Chemoembolization Plus Ablation: Current Status

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The treatment landscape for HCC has evolved significantly over the past decade, with several modalities available to treat various stages of disease. The Barcelona Clinic Liver Cancer (BCLC) system provides a foundation for treatment guidance. However, given the complex nature of HCC, a more nuanced approach is often required, especially for lesions sized between 3 and 5 cm. This review aims to analyze the available treatments for early-stage HCC lesions between 3 and 5 cm, with a focus on the therapeutic potential and efficacy of transarterial chemoembolization (TACE)–ablation. Additional therapies including TACE, ablation, transarterial radioembolization, and surgical resection are also reviewed and compared with TACE–ablation. TACE–ablation is a viable therapeutic option for early-stage HCC lesions between 3 and 5 cm. Surgical resection remains the gold standard. Although recent studies suggest radiation segmentectomy may be a curative approach for this patient population, further studies are needed to compare the relative efficacies between TACE–ablation and radiation segmentectomy.

Liver cancer has afflicted over 900,000 individuals worldwide in 2022 alone, and hepatocellular carcinoma (HCC) comprised a staggering 75 to 85% of these cases. ¹ HCC prevalence is primarily driven by risk factors like chronic hepatitis B and C infections, aflatoxin exposure, alcohol abuse, obesity, diabetes, and smoking. While viral hepatitis-related HCC rates have declined due to advances in vaccination and antiviral therapies, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) now contribute to its rising incidence. ¹ Diagnosis of HCC involves tissue biopsy or imaging, with liver imaging reporting and data system (LI-RADS) criteria aiding in noninvasive identification. ² HCC prognosis depends on tumor attributes and liver disease severity. Elevated α-fetoprotein (AFP) levels are significantly associated with increased mortality risk. ³ The Barcelona Clinic Liver Cancer (BCLC) system guides staging, prognosis assessment, and treatment recommendations. ⁴

Treatment for HCC includes systemic therapies, surgery, liver transplantation, ablation, and intra-arterial therapies with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE). In this review article, we will discuss the current guidelines for the treatment of early-stage HCC, with a focus on lesions larger than 3 cm. We will also explore the current literature evaluating the role and efficacy of surgical resection (SR) and radiation segmentectomy when compared with TACE–ablation and other treatment options in this patient population.

Therapies Available for Early-Stage HCC

The BCLC staging system is a widely accepted system for staging, prognosis, and treatment recommendations for HCC. The guidelines take into consideration factors such as (1) tumor characteristics, including size, number, vascular invasion, and extrahepatic disease; (2) performative status as defined by the Eastern Cooperative Oncology Group (ECOG) scale; and (3) liver function with a Child-Pugh score calculated by using the laboratory values for bilirubin, albumin, INR, and the presence of ascites. ⁵ This model is divided into stages, including very early (BCLC-0), early stage (BCLC-A), intermediate stage (BCLC-B), advanced stage (BCLC-C), and end stage (BCLC-D), each associated with their respective recommendations. ⁶ Early-stage HCC (BCLC-A), which is the focus of this review article, is defined as solitary HCC irrespective of size or three lesions up to 3 cm, no macrovascular invasion, extrahepatic spread, or cancer-related symptoms, with preserved liver function.

Surgical Resection

Liver transplantation in carefully selected patients has been the standard curative therapy in very early to early HCC (BCLC-0–A), with 5-year survival greater than 70% and recurrence rate ranging from 8 to 15%. ^{7 8 9} Unfortunately, liver transplant wait times can be long and supply of organs may be sparse, which puts patients at risk for progression of disease if left untreated. ⁹ SR, another curative option for patients with adequate liver function, has been shown to have a 5-year survival rate between 60 and 80% and recurrence rates of 70%. ^{10 11} SR is typically the first-line treatment option for patients without clinically significant portal hypertension (CSPH) which allows for assessment of the pathologic profile of the resected HCC to evaluate for markers indicating high risk of recurrence, as liver transplantation could be considered in these patients. For those with CSPH, liver transplantation may be considered. If liver transplantation is not feasible, recommendations are for thermal ablation. SR may be considered in patients with solitary, peripheral HCC; however, both are associated with risks and minimal data to result in robust recommendations. ⁶ If liver transplantation is not feasible, the recommendations do not specify between SR and ablation. While surgery is successful in many patients, the potential for recurrence has promoted use of other less invasive potentially curative therapies. Moreover, many patients may not be surgical candidates due to a variety of reasons, including but not limited to tumor location, liver dysfunction, and underlying medical conditions.

