Feasibility of High Dose PROton Therapy On Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial

Study Overview
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Brief Summary
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The standard treatment of unresectable hepatocellular carcinoma (HCC) is transarterial chemoembolization (TACE) or sorafenib. Though the TACE and the agent showed survival benefit in several randomized phase III trials, the benefit was modest. Recently, radiotherapy (RT), especially conformal and higher dose with the advancement of RT techniques, showed favorable response rate with acceptable local control rate. Based on those promising results, RT was actively applied in HCC who are not indicated with surgery and/or radiofrequency ablation. Many researchers reported that there is a relationship between RT dose and tumor response rate. RT dose, however, is frequently limited because the complications (like radiation induced liver disease (RILD), radiation induced gastro-duodenal toxicity, etc.) are also closely related with higher exposed RT dose. Proton beam has characteristic depth-dose distribution contrast to photon, the Bragg peak. The advantage of this dose distribution could be more highlighted in HCC management, because of the weakness and maintenance importance of liver function itself in HCC patients. In fact, the superior results of proton beam therapy in HCC were constantly reported in several groups as prospectively as well as retrospectively. In this background, the investigators planned the present study to evaluate the efficacy and safety of proton beam therapy in HCC patients who are not indicated with surgery and/or radiofrequency ablation (RFA).

Conditions
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Liver Neoplasm, Proton Therapy

Intervention / Treatment
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* Radiation: Proton arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatocellular carcinoma (HCC) patients (Pathologically proven or HCC diagnosed based on American Association for the Study of Liver Diseases (AASLD) guideline) Not indicated with surgical resection and/or RFA Discussion in tumor board including gastroenterologist, radiologist, radiation oncologist Eastern Cooperative Oncology Group performance status 0 to 2 within 1 week before participate Adequate bone marrow function (absolute neutrophil count ≥ 1.0 x 109/l, platelet ≥ 30 x 109/l, hemoglobin ≥ 8 g/dl) Adequate liver/renal function within 1 week before participate Total bilirubin <3.0 mg/dL, Prothrombin time/International normalized ratio <1.7, Albumin≥2.8g/dL, Aspartate aminotransferase/alanine aminotransferase<6 times of upper normal limit Serum creatinine < 1.5 x upper normal limit, glomerular filtration rate > 50 ml/min Informed consent If viable tumor is single, 1 cm to 10 cm Less than 3 nodules Child-Pugh class A, B, or early C (score ≤ 10) Women of childbearing potential and male participants must agree to practice adequate contraception while on study and for at least 6 months following the last dose of RT Exclusion Criteria: Uncontrolled hepatic encephalopathy Previous history of upper abdominal radiotherapy Status of pregnancy or breast feeding Less than 12 weeks of expected survival Uncontrolled ascites Combined with disease known as radiosensitive disorder (connective tissue disorder, Ataxia-telangiectasia) Hard to maintain stable respiration less than 5 minutes related with respiratory disease Combined with uncontrolled severe acute disease other than liver

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proton arm<br>Proton beam therapy | Radiation: Proton arm<br>* Proton beam therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| two-year overall survival |  | two-year after proton beam therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 month objective response rate | Modified Response Evaluation Criteria In Solid Tumors (mRECIST) will be used. | 1 month after proton beam therapy | 
| 3 month objective response rate | Modified Response Evaluation Criteria In Solid Tumors (mRECIST) will be used. | 3 months after proton beam therapy | 
| 6 month objective response rate | Modified Response Evaluation Criteria In Solid Tumors (mRECIST) will be used. | 6 months after proton beam therapy | 
| 1 year progression free survival | Modified Response Evaluation Criteria In Solid Tumors (mRECIST) will be used. | one-year after proton beam therapy | 
| 1 year local progression free survival | Modified Response Evaluation Criteria In Solid Tumors (mRECIST) will be used. | one-year after proton beam therapy | 
| 6 months adverse event | Common Terminology Criteria for Adverse Event v4.0 (CTCAE v4.0) will be used. | 6 months after proton beam therapy | 
| 1 year adverse event | Common Terminology Criteria for Adverse Event v4.0 (CTCAE v4.0) will be used. | 1 year after proton beam therapy | 
| Baseline Quality of life assessment by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ C-30) |  | Within 2 week before proton beam therapy started | 
| 1 month Quality of life assessment by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ C-30) compared with baseline |  | 1 month after proton beam therapy | 
| 3 month Quality of life assessment by EORTC QLQ C-30 compared with baseline |  | 3 month after proton beam therapy | 
| 6 month Quality of life assessment by EORTC QLQ C-30 compared with baseline |  | 6 month after proton beam therapy | 
| Baseline Indocyanine green (ICG) | ICG Retention rate at 15 minute will be used. | Within 2 week before proton beam therapy started | 
| Indocyanine green (ICG) test change compared with baseline | ICG Retention rate at 15 minute will be used. | 3 month after proton beam therapy | 
| Baseline hepatobiliary phase signal | Hepatobiliary phase (20 minute after gadoxetate disodium injection) will be used to evaluate functioning liver volume. | Within 2 week before proton beam therapy started | 
| Hepatobiliary phase signal change after proton beam therapy | Hepatobiliary phase (20 minute after gadoxetate disodium injection) will be used to evaluate functioning liver volume. | 3 month after proton beam therapy |