Benefits and drawbacks of radiofrequency ablation via percutaneous or minimally invasive surgery for treating hepatocellular carcinoma

Abstract

The management of early stage hepatocellular carcinoma (HCC) presents significant challenges. While radiofrequency ablation (RFA) has shown safety and effectiveness in treating HCC, with lower mortality rates and shorter hospital stays, its high recurrence rate remains a significant impediment. Consequently, achieving improved survival solely through RFA is challenging, particularly in retrospective studies with inherent biases. Ultrasound is commonly used for guiding percutaneous RFA, but its low contrast can lead to missed tumors and the risk of HCC recurrence. To enhance the efficiency of ultrasound-guided percutaneous RFA, various techniques such as artificial ascites and contrast-enhanced ultrasound have been developed to facilitate complete tumor ablation. Minimally invasive surgery (MIS) offers advantages over open surgery and has gained traction in various surgical fields. Recent studies suggest that laparoscopic intraoperative RFA (IORFA) may be more effective than percutaneous RFA in terms of survival for HCC patients unsuitable for surgery, highlighting its significance. Therefore, combining MIS-IORFA with these enhanced percutaneous RFA techniques may hold greater significance for HCC treatment using the MIS-IORFA approach. This article reviews liver resection and RFA in HCC treatment, comparing their merits and proposing a trajectory involving their combination in future therapy.

Key Words: Percutaneous radiofrequency ablation; Minimally invasive surgery; Hepatocellular carcinoma; Intraoperative radiofrequency ablation; Contrast-enhanced ultrasound

Core Tip: This article reviews the role of liver resection and radiofrequency ablation (RFA) in the treatment of early-stage hepatocellular carcinoma (HCC), comparing their pros and cons and proposing a potential trajectory involving the combination of surgical resection and RFA in future therapy. Despite percutaneous RFA's advantages, its high recurrence rate compared to resection remains a challenge. Techniques like artificial ascites and imaging enhancements aim to improve percutaneous RFA's efficacy and reduce recurrence. Minimally invasive surgery with intraoperative RFA (MIS-IORFA) enhances RFA's precision and safety. Applying these refined techniques to MIS-IORFA could yield long-term benefits in HCC management.

INTRODUCTION

Liver malignant tumors comprise primary liver cancers, such as hepatocellular carcinoma (HCC), cholangiocarcinoma, and hepatocellular-cholangiocarcinoma, as well as secondary liver cancers originating from metastases, including those from colorectal cancer, pancreatic cancer, breast cancer, and other primary tumors located elsewhere in the body[1]. These tumors exhibit characteristics of high malignancy, rapid growth, and a propensity for metastasis and invasion. Severe complications often manifest in the advanced stages of the disease, such as portal vein thrombosis, worsening ascites, variceal bleeding, obstructive jaundice, pyogenic liver abscess, and hepatic encephalopathy[2]. The new estimates available on the International Agency for Research on Cancer's Global Cancer Observatory show that liver and intrahepatic bile duct cancer is the third leading cause of cancer-related deaths, with 866136 new cases reported worldwide in 2022[3]. However, liver cancer is the fourth most common cause of cancer deaths, with an estimated 841080 new cases in 2018[4]. The global burden of liver cancer has increased over the past four years. HCC is the predominant type of primary liver cancer composed of epithelial cells, arising from liver cells and accounting for 75%-85% of all cases[5].

HCC is frequently observed in patients with chronic liver diseases, including those with cirrhosis caused by infections such as hepatitis B and hepatitis C viruses[6] as well as individuals with alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD)[7]. HCC is more prevalent in Asia and Africa compared to Western countries[8]. It is noteworthy that an epidemiological shift towards non-viral liver diseases such as ALD and MASLD has been observed following the implementation of national preventive measures, such as vaccination against hepatitis B virus and the introduction of direct-acting antiviral agents for treating hepatitis C virus infection[9].

There are various treatment modalities available for HCC, requiring a multidisciplinary and multimodal approach. These include liver resection, liver transplantation, radiofrequency ablation (RFA), percutaneous ethanol injection, cryotherapy, bland embolization, transarterial chemoembolization, radioembolization, sorafenib, external beam radiation, and stereotactic radiotherapy[10]. However, the optimal treatment decisions for individual patients are best determined by multidisciplinary teams comprising healthcare professionals such as transplant hepatologists, surgeons, interventional radiologists, and medical oncologists, as well as nurses and patient navigators[9].

