Clinical applicability of synchronous vs sequential transarterial chemoembolization and microwave ablation in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma remains one of the leading causes of cancer-related mortality worldwide, and locoregional therapies play a pivotal role in patients who are not eligible for surgical resection or liver transplantation. Among these, the combination of transarterial chemoembolization and microwave ablation has emerged as a promising therapeutic strategy owing to their complementary mechanisms of action. However, the optimal sequencing of these modalities - whether performed synchronously or sequentially - remains a matter of ongoing debate. Although current evidence suggests comparable short-term efficacy and safety between the two approaches, significant limitations persist, including heterogeneity in patient populations, lack of stratification by tumor burden, and insufficient long-term follow-up. In this opinion review, we critically appraise the existing literature, highlight key controversies, and present our perspective on individualized treatment selection. We emphasize that tumor characteristics, liver function, and procedural considerations should guide clinical decision-making. Finally, we outline future research priorities, including prospective stratified studies, standardized protocols, and integration with systemic therapies.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Precision medicine; Sequential treatment; Clinical applicability

Core Tip: Combination of transarterial chemoembolization and microwave ablation is an effective locoregional treatment for hepatocellular carcinoma. Synchronous and sequential strategies show similar short-term efficacy and safety, but current evidence is limited by heterogeneity, non-standardized protocols, and insufficient long-term data. Synchronous therapy is suitable for small, solitary tumors with good liver function, whereas sequential therapy is better for large, multifocal tumors or impaired liver reserve. Individualized selection and future prospective, stratified, biomarker-driven studies are needed to optimize clinical practice.

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal malignancies worldwide, accounting for a substantial proportion of global cancer-related mortality and representing a major public health challenge[1-3]. Its incidence continues to rise in many regions, driven by chronic liver diseases such as viral hepatitis, alcohol-related liver disease, and non-alcoholic fatty liver disease. Despite notable advances in surveillance programs and therapeutic strategies, a significant proportion of patients are still diagnosed at intermediate or advanced stages, when curative options such as surgical resection, liver transplantation, or local ablation are no longer feasible[4-6]. This underscores the urgent need for effective and widely applicable treatment strategies.

In this context, locoregional therapies have become the cornerstone of management for patients who are not candidates for curative treatment. Among these, transarterial chemoembolization (TACE) remains the standard of care for intermediate-stage HCC and is widely used in clinical practice due to its ability to selectively target tumor vasculature while preserving surrounding liver parenchyma[7-9]. However, the therapeutic efficacy of TACE alone is often limited by incomplete tumor necrosis and high recurrence rates, particularly in patients with larger or multifocal tumors[10].

To overcome these limitations, combination strategies integrating TACE with thermal ablation techniques have been increasingly explored. Microwave ablation (MWA), in particular, has gained attention due to its ability to generate higher intratumoral temperatures, produce larger and more predictable ablation zones, and reduce procedural time compared with conventional radiofrequency ablation[11-13]. The combination of TACE and MWA has therefore emerged as a promising approach to enhance local tumor control and potentially improve long-term outcomes[14].

The rationale for this combined approach lies in the complementary mechanisms of action. TACE induces tumor ischemia and cytotoxicity by embolizing the arterial blood supply and delivering chemotherapeutic agents, thereby sensitizing tumor tissue to subsequent thermal injury. Meanwhile, MWA achieves rapid and effective tumor destruction through coagulative necrosis, further enhancing treatment efficacy[15,16]. Importantly, embolization prior to ablation can mitigate the heat-sink effect, allowing for more complete and homogeneous thermal destruction of tumor tissue[17].

Despite these theoretical and clinical advantages, the optimal sequencing of TACE and MWA - whether performed synchronously within a single session or sequentially over multiple sessions - remains a matter of ongoing debate[18]. Current evidence is limited by heterogeneity in study design, patient selection, and outcome assessment, making it difficult to draw definitive conclusions. As such, clarifying the clinical applicability of different sequencing strategies remains a critical issue in the management of HCC.

CURRENT ADVANCES IN TACE-MWA COMBINATION THERAPY

Combined TACE-MWA therapy has been increasingly recognized as an effective strategy for improving local tumor control, primarily through the reduction of the heat-sink effect and the enhancement of ablation efficiency[19,20]. By decreasing tumor perfusion, TACE creates a more favorable thermal environment for subsequent ablation, enabling more complete and homogeneous tumor necrosis. This synergistic interaction is particularly relevant in hypervascular tumors, where blood flow would otherwise dissipate thermal energy and limit the effectiveness of ablation.

