Radiofrequency Ablation of Liver Tumors

Abstract

Radiofrequency ablation (RFA) is an alternative therapy for hepatocellular carcinoma and liver metastases when resection cannot be performed or, in the case of hepatocellular carcinoma, when transplant cannot be performed in a timely enough manner to avoid the risk of dropping off the transplant list. RFA has the advantage of being a relatively low-risk minimally invasive procedure used in the treatment of focal liver tumors. This review article discusses the current evidence supporting RFA of liver tumors, as well as the indications, complications, and follow-up algorithms used after RFA.

Objectives: Upon completion of this article, the reader will be able to explain the role of radiofrequency ablation in the treatment of primary and secondary tumors of the liver.

Accreditation: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Tufts University School of Medicine (TUSM) and Thieme Medical Publishers, New York. TUSM is accredited by the ACCME to provide continuing medical education for physicians.

Credit: Tufts University School of Medicine designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Radiofrequency ablation (RFA) is an alternative therapy for hepatocellular carcinoma (HCC) and liver metastases when resection cannot be performed or, in the case of HCC, when transplant cannot be performed in a timely enough manner to avoid the risk of dropping off the transplant list. RFA has the advantage of being a relatively low-risk minimally invasive procedure for the treatment of focal liver tumors. In this review article we discuss the science, complications, and imaging follow-up after RFA, as well as its indications.

Technique

The goal of RFA is to completely destroy a tumor without damaging the surrounding liver tissue by inducing thermal injury to the tissue through electromagnetic energy deposition. In the most common configuration of clinical RFA, monopolar RFA, the patient is a part of a closed-loop circuit that includes an RF generator, a needle electrode, and a large dispersive electrode (grounding pads).¹ This creates an alternating electric field within the tissue that causes agitation of the ions present in the target tissue that surrounds the electrode, resulting in frictional heat around the electrode.² The discrepancy between the small surface area of the needle electrode and the large area of the grounding pads causes the generated heat to be focused and concentrated around the needle electrode while the grounding pads disperse the energy over a larger area to avoid skin burns.³

Permanent tissue destruction occurs at temperatures of ≥45°C. With temperatures from 46°C to 60°C, irreversible cellular damage is produced only after relatively longer periods of exposure; in contrast, temperatures between 60°C and 100°C cause almost instantaneous protein coagulation with irreversible damage to mitochondria and cytosolic cell enzymes. When temperatures exceed 100°C, tissue fluids undergo boiling, vaporization, and ultimately carbonization.³ Vaporization, which occurs when tissues are heated to >100 to 110°C, produces significant gas that both serves as an insulator and retards the ability to effectively establish a RF field.¹ Therefore, the key aim of RFA is to achieve and maintain a 50 to 100°C temperature range throughout the entire target volume.

Another important factor that affects the success of RFA is the ability to ablate all viable tumor tissue and an adequate tumor-free margin. To achieve rates of local tumor recurrence with RFA that are comparable with those obtained by hepatic resection, a 360-degree 1-cm-thick tumor-free margin around each tumor should be obtained, which may require multiple overlapping ablations.⁴ Thus the target diameter of an ablation must be 2 cm larger than the diameter of the tumor that undergoes treatment (Fig. 1).² Inadequate ablation can be due either to heterogeneity of tissue composition, by which differences in tumor density, including fibrosis and calcification, alter electrical and thermal conductance, and blood flow, by which perfusion-mediated tissue cooling (vascular flow) reduces the extent of thermally induced coagulation.¹

Figure 1.

A 74-year-old man with cirrhosis secondary to alcohol abuse. (A) Axial T1 fat-saturated image postgadolinium demonstrates a 1.8-cm arterially enhancing lesion (arrow). (B) One month postablation, axial T1 fat-saturated image demonstrates a zone of ablation (arrow) that is larger than the original tumor with no evidence of residual enhancing tumor.

RFA is usually performed following the administration of intravenous sedation and analgesia with standard cardiac, blood pressure, and oxygen monitoring. Targeting of the lesion can be performed with ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI), depending on operator preference and the local availability of dedicated equipment.

Complications

RFA is a safe procedure with very low rates of death and major complications. Complications include abdominal hemorrhage (Fig. 2), hepatic abscess, pleural effusion, hepatic infarction, bronchobiliary fistula, bile peritonitis, biloma, hemobilia, thrombosis of vessels in the hepatic venous system, skin burn, tumor seeding, and perforation of the stomach, intestine, or diaphragm.

