Which is better local therapy for HCC, RFA or TACE?

Đây là 1 câu hỏi trong sách “Diffi cult Decisions in Hepatobiliary and Pancreatic Surgery ‘- An Evidence-Based Approach” (sách chỉ so sánh RFA vs TACE thôi), thực ra đọc guideline thì ai cũng hiểu rằng trường hợp A phải làm phương án 1, B phải phương án 2,…nhưng tại sao không phải ngược lại, hoặc thậm chí làm cả 2 phương án thì sao?. Bài này bắt nguồn từ 1 lần hội chẩn U gan, nghe các anh chốt phương án là TACE + RFA mình mới giật mình, “ủa được luôn?”. Vậy, “Đối với HCC không thể phẫu thuật, liệu pháp điều trị tại chỗ nào tốt hơn, RFA, TACE hay RFA + TACE?”

 

I. COMPARATIVE EFFICACY AND SAFETY OF RFA, TACE, AND RFA+TACE

1. Radiofrequency Ablation (RFA)

Radiofrequency ablation is widely recognized as a first-line, potentially curative therapy for patients with very-early and early-stage HCC, particularly for solitary tumors ≤3 cm, as recommended by the American Association for the Study of Liver Diseases. In patients with Child-Pugh A liver function and no portal vein invasion, RFA achieves high rates of complete response, with 3-year overall survival (OS) rates of approximately 76% and recurrence-free survival (RFS) rates of about 46% for unifocal HCC ≤3 cm. The safety profile of RFA is favorable, with low rates of major complications such as bleeding, abscess, and pleural effusion. For tumors >3 cm, the efficacy of RFA diminishes, with higher rates of local recurrence and lower OS, although select patients with Child-Pugh A and favorable tumor biology may still benefit from RFA, especially if pre-ablation des-γ-carboxy prothrombin (DCP) levels are <200 mAU/mL and distant tumor recurrence is absent.^[7]

A large propensity score-matched analysis demonstrated that, for single HCC ≤3 cm and Child-Pugh A function, RFA was associated with significantly better OS, local tumor recurrence, and recurrence-free survival compared to TACE. Specifically, the 5- and 10-year OS rates were 81% and 61% for RFA, versus 77% and 51% for TACE (p = 0.021), with consistently better outcomes across all subgroups.^[8] These findings are corroborated by nationwide registry data, which show that both surgical resection and RFA provide superior overall survival compared to transarterial therapy in Child-Pugh A patients with a single small HCC, with the greatest benefit seen in tumors <2 cm and in younger patients.^[9]

2. Transarterial Chemoembolization (TACE)

TACE is the standard of care for intermediate-stage HCC (multinodular, preserved liver function, no vascular invasion or extrahepatic spread), but is also used in some settings for early-stage disease when ablation or resection are not feasible. The AASLD guidelines state that TACE achieves objective response rates of approximately 52.5% and median survival of 19.4 months in BCLC B patients.^[1] In Child-Pugh A patients with solitary small HCC (≤3 cm), TACE can achieve complete remission in over half of cases, with median OS approaching 6.5 years in those who achieve complete response.^[10] However, when directly compared to RFA in this population, TACE is associated with lower OS and higher recurrence rates.^[8-9] The safety profile of TACE is generally acceptable in Child-Pugh A patients, with most adverse events being mild and a low mortality rate (0.6%).^[1] Patient selection and vascular selectivity are critical to optimize TACE outcomes and minimize hepatic toxicity.

3. Combination Therapy: RFA Plus TACE

The rationale for combining RFA and TACE is to overcome the limitations of each modality. TACE can reduce tumor vascularity and mitigate the heat sink effect, thereby enhancing the efficacy of subsequent RFA, while RFA can provide definitive local control. Multiple meta-analyses and randomized studies have evaluated this combination. A recent meta-analysis of randomized controlled trials found that RFA+TACE significantly improved objective response rate, disease control rate, and survival compared to RFA or TACE alone, without a significant increase in adverse events.^[11] Specifically, the combination was associated with a 34–45% reduction in risk of death and recurrence compared to RFA alone, with median OS exceeding 5 years and median RFS around 4 years in early-stage HCC.^[12-13] The benefit of combination therapy is most pronounced in tumors >2–3 cm, in challenging locations (perivascular, subphrenic), or when there is concern for microvascular invasion or incomplete ablation.^[12][14] For small tumors (≤3 cm), the incremental benefit of adding TACE to RFA is less clear, with some studies showing improved local tumor progression rates but not OS.^[14-15] For tumors >3 cm, combination therapy consistently outperforms RFA or TACE alone in terms of both OS and RFS.^[13]

Safety data indicate that the combination of RFA and TACE does not significantly increase the risk of major complications compared to either modality alone in well-selected patients with preserved liver function.^[11][13-14] The most common adverse events are post-procedural pain, fever, and transient liver enzyme elevations, with serious complications being rare.

