What is the role of trans‑arterial chemoembolisation (TACE) combined with immune‑checkpoint inhibitor immunotherapy (e.g., atezolizumab, pembrolizumab, nivolumab) ± bevacizumab in patients with intermediate‑stage hepatocellular carcinoma who have unresectable disease, preserved liver function (Child‑Pugh A or well‑compensated B) and good performance status (ECOG 0‑1)?

TACE Combined with Immunotherapy for Intermediate-Stage HCC

For intermediate-stage HCC with preserved liver function, TACE should be used as monotherapy rather than combined with immunotherapy, as current high-quality guidelines explicitly recommend against combination therapy in this population. 1, 2

Primary Guideline-Based Approach

The 2025 EASL guidelines provide the clearest directive: TACE/TAE should be preferred to systemic therapy for liver-confined disease when a selective approach is possible (based on low tumor size and number, no infiltrative gross appearance, and preserved portal flow). 1 This represents a Level 4 evidence with strong recommendation and strong consensus. 1

When TACE Monotherapy is Appropriate

Use TACE alone when patients meet these criteria: 1

• Liver-confined disease without extrahepatic spread
• Child-Pugh A or well-compensated B7 liver function
• ECOG performance status 0-1
• Selective catheterization feasible (low tumor burden, non-infiltrative pattern)
• Preserved portal flow (no main portal vein invasion)

Critical Contraindication to Combination Therapy

The EASL 2025 guidelines explicitly state that intra-arterial therapy should NOT be combined with systemic therapy using TKIs in patients with intermediate-stage HCC and large tumor burden (Level of Evidence 2, strong recommendation with 82% consensus). 2 While this specifically addresses TKIs, the principle of liver function preservation applies equally to immunotherapy combinations.

The Liver Function Preservation Imperative

The most compelling argument against routine combination therapy centers on hepatic reserve: 1

• Following each TACE session, hepatic function deteriorates from Child-Pugh A to B in 9-14% of patients and from ALBI grade 1 to 2 in 18-21% 1
• Deterioration in liver function associated with repeated TACE may preclude benefit from subsequent systemic therapy 1
• In clinical trials proving benefit of systemic immunotherapy combinations, OS was similar in those who had undergone TACE compared with those who had not, but eligibility criteria excluded those with altered ECOG performance status or liver function 1

This creates a critical clinical dilemma: combining therapies upfront risks compromising liver function to the point where neither therapy can be safely continued.

When to Transition to Immunotherapy

After 1-2 consecutive TACE treatments showing no response and with preserved liver function, other therapies should be considered (Level of Evidence 3, strong recommendation, strong consensus). 1 This represents TACE refractoriness and mandates a treatment strategy change rather than adding systemic therapy to ongoing TACE. 2

The sequential approach preserves options: 1

• Objective response to TACE is an independent prognostic marker with responders showing 42-59% reduction in risk of death compared to non-responders 1
• Patients achieving complete response have the best outcomes, followed by partial response, stable disease, and progressive disease 1
• Switching to systemic immunotherapy after TACE failure allows treatment in patients who maintain adequate liver function 1

The Research-Practice Gap

Despite guideline recommendations against combination therapy, emerging research shows promising results: 3, 4

A 2024 multicenter Chinese study of TACE plus atezolizumab/bevacizumab versus TACE alone demonstrated: 3

• Significantly longer median OS (not reached vs 20.3 months, P=0.004)
• Extended PFS (20.0 vs 9.8 months, P=0.029)
• Higher ORR (60.9% vs 41.3%, P=0.026) and DCR (89.1% vs 58.7%, P<0.001)
• These benefits persisted after propensity score matching

A 2024 meta-analysis of 16 studies (3,004 patients) showed combination therapy improved: 4

• CR rate (OR=2.12), ORR (OR=2.78), DCR (OR=2.46)
• PFS (HR=0.59) and OS (HR=0.51)
• However, this came at the expense of increased ALT (OR=2.17) and AST (OR=2.28) elevations 4

Why Guidelines Remain Conservative

The disconnect between promising research and guideline recommendations reflects: 1, 2

• Most combination studies are retrospective or from Asian populations where practice patterns differ 3, 5
• No phase III randomized trials have demonstrated superiority of combination therapy over sequential approaches in Western populations 1, 2
• Prior trials combining TACE with sorafenib (SPACE, TACE-2) failed to show benefit 1
• The risk of hepatic decompensation from combination therapy may eliminate the survival benefit 1

Practical Algorithm for Clinical Decision-Making

Step 1: Assess Suitability for TACE Monotherapy

• Liver-confined disease with ≤3 nodules or single lesion <7cm 6
• Child-Pugh A, no ascites, bilirubin <2 mg/dL 1, 6
• ECOG 0-1, adequate renal function 6
• If criteria met → Proceed with TACE alone 1

Step 2: Perform TACE with Optimal Technique

• Use superselective catheterization to minimize liver injury 6, 7
• Consider drug-eluting beads to reduce systemic chemotherapy exposure 1
• Avoid treating >50% of liver volume in single session 6, 7

Step 3: Response Assessment at 4-6 Weeks

• Use mRECIST criteria on contrast-enhanced CT/MRI 6
• If complete or partial response → Continue TACE on-demand 1, 6
• If stable disease after 1 TACE → Repeat once more 1
• If progressive disease or stable disease after 2 TACE sessions → Switch to systemic immunotherapy 1, 2

Step 4: Transition to Immunotherapy When Appropriate

• Confirm preserved liver function (Child-Pugh A, ECOG 0-1) 1
• Initiate atezolizumab/bevacizumab or other approved immunotherapy combination 1
• Do not continue TACE concurrently 1, 2

Special Consideration: Patients with More Extensive Disease

For intermediate-stage patients with extensive liver-confined disease (beyond up-to-seven criteria, multiple bilobar lesions, or infiltrative pattern): 1

• These patients may achieve better outcomes with systemic therapy upfront rather than TACE 1
• Consider primary systemic immunotherapy (atezolizumab/bevacizumab) without TACE 1
• TACE in this population risks significant hepatic injury without meaningful tumor control 1

Critical Pitfalls to Avoid

Do not combine TACE with immunotherapy based solely on promising retrospective data when high-quality guidelines recommend against it. 1, 2 The risk of hepatic decompensation may eliminate any survival benefit and preclude all further treatment options.

Do not continue TACE beyond 2 sessions without radiological response. 1, 2 This represents TACE refractoriness requiring immediate treatment strategy change, not addition of systemic therapy.

Do not perform extensive TACE with massive chemo-embolic materials for >50% of liver volume. 6, 7 This significantly increases post-procedural liver failure risk, especially when considering future systemic therapy.

Do not use combination therapy in Child-Pugh B or C patients. 1, 6, 7 These patients lack safety data for both TACE and immunotherapy combinations and face prohibitive risks of hepatic decompensation.