Figure 2.

A 58-year-old man with hemophilia A and cirrhosis secondary to hepatitis C. (A) Axial T1 fat-saturated image postgadolinium demonstrates a 4.2-cm lesion (arrow) with a pseudocapsule that was a biopsy-proven hepatocellular carcinoma (HCC). (B) Coronal noncontrast computed tomography postablation, demonstrating an area of low attenuation at the ablation zone (star) and a subcapsular high attenuation hematoma (arrow). Two months postablation the patient underwent a liver transplant.

In a multicenter study by Koda et al on 16,346 treated nodules in 13,283 patients, 579 complications (3.5%) were observed; five patients (0.04%) died due to complications of RFA.⁵ A total of 276 hepatic injuries (1.69%) occurred including 75 liver infarctions (0.469%) and 32 liver abscesses (0.19%), 110 bile duct injuries (0.67%), and 37 bilomas (0.23%). Other hepatic injuries included portal thrombosis, refractory ascites, and hepatic failure.⁵ Another study found that bilomas occurred in 3.3% of cases (109 of 3284) following RFA but only one required percutaneous drainage.⁶ One study demonstrated that intraoperative central bile duct cooling could prevent biliary complications in patients undergoing RFA for periductal HCC.⁷ Other studies have found that intraductal chilled saline perfusion through a nasobiliary tube was a potential intervention to prevent biliary injury by percutaneous RFA.^8,9 These are small studies, and this practice is not yet widespread.

Koda et al found that a total of 113 extrahepatic organ injures occurred (0.69%) including 2 patients with cardiac tamponade, 9 cases of pneumothorax (Fig. 3) (0.06%), 9 gastrointestinal injuries, 5 gallbladder injuries, 8 diaphragmatic injuries, 43 refractory pleural effusions, and 32 skin burns.⁵ Most of the extrahepatic complications due to thermal damage may be prevented by artificial ascites or pleural effusion, which creates a space between the tumor and adjacent organs such as the abdominal wall, diaphragm, gastrointestinal tract, or gallbladder (Fig. 4).^10,11,12 Artificial ascites, however, poses a theoretical risk of a heat-sink effect that may decrease the effectiveness of the ablation. This risk was not proven in a study on percutaneous RFA of hepatic tumors abutting the diaphragm.¹³

Figure 3.

A 76-year-old man with cirrhosis secondary to hemochromatosis. (A) Axial T1 fat-saturated image postgadolinium demonstrates a 1-cm arterially enhancing lesion (arrow) that was a biopsy-proven hepatocellular carcinoma. (B) A computed tomography scan performed during the ablation procedure shows the cluster ablation electrode traversing the lung. (C) Postprocedure image demonstrates a pneumothorax (star). The track of the electrode through the lung is also seen (arrow). The patient required chest tube insertion because the pneumothorax increased in size on follow-up imaging.

Figure 4.

A 51-year-old man with cirrhosis secondary to hepatitis C. (A) Contrast-enhanced computed tomography demonstrates a 2.8-cm arterially enhancing lesion (arrow) consistent with a hepatocellular carcinoma (HCC). (B) During the procedure, hydrodissection was performed with 800 mL of 5% dextrose in water (star), which displaced the lung anteriorly allowing insertion of the electrode (arrow) without traversing the lung. (C) T1 fat-saturated magnetic resonance image postgadolinium 3 months postablation demonstrates a thin enhancing rim without nodularity (arrow), compatible with a complete ablation.

Koda et al also found tumor seeding at the needle tract in seven cases (0.04%) and eight cases of peritoneal dissemination (0.05%),⁵ which was significantly lower than the 12% reported in an earlier study.¹⁴ A recent literature review found that the risk of seeding was 0.61% (0 to 5.56%) for RFA without biopsy and 0.95% (0 to 12.5%) for RFA with biopsy.¹⁵ Subcapsular location and poor differentiation have been associated with an increased risk of seeding.¹⁴

Another major drawback of RFA is the high rate of disease recurrence after treatment (Figs. 5 and 6). A few studies, predominantly from early experiences with RFA, found a statistically significantly shorter recurrence-free interval in patients with subcapsular tumors compared with nonsubcapsular tumors following RFA.^16,17,18 However, more recent studies have found that the expected morbidity and local tumor progression in patients with subcapsular liver tumors who undergo percutaneous RFA was comparable with those in patients with nonsubcapsular tumors.^19,20 Another early study found that the presence of vessels at least 3 mm in size contiguous to the hepatic tumors is a strong independent predictor of incomplete tumor destruction by RFA.²¹ Again, a more recent study found that RFA was an effective procedure, even for high-risk tumors adjacent to large blood vessels.²²

Figure 5.