4. Quantitative Comparison Table

The following table provides a quantitative summary of the comparative efficacy and safety of RFA, TACE, and RFA+TACE for local HCC in Child-Pugh A patients without portal vein invasion.

Modality	Efficacy (OS/RFS)	Safety Profile	Preferred Indications
RFA	Highest OS/RFS for ≤3 cm tumors	Low complication rate	Solitary HCC ≤3 cm, Child-Pugh A
TACE	Lower OS/RFS vs RFA for ≤3 cm	Acceptable in Child-Pugh A	Unresectable, multifocal, or >3 cm tumors
RFA+TACE	Superior OS/RFS for >2–3 cm	Similar to RFA/TACE alone	Tumors >2–3 cm, perivascular, subphrenic

II. GUIDELINE-BASED TREATMENT RECOMMENDATIONS

1. International Guideline Consensus

The American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Association for the Study of the Liver (APASL) all support ablation as first-line therapy for very early and early-stage HCC in patients with preserved liver function who are not candidates for resection or transplantation, and recommend TACE for intermediate-stage disease (multinodular HCC without vascular invasion).^[1-2][17-18] The AASLD specifically recommends thermal ablation (RFA or microwave ablation) as the treatment of choice for early-stage HCC ≤3 cm, with a strong recommendation and high level of evidence.^[1] For solitary HCC >3 cm, resection is preferred if feasible; otherwise, ablation or alternative locoregional therapies may be considered, but the efficacy of RFA diminishes with increasing tumor size.^[1][19] For multinodular early-stage HCC (≤3 nodules, all ≤3 cm), ablation is recommended, with TACE reserved for cases where ablation is not feasible.^[18-19] For intermediate-stage HCC (BCLC stage B), TACE is the primary treatment modality.^[1][19] Combination therapy (RFA + TACE) may offer some benefit in recurrence-free survival at one year, but current evidence does not support a significant improvement in overall survival, and guidelines do not recommend routine use of combination therapy outside of clinical trials.^[1][20]

The updated 2022 Barcelona Clinic Liver Cancer (BCLC) staging and treatment algorithm, as shown in the following figure, provides a visual summary of the recommended treatment pathways for HCC based on tumor stage, liver function, and performance status.

The BCLC algorithm highlights that ablation is recommended for very early and early-stage HCC (single lesion <2 cm or ≤3 nodules, all ≤3 cm) in patients with preserved liver function, while TACE is reserved for intermediate-stage disease. Resection is preferred for single lesions >2 cm if feasible, and combination therapies are considered in select cases.

Updated 2022 Barcelona Clinic Liver Cancer (BCLC) Staging and Treatment Algorithm

Management of Hepatocellular Carcinoma: A Review. JAMA Surg. April 1, 2023.

2. Indications and Contraindications

Eligibility for ablation is determined by tumor size, number, and location, as well as the ability to achieve adequate ablation margins. RFA is most effective for solitary tumors ≤3 cm, and its efficacy diminishes for larger tumors or those located near major vessels or bile ducts due to the risk of incomplete ablation or heat sink effect.^[1-2][7] TACE should be performed using selective catheterization of segmental or distal branches to maximize delivery to the tumor and minimize ischemic injury to the background liver.^[1-2] Patient selection for TACE must carefully consider liver dysfunction and tumor burden to minimize toxicity, and patients with significant liver dysfunction, portal vein tumor thrombosis, or large intrahepatic tumor burden may be unsuitable for TACE.^[1-2] Combination therapy is reserved for tumors >2–3 cm, in challenging locations, or when there is concern for microvascular invasion or incomplete ablation.^[12][14]