Radioembolization/Radiation Segmentectomy

Radioembolization performed with yttrium-90, also commonly referred to as selective internal radiation therapy or TARE, or more colloquially as Y90, uses internal radiation therapy to target and destroy tumors. The procedure involves selective administration of an intra-arterial ablative dose of ⁹⁰ yttrium (Y90) microspheres. When delivered to two or less Couinaud segments, the technique is called radiation segmentectomy with the concept similar to an anatomic SR. Given the increased arterial supply of the tumor(s) and increased tumor to normal parenchymal blood flow ratio, most of the treatment is delivered preferentially to the tumor compared with the background liver. Furthermore, by performing a selective injection, most of the noninvolved hepatic parenchyma is spared, allowing for high doses of radiation to be safely delivered. Some technical advantages of radiation segmentectomy over thermal ablative techniques are the decreased bleeding risk as transarterial therapy does not require transhepatic puncture. ¹² This also eliminates the risk of tract seeding, which may compromise the eligibility for liver transplantation. Furthermore, ablation near major vascular and biliary structures, hollow viscera, and diaphragm may lead to potential damage to surrounding structures or incomplete treatment. ^{12 13}

In 2018, Lewandowski et al further assessed radiation segmentectomy's curative potential for solitary lesions up to 5 cm, showing a 5-year survival rate of 55% and suggesting it as a viable treatment for early-stage HCC unsuitable for ablation or resection. ⁹ LEGACY, a retrospective multicenter study conducted by Salem et al, established radioembolization's efficacy using Y90 glass microspheres for solitary, unresectable HCC of up to 8 cm. ¹⁴ The study demonstrated a high objective response rate and competitive local tumor recurrence rates compared with thermal ablation. It also highlighted radiation segmentectomy's potential as a neoadjuvant treatment and identified a threshold dose for an ablative effect. The RASER trial, a prospective phase 2 study, focused on radiation segmentectomy for unresectable early-stage HCC. It reported an 89% target lesion complete imaging response, with most adverse events being grade 1/2, emphasizing radiation segmentectomy's safety and efficacy. ¹⁵ Given the LEGACY study's outcomes, the FDA has approved TARE for treating solitary HCC, and it is now part of the BCLC treatment algorithm for early-stage HCC.

Ablation

The goal of thermal ablation, typically performed with radiofrequency or microwave technology, is to achieve complete thermal coagulation of the tumor, ideally leaving no viable malignant tissue behind with adequate margins. Thermal ablation, using both radiofrequency ablation (RFA) and microwave ablation (MWA), has shown promise in treating HCC tumors up to 7 cm. ¹⁶ Both methods are effective, but there is no evidence to suggest superiority of one modality over the other with respect to complete ablation rate, local and distant recurrence, and long-term survival. The safety profiles for both techniques are favorable, with a low complication and morbidity. ^{16 17} An 80% complete ablation rate has been shown to be achieved for tumors measuring 5 to 7 cm. ¹⁶ Specifically, Lee et al have shown a 5-year survival of 67.9% in patients who meet the BCLC criteria for resection (BCLC stage A), making it comparable to hepatic resection outcomes. ¹⁷

While RFA showed promising results, it faces challenges including incomplete ablation near major hepatic vessels and a higher risk of local tumor progression (LTP) compared with hepatic resection. Despite these challenges, the procedure's lower morbidity and mortality rates, combined with its repeatability in the face of tumor recurrence, solidify its position as a viable first-line treatment for early-stage HCC. Liver function, baseline serum AFP levels, and the presence of portosystemic collaterals are notable prognostic factors. Furthermore, while LTP did not drastically alter overall survival (OS), it did lead to shorter tumor-free periods, necessitating more interventional procedures to maintain comparable survival outcomes. ¹⁷

Thermal ablation has been demonstrated to be a curative treatment option for lesions measuring up to 3 cm and has such been incorporated into the treatment algorithm for patients with BCLC-0–A HCC. ¹⁸ However, lesions greater than 3 cm have limitations associated with ablation zone size creation that may lead to local recurrence. ^{16 19 20} When evaluating the width of the ablative margin via CT image fusion, a 3-mm margin or more has been shown to be associated with a reduced rate of LTP after percutaneous RFA of HCC. ¹⁹ Risk of local recurrence significantly increases with tumors of increasing size (14.9% for tumors measuring 3 to 5 cm, and as high as 40.9% for tumors measuring 5–8 cm). ²⁰ Ablation of larger tumors is further limited when a major bile duct or structure is adjacent to the lesion and contraindicates a sufficient ablation margin to avoid bile duct injury. The local recurrence rate thus increases due to insufficient ablation margins. It has been established that local tumor size is an independent prognostic factor for long-term survival following ablation. ²⁰

