RFA Versus SBRT for Recurrent Small HCC

Study Overview
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Brief Summary
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Recurrence rate of hepatocellular carcinoma (HCC)after resection is as high as 65.0%-83.7%.The recurrence of HCC is the most important factor affecting prognosis. Reasonable and effective treatment of recurrent lesion can significantly improve the long-term treatment efficacy of HCC. The recurrent lesion is usually detected when it's small and is the best indication for local treatment. Local ablation therapy represented by radiofrequency ablation (RFA) is one of the main treatments for recurrent small HCC. Our previous study showed that for recurrent small HCC(≤5cm), RFA has the efficacy equivalent to re-excision, with the advantages of small trauma, quick recovery, low cost, and high quality of life. With the advancement of radiotherapy equipment and the development of precise radiotherapy technology, stereotactic radiotherapy (SBRT) has become one of the routine treatments for HCC, especially for small HCC. Retrospective controlled studies have shown that SBRT is similar to RFA in treating small HCC, and the local control rate may be better than RFA. This project is to conduct a prospective, open, randomized, controlled clinical study of RFA versus SBRT for the treatment of recurrent small hepatocellular carcinoma (1-2 lesions, Sum of diameter≤ 5.0 cm). The primary end point is the 2-year local progression-free survival. As for secondary end points, we aim to compare 1-, 2-, 3- progression-free survival, overall survival rate, local control rate, and rate of complications. Stratified analysis will also be performed according to Sum of tumor diameter (≤2.0 cm; 2.1-5.0 cm). The results of these study will help to further improve the long-term treatment efficacy of HCC and establish a rational and effective treatment model for HCC.

