Clinical trial NCT04047173: RFA Versus SBRT for Recurrent Small HCC
Official title: Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Recurrent Small Hepatocellular Carcinoma: a Randomized, Open-label, Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Keywords: recurrent small hepatocellular carcinoma
Radiofrequency Ablation
Stereotactic Body Radiotherapy
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2019-08-06
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 (single lesion ≤ 5 cm, without extra-hepatic metastasis or vascular invasion). The primary endpoint is local progression-free survival (LPFS), and secondary endpoints are progression-free survival (PFS), overall survival (OS), local control rate (LCR), and safety. Data analysis will be performed according to intention-to-treat (ITT) principles. Subgroup analyses will be conducted according to the predefined stratification factor (tumor diameter ≤ 2 cm vs. 2-5 cm) and other baseline characteristics. 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: 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 (single lesion ≤ 5 cm, without extra-hepatic metastasis or vascular invasion). The primary endpoint is local progression-free survival (LPFS), and secondary endpoints are progression-free survival (PFS), overall survival (OS), local control rate (LCR), and safety. Data analysis will be performed according to intention-to-treat (ITT) principles. Subgroup analyses will be conducted according to the predefined stratification factor (tumor diameter ≤ 2 cm vs. 2-5 cm) and other baseline characteristics. 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. Eligible subjects are stratified by maximum tumor diameter (≤ 2 cm vs. 2-5 cm) and randomly assigned in a 1:1 ratio to receive either SBRT or RFA using a computer-generated random assignment system.

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 5-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. Dose constraints to OARs were as follows: mean dose of normal liver \< 10 Gy, V15Gy (percentage of the normal liver volume receiving ≥ 15 Gy) \< 35%; kidneys Dmean \< 6 Gy; esophagus D0.5cc \< 21 Gy; stomach D0.5cc \< 21 Gy; small intestine D0.5cc \< 21 Gy; colon D0.5cc \< 24 Gy; heart D0.5cc \< 30 Gy; ribs D0.5cc \< 39 Gy; and spinal cord Dmax \< 18 Gy. SBRT is planned using volumetric arc therapy techniques with a prescription dose of 36-54 Gy in 3 fractions, irradiated every other day, and completed within one week. Cone-beam CT is performed before each treatment.

As for RFA group, RFA is performed under intravenous, epidural, or general anesthesia guided by computed tomography (CT) or ultrasound, preferably through a percutaneous or laparoscopic approach. The ablation electrode is precisely inserted into the center of the tumor and ablated at 30-50W power for 5-10 minutes depending on the size and shape of the tumor. Adequate coverage of the tumor lesion with a defined "safety margin" is ensured during ablation. After the completion of tumor ablation, the instrument will remaine active as the electrode is retracted, facilitating needle tract ablation. Contrast-enhanced CT, MRI, and ultrasonography will be performed one month after RFA to detect residual disease. Patients with confirmed complete ablation will undergo periodic follow-up, whereas those with residual tumors undergo repeat RFA procedures. Persistent tumor residue after two consecutive RFA sessions is deemed a treatment failure, and RFA treatment will be discontinued.

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. Logistic regression was used to calculate the odds ratios (OR) for LCR. Subgroup analyses were conducted according to the predefined stratification factor (tumor diameter ≤ 2 cm vs. 2-5 cm) and other baseline characteristics. Safety assessments will be also performed by comparing adverse events in the two groups of patients.

Eligibility criteria: Inclusion criteria

1. Aged 18-75 years;
2. Diagnosed with HCC: The diagnosis of HCC will be confirmed according to the " Chinese Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition) " formulated by the National Health Commission of China and the Barcelona Clinic Liver Cancer (BCLC) strategy for prognosis prediction and treatment recommendation of the European Association for the Study of the Liver (EASL);
3. Recurrent small HCC: Single hepatocellular carcinoma ≤ 5 cm that recurs after previous curative resection or thermal ablation, with the recurrence time ≥ 3 months from resection/ablation, and without extrahepatic metastasis or vascular invasion at recurrence;
4. No contraindications for RFA and SBRT treatment;
5. Karnofsky performance score (KPS) ≥ 90;
6. Liver function Child-Pugh class A;
7. Normal liver volume greater than 800 cm3;
8. Expected survival time longer than 6 months;
9. The function of important organs meets the following requirements: a. white blood cell ≥ 3×109/L; b. hemoglobin ≥ 80 g/L; c. platelets ≥ 50×109/L; d. blood creatinine ≤ 1.5 times the upper limit; e. prothrombin time (PT) ≤ 3 seconds above control;
10. Subject has signed the informed consent form and agreed to the treatment and follow-up schedules according to this protocol;
11. Subject must have the ability to understand and voluntarily sign the written informed consent form prior to starting any specific procedure in the study.

Exclusion criteria

1. Presence of extrahepatic metastasis or intrahepatic vascular invasion;
2. More than one recurrent lesion, or maximum diameter \> 5 cm;
3. Concomitant severe cardiac, pulmonary, renal, or other major organ dysfunction, severe infection or other comorbidities, unable to tolerate treatment;
4. History of other malignancies;
5. History of allergic reactions to relevant drugs;
6. History of organ transplantation;
7. During pregnancy or lactation;
8. Unable to undergo one of the treatments (RFA or SBRT);
9. Concomitantly receiving other anti-tumor therapy (including immunotherapy and targeted therapy);
10. Other factors that may affect patient enrollment and evaluation results;
11. Refusal to comply with the study protocol requirements for follow-up and refusal to sign the informed consent form.

Primary outcomes:
measure: Local progression-free survival (LPFS)
timeFrame: From date of randomization until the date of first documented local tumor progression or date of death from any cause, whichever came first, assessed up to 2 years.
Secondary outcomes:
measure: Progression-free survival (PFS)
timeFrame: From date of randomization until the date of first documented tumor progression or date of death from any cause, whichever came first, assessed up to 2 years.
measure: Overall survival (OS)
timeFrame: From date of randomization until the date of death from any cause, assessed up to 2 years.
measure: 1-,2-,and 3-year local control rate (LCR)
timeFrame: 1, 2, or 3 years after treatment completion.
measure: Safety and adverse events
timeFrame: Acute complications are defined as adverse events occurring within 90 days after treatment; late complications are defined as adverse events occurring after 90 days of treatment completion.
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: Sun Yat-sen University Cancer Center
state: Guangdong
Study officials:
affiliation: Sun Yat-sen University
name: Zhang Yao-Jun, MD.
role: STUDY_CHAIR
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