HCC is typically associated with a 5-year overall survival (OS) rate of 10%-15%, primarily due to late diagnosis. However, when patients are diagnosed at an early stage and have access to curative treatments such as liver resection, liver transplantation, and RFA, the 5-year OS rate significantly improves to 50%-70%[11]. Recent studies indicate promising outcomes even in more advanced stages with the extension of liver resection[11] and the combination of RFA during surgery[12]. These findings underscore the necessity to reconsider the boundaries of surgical resection and its role within the treatment algorithm. In this article, we first summarize the current indications for liver resection and percutaneous RFA in HCC management, then describe the innovations in minimally invasive surgery with RFA that could overcome the current challenges.

LIVER SURGICAL RESECTION

Surgery, either in the form of liver resection or liver transplantation, represents the sole potential curative modality for early-stage HCC[10,13]. Well-selected patients undergoing surgical resection can achieve a median OS exceeding 5 years, while liver transplantation can yield a median OS exceeding 10 years[9]. While liver transplantation remains the sole treatment offering a chance of cure for both the tumor and underlying cirrhosis through complete extirpation of both, its widespread use is limited by insufficient donor availability and regulatory constraints[14,15]. For HCC patients with resectable tumors and good liver function, liver resection stands as the most popular treatment strategy[10,16]. However, it is essential to note that careful patient selection is critical for liver resection to strike a balance between the risk of postoperative liver failure and the potential long-term outcomes[11].

The Barcelona-Clinic Liver Cancer (BCLC) classification, updated in 2022, comprises five BCLC scores (0, A, B, C, and D), which have emerged as the standard for classifying and selecting the most appropriate treatment for managing HCC[17,18]. The evaluation criteria for liver resection in HCC necessitate careful consideration of various factors, including the number and size of tumor nodules, vascular involvement, underlying liver dysfunction assessed by the Child-Pugh score, and overall patient performance status (PS)[19].

Very early stage (0) is defined by a single nodule ≤ 2 cm in size with preserved liver function and PS 0, while early stage (A) encompasses a single nodule or up to 3 nodules ≤ 3 cm in size with preserved liver function and PS 0[15]. Patients classified as very early (0) and early stage (A) according to the BCLC classification are considered ideal candidates for surgical resection. However, the feasibility of surgery is limited, with only 9%-29% of HCC patients being able to tolerate it, a constraint often attributed to compromised hepatic reserves due to chronic liver disease or the multifocal distribution of tumor nodules[16].

PERCUTANEOUS RADIOFREQUENCY ABLATION

While surgical resection remains the primary treatment for most solid tumors, it may not always be possible for patients with concurrent morbidities or poor functional status, as it carries a significant risk of morbidity and mortality[20]. In such cases, RFA presents an alternative to surgical resection. RFA employs high-frequency alternating current (approximately 400-500 kHz) delivered through the distal end of an uninsulated portion of the puncture needle. This current heats the tissue surrounding the needle electrode through friction of water molecules, inducing zones of coagulative necrosis and protein degeneration within the tumor tissue while minimizing damage to surrounding tissues[20,21]. Similar to liver resection, RFA is recommended for the treatment of HCC at stage 0 and 1 according to the BCLC 2022 guidelines[15]. Additionally, RFA is suggested for patients with very early-stage or early-stage HCC who may not have optimal indications for surgery or transplantation[12].

Most RFA procedures are performed using an image-guided percutaneous approach, although in certain cases, laparoscopic RFA is recommended[22]. The majority of procedures can be carried out under local anesthesia and conscious sedation, often on an outpatient basis or with a short hospitalization lasting 2-3 days. Despite RFA's demonstrated safety and effectiveness in treating malignant liver tumors, with lower mortality rates and shorter hospital stays[16,23], its high recurrence rate remains a significant challenge[24].

COMPARE SURGICAL RESECTION AND PERCUTANEOUS RADIOFREQUENCY ABLATION

Compared to surgical resection and liver transplantation, percutaneous RFA offers several advantages, including lower risk of complications, shorter treatment duration, minimal blood loss, lower cost, preservation of normal tissue, lower complication rate, use of local anesthesia, and shorter hospital stays[24,25]. While percutaneous RFA provides numerous benefits for early-stage HCC therapy, it is crucial to consider treatment outcomes and HCC recurrence rates compared to surgical resection. Image-guided percutaneous RFA may outperform other percutaneous treatments, such as percutaneous ethanol injection and percutaneous acetic acid injection, for HCCs smaller than 3 cm[26,27]. However, it does not appear to be superior to liver resection. While some studies suggest that RFA is equally effective as resection for treating solitary and small HCC tumors[28-30], there are conflicting results[24,31,32].