Detailed Description
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Recurrence rate of hepatocellular carcinoma (HCC)after resection is as high as 65.0%-83.7%.The recurrence of HCC is the most important factor affecting prognosis. Reasonable and effective treatment of recurrent lesion can significantly improve the long-term treatment efficacy of HCC. Resection is the preferred treatment for recurrent HCC. Although liver surgery has been progressing in recent years, the alteration of anatomical structure after the first operation, the reduction of liver volume, and the mostly multi-centered origin recurrent lesions, lead to low surgical resection rate, difficult operation, high risk, multiple complications, and high recurrence rate of resection surgery. Salvage liver transplantation is difficult to apply widely due to donor shortages and other problems. Local ablation, represented by radiofrequency ablation (RFA), is the third major treatment for liver cancer after surgical resection and transcatheter arterial chemoembolization (TACE). Many studies， by us and domestic and foreign scholars， have shown that the long-term efficacy of RFA in the treatment of small HCC is close to that of surgical resection, with a 5-year survival rate of 50%-60%. Therefore，RFA has been recommended as a frontline treatment for small HCC by many international guidelines. The recurrent lesion is usually detected when it's small and is the best indication for RFA. Our previous study showed that for recurrent small HCC(≤5cm), RFA has the efficacy equivalent to re-excision, with the advantages of small trauma, quick recovery, low cost, and high quality of life. With the development of radiotherapy equipment and the precision imaging technology, especially the emergence of stereotactic radiotherapy (SBRT), the status of radiotherapy in the treatment of HCC is increasing. SBRT is defined as the use of external irradiation technology, which is divided into several fractions, and the high dose of radiotherapy is accurately delivered into the tumor. As a result, tumor is subjected to high dose and the normal tissue around the tumor is exposed to relatively low dose. Compared with conventional fractionated radiotherapy (CRT), SBRT possessed fewer segmentation times (1 to 6 F), higher fractional doses (5 to 20 Gy), and steeper gradients at the edge of the target region, so it has stronger biological effect. Meanwhile, SBRT can also protect the normal organs better, especially for the radiotherapy of smaller tumors. Multiple clinical studies and meta-analyses have shown that SBRT is superior to traditional CRT in the treatment of HCC, and the side effects are lower in the acute phase. SBRT has become a mainstream technology for HCC, and has been recommended as a routine local treatment for HCC by National Comprehensive Cancer Network (NCCN) guidelines and NCI radiotherapy guidelines. Both RFA and SBRT have been recommended by the NCCN guidelines as a routine local treatment for liver cancer. They are also widely used in the treatment of liver cancer, and their therapeutic efficacy and safety have been widely approved. However, which treatment of recurrent small HCC is superior is still unknown.This project is to conduct a prospective, open, randomized, controlled clinical study of RFA versus SBRT for the treatment of recurrent small HCC(1-2 lesions, Sum of diameter≤ 5.0 cm). The primary end point is the 2-year local progression-free survival. Secondary end points include 1-, 2-, 3- progression-free survival, overall survival rate, local control rate, and rate of complications.. Stratified analysis will also be performed according to Sum of tumor diameter (≤2.0 cm; 2.1-5.0 cm). The results of these study will help to further improve the long-term treatment efficacy of HCC and establish a rational and effective treatment model for HCC. Patients enrolled in this clinical trail received either SBRT or RFA depending on the randomization allocation. As for SBRT group, the treatment follows the protocol below.Immobilization: Patients are immobilized with vacuum bags or styrofoam in the supine position, with the arms raised above the head. 4 dimensional computed tomography (4DCT) scanning: Simple breathing training is conducted before simulation, so that the patient can keep breathing quietly and evenly. A plastic box with reflective marker is placed on the patient's anterior abdominal surface where the respiratory amplitude is relatively large, approximately midway between the xiphoid and the umbilicus. The movement of the marker is recorded by an infrared camera, which is converted into breathing curve by computer software. After the breathing curve becomes stable, the CT data of different respiratory phases is collected by 4DCT in axial cine mode. CT scanning region: From 3-4 cm above the diaphragm to the 4th lumbar vertebra. The intravenous contrast is administered during CT scanning and the slice thickness is 3.0 mm. After 4DCT scanning, images are sorted into 10 phases by the software. Each respiratory cycle is divided into 10 respiratory phases. Delineation of the target volumes and organs at risk: Gross tumor volume (GTV) and organs at risk (OARs) are contoured on the 20% CT image (mid-exhalation). Then the GTV is registered to the other respiratory phases of 4DCT scan by a physicist using Atlas-based Auto-segmentation (ABAS, Electa CMS), and the target volumes are modified and confirmed by a radiation oncologist using the standard window/level settings. GTV is defined as the intrahepatic lesion on images. Internal target volume (ITV) is defined as the combined volume of GTVs on 10 respiratory phases. Planning target volume (PTV) is generated by adding a 6-mm margin to the ITV. OARs include liver, kidney, stomach, small intestine, and spinal cord. Normal liver volume is defined as the entire liver minus GTV. Treatment planning: The plan of volumetric modulated arc therapy (VMAT) is designed on the 20% CT image using an optimization algorithm based on a combination of radiobiological and physical cost functions. Monte Carlo algorithm (MC) is performed in the optimization process and a single arc is conducted. Dosimetric evaluation: For PTV, 95% ≥95%, max < 110%, min >90%. For OARs, dose mean dose to normal liver (MDTNL) < 13 Gy, 15 Gy of liver < 35%; dose mean of kidneys <6 Gy, D0.5cc of esophagus < 21 Gy; D0.5cc of stomach < 21 Gy; D0.5cc of small intestine < 21 Gy; D0.5cc of colon < 24 Gy; D0.5cc of heart < 30 Gy; D0.5cc of ribs < 39 Gy; Dose max of spinal cord < 18 Gy. The planning is evaluated according to the dose volume histogram (DVH) and the dose distribution of each layer. As for RFA group, contrast-enhanced ultrasonography (CEUS) was carried out for all patients before treatment.RFA is carried out under intravenous anesthesia/epidural anesthesia/general anesthesia, with CT or B-ultrasound guidance, through percutaneous or laparoscopic means as far as possible. The ablation range requires complete coverage of the tumor, and has a certain safe margin. CT/MRI/sonography will be performed 1 month after RFA. If residual tumor was found after treatment, RFA will be carried out again. If there are still residual tumor after two or more RFA treatments, the RFA treatment will be determined to be a failure and stopped. After the local progression of the tumor, surgical treatment or other treatment methods are considered according to the specific condition. This study is expected to complete enrollment in 2 years and to follow up for 2 years. The primary analysis is performed in the intention-to-treat population. Kaplan-Meier curves will be used to describe the patient's local recurrence-free survival, and the corresponding statistical dates are calculated, such as median local progression-free survival (LPFS) and bilateral 95% confidential interval(CI). The secondary analysis used hypothesis test and two-sided 95% CIs to compare the time of first local recurrence. Kaplan-Meier curves will also be used to describe the patient's disease progression, and calculated the corresponding statistical data, such as the median overall survival(OS) and bilateral 95% CIs. Safety assessments will be also performed by comparing adverse events in the two groups of patients.

Official Title
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Radiofrequency Ablation (RFA) Versus Stereotactic Body Radiotherapy (SBRT) for the Treatment of Recurrent Small Hepatocellular Carcinoma: a Prospective, Open, Randomized, Controlled Clinical Study

Conditions
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Hepatocellular Carcinoma

