Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates eligible for local ablation
Executive Summary
This document synthesizes key insights on liver-directed therapies for localized hepatocellular carcinoma (HCC) in patients who are not candidates for surgery but are eligible for local ablation. HCC is an aggressive tumor, and prognosis is primarily determined by tumor mass and the patient's underlying hepatic reserve.
For patients with liver-isolated HCC who are ineligible for surgical resection or liver transplantation, liver-directed therapies are preferable to systemic therapy due to a more favorable side effect profile. A multidisciplinary team approach, involving specialists from hepatobiliary and transplant surgery, interventional radiology, radiation oncology, medical oncology, and hepatology, is strongly recommended by the American Association for the Study of Liver Diseases (AASLD) as it has been demonstrated to improve patient satisfaction, ensure more timely and appropriate care, and increase overall survival.
The choice of therapy is stratified by liver function (Child-Turcotte-Pugh class) and tumor size. For patients with Child-Pugh class A or B cirrhosis and small HCCs (≤3 cm), local thermal ablation—specifically radiofrequency ablation (RFA) or microwave ablation (MWA)—is the preferred treatment. For intermediate-sized HCCs (3-5 cm), transarterial chemoembolization (TACE) plus RFA or MWA is often recommended due to a higher risk of local recurrence with ablation alone. Patients with Child-Pugh class C cirrhosis are typically managed with best supportive care, as their survival is more limited by liver function than by the cancer itself.
RFA is the most extensively studied local ablation technique, achieving complete radiographic response rates of 90 to 99 percent for tumors under 5 cm. MWA is an effective alternative that can perform multiple ablations simultaneously and may be less susceptible to the "heat sink" effect of nearby blood vessels. Other techniques such as percutaneous ethanol injection (PEI), cryoablation, and irreversible electroporation (IRE) have specific applications but are generally not first-line choices where RFA or MWA are available. Post-treatment surveillance with contrast-enhanced multiphase CT or MRI is critical for assessing response and monitoring for recurrence.
1. Introduction to Hepatocellular Carcinoma (HCC)
Hepatocellular carcinoma (HCC) is an aggressive tumor that most frequently occurs in the context of cirrhosis. The two most critical factors in determining a patient's prognosis and guiding treatment options are the tumor mass and the patient's hepatic reserve (underlying liver function).
Treatment options are broadly divided into:
Curative Surgical Therapies: Resection and orthotopic liver transplantation.
Nonsurgical Therapies: These can be liver-directed or systemic.
Liver-Directed: Preferred for liver-isolated HCC in nonsurgical candidates. These include:
Local Thermal Ablation: The focus of this review, including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, laser ablation, and high-intensity focused ultrasound (HIFU).
Other Liver-Directed Therapies: Transarterial chemoembolization (TACE), bland embolization, radioembolization (TARE), and stereotactic body radiotherapy (SBRT).
Systemic: Generally reserved for patients with disease spread outside the liver.
2. General Approach and Patient Selection
The Importance of Multidisciplinary Care
A strong recommendation exists for all patients with HCC to be referred to specialized centers with multidisciplinary expertise. This team-based approach ensures a comprehensive evaluation of all available treatment options, monitoring, and management of the underlying liver disease.
Benefits: This approach has been demonstrated to improve patient satisfaction, result in more timely and appropriate care, and increase overall survival.
Process: Evaluation and planning typically occur in the setting of a tumor board, where specialists from diagnostic radiology, pathology, hepatobiliary and transplant surgery, interventional radiology, radiation oncology, medical oncology, and hepatology convene to provide optimal therapy recommendations.
Underlying Liver Disease: The majority of HCC patients have underlying liver disease, which places them at high risk for progression to liver failure. Comprehensive care includes managing the cirrhosis (e.g., antiviral therapy for hepatitis B/C), regular surveillance, and management of complications like varices.
Patient Stratification and Treatment Indications
Treatment decisions are heavily influenced by the patient's liver function, as classified by the Child-Turcotte-Pugh (CTP) score, and the size and number of tumors.
Indications for Local Ablation Based on Tumor Size:
Small HCCs (≤3 cm): Local thermal ablation (RFA or MWA) is the preferred treatment over other nonsurgical options like embolization or radiation therapy.
Intermediate-sized HCCs (>3 cm but no larger than 5 cm): Transarterial chemoembolization (TACE) is often combined with RFA or MWA due to the higher risk of local recurrence with ablation alone. Other options include TARE or SBRT.
3. Local Ablation Modalities: Efficacy and Complications
The choice among ablation techniques is often based on institutional expertise and preference rather than significant differences in efficacy.
3.1. Radiofrequency Ablation (RFA)
RFA is a well-established technique that delivers a high-frequency alternating current via a needle electrode into the tumor, causing frictional heating and coagulative necrosis.
Patient Selection:
Ideal Candidates: Patients with CTP class A or B cirrhosis who are not candidates for resection or transplant.
Tumor Size: Best outcomes are in patients with one or two lesions <3 cm. Tumors >3 cm can be treated first with TACE or TARE to reduce their size before RFA.
Contraindications: Avoided for tumors near major blood vessels (due to heat sink effect) or in the liver hilum near major bile ducts. Lesions adjacent to the diaphragm, gallbladder, or bowel also pose a risk of injury.
Technique and Imaging:
The needle electrode is guided into the tumor percutaneously, laparoscopically, or via an open approach.
Postablation Imaging: A "zone of ablation" should encompass the tumor plus a 5-10 mm circumferential margin. Postprocedure MRI is preferred over CT for assessing viable remnant tissue.