III. QUANTITATIVE OUTCOMES AND SUBGROUP ANALYSIS

Recent meta-analyses and large cohort studies provide robust quantitative data on the efficacy of RFA, TACE, and RFA+TACE. For solitary HCC ≤3 cm, RFA achieves 5-year OS rates of 81% and 10-year OS rates of 61%, compared to 77% and 51% for TACE, respectively.^[8] Median OS for TACE in patients achieving complete remission is 89.1 months, with median RFS of 19.1 months.^[10] Combination therapy with RFA+TACE is associated with a 45% reduction in risk of death and a 34% reduction in risk of HCC recurrence compared to RFA alone, with median OS exceeding 5 years and median RFS around 4 years in early-stage HCC.^[12-13] The benefit of combination therapy is most pronounced in tumors >2–3 cm, in challenging locations, or when there is concern for microvascular invasion or incomplete ablation.^[12][14] For small tumors (≤3 cm), the incremental benefit of adding TACE to RFA is less clear, with some studies showing improved local tumor progression rates but not OS.^[14-15]

IV. PRACTICAL, QUANTITATIVE, AND ACTIONABLE RECOMMENDATIONS

For a patient with local HCC, Child-Pugh A liver function, and no portal vein invasion, the optimal therapy depends on tumor size and number. In the absence of specific lesion details, the following recommendations are based on the best available evidence and guideline consensus:

For solitary tumors ≤3 cm, RFA alone is the preferred modality, offering the best balance of efficacy and safety. RFA should be performed percutaneously under ultrasound or CT guidance, with the goal of achieving complete ablation of the tumor and a 0.5–1 cm margin of surrounding liver tissue. The procedure is typically performed in a single session, with post-procedural imaging to confirm complete ablation. The expected 5-year OS rate is 81%, with a recurrence-free survival rate of approximately 46% at 3 years.^[1][8]

For single lesions >3 cm (up to 5–7 cm), combination therapy with RFA+TACE provides superior local control and survival compared to either modality alone, without a significant increase in adverse events. TACE should be performed first, using selective catheterization and embolization with doxorubicin or cisplatin, followed by RFA within 1–2 weeks. The expected median OS exceeds 5 years, with a 45% reduction in risk of death and a 34% reduction in risk of recurrence compared to RFA alone.^[11-13] 

For multiple lesions (especially >3 or >3 cm), TACE is the mainstay, as ablation is generally not feasible. TACE should be performed using selective catheterization and embolization with doxorubicin or cisplatin, with repeat treatments every 4–8 weeks as needed based on tumor response and liver function. The expected objective response rate is approximately 52.5%, with median survival of 19.4 months in BCLC B patients.^[1-2]

All therapies require preserved liver function (Child-Pugh A) and absence of major vascular invasion or extrahepatic disease. Contraindications to RFA include tumor size >3 cm (relative), multiple lesions not amenable to ablation, lesions adjacent to major vessels or bile ducts, poor liver function (Child-Pugh B/C), and extrahepatic disease or vascular invasion. Contraindications to TACE include significant liver dysfunction (Child-Pugh C, ALBI grade 2–3, or bilirubin >3 mg/dL), main portal vein thrombosis, extensive bilobar disease (>50% liver involvement), extrahepatic disease (relative), and poor performance status.^[1-2]

V. MONITORING, FOLLOW-UP, AND MULTIDISCIPLINARY CARE

After local therapy, patients should undergo regular surveillance with multiphasic CT or MRI every 3–6 months for the first 2 years, then every 6–12 months thereafter, to monitor for recurrence or progression. Laboratory monitoring should include liver function tests, alpha-fetoprotein (AFP), and complete blood count at each visit. Adverse events should be monitored closely, with prompt management of complications such as pain, fever, bleeding, abscess, or pleural effusion. 

If recurrence or progression is detected, repeat ablation, TACE, or transition to systemic therapy (e.g., atezolizumab plus bevacizumab for high-risk patients) should be considered based on tumor characteristics and liver function.^[1] For patients with high-risk features (tumor size >2 cm but ≤5 cm, multifocal HCC), adjuvant therapy may be considered to improve recurrence-free survival.^[1]

SUMMARY AND NEXT STEPS

In summary, for local HCC in Child-Pugh A patients without portal vein invasion, RFA is preferred for small, solitary tumors (≤3 cm), while RFA+TACE is superior for larger or more complex lesions (>3 cm, up to 5–7 cm), with both approaches demonstrating favorable safety profiles in this population. TACE alone is reserved for multifocal or unresectable disease.