Stereotactic Body Radiotherapy for Unresectable Hepatocellular Carcinoma (SBRT for HCC)

Effectiveness and Safety of the Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma: Prospective Phase II Trial

1. Background 1.1. Hepatocellular carcinoma (HCC) HCC is the third most common cause of cancer death globally. It is also the second cause of cancer mortality in Korea, despite the incidence of HCC was fifth. The most important cause of this discrepancy is connected with the fact that the significant portion of the HCC is detected as unresectable status.

1.2. Standard treatment of the HCC At the point of HCC diagnosis, only 30% of the patients could receive standard curative treatment, like resection, liver transplantation, and radiofrequency ablation (RFA). Transcatheter arterial chemoembolization (TACE) has been shown in randomized trials to improve survival compared with symptomatic therapy alone, in the patients without macrovascular involvement, extrahepatic disease and tumor related symptoms. However, in the recent review of TACE, TACE might be contraindicate or not recommended in the patients who showed vascular tumor invasion, more than 10 cm size, poor portal blood flow and/or repeated poor response.

Recently, Sorafenib, which is one of the target agents, showed survival advantage on unresectable HCC patients in two randomized study. In those study, sorafenib improved approximately three month overall survival increment, however, the median survival duration was only 10.7 months in experiment group (received sorafenib), and even 6.5 months in Asian-Pacific trial. Additionally, the possibility that sorafenib effect could be reduced in the patients had hepatitis B virus (HBV) was suggested in the subgroup analysis.

1.3 Radiation therapy (RT) for the HCC The use of RT in HCC is increased with the radiation technological advances. In the unresectable patients, RT showed 50 to 60% response rate with the dose response relationship. Recently, stereotactic body radiation therapy (SBRT) showed excellent local control and comparable survival rate in thoracic tumor. In the HCC, SBRT also showed 75 to 100% local control rate without significant elevation of the toxicities. One study reported that 24 to 54 Gy SBRT achieved 87% 1year local control and 17 months overall survival. The standard treatment of unresectable HCC is sorafenib, but Korean Liver Cancer Study Group (KLCSG) recommend RT as an option in localized unresectable HCC. Furthermore, Radiation Therapy Oncology Group (RTOG) started randomized trial to confirm the effect of SBRT in unresectable HCC (RTOG 1112).

Investigators previously reported the retrospective result that the higher dose SBRT achieved 2 year overall survival 87.9% and local control 85% in the patient who showed less than 5 cm solitary HCC without portal vein involvement.

Based on those studies, we start this prospective study to evaluate the effectiveness and adverse event of SBRT in the patients who had solitary 3 cm or less size HCC without extrahepatic lesion and vascular involvement.

Study Overview

• Status: Completed
• Conditions: Localized Non-Resectable Adult Hepatocellular Carcinoma
• Intervention / Treatment: Radiation: Stereotactic body radiotherapy

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 135-710
    • Samsung Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients must have a diagnosis of HCC by at least one criterion listed below (KLCSG guideline 2009) 1.1 Pathologically (histologically or cytologically) proven diagnosis of HCC 1.2 Liver nodule in high risk group 1.2.1 If alpha feto protein (AFP)≥200 ng/mL , ≥ 1 typical HCC enhancing pattern on dynamic contrast enhanced CT or MRI 1.2.2 If AFP<200 ng/mL, ≥2 typical HCC enhancing pattern on dynamic contrast enhanced CT, MRI, and angiography 1.3 ≥ 2 cm nodule in liver cirrhosis (LC), ≥ 1 typical HCC enhancing pattern on dynamic contrast enhanced CT or MRI
2. Eastern cooperative oncology group performance status 0 or 1
3. Size of the HCC ≤ 3 cm or less
4. Age ≥ 20
5. Unsuitable for resection or transplant or RFA
6. Unsuitable for or refractory to TACE or drug eluting beads (DEB)
7. Agreement of study-specific informed consent
8. Assessment by radiation oncologist and medical oncologist or hepatologist within 28 days prior to study entry?
9. Child-Pugh score A within 14 days prior to study entry
10. normal liver (Liver minus gross tumor volume) ≥ 700 cc
11. Target is only one viable hepatocellular carcinoma

