Proton Radiotherapy Versus Radiofrequency Ablation for Patients With Medium or Large Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan, where chronic viral hepatitis is common. Patients with HCC typically have impaired liver function because of virus- or alcohol- induced cirrhosis and viral hepatitis, and only approximately 20% of them are appropriate candidates for surgery. The 5-year overall survival for patients treated by surgery is approximately 30%-70%. For those not treated with surgery, liver function affected by an underlying liver disease has a strong influence on clinical outcomes, and complicates treatment strategies further than for other tumors. Maximal preservation of normal liver volume and function is an important consideration in the choice of treatment. Proton beam has been applied to HCC treatment in Japan for longer than a decade, and several retrospective results showed excellent 3-5 years local control rate ranging from 85-95% and nearly no major complications. The investigators also retrospectively reviewed 75 index tumors sized 3.1-7.0cm in 70 patients receiving multiple-electrode radiofrequency ablation with switching controller (ME-SWC RFA) treatments in the period between 1 January 2009 and 31 December 2011 (Oral report in Taiwan Digestive Disease Week, October, 2012). Estimated 1-, 2-, and 3-year cumulative overall survival rates and local control rates were 94%, 85%, 81% and 89%, 83%, 67%, respectively. Since ME-SWC RFA is the present one of standard modalities for non-surgery, moderate to larger (3-7 cm) HCC, and based on retrospective studies the local control rate of proton therapy was better than radiofrequency ablation, this prospective trial is aimed to compare the effects of these two modalities in 3-7 cm HCC patients who are not candidates for surgery or refuse surgery. This prospective study has high possibility to confirm the role of proton beam in HCC. Along with the clinical trial, the investigators will also use next generation sequencing (NGS) to exam gene expression profile of tumor samples and find out candidate genes related to local control, intrahepatic control (treatment out-field control in liver), regional lymph node relapse, distant metastasis, and treatment response in HCC.

Official Title
-----------------
Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≦5 cm) or Large (>5, ≦7cm) Treatment-naive Hepatocellular Carcinoma

Conditions
-----------------
Carcinoma, Hepatocellular

Intervention / Treatment
-----------------
* Radiation: Proton radiotherapy
* Procedure: Radiofrequency Ablation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed hepatocellular carcinoma or lesion with typical triphasic CT or MRI imaging features for HCC Single tumor and tumor size > 3cm, ≦7cm in diameter Patients are unsuitable for resection or unwilling to accept surgery. Age ≥20 years old Eastern Cooperative Oncology Group performance status score of 0 or 1 Child-Pugh score ≦ 8 Willing to sign informed consent regarding participation in this study Exclusion Criteria: Patients have received any treatment for HCC before this study Pregnancy/breast feeding women Tumor adjacent to bowel <1cm Extrahepatic metastasis Extrahepatic invasion Portal or hepatic vein tumor invasion/thrombosis Uncontrolled ascites Glomerular filtration rate (GFR) < 30 ml/min* Platelet count < 50,000/L* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 5 years Ongoing medically significant active infection. MRI incompatible devices * Baseline laboratories results must be within the protocol range prior to sign informed consent. Repeat lab tests are permitted to evaluate eligibility during the Screening Period.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 85 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proton radiotherapy<br>Proton radiotherapy will be totally 66 cobalt gray equivalent (CGE) in 10 fractions and delivered once daily, 5 fractions per week, over 2 weeks for HCC more than 1 cm away from the alimentary tract. | Radiation: Proton radiotherapy<br> <br> |
| Experimental: Radiofrequency Ablation<br>Multiple-electrode radiofrequency with switch-controller system (ME-SWC RFA) can create a large coagulation necrosis volume and successful treat HCC sized more than 3 cm, extending to 8.5 cm. ME-SWC RFA system uses up to 3 electrodes parallel insertion to inside of the tumors with an equilateral triangular confirmation before initiation of ablation. The distances between electrodes are about 1.5-2 cm, estimated by ultrasound measuring. The switching machine is set on the auto-mode, and all electrodes work alternately and switching each other automatically after impendence surge. | Procedure: Radiofrequency Ablation<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local control rate (treatment in-field control rate) |  | 3-year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate |  | 3-year | 
| Intrahepatic control rate |  | 3-year | 
| Distant metastasis free survival rate |  | 3-year | 
| Local control rate (treatment in-field control rate) |  | 5-year | 
| Overall survival rate |  | 5-year | 
| Intrahepatic control rate |  | 5-year | 
| Distant metastasis free survival rate |  | 5-year | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |  | 3-year | 
| Patient report outcome - quality of life as assessed by the functional assessment of cancer therapy - hepatobiliary (FACT-Hep) | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 
| Patient report outcome - fatigue as assessed by the functional assessment of cancer therapy (FACT-F) | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 
| Patient report outcome - pain as assessed by the brief pain inventory-short form (BPI-SF) | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 
| Patient report outcome - symptom distress as assessed by the Memorial symptom assessment scale-short form (MSAS-SF) | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 
| Patient report outcome - treatment satisfaction as assessed by the functional assessment of chronic illness therapy-treatment satisfaction-general (FACIT-TS-G) | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 
| Patient report outcome - quality of life as assessed by the EQ-5D-3L | The data will be collected 17 times from enrollment to the 36th month after treatment. Specific measurement points are: baseline, day 3, day 7, day 14, month 1, month 3, then every 3 months to the 36th month after treatment. | 3-year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatocellular carcinoma, Proton therapy, Radiation therapy, Switching control radiofrequency ablation