Intervention / Treatment
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* Radiation: stereotactic body radiotherapy (SBRT)
* Procedure: Radiofrequency ablation (RFA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.Hepatocellular Carcinoma: Diagnostic criteria are based on the Diagnostic Criteria for Liver Cancer in the 2017 edition of Guidelines for the Diagnosis and Treatment of Primary Liver Cancer by National Health Commission of the People's Republic of China. 2.Recurrent small hepatocellular carcinoma: tumor recurred 3 months after surgical resection or local ablation,with1-2 recurrent lesions, sum of diameter≤5.0 cm, no distant metastasis or vascular invasion. 3.No RFA and SBRT treatment contraindications. 4.KPS≥90;liver function: Child-Pugh class A; normal liver volume is more than 800cm3. 5.The estimated survival time of the patient is more than 6 months. 6.The following conditions are met: Platelet≥50×109/L; White blood cell≥3.0×109/L; Hemoglobin≥80 g/L; Serum creatinine≤1.5 × upper limit; PT≤3 second extension. 7.Agree to accept the treatment and postoperative follow-up required by the design of this study. 8.Patients must have the ability to understand and voluntarily sign the informed consent, and must sign an informed consent before starting any specific procedure for the study. Exclusion Criteria: 1.In combined with extrahepatic metastasis or intrahepatic vascular invasion. 2.The number of recurrent lesions > 2, or sum of diameter > 5.0 cm. 3.In combined with severe heart, lung, kidney or other important organ dysfunction, or combined with serious infection or other serious associated diseases (> CTCAE Version 3.0 adverse events of grade 2), that can not tolerate treatment. 4.Patients have a history of other malignancies. 5.Patients have a history of allergic reactions to related drugs. 6.Patients have a history of organ transplantation. 7.Pregnant women, nursing mothers. 8.Patients cannot be performed RFA or SBRT treatment. 9.Patients have other factors that may affect patient enrollment and assessment results. 10. Those who receive other anti-tumor treatments (including immunotherapy or targeted therapy). 11.Refuse the follow-up regulations as required by this study protocol and refuse to sign informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stereotactic Body Radiotherapy (SBRT)<br>The planned target volume (PTV) was constructed by adding a 5-mm geometric uncertainty margin around the clinical target volume (CTV). The dose-volume constraints used during SBRT planning are fairly standardized: care was taken to ensure that at least 700 cm3 of normal liver parenchyma was exposed to <15 Gy over the course of SBRT, consistent with published recommendation. Radiotherapy dose was prescribed to the isodose surface covering 99.5% of the PTV, typically 75% to 85% of the maximum PTV dose, accepting regional underdosing when necessary to satisfy normal tissue limits. | Radiation: stereotactic body radiotherapy (SBRT)<br>* Radiotherapy dose is 33-54 Gy, irradiated in 3 times, every other day, completed within 1 week.<br>|
| Active Comparator: Radiofrequency Ablation (RFA)<br>Radiofrequency Ablation is carried out under intravenous anesthesia/epidural anesthesia/general anesthesia, with CT or B-ultrasound guidance, through percutaneous or laparoscopic means as far as possible. The ablation range requires complete coverage of the tumor, and has a certain safe margin. CT/MRI/sonography will be performed 1 month after RFA. If residual tumor was found after treatment, RFA will be carried out again. If there are still residual tumor after two or more RFA treatments, the RFA treatment will be stopped. After the local progression of the tumor, surgical treatment or other treatment methods are considered according to the specific condition. | Procedure: Radiofrequency ablation (RFA)<br>* RFA with a safe margin, RFA again if residual,no more than 2 times.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year local progression-free survival rate | After 2 years of follow-up, the percentage of the alive subjects with no signs of local tumor progression. Tumor progression was the end point of follow-up. For patients who suffer unexplained death or other anti-tumor treatment were found before tumor progression, the LPFS calculation is up to this point. Determination of tumor progression is based on imaging examination (CT or MRI), and the evaluation criteria refers to the modified Response Evaluation Criteria in Solid Tumors(mRECIST) criteria. | From the end of treatment to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1-, 2-, and 3-year progression-free survival rate | After 1, 2, and 3 years of follow-up, the percentage of the alive subjects with no signs of tumor progression. Tumor progression was the end point of follow-up. For patients who suffer unexplained death or other anti-tumor treatment were found before tumor progression, the PFS calculation is up to this point. Determination of tumor progression is based on imaging examination (CT or MRI), and the evaluation criteria refers to the mRECIST criteria. | From the end of treatment to 3 years | 
| 1-, 2-, and 3-year Overall survival | The percentage of subjects who are still alive at 1, 2, and 3 years of follow-up after treatment; death is the end point of observation. | From the end of treatment to 3 years | 
| 1-,2-,and 3-year Local control rate | the percentage of the alive subjects with no signs of local tumor progression at 1, 2, and 3 years follow-up after treatment. The local tumor progression is the end point of follow-up. Definition of local tumor progression is based on imaging examination (CT or MRI), and the evaluation criteria refers to the mRECIST criteria. | From the end of treatment to 3 years | 
| incidence of complications | The safety of the treatment was evaluated by the incidence of complications. Acute complications are defined as the occurrence of adverse events within 30 days of treatment; long-term complications are defined as the occurrence of adverse events 30 days after the end of treatment. | 30 days after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent small hepatocellular carcinoma, Radiofrequency Ablation, Stereotactic Body Radiotherapy