Transarterial Chemoembolization

TACE is a standard LRT typically used for intermediate-stage HCC (BCLC B). There are two main types of TACE, conventional TACE (cTACE) and drug-eluting bead TACE (DEB-TACE). cTACE is the intra-arterial injection of cytotoxic agents (such as doxorubicin or cisplatin) emulsified in an oil-based radiopaque agent (typically lipiodol), followed by injection of a bland embolic agent. DEB-TACE contains non-absorbable embolic microspheres which release a cytotoxic drug loaded onto the beads with simultaneous cytotoxic and tumor embolic effects. While DEB-TACE was theorized to overcome some limitations of cTACE, when directly compared in an RCT, no significant difference was found in local and overall response between the two methods in intermediate-stage patients. ²¹ The only advantage of DEB-TACE was reduced postprocedural pain (24.7 vs. 71.6%, p  < 0.001). However, given the higher cost of DEB-TACE and equivalent clinical outcomes to cTACE, its routine use is questioned. Factors like patient performance status, liver function, and tumor multiplicity influence survival more than the choice between DEB-TACE and cTACE.

A recent RCT comparing TACE to TARE, the TRACE trial, showed the median time to progression (TTP) was 17.1 months in the Y90 TARE arm versus 9.5 months in the DEB-TACE arm (hazard ratio [HR], 0.36; p  = 0.002), justifying early termination of the study. ²² Median OS was 30.2 months after TARE versus 15.6 months after DEB-TACE (HR, 0.48; p  = 0.006). ²² These findings align with an earlier study of HCC patients of BCLC stages A or B, where Y90 radioembolization resulted in a significantly longer median TTP than cTACE (>26 vs. 6.8 months). ²³ Fewer patients in the Y90 group experienced side effects like diarrhea or hypoalbuminemia compared with the cTACE group, with comparable survival times between the two groups. These studies suggest that Y90 radioembolization offers better tumor control and might decrease drop-outs from transplant waitlists compared with cTACE.

Transarterial Chemoembolization–Ablation

TACE failure or refractoriness has been repeatedly described in the literature. ^{24 25} The updated criteria for TACE failure or refractoriness, based on consensus from HCC experts, emphasize the importance of transitioning from TACE to systemic therapy once TACE failure criteria are met, even if HCC remains in the intermediate stage. ²⁵ The criteria for TACE failure include insufficient necrosis of intrahepatic lesions, emergence of new lesions within 3 months, or local recurrence within 3 months post-TACE. Continuous elevation of tumor markers and two consecutive poor responses to TACE are also indicative of TACE failure.

This led to the combination treatment of TACE with thermal ablation (TACE–ablation) for solitary recurrent HCC < 5 cm, which now shows significant OS when compared with ablation alone. ²⁶ An early RCT demonstrated no significant differences in the rates of LTP, OS, local progression-free survival, or event-free survival between the two groups. ²⁷ Yet for HCC recurrence, a subsequent trial highlights the potential benefits of TACE–ablation, especially for recurrent HCCs smaller than 5 cm, showing superior overall and recurrence-free survival rates compared with RFA alone ( p  = 0.037 and p  = 0.005, respectively). ²⁶ The study suggests that sequential TACE–RFA is particularly beneficial for patients with HCC recurrence within a year of initial treatment, tumors measuring between 3.1 and 5.0 cm, and those with recurrence after initial RFA treatment. Other studies combining DEB-TACE with ablation have demonstrated similar results and improved recurrence-free survival compared with the established literature for ablation alone for intermediate-stage HCC. ²⁸ Among the techniques employed during ablation following TACE for lesion guidance include biplane fluoroscopy and ultrasonography. ²⁹

Stereotactic Body Radiation Therapy

The role of radiation therapy for HCC has been refined with the increasing use of stereotactic body radiation therapy (SBRT). Recent prospective and retrospective studies have shown the safety and efficacy of SBRT with 2-year local control ranging from 68 to 95%. ³⁰ However, high-quality level 1 evidence supporting its use is currently lacking. One retrospective study found that differences in acute grade ≥3 toxicities were not statistically significant in the SBRT and RFA patients (1.6 and 2.6%, p  = 0.268, respectively). ³¹ Smaller randomized trials of external beam radiation therapy suggest high efficacy of radiation therapy for patients with unresectable HCC, and phase III trials comparing SBRT with other modalities are ongoing.

