The Role and Safety of Radiofrequency Ablation in Recurrent Liver Metastasis of Colorectal Cancer

Not Applicable

Not yet recruiting

• Conditions: Colo-rectal Cancer; Liver Metastasis
• Interventions: Procedure: Radiofrequency ablation

• Registration Number: NCT06609434
• Lead Sponsor: Peking University Cancer Hospital & Institute

Brief Summary

The goal of this clinical trial is to learn if radiofrequency ablation works to treat recurrent colorectal cancer liver metastases after surgery in adults. It will also learn about the safety of radiofrequency ablation. The main questions it aims to answer are:

Is radiofrequency ablation safe and effective in the treatment of recurrent colorectal cancer liver metastases? What medical problems do participants have when treating with radiofrequency ablation? Does radiofrequency ablation enable patients with recurrent colorectal cancer liver metastases to live longer? Researchers will compare systemic therapy combined with radiofrequency ablation to systemic therapy to see if radiofrequency ablation works to treat liver metastases better.

Participants will:

Receive systemic treatment for colorectal cancer liver metastases. Undergo (or not) radiofrequency ablation for colorectal cancer liver metastases.

Visit the hospital once every 3 months for checkups and tests.

Detailed Description

1. Study purpose:

This study is for patients with intrahepatic multifocal recurrence after surgery for liver metastasis of colorectal cancer. Systemic therapy with/without radiofrequency ablation will be performed of intrahepatic lesions. The feasibility, efficacy and safety of the treatment strategy will be evaluated and analyzed through follow-up, which will provide a new treatment mode and a basis for clinical decision-making for patients with multiple lesions of progressive colorectal cancer.

2. Study design:

A single-center, prospective, non-randomized controlled study was conducted to investigate the clinical efficacy of ultrasound-guided percutaneous radiofrequency ablation for the treatment of cases of multifocal recurrence after surgery for liver metastases from colorectal cancer, which was divided into the group of systemic therapy combined with radiofrequency therapy and the group of systemic therapy alone. The final treatment plan of the patients was decided by the discussion of multidisciplinary consultation. Patients signed informed consent and completed all screening tests, and those who were qualified enrolled into the study. Patients enrolled were followed up and analyzed for liver progression-free survival, overall survival, complications, and were compared with the control group. The prognostic factors of radiofrequency combined systemic therapy in patients were analyzed, and a prognostic model was established.

3. Study content:

3.1 Multimodal ultrasonographic features of intrahepatic recurrent lesions after surgery for colorectal cancer liver metastases: With reference to enhanced CT or MRI, ultrasonographic examinations of intrahepatic lesions were performed to determine the number, size, location, and adjacent vital structures of the lesions, analyze the blood perfusion characteristics, extent of infiltration, and biologic behaviors, and preliminarily formulate treatment strategies. Based on the imaging patterns and with reference to other clinical imaging information, the first batch of intrahepatic lesions that were suitable (e.g., large size, adjacent to important structures, high activity, etc.) were selected for radiofrequency treatment.

3.2 Exploration of radiofrequency ablation strategy based on molecular features of colorectal cancer: According to the gene expression features (KRAS, BRAF, MSI, etc.) of previous clinical test results to decide corresponding radiofrequency ablation treatment plans. In mutant cases, the safe ablation range of radiofrequency ablation is appropriately extended to minimize local recurrence.

3.3 The efficacy of ultrasound-guided radiofrequency ablation combined with systemic therapy: For patients with multiple intrahepatic metastatic lesions, who are not suitable for or refuse to undergo surgical re-resection, explore the feasibility of a modality treatment of radiofrequency batch therapy combined with systemic therapy. First, 2-4 cycles of systemic therapy should be performed, and the response to treatment should be evaluated by enhanced CT/MRI combined with multimodal ultrasonography, and radiofrequency ablation should be performed for patients who have effective systemic therapy (partial response+ stable disease). Before radiofrequency ablation treatment, relevant hematological tests, such as blood routine, biochemistry, coagulation function, etc., were performed to ensure that the enrollment criteria were met. For patients who do not meet the enrollment criteria, radiofrequency ablation treatment will be postponed and clinical treatment will be performed until the enrollment criteria are met, and those patients who cannot meet the enrollment criteria will be withdrawn from the study. The 2-6 intrahepatic lesions for the first radiofrequency ablation were confirmed according to the ultrasound model and other clinical factors. After radiofrequency treatment, 1-2 cycles of systemic treatment were carried out, and after effective evaluation, radiofrequency ablation was performed again for 2-6 foci (the selection criteria were the same as the above), and so on, with a maximum of 3 times of ablations, to ablate all the visible foci as far as possible, and to achieve a basically no evidence of disease in the liver. Systemic therapy was separated from radiofrequency ablation therapy by 1 week to minimize the impact of treatment side effects. The control group was patients treated with systemic therapy alone, without localized treatment.