A 72-year-old man with colorectal carcinoma. (A) Postcontrast computed tomography (CT) demonstrates a 3-cm hypoattenuating lesion (arrow) consistent with a metastasis. (B) Postcontrast CT 1-month postablation demonstrates a low attenuation ablation zone (star) with a focus of residual tumor posteriorly (arrow). (C) Postcontrast CT 6-months postablation shows the ablation zone (star) and that the focus of residual tumor has increased in size (arrow).

Figure 6.

A 66-year-old man with cirrhosis secondary to alcohol dependency. (A) T1 fat-saturated image postgadolinium demonstrates a 3-cm arterially enhancing lesion (arrow). (B) Postgadolinium image 9 months postablation shows an ablation zone (arrow) without evidence of residual disease. (C) Postgadolinium image 2 years postablation demonstrates multiple areas of washout on delayed images (arrows) adjacent to the ablation zone (star), consistent with recurrent disease.

Follow-Up After Ablation

Because tumor is treated in situ, imaging follow-up is necessary to assess treatment response. Protocols vary among institutions, but ongoing surveillance is performed with shorter intervals initially. At our institution, contrast-enhanced imaging with CT or MRI (with subtraction images) is performed at 1, 3, 6, 9, and 12 months after treatment and at 6-month intervals thereafter. On the initial follow-up imaging, successful ablation is seen as a nonenhancing area with or without an enhancing rim. The enhancing rim that may be observed along the periphery of the ablation zone appears to be a relatively concentric, symmetrical, and uniform process in an area with smooth inner margins and without nodularity (Fig. 4).²³ Benign peri-ablation enhancement must be differentiated from irregular peripheral enhancement due to residual tumor that occurs at the treatment margin. Ablation site recurrence can present as focal enhancing lesions within or around the ablation zone or as an overall increase in the size of the ablation zone.²⁴

Primary Liver Tumors

Hepatocellular Carcinoma

HCC is well suited to treatment with locoregional therapy because it has a tendency to stay within the liver, with distant metastasis generally occurring late. RFA plays a role in multiple situations: resectable HCC, unresectable HCC, as a bridge to transplant, and in recurrent HCC.

Resectable HCC

Prior to the routine use of liver transplant, surgical resection was the only modality for curative treatment of HCC. Based on the Barcelona-Clinic Liver Cancer (BCLC) treatment strategy, resection is considered the first treatment option for early-stage patients (single tumor <2 cm).²⁵ A recent study, however, reported that the efficacy and safety of percutaneous RFA were better than those of surgical resection with HCC measuring ≤2 cm, especially those with central HCC.²⁶ A study comparing resection or RFA in patients with a solitary HCC <5 cm reported 1- and 4-year overall survival rates after percutaneous RFA and surgery of 96%, 68%, and 93%, 64%, respectively.²⁷ The corresponding disease-free survival rates were 86%, 46%, and 87%, 52%, respectively.²⁷ A randomized trail comparing RFA and surgical resection for HCC conforming to the Milan criteria reported a 1-, 2-, 3-, 4- and 5-year overall survival rates for the RFA group and the resection group of 87%, 77%, 70%, 66%, 55%, and 98%, 97%, 92%, 83%, 76%, respectively.²⁸ The 1-, 2-, 3-, 4-, and 5-year overall recurrence rates were 17%, 38%, 50%, 59%, and 63% for the RFA group and 12%, 23%, 34%, 39%, and 42% for the resection group.²⁸

Unresectable HCC

A retrospective study comparing the outcome of RFA and trans-arterial chemoembolization (TACE) in patients with unresectable HCC found that the 1- and 2-year overall survival rates were 82% and 72%, respectively, in the RFA group and 80% and 58%, respectively, in the TACE group.²⁹ A second study found that the overall recurrence-free rate was significantly higher in the RFA group than in the TACE group: The 2-year local recurrence-free rates in the RFA and TACE groups were 60% and 49%, respectively.³⁰ A meta-analysis of five randomized controlled trials comparing RFA and percutaneous ethanol injection (PEI) demonstrated that patients treated with RFA had better 1- and 3-year overall survival rates than those treated with PEI.³¹ Disease recurrence rates at the ablation site were also significantly lower in the RFA group than in the PEI group (2 to 14% versus 11 to 35%).³¹ The combination of RFA with other locoregional treatments such as PEI or TACE has been shown to result in better survival and lower recurrence rates than RFA alone.^32,33,34

