Recurrent Hepatocellular Carcinoma, Stage III Hepatocellular Carcinoma AJCC v7, Unresectable Hepatocellular Carcinoma
Conditions
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.
Interventions
PROCEDUREBiospecimen Collection
Undergo blood sample collection
PROCEDUREComputed Tomography
Undergo CT scan
OTHERLaboratory Biomarker Analysis
Correlative studies
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
OTHERQuality-of-Life Assessment
Ancillary studies
RADIATIONRadiation Therapy
Undergo proton therapy
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | From the date of randomization to the date of death due to any cause assessed up to 48 months after accrual closure | 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. |
| Treatment effect | Up to 48 months after accrual closure | Will be performed using the Cox proportional hazard regression model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | 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 | Will be estimated by the Kaplan-Meier method and compared using the log rank test. The Cox proportional hazard regression model will be used. |
| Local progression (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 9 years | Will be estimated by the cumulative incidence method and compared using Gray's test. The Fine-Gray regression model will be used to analyze. |
| Incidence of adverse events | Up to 9 years | 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. |
| Fatigue | Baseline up to 6 months | Will be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue short form version 1.0 8a. |
| Change in fatigue | Baseline up to 1 month | 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. |
| Quality-adjusted survival | Baseline up to 12 months | Will be evaluated and compared using European Quality of Life Five Dimension Three Level Questionnaire (EuroQol 5D). |
| Plasma hepatocyte growth factor (HGF) levels | At baseline | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORTheodore S Hong
NRG Oncology
Outcome results
None listed