12. Blood work requirements

    • Absolute neutrophil count (ANC) ≥ 1,500 /mm3, Platelet ≥ 70,000/mm3, Hgb ≥ 8 g/dl
    • Liver function test (LFT): T. bilirubin<3.0 mg/dL, International normalized ratio (INR) < 1.7, Albumin ≥ 2.8g/dL, Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT)< 6 X normal
    • Serum creatinine < 1.5 X normal, or Creatinine clearance rate ≥ 60 mL/min
13. Male, consent contraception at least 6 months Childbearing potential woman, consent contraception at least 6 months
14. Life expectancy more than 12 weeks
15. Stable breathing more than 10 minutes
16. Consent to fiducial marker insertion ( if needed )

Exclusion Criteria:

1. Extrahepatic metastasis or malignant nodes
2. Pregnant and/or breastfeeding woman
3. Macroscopic vascular tumor involvement
4. Previous upper abdominal RT history
5. Uncontrolled active co-morbidity

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: Stereotactic body radiotherapy; Stereotactic body radiotherapy 60 Gy/3 fraction standard dose The highest allowable dose with maintain normal tissue constraints

Radiation: Stereotactic body radiotherapy; Respiration training will be done on the day that patient decided participate this study with wearing video goggle and headphone assisted respiration by visual and voice. Four dimensional CT simulation with wearing video goggle and headphone assisted respiration by visual and voice and real time position management system (PRM) signal will be adopted. Planning MRI with diffusion image also be acquired in same condition with CT simulation. SBRT will be delivered daily 20 Gy for 3 fractions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the SBRT effect on local progression free survival rate	Radiologic response will be evaluated at 1, 3 month after SBRT, and then every 3 month imaging follow up will be continued. Local progression will be defined by modified Modified response evaluation criteria for solid tumor (mRECIST). Local progression was defined as 20% or more size increase of contrast enhanced primary lesion or new contrast enhanced lesion in planning target volume.	Radiologic response will be evaluated at 3 month.
To evaluate the SBRT effect on adverse events	Adverse events will be evaluated at 1 and 3 month after SBRT, and then every 3 month follow up will be continued.. Adverse event will be evaluated with common terminology criteria for adverse events (CTCAE version 4.0) during follow up.	Adverse events will be evaluated at 3 month after SBRT.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the SBRT objective response rate		Response will be evaluated at 3 month
To measure the time to local tumor progression	Response will be evaluated at 3 month after SBRT, then every 3 month follow up with imaging will be continued. mRECIST will be used to define local tumor progression.	Response will be evaluated at 3 month after SBRT.
To measure the overall survival	Survival will be evaluated at 3 month after SBRT, then every 3 month follow up will be continued. Overall survival will be measured from the data of SBRT start to the date of death or to the date of last follow up visit.	Survival will be evaluated at 3 month after SBRT.
To measure the progression free survival	Response will be evaluated at 3 month after SBRT, then every 3 month follow up with imaging will be continued. mRECIST will be used to define response. Progression free survival will be measured from the date of SBRT to the date of progression recognition or to the date of lat follow up visit.	Response will be evaluated at 3 month after SBRT.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life(QOL)change before and after RT	To measure the quality of life(QOL) before and after RT, European Organization for Research and Treatment of Cancer (EORTC) core Quality of Life Questionnaire (QLQ)-C30, Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) will be used. Before simulation of RT, baseline QOL assessment will be obtained, then QOL will be assessed at 1, 3, 6 months after RT, before physician interview.	QoL will be assessed before, and 1, 3, 6 months after SBRT.
RT response prediction probability evaluation by diffusion-weighted (DW) MRI and positron emission tomography		At 1 month after RT

Collaborators and Investigators

• Sponsor: Samsung Medical Center
• Investigators: Principal Investigator: Hee Chul Park, M.D., Ph.D., Samsung Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2013
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: July 17, 2013
• First Submitted That Met QC Criteria: July 25, 2013
• First Posted (Estimated): July 30, 2013

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Hepatocellular carcinoma; unresectable; small size; Stereotactic body radiotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 2013-06-005-001