Recent retrospective studies and randomized controlled trials have consistently shown that surgical resection yields better outcomes compared to RFA for treating HCC. Hsiao et al[33] demonstrated that surgical resection provides superior OS and recurrence-free survival outcomes when compared to percutaneous RFA in patients with very early-stage HCC according to BCLC classification, even during long-term follow-up. Similar results were observed in elderly patients (> 70 years) with HCC at BCLC stage 0/A and tumors within Milan criteria[34]. Furthermore, a randomized clinical trial has shown that RFA is not superior to hepatic resection for treating early-stage HCC in terms of tumor recurrence or 10-year overall and disease-free survival[24]. Additionally, the results of a systematic review and meta-analysis study indicated that hepatic resection is superior to RFA in promoting the survival of selected patients with resectable HCC[16]. These findings support the conclusions drawn by Mulier et al[35], in 2005, who stated that the short-term benefits of less invasiveness associated with the percutaneous route do not outweigh the longer-term higher risk of local recurrence.

Improving the feasibility of percutaneous radiofrequency ablation

As mentioned above, the high recurrence rate remains a significant challenge in the use of percutaneous RFA. One reason for this is the difficulty in accurately determining the extent of the safe margin of the coagulation zone, which is ideally 1 cm of normal tissue surrounding the tumor on all sides[20]. This difficulty may lead to incomplete ablation and the potential for leaving microscopic malignant cells, thereby causing local recurrence[36,37]. The achievement of safe ablation margins is influenced by various factors related to both the devices used and the tumors themselves. Factors related to the devices include overall energy deposition, duration of application, electrode types or tip length, and gauge[16]. Tumor-related factors, such as tumor location and volume, also play a crucial role in determining the success of the ablation process[38].

It is essential to consider the heat dissipation (heat-sink) effect caused by tumor size and surrounding tissues, particularly those adjacent to critical structures such as the diaphragm, vessels (portal vein and hepatic vein), major bile ducts (common bile duct, common hepatic, right and left hepatic ducts), or vulnerable organs (colon, gallbladder, etc.), due to poor conductive heating[39]. To overcome the limitations posed by the heat-sink effect, several technical approaches have been developed, including innovative guiding modalities, the use of artificial fluids or air, and combined treatment strategies[38]. For example, RFA for the gallbladder has proven to be a safe and effective treatment option, thanks to techniques such as hydrodissection and real-time temperature monitoring[40]. Additionally, the use of artificial ascites to assist with ablation has been shown to enhance image-guided percutaneous RFA and improve safety by displacing the liver downward[38].

Improving ultrasound imaging for guiding and monitoring percutaneous radiofrequency ablation

Imaging plays a crucial role in percutaneous RFA procedures for treating HCC. It is essential for various stages of the procedure, including pretreatment diagnosis, peri-treatment electrode placement, guiding energy deposition, and accurate real-time monitoring during the procedure, as well as post-treatment outcome evaluations[41]. Effective guidance imaging during RFA should not only provide clear contours of the HCC and surrounding organs, minimizing the risk of injury to critical structures during the ablative procedure, but it should also facilitate precise electrode placement within the tumor and offer accurate real-time monitoring and control throughout the procedure[42].

Ultrasound (US) and computerized tomography (CT) are the most commonly employed modalities for guiding percutaneous RFA. Among these, US is widely utilized due to its ease of operation, absence of ionizing radiation, low cost, and ability to provide real-time multiplanar images[43]. However, US-guided RFA has limitations such as low contrast visualization of HCC, difficulty in targeting deep-seated tumors, particularly in obese patients, and significant operator dependency[23]. Consequently, approximately 33%-45% of HCC RFA procedures are deemed infeasible with US guidance, attributed to the inconspicuousness of tumors, inadequacy of electrode paths, and vulnerability of surrounding organs to collateral thermal damage[44,45]. To address these limitations, various imaging techniques have been developed to enhance the feasibility of performing HCC RFA under US guidance.