Comparison of TACE–Ablation to Other Modalities

Thermal ablation has been shown to be equivalent to SR for lesions smaller than 3 cm as a curative therapeutic option; however, ablation does not offer lesions greater than 3 cm the same curative potential. ^{32 33} TACE is a palliative therapeutic option. However, it is mainly used in the setting of intermediate-stage HCC as failure and refractoriness have frequently been described in the literature. ^{24 25} This leads to the development of a combination of the two therapies, TACE–ablation, which has been found to be superior when compared with TACE alone and is often used for the treatment of solitary HCC between 3 and 5 cm. ^{28 34} Of note, the literature has shown there is no advantage of combination therapy with TACE–ablation versus ablation alone in lesions less than 3 cm. ³⁵

TACE–ablation has been shown in the literature to be a feasible option for single HCC lesions sized between 3 and 5 cm, some studies even showing comparable outcomes to SR with fewer major complications and shorter hospital stay. ^{36 37 38} A retrospective study conducted by Peng et al in 2018 found that TACE–RFA provided similar OS and disease-free survival (DFS) when compared with repeat hepatectomy for recurrent HCC ≤ 5 cm. ³⁷ Additionally, in a prospective, observational, single-center pilot study, 25 patients with compensated cirrhosis who had HCC lesions ≥3 cm unsuitable for liver resection (LR) or liver transplantation were compared with a group of retrospectively selected 29 patients who underwent local resection with a median HCC size of 4 cm. The authors found that while LR resulted in lower tumor recurrence and lower tumor progression, 3-year OS was similar between the two groups. ³⁸

However, when comparing TACE–ablation to SR as first-line therapy in this patient population, a meta-analysis conducted by Dan et al evaluated OS, DFS, and major complications in HCC patients who were treated with SR or TACE–ablation. ³⁹ SR was found to have superior long-term survival outcomes in regard to 5-year OS, 3-year DFS, and 5-year DFS. ³⁹ While the study initially found no significant differences in 1-year OS, 3-year OS, and 1-year DFS, significant heterogeneity was found between many of the groups and an additional meta-analysis was subsequently conducted with propensity score-matched cohorts. This revealed superior 3-year OS and 5-year OS in the SR group when compared with TACE–ablation. Notably, SR had a higher long-term survival rate in HCC with diameters greater than 3 cm. ³⁹ A study conducted by Saviano et al specifically evaluated LR versus TACE–ablation in the treatment of lesions 3 cm or greater. ³⁸ LR achieved significantly lower tumor recurrence as well as lower rates of LTP. ³⁸ These studies reiterate the role of SR as a superior treatment option in HCC greater than 3 cm.

Repeated treatments with TACE can lead to decreased liver function in this patient population that typically has concomitant cirrhosis or portal hypertension. ²⁴ A prospective trial noted that DEB-TACE can achieve tumor responses in patients with HCC and compromised liver function, but also carried a significant risk of severe toxicity (76% of patients with baseline hepatic dysfunction developed grade 3 or grade 4 adverse events attributable to the procedure). ⁴⁰ As such, TACE–ablation may not be a safe strategy for bridging or downstaging liver transplant candidates with HCC and limited liver reserve.

While TACE–ablation has shown promising results for palliative treatment of lesions greater than 3 cm when compared with TACE or ablation individually, recent literature has elucidated the role of radiation segmentectomy as more than a palliative, but rather as a potential curative therapeutic option for patients in the BCLC-0–A category. ^{41 42} However, the data directly comparing TACE–ablation to TARE are lacking. Biederman et al compared treatment of unresectable, solitary HCC that was 3 cm or less in treatment-naive patients with radiation segmentectomy and TACE–ablation. ⁴³ The study included 121 patients who underwent radiation segmentectomy and 80 patients who underwent TACE–MWA between January 2010 and June 2015. After propensity score matching, the results showed no significant difference in imaging response, progression outcomes, 90-day mortality, or survival between the radiation segmentectomy and TACE–MWA groups, indicating that both treatments are viable options for patients with solitary HCC up to 3 cm. However, further research is needed to directly compare the two treatment modalities in lesions larger than 3 cm, especially for BCLC-A HCC between 3 and 5 cm.

Conclusion

With HCC being such a prevalent cause of morbidity and mortality in the global population, tailored therapy becomes crucial. The BCLC system provides a structured framework for the treatment of HCC. However, the heterogeneity of HCC demands a nuanced, individualized approach. This review presents a detailed exploration of the treatments available for early-stage HCC lesions 3 to 5 cm, with a focus on TACE–ablation as a therapeutic approach. Although TACE–ablation has shown to be a compelling treatment option, SR remains the mainstay of treatment in this patient population. Moving forward, more comparative research is needed to delineate the relative efficacies of TACE–ablation and radiation segmentectomy, specifically in BCLC-A HCC lesions sized between 3 and 5 cm.