3.4 Safety of radiofrequency ablation combined with systemic therapy: Due to the large number of lesions treated with radiofrequency, the occurrence of post-radiofrequency complications is closely monitored, as well as the effect on the patient's hepatic and renal function after radiofrequency ablation. As radiofrequency ablation may reduce the times of systemic therapy, it may reduce the toxic side effects of systemic therapy. Patients in both groups were tested regularly, asked about their condition, underwent physical examination, recorded vital signs and laboratory indicators, electrocardiograms, adverse events such as drug side effects and complications of radiofrequency therapy.

3.5 Analysis of prognostic factors and exploration of prognostic model: To explore the relationship between the treatment outcome of the patients in this study and the characteristics of the primary lesions, RAS/RAF wild/mutant type, with/without extrahepatic metastasis, characteristics of the intrahepatic resected lesions, characteristics of the postoperative recurrent lesions, such as the number, size, time to recurrence, ultrasonographic pattern, response to systemic therapy, genetic status, and whether or not all intrahepatic lesions were able to achieve A0 ablation. Clinical and genetic characteristics as well as ultrasonographic information were applied to develop a preliminary prediction model for liver progression-free survival.

4. Follow-up:

Enhanced CT/MRI will be performed 1 month after radiofrequency ablation treatment to evaluate the effectiveness of the technique. Ultrasound/contrast-enhanced ultrasound imaging, enhanced CT/MRI, laboratory tests (hematology, blood biochemistry, tumor markers, etc.), electrocardiogram will be performed every 3 months within 2 years after treatment. Ultrasound/contrast-enhanced ultrasound imaging, laboratory tests, electrocardiogram will be performed every 3 months and enhanced CT/MRI every 6 months after 2 years of treatment.

5. Safety evaluation:

Ask about the condition of the patient, conduct a physical examination, record vital signs and laboratory indicators (hematology, blood biochemistry, etc.), electrocardiography, drug side effects and radiofrequency treatment complications and other adverse events. Side effects include gastrointestinal reactions (diarrhea, nausea, vomiting, mucositis, etc.), hematologic reactions (neutropenia, thrombocytopenia, decreased hemoglobin, etc.), hepatic and renal injuries, skin rashes, and neurological toxicity (according to the specifications of the respective drugs). Classification and grading of complications after radiofrequency treatment: they can be categorized into mild and severe complications.

1. Minor complication. Grade A: No need for treatment, no adverse effects; Grade B: Minor treatment with no adverse effects, including 1 night of observation.

2. Major complication. Grade C: requires treatment, prolonged hospitalization\<48h; Grade D: Requires extensive treatment, increased level of care, prolonged hospitalization \>48h; Grade E: long-lasting sequelae; Grade F: death.

6. Statistical Analysis Plan： 6.1 Basis of sample size calculation: According to the results of the previous retrospective study in our center and the reported results of related retrospective studies, for multiple intrahepatic metastatic lesions of colorectal cancer, the 2-year intrahepatic progression-free survival rate of systemic chemotherapy combined with radiofrequency ablation was 20.3%, while the 2-year intrahepatic progression-free survival rate of receiving systemic chemotherapy alone was 1.6%, when the certainty power was 0.9, α=0.05 (bilaterally), and considering that during the course of the trial, the loss-to-follow-up rate was approximately 30% in both groups, and the proportion of those who switched from receiving chemotherapy alone to receiving chemotherapy combined with radiofrequency ablation was approximately 40%, it was presupposed that all the trial cases would be collected within 1 year, with a follow-up of 2 years, for a total of 3 years for the entire trial, and the required sample size was calculated to be 111 (55 in the control group and 56 in the experimental group).

