    type
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Source notices and limitations
    Discovery and provenance
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      1. context exact
        dose-escalation to the liver tumor.[<a href="#cit/section_6.32">32</a>,<a href="#cit/section_6.33">33</a>] Clinical trials, including <a href="/clinicaltrials/NCT03186898">NRG-GI003</a> (NCT03186898), are evaluating whether photon or proton therapy is superior for patients with HCC. </p> <p id="_470" tabindex="-1">Pallia
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        r tumor.[<a href="#cit/section_6.32">32</a>,<a href="#cit/section_6.33">33</a>] Clinical trials, including <a href="/clinicaltrials/NCT03186898">NRG-GI003</a> (NCT03186898), are evaluating whether photon or proton therapy is superior for patients with HCC. </p> <p id="_470" tabindex="-1">Palliative radiation therapy impro
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      source title
      Primary Liver Cancer Treatment (PDQ®)–Health Professional Version
      source update dates
      1. context
        Updated: April 17, 2025
        datetime
        2025-04-17T12:00:00Z
        display
        April 17, 2025

    Preserved source evidence · Not medical advice