Efficacy and Survival:
Complete Response: Series report complete radiographic response rates of 90 to 99 percent for tumors <5 cm. Rates are lower for larger lesions.
Local Recurrence: Post-therapy recurrence rates range from 3 to 29 percent at three years and 3 to 32 percent at five years.
Survival Rates: Long-term survival is well-documented.
One series reported three- and five-year survival rates for lesions ≤2, 2.1 to 5, and >5 cm were 91, 74, and 59 percent, respectively.
A Japanese analysis of 1170 patients fulfilling Milan criteria showed five- and 10-year survival rates of 60 percent and 27 percent, respectively.
Adverse Effects:
RFA is relatively well-tolerated, but severe complications can occur.
Major Complications: Occur in 2.2 to 11 percent of cases.
Procedural Mortality: 0.1 to 0.8 percent.
Specific Complications: Liver abscess, portal vein thrombosis, pleural effusion, pneumothorax, and injury to adjacent organs (diaphragm, biliary structures).
3.2. Microwave Ablation (MWA)
MWA uses electromagnetic microwaves to agitate water molecules, generating heat and causing tumor destruction. It is an acceptable alternative to RFA.
Advantages over RFA: Ability to perform multiple ablations simultaneously, potentially achieving larger ablation volumes, faster tumor ablation, and a lower heat sink effect.
Experience: Widely used in China and Japan for years; experience is increasing in the United States.
Efficacy:
Reported complete response rates range from 89 to 95 percent.
Three-year survival rates range from 51 to 81 percent.
A meta-analysis of randomized trials found similar efficacy (complete response, local recurrence, overall survival) between MWA and RFA, but local recurrence rates were significantly less for MWA in larger lesions (>2 cm).
Complications: Complication rates are comparable to RFA. One trial reported a major complication rate of 3.4 percent for MWA versus 2.5 percent for RFA.
3.3. Percutaneous Ethanol Injection (PEI)
PEI involves injecting 95 percent ethanol directly into the tumor, causing coagulation necrosis. Before RFA, PEI was the most widely accepted minimally invasive treatment.
Current Role: In the U.S., PEI is not recommended if other local ablative techniques (RFA, MWA) are available. It remains an option in resource-limited settings or for tumors in difficult locations (e.g., adjacent to the gallbladder or major blood vessels) where thermal ablation is unsafe.
Limitations: The procedure is uncomfortable, often requires multiple sessions, and visualization of ethanol diffusion on ultrasound can be difficult.
Efficacy:
Complete Response: Highly dependent on tumor size. Rates are 90-100% for tumors <2 cm, but only 50-60% for larger tumors.
Recurrence: Local recurrence is high, reported up to 38 percent for tumors up to 3 cm.
Versus RFA: Multiple studies and meta-analyses support the superiority of RFA over PEI.
Adverse Effects: Generally well-tolerated. Serious complications are rare (incidence of 2.2 percent), with a reported mortality rate of 0 percent in one large series.
3.4. Other Ablation Techniques
Cryoablation: Uses subfreezing temperatures to cause irreversible tissue destruction. It is technically easier than RFA but may be associated with higher local recurrence and complication rates. It is predominantly used in China.
Irreversible Electroporation (IRE): A non-thermal ablation method using high-voltage electrical pulses to create pores in cell membranes, inducing apoptosis. It may be preferred for tumors in "risky" locations near blood vessels, as it preserves the extracellular matrix. Long-term efficacy data is limited.
Laser Ablation: Uses light energy to induce necrosis. Although results are promising, the equipment is expensive and not widely available, with most experience being in Europe.
High-Intensity Focused Ultrasound (HIFU) & Histotripsy:
HIFU: Uses externally generated sound waves to create thermal energy. Its overall place in HCC treatment is undefined.
Histotripsy: Uses focused sound energy to create microbubbles that mechanically destroy tumor tissue. The Edison System is FDA-approved for noninvasive liver tumor destruction. Long-term outcomes data is limited.
4. Assessing Treatment Response and Post-Treatment Surveillance
Imaging and Response Criteria
Accurate assessment of response is crucial for determining treatment effectiveness and guiding further management.
Imaging Modality: Multiphase, contrast-enhanced cross-sectional imaging (CT or MRI) is required. MRI with a gadolinium-based agent is preferred due to its higher sensitivity and specificity (88 and 94 percent, respectively).
LI-RADS: The American College of Radiology's Liver Imaging Reporting and Data Systems (LI-RADS) treatment response algorithm is used to standardize the assessment.
Viable Tumor: Indicated by arterial phase hyperenhancement and washout. The absence of contrast uptake signifies nonviable tissue.
Equivocal Response: Atypical enhancement patterns are deemed equivocal.
Recurrence: Signaled by the reappearance of vascular enhancement or a new nodular, mass-like lesion in or along the treated area.
Assessing radiographic treatment response to hepatocellular carcinoma following radiation therapy
Assessing radiographic treatment response to hepatocellular carcinoma following locoregional therapy other than radiation therapy
Post-Treatment Surveillance Schedule
Patients are at risk for both local recurrence and the development of new primary tumors.
Initial Follow-up: Dynamic contrast-enhanced imaging (CT or MRI) is recommended four to six weeks after the procedure.
Ongoing Surveillance:
Imaging: Continued monitoring for recurrence or new disease every three months for at least the first year, then every six months. After two years with no evidence of disease, surveillance reverts to standard cross-sectional imaging every six months.
Alpha-fetoprotein (AFP): For patients with initially elevated levels, serum AFP should be assayed every three months for two years, then every six months.
