Stereotactic Body Radiotherapy for Unresectable Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Localized Non-Resectable Adult Hepatocellular Carcinoma

Intervention / Treatment
-----------------
* Radiation: Stereotactic body radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Eastern cooperative oncology group performance status 0 or 1 Size of the HCC ≤ 3 cm or less Age ≥ 20 Unsuitable for resection or transplant or RFA Unsuitable for or refractory to TACE or drug eluting beads (DEB) Agreement of study-specific informed consent Assessment by radiation oncologist and medical oncologist or hepatologist within 28 days prior to study entry? Child-Pugh score A within 14 days prior to study entry normal liver (Liver minus gross tumor volume) ≥ 700 cc Target is only one viable hepatocellular carcinoma 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 Male, consent contraception at least 6 months Childbearing potential woman, consent contraception at least 6 months Life expectancy more than 12 weeks Stable breathing more than 10 minutes Consent to fiducial marker insertion ( if needed ) Exclusion Criteria: Extrahepatic metastasis or malignant nodes Pregnant and/or breastfeeding woman Macroscopic vascular tumor involvement Previous upper abdominal RT history Uncontrolled active co-morbidity

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stereotactic body radiotherapy<br>Stereotactic body radiotherapy 60 Gy/3 fraction standard dose The highest allowable dose with maintain normal tissue constraints | Radiation: Stereotactic body radiotherapy<br>* 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.<br>|

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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
unresectable, Hepatocellular carcinoma, small size, Stereotactic body radiotherapy