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

A Phase III Randomized Trial of Protons Versus Photons for Hepatocellular Carcinoma

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Unresectable Hepatocellular Carcinoma; Recurrent Hepatocellular Carcinoma; Stage III Hepatocellular Carcinoma AJCC v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Radiation: Radiation Therapy; Radiation: Radiation Therapy

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 for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 186
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Radiation: Radiation Therapy; Undergo proton therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type; Radiation: Radiation Therapy; Undergo photon therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type
Experimental: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Radiation: Radiation Therapy; Undergo proton therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type; Radiation: Radiation Therapy; Undergo photon therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Energy Type

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From the date of randomization to the date of death due to any cause assessed up to 4 years
Treatment effect	Will be performed using the Cox proportional hazard regression model.	Up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 4 years
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.	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 4 years
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.	Up to 4 years
Fatigue	Will be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue short form version 1.0 8a.	Baseline up to 6 months
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.	Baseline up to 1 month
Quality-adjusted survival	Will be evaluated and compared using European Quality of Life Five Dimension Three Level Questionnaire (EuroQol 5D).	Baseline up to 12 months
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.	At baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall quality of life by Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) version 4	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.	Baseline up to 12 months

Collaborators and Investigators

• Sponsor: NRG Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Theodore S Hong, NRG Oncology

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2018
• Primary Completion (Actual): January 20, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: June 12, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: HCC; hepatocellular carcinoma; Liver cancer; Proton Therapy; Photon Therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Physical Phenomena; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Radiation; Specimen Handling; Magnetic Resonance Spectroscopy
• Other Study ID Numbers: NRG-GI003 (Other Identifier: CTEP); U10CA180868 (U.S. NIH Grant/Contract); NCI-2016-02009 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No