While contrast-enhanced CT and magnetic resonance imaging (MRI) offer high contrast and spatial resolution for detecting HCC, they present limitations for image-guided percutaneous RFA. CT involves radiation exposure, and MRI equipment is often limited in availability, both requiring expensive equipment and lacking real-time capability[43]. US-CT/magnetic resonance (MR) fusion imaging is a technique that automatically registers fused images with current US images and previously acquired CT or MRI volume datasets using a disposable locating device and an electromagnetic sensor[43]. Fusion imaging, combining conventional US with liver CT/MRI, has been shown to improve HCC detection rates by up to 45% and enhance procedural feasibility[46]. US/CT-MR fusion imaging guidance has demonstrated improved tumor visibility and technical feasibility of RFA in patients with HCC[43,47].

Contrast-enhanced US (CEUS), utilizing microbubble contrast agents as acoustic enhancers, offers an alternative modality to enhance the characterization of HCC for guiding RFA procedures. Standardized criteria for CEUS have been established within the American College of Radiology Liver Imaging Reporting & Data System (CEUS LI-RADS) by the American College of Radiology. These criteria aid in the characterization of focal liver lesions in high-risk populations and provide an accurate categorization of liver nodules in individuals at risk for HCC[48]. SonoVue, characterized by its pure blood agent and faster washout rate in the arterial phase, serves as a strong independent predictor of microvascular invasion. In contrast, Sonazoid, with its additional Kupffer phase, potentially extends the assessment of wash-out related findings into the late phase for a longer duration compared to blood pool agents[49]. CEUS plays a highly beneficial role in treatment planning, providing real-time guidance during treatment, and monitoring HCC response to locoregional therapies. This enables the identification of patients in need of retreatment much earlier than contrast-enhanced CT and MRI scans[50]. The overall diagnostic efficacy of CEUS for HCC has been found to be comparable, and in some reports, superior to that of contrast-enhanced CT or MRI[51].

COMBINATION OF MINIMALLY INVASIVE SURGERY AND RADIOFREQUENCY ABLATION

US-guided RFA can be applied using percutaneous, open, or minimally invasive surgical (MIS) approaches[52,53]. MIS techniques, including laparoscopic and robotic surgery, commonly offer advantages such as reduced blood loss, less wound pain, and superior cosmetic results, making them a trend in various surgical fields over the last two decades[54]. Surgery combined with intraoperative RFA (IORFA) is feasible for the resection of superficial or multifocal HCCs confined to a single lobe. Additionally, IORFA can be applied to small, surgically unfavorable, and unresectable HCCs located deep in the liver or near major vasculature. This approach is safer than percutaneous RFA and maximizes the future liver remnant compared to surgical resection[55].

Compared to percutaneous RFA, IORFA offers several advantages, including more accurate and safe placement of the RFA electrode and extending the feasibility of surgery in cases of multiple tumors[56]. Additionally, by controlling the patient's breathing using general anesthesia, IORFA allows for more precise and safe ablation than percutaneous RFA[57]. Laparoscopic RFA has been explored to address the technical challenges of percutaneous RFA for subphrenic HCC and has shown better therapeutic outcomes in terms of local tumor progression and OS[57]. Therefore, laparoscopic RFA can be a valuable treatment option for subphrenic HCC if accessible using the laparoscopic approach[12]. Needle tract seeding is a well-known complication of RFA. Nevertheless, it is hypothesized that IORFA may reduce the likelihood of needle tract seeding due to the direct and shorter pathway of the probe.

CONCLUSION

Surgery remains a potent curative modality for HCC therapy, yet its application is limited by specific criteria such as single tumor presence, tumor size, and functional liver remnant. Percutaneous RFA, on the other hand, is suitable for multifocal tumors, offers more normal tissue preservation, and entails shorter treatment duration and hospital stays. However, it is influenced by factors like tumor location and a high recurrence rate. Several techniques have been developed to improve US imaging for guiding and monitoring percutaneous RFA, including artificial ascites, US-CT/MR fusion imaging, and CEUS, aimed at reducing recurrence rates. To date, the combination of MIS with IORFA has proven safe and effective for various multifocal primary and secondary liver malignancies, offering a potential curative treatment option for eligible patients with BCLC B HCC. However, these techniques to enhance RFA guidance are seldom utilized in IORFA procedures. Techniques such as artificial ascites, US-CT/MR fusion imaging, and CEUS should be incorporated to assist IORFA in detecting HCC and monitoring residual tumor near the safe margin. Indeed, a recent study has shown that the promising results with CEUS-guided ablation for deep-seated liver lesions by aiding in visualization and confirming successful ablation in one case report[58]. However, further validation of this promising treatment approach for HCC is necessary, along with establishing the optimal application through additional studies.