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

Study Overview
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Brief Summary
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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
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PRIMARY OBJECTIVES: 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 HGF and outcomes (OS/PFS/fatigue). EXPLORATORY OBJECTIVES: I. To determine differences in overall Quality of Life, measured by 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. After completion of study treatment, patients are followed every 3 months for 2 years, and then every 6 months for 3 years.

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

Conditions
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Unrectable or Locally Recurrent Hepatocellular Carcinoma

Intervention / Treatment
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* Radiation: Proton Therapy (Radiation Therapy)
* Radiation: Photon Therapy (Radiation Therapy)


Participation Criteria
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Eligibility Criteria
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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 Patients 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 legion that is ≥ 1 cm and ≤ 15 cm in greatest dimension is allowed. 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 >= 2.5mg/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 RANDOMIZATION: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proton Therapy (Radiation Therapy)<br>Patients undergo proton therapy over 15-24 days for 5 or 15 fractions. | Radiation: Proton Therapy (Radiation Therapy)<br>* Undergo proton therapy<br>* Other names: Therapy, Radiation;|
| Experimental: Photon Therapy (Radiation Therapy)<br>Patients undergo photon therapy over 15-24 days for 5 or 15 fractions. | Radiation: Photon Therapy (Radiation Therapy)<br>* Undergo photon therapy<br>* Other names: Therapy, Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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 Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with OS. | From the date of randomization to the date of death due to any cause or date of last follow-up for alive patients. This analysis occurs after 125 deaths have been observered; estimated to occurs around 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS is defined as local/regional/distant progression or death due to any cause and will be estimated by the Kaplan-Meier method. The distributions of PFS between treatment arms will be compared using the log rank test. | 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 5 years. | 
| Local Progression (LP) | 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 the effects of factors, in addition to treatment, which may be associated with LP. | 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 5 years. | 
| Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events version 5 | 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. | From baseline up to 5 years | 
| Fatigue as measured by the PROMIS fatigue short form version 1.0 8a | Change in fatigue will be compared between treatment arms using a t-test. If the data do not satisfy the normality assumption, a Wilcoxin test may be used instead. | From baseline to the assessment at 1 month post treatment completion. | 
| Correlation of Hepatocyte Growth Factor (HGF) biomarker with OS, PFS and fatigue | HGF will be dichotomized at 2311 pg/mL and evaluated for prognostic significance using Cox regression model. | This analysis occurs after the primary endpoint has been reported; estimated to occur around 5 years. | 
| Quality Adjusted Survival (if primary endpoint is met) | The EuroQol (EQ-5D) will be used to assess quality-adjusted survival. | This analysis occurs after the primary endpoint has been reported; estimated to occur around 5 years. | 
| Exploratory - Overall Quality of Life (QOL) | QOL will be measured by the FACT-Hep v 4. An improvement in the FACT-HEP, defined as an increase of 5 points, will be assessed. | From baseline to the assessment at 6 months post treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatocellular carcinoma, HCC, Proton Therapy, Photon Therapy, Liver cancer