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

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).

Study Overview

• Status: Unknown
• Conditions: Liver Neoplasm; Proton Therapy
• Intervention / Treatment: Radiation: Proton arm

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Recruiting
    • Samsung Medical Center
    • Sub-Investigator: Jeong Il Yu, MD
    • Contact: Joon Hyeok Lee, MD, PhD; Phone Number: 82-2-3410-3409; Email: gijhlee.lee@samsung.com
    • Contact: Hee Chul Park, MD, PhD; Phone Number: 82-2-3410-2612; Email: hee.ro.park@samsung.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Proton arm; Proton beam therapy	Radiation: Proton arm; Proton beam therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Joon Hyeok Lee, MD, PhD, Samsung Medical Center

Study record dates

Study Major Dates

• Study Start: December 1, 2015
• Primary Completion (Anticipated): October 1, 2019
• Study Completion (Anticipated): November 1, 2022

Study Registration Dates

• First Submitted: December 7, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimate): December 17, 2015

Study Record Updates

• Last Update Posted (Actual): April 12, 2018
• Last Update Submitted That Met QC Criteria: April 11, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms
• Other Study ID Numbers: 2015-08-004