RFA Versus SBRT for Recurrent Small HCC

  • STATUS
    Recruiting
  • End date
    Aug 1, 2023
  • participants needed
    166
  • sponsor
    Sun Yat-sen University
Updated on 27 January 2021

Summary

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.

Description

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%. ThereforeRFA 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.

Details
Condition Adenocarcinoma, Malignant Adenoma, Adenocarcinoma, HEPATIC NEOPLASM, Liver Cancer, HEPATOCELLULAR CARCINOMA, Liver Cancer, Malignant Adenoma, liver cell carcinoma
Treatment radiofrequency ablation (RFA), Stereotactic Body Radiotherapy (SBRT)
Clinical Study IdentifierNCT04047173
SponsorSun Yat-sen University
Last Modified on27 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Recurrent small hepatocellular carcinoma: tumor recurred 3 months after
surgical resection or local ablation,with1-2 recurrent lesions, sum of
diameter5.0 cm, no distant metastasis or vascular invasion
No RFA and SBRT treatment contraindications
KPS90;liver function: Child-Pugh class A; normal liver volume is more than
cm3
The estimated survival time of the patient is more than 6 months
The following conditions are met: Platelet50109/L; White blood cell3.0109/L
Hemoglobin80 g/L; Serum creatinine1.5 upper limit; PT3 second extension
Agree to accept the treatment and postoperative follow-up required by the
design of this study
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

In combined with extrahepatic metastasis or intrahepatic vascular invasion
The number of recurrent lesions > 2, or sum of diameter > 5.0 cm
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
Patients have a history of other malignancies
Patients have a history of allergic reactions to related drugs
Patients have a history of organ transplantation
Pregnant women, nursing mothers
Patients cannot be performed RFA or SBRT treatment
Patients have other factors that may affect patient enrollment and
assessment results
\. Those who receive other anti-tumor treatments (including immunotherapy or
targeted therapy)
Refuse the follow-up regulations as required by this study protocol and
refuse to sign informed consent
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