6.2 Statistical analysis methods: Statistical analyses of all patients' clinical data were processed and analyzed using R software (4.0.3, Vienna, Austria), GraphPad Prism 8 software (GraphPad Software, San Deigo, USA) and SPSS 24.0 software (SPSS, Chicago, IL, USA). Categorical information was described by rates and component ratios, and the chi-square test was applied to compare between groups; normally distributed quantitative variables were expressed as mean ± standard deviation, and they were compared between groups using t-test or U-test; LPFS was assessed using the Kaplan-Meier method, and differences between groups were tested using the log-rank test. Cox proportional risk model was applied to explore the independent risk factors affecting patients' LPFS, and the clinical prediction model and clinical combined imaging prediction model were established accordingly. The Bootstrap method was used for internal validation of the samples with 2000 iterations of repeated sampling, the C-index and calibration curves were used to assess the predictive ability of the column line graph, and the decision curves were used to evaluate the clinical application value of the model. AUCs were determined using the subject's work characteristic curve (ROC curve). Diagnostic sensitivity, specificity and accuracy were compared using the McNemar test. P\<0.05 was defined as statistically significant.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-21
• Study First Submitted QC: 2024-09-22
• Last Update Submitted: 2024-09-22
• Study First Posted: 2024-09-24
• Last Update Posted: 2024-09-24
• Study Start: 2024-10
• Primary Completion: 2026-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 111

Inclusion Criteria

1. Patients with colorectal cancer whose primary lesions have been resected or can be controlled;
2. Multiple confined lesions in the liver, the number of which can be defined;
3. The liver contains at least 2 lesions suitable for radiofrequency ablation;
4. The maximum diameter of the intrahepatic tumor is <5 cm;
5. The location of the hepatic lesion does not show obvious invasion with neighboring organs or large blood vessels;
6. No extrahepatic metastases or stable extrahepatic metastases;
7. Re-operative hepatic surgical resection is not indicated or refused;
8. Ultrasound or ultrasonography can show intrahepatic lesions;
9. The patient and his/her family request active treatment;
10. Voluntary informed consent;
11. Male or female at least 18 years of age;
12. Platelet count >50, 000/mm3 and prothrombin activity >50%;
13. Subjects are willing to return to the study center for study follow-up;
14. Life expectancy ≥ 6 months.

Exclusion Criteria

1. Suffering from, but not limited to, the following serious illnesses: congestive heart failure, myocardial infarction or cerebrovascular accident, or life-threatening cardiac arrhythmia within the last 6 months;
2. Pregnancy or lactation. Women of childbearing potential must have a negative serum pregnancy test prior to receiving study treatment;
3. Known hypersensitivity to any of the intravenous imaging agents that will be used in the study;
4. Have portal or hepatic vein tumor infiltration/cancer embolism;
5. Prothrombinogen international normalized ratio >1.5 times the upper limit of normal (UNL) at the study center;
6. Platelet count <50, 000/mm3, absolute neutrophil count <1500/mm3, or hemoglobin value <10.0 g/dL;
7. Serum creatinine ≥ 2.5 mg/dL or calculated creatinine clearance (CrCl) ≤ 25.0 ml/min;
8. Serum bilirubin >3.0 mg/dL;
9. Serum albumin <2.8 g/dL;
10. Body temperature >101°F (38.3°C) immediately prior to study treatment;
11. Being treated with other investigational drugs;
12. Heart failure NYHA functional class III or IV.
13. Any other circumstances that the investigator deems inappropriate for enrollment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
systemic therapy combined with radiofrequency ablation	Radiofrequency ablation	This arm includes patients with intrahepatic recurrence of colorectal cancer liver metastases who underwent systemic therapy combined with radiofrequency ablation.

Primary Outcome Measures

Name	Time	Method
liver progression-free survival	2 years	Time from initial treatment to intrahepatic disease progression or patient death

Secondary Outcome Measures

Name	Time	Method
overall survival	2 years	Time from initial treatment to patient death