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Recurrent Hepatocellular CarcinomaPhase 3NCT03186898

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

A Phase 3 study testing Proton Therapy and Photon Therapy in people with Recurrent Hepatocellular Carcinoma and Stage III Hepatocellular Carcinoma AJCC v7, run by NRG Oncology at 27 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Proton Therapy and Photon Therapy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
116 participants
Where
27 sitesUnited States
Study dates
26 Jan 2018to 20 Jan 2031
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

27 sites in 1 country.

27 sites in 1 country

United States27 sites

  • Emory Proton Therapy Center

    Atlanta, Georgia, 30308

  • Emory University Hospital Midtown

    Atlanta, Georgia, 30308

  • Emory University Hospital/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Emory Saint Joseph's Hospital

    Atlanta, Georgia, 30342

  • Maryland Proton Treatment Center

    Baltimore, Maryland, 21201

  • University of Maryland/Greenebaum Cancer Center

    Baltimore, Maryland, 21201

  • Memorial Sloan Kettering Basking Ridge

    Basking Ridge, New Jersey, 07920

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02114

  • University of Cincinnati Cancer Center-UC Medical Center

    Cincinnati, Ohio, 45219

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Memorial Sloan Kettering Commack

    Commack, New York, 11725

  • Corewell Health Dearborn Hospital

    Dearborn, Michigan, 48124

  • Memorial Sloan Kettering Westchester

    East White Plains, New York, 10604

  • UT MD Anderson Cancer Center

    Houston, Texas, 77030

  • Memorial Sloan Kettering Monmouth

    Middletown, New Jersey, 07748

  • Memorial Sloan Kettering Bergen

    Montvale, New Jersey, 07645

  • New York Proton Center

    New York, New York, 10035

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • Corewell Health William Beaumont University Hospital

    Royal Oak, Michigan, 48073

  • Fred Hutchinson Cancer Center

    Seattle, Washington, 98109

  • University of Washington Medical Center - Montlake

    Seattle, Washington, 98195

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • Corewell Health Beaumont Troy Hospital

    Troy, Michigan, 48085

  • Memorial Sloan Kettering Nassau

    Uniondale, New York, 11553

  • Northwestern Medicine Cancer Center Warrenville

    Warrenville, Illinois, 60555

  • University of Cincinnati Cancer Center-West Chester

    West Chester, Ohio, 45069

Other trials in United States

About this study

Official title: 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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To determine if overall survival (OS) is different for hepatocellular carcinoma patients treated with protons compared to photons.

SECONDARY OBJECTIVES:

  1. 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.

  1. To determine if there are correlations between the baseline values of hepatocyte growth factor (HGF) and outcomes (OS/PFS/fatigue).

EXPLORATORY OBJECTIVES:

  1. 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.

Being tested
Proton Therapy, Photon Therapy
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Proton TherapyRadiation

    Also called Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate

    Fractions

  • Photon TherapyRadiation

    Also called Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate

    Fractions

Study groups in NCT03186898
Study groupRoleWhat they receive
Proton Therapy (Arm 1)ExperimentalProton therapy delivered in 5 fractions over 15 days or 15 fractions over 24 days, determined by the treating physician.
Receives: Radiation: Proton Therapy
Photon Therapy (Arm 2)ExperimentalPhoton therapy delivered in 5 fractions over 15 days or 15 fractions over 24 days, determined by the treating physician.
Receives: Radiation: Photon Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants Alive (Overall Survival)

    Survival rates are estimated using the Kaplan-Meier method, censoring participants alive at last known follow-up.

    Measured: 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 outcomes (8)

  1. Percentage of Participants Alive Without Progression (Progression-free Survival)

    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.

    Measured: 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.

  2. Percentage of Participants With Local Progression

    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.

    Measured: 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.

  3. Percentage of Participants With Grade 3+ Treatment-Related Adverse Events

    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.

    Measured: From randomization to death or last follow-up. Median follow-up time for all patients at time of analysis was 20.4 months.

  4. Change From Baseline to One Month in the Patient Reported Outcomes Measurement Information System - Fatigue Short Form version1.0 8a [PROMIS Fatigue Score]

    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.

    Measured: Baseline and one month

  5. Quality-adjusted LIfe Years

    Was to be calculated using the EuroQol 5-Dimension Three Level Questionnaire (EQ-5D-3L).

    Measured: Baseline up to 12 months

  6. Percentage of Participants Alive (Overall Survival) by Plasma Hepatocyte Growth Factor (HGF) Level

    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.

    Measured: From randomization to death or last follow-up. One- and two-year estimates will be reported.

  7. Percentage of Participants Alive Without Progression (Progression-free Survival) by HGF Level

    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.

    Measured: From randomization to progression, death, or last follow-up, whichever occurs first. One- and two-year estimates will be reported.

  8. Change From Baseline to One Month in PROMIS Fatigue Score by HGF Level

    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.

    Measured: Baseline and one month

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jun 2017
  2. Study start26 Jan 2018
  3. Primary completion20 Jan 2026
  4. Study completion20 Jan 2031 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
116 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03186898
Sponsor's protocol ID
NRG-GI003
Other IDs
NCI-2016-02009, NRG-GI003, NRG-GI003, U10CA180868
Status last verified
Oct 2026
First submitted
12 Jun 2017
Last updated
3 Nov 2026
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

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.

    PubMed 36155490

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Proton Therapy and Photon Therapy in people with Recurrent Hepatocellular Carcinoma and Stage III Hepatocellular Carcinoma AJCC v7, run by NRG Oncology at 27 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 3 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 27 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Nov 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants Alive (Overall Survival) (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.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03186898, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Nov 2026.

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