Compared with radiofrequency ablation, MWA offers several technical and clinical advantages. These include the ability to achieve higher intratumoral temperatures, generate larger and more predictable ablation zones, and reduce procedural time due to its independence from electrical conductivity[21-23]. Moreover, MWA demonstrates superior performance in minimizing the heat-sink effect compared with radiofrequency ablation, making it particularly suitable for tumors adjacent to large vessels[24]. As a result, MWA is particularly advantageous in the treatment of larger tumors or lesions located in challenging anatomical regions, where complete ablation may be difficult to achieve with conventional techniques.

Accumulating clinical evidence supports the superiority of combined TACE-MWA therapy over monotherapy in selected patient populations. Multiple clinical studies and meta-analyses have demonstrated improved local tumor control, progression-free survival, and, in some cases, overall survival with combination therapy[25-28]. However, these benefits are often influenced by tumor burden, liver function, and patient selection, highlighting the importance of individualized treatment strategies.

Beyond its local effects, emerging research suggests that TACE-MWA may also exert systemic immunomodulatory effects. Locoregional therapies can induce immunogenic cell death and promote the release of tumor-associated antigens, potentially enhancing the efficacy of immune checkpoint inhibitors[29]. This has led to growing interest in combining TACE-MWA with immunotherapy as part of a multimodal treatment approach[30].

In parallel, advances in imaging technology, navigation systems, and artificial intelligence are further refining the precision and safety of locoregional therapies. Techniques such as image fusion, real-time monitoring, and artificial intelligence-assisted planning allow for more accurate tumor targeting and treatment personalization[31-33]. These developments are expected to play a crucial role in optimizing treatment outcomes and expanding the clinical applicability of combined TACE-MWA strategies[34].

CONTROVERSIES IN TREATMENT SEQUENCING

The superiority of synchronous vs sequential TACE-MWA therapy remains unclear, and this issue continues to represent one of the most debated topics in the field[35]. Although several studies have attempted to compare these two approaches, the available evidence has not established a definitive advantage for either strategy, particularly with respect to long-term survival outcomes[36].

A major challenge lies in the substantial heterogeneity of patient populations included in existing studies[37]. Variations in tumor size, number, vascularity, and anatomical location - as well as differences in underlying liver function - can significantly influence treatment response. However, many studies fail to adequately stratify patients according to these critical factors, thereby limiting the interpretability and generalizability of their findings.

Another important limitation is the lack of standardized definitions for sequential therapy[38]. The interval between TACE and MWA varies considerably across studies, ranging from a few days to several weeks. This inconsistency not only complicates comparisons between studies but also raises questions regarding the biological and clinical implications of treatment timing[39].

Furthermore, the predominance of retrospective study designs represents a significant source of bias[40]. Retrospective analyses are inherently subject to selection bias, confounding variables, and variability in treatment protocols, which may obscure true differences between synchronous and sequential approaches. The absence of adequately powered randomized controlled trials remains a critical gap in the current evidence base[41] (Tables 1 and 2). Taken together, these limitations underscore the need for well-designed prospective studies with standardized protocols and stratified patient populations. Until such evidence becomes available, the choice between synchronous and sequential TACE-MWA should be guided by clinical judgment and individualized patient assessment rather than rigid treatment paradigms.

Table 1 Representative evidence comparing synchronous and sequential transarterial chemoembolization-microwave ablation in hepatocellular carcinoma.

Ref.	Study design	Sample size	Treatment strategy	Key outcomes	Major limitations
Wang et al[49]	Retrospective (PSM)	180	Sync vs seq	Similar short-term efficacy	Short follow-up
Shi et al[8]	Prospective	96	Sync + Immunotherapy	Improved response	No control group
Xu et al[52]	Prospective	110	TACE + MWA	Better local control	Limited generalizability
Zhao et al[17]	Meta-analysis	12 studies	Combo vs monotherapy	Better PFS	Heterogeneity
Ni et al[13]	Meta-analysis	-	Combo vs monotherapy	Better tumor control	No RCT
Abdelaziz et al[14]	Clinical trial	73	TACE + MWA	Feasible and safe	Small sample
Peng et al[12]	RCT	189	TACE + ablation	Better survival	Radiofrequency ablation-based

PSM: Propensity score matching; TACE: Transarterial chemoembolization; MWA: Microwave ablation; PFS: Progression-free survival; RCT: Randomized controlled trial.

Table 2 Clinical decision framework for synchronous vs sequential transarterial chemoembolization-microwave ablation.

Clinical factor	Synchronous approach	Sequential approach
Tumor size	Small (≤ 3 cm)	Large (> 3 cm)
Tumor number	Solitary or oligofocal	Multiple/multifocal
Liver function	Good (Child-Pugh A)	Borderline (Child-Pugh B)
Tumor location	Accessible/superficial	Complex/deep/perivascular
ECOG performance	0-1	2
Treatment goal	Curative intent	Palliative/control
Expected tolerance