Bridge to Transplant

The concept of liver transplant as the treatment of HCC is evolving. According to the Milan criteria, patients with a large single (≤5 cm) or multiple tumors (fewer than three and ≤3 cm in size) are eligible for transplantation (Fig. 2). However, because of the discrepancy between the increasing demand and the inadequate supply of liver from deceased donors, many potential recipients either die before an organ becomes available or drop off the transplant waiting list because of tumor progression. RFA and other locoregional treatments, such as TACE and PEI, have an emerging role to play as bridging interventions. Using the UNOS inclusion criteria, a study found that the respective dropout probabilities at 6, 12, and 18 months would have been 11.0%, 57.4%, and 68.7%, respectively.³⁵ In comparison, a study that used multimodality ablative techniques, such as RFA, TACE, ethyl alcohol ablation, or a combination of techniques as a bridge for transplantation, found a dropout rate of 0%, 0%, and 6% at 6, 12, and 24 months using the same exclusion criteria.³⁶ The role of RFA alone as a bridge to transplantation was specifically addressed in two studies. One study reported a dropout rate of 14% after a waiting time of 11.9 months,³⁷ and the other a rate of 5.8% after a mean waiting time of 12.7 months.³⁸

Recurrent HCC

Recurrent HCC occurs in 50 to 80% of patients at 5 years after resection, with the majority occurring within 2 years after resection.³⁹ RFA has been increasingly used in these patients, with cohort studies reporting the 5-year overall survival rate ranging from 18 to 52%.³⁹

Intrahepatic Cholangiocarcinoma

Hepatic resection is the only curative treatment option for intrahepatic cholangiocarcinoma; however, most patients are not candidates for this option because of either advanced disease at the time of presentation, likely insufficient function of the remaining portion of the liver, or poor surgical candidacy. Patients with untreated unresectable cholangiocarcinoma have a median survival of 3.9 months.⁴⁰ A recent study reported a median overall survival period of 38.5 months in patients with unresectable primary intrahepatic cholangiocarcinoma treated with RFA.⁴¹ This is likely highly influenced by patient selection with tumors small enough in both size and number to be treated with RFA.

Metastatic Disease

Over the last 2 decades, advances in surgical techniques have led to effective treatment for selected patients with hepatic metastases. However, only 10 to 25% of patients with metastases isolated to the liver are eligible for resection because of extent and location of disease or concurrent medical conditions.¹ RFA has proved to be a safe and feasible treatment option for extending survival in select patients with liver metastases from many different primaries such as colorectal cancer (Fig. 5),^42,43 pancreatic cancer,⁴⁴ cholangiocarcinoma,⁴⁵ neuroendocrine tumors,⁴⁶ breast cancer,⁴⁷ and gastric cancer.⁴⁸

Studies on the long-term survival of nonsurgical patients with hepatic colorectal metastases who underwent RFA reported a 1-year survival rate of 86 to 99%, a 3-year survival rate of 46 to 68%, and a 5-year survival rate of 24 to 44%.¹ Another study found that the 3-year survival rate in patients with a solitary colorectal metastases was 55% for patients treated with surgery and 52% for those who underwent RFA.⁴⁹ A more recent study reported that the overall survival and disease-free survival did not differ between patients treated with resection or RFA in patients with a solitary colorectal metastasis < 3 cm; however, in patients with a solitary metastasis >3 cm, the disease-free survival was significantly lower in the RFA group as compared with the resection group.⁴² A recently published systematic review, however, concluded that the available evidence was insufficient to recommend RFA for a radical oncologic treatment of colorectal liver metastases.⁵⁰

Conclusion

RFA has been shown to achieve effective and reproducible local tumor control with minimal morbidity in patients with small HCC and metastases. It is a desirable treatment option in patients with early-stage HCC when resection or transplant is precluded or delayed. It has also been proven a viable treatment option in patients with limited hepatic metastatic disease. For large tumor burdens, RFA is limited in effectiveness, and alternatives such as TACE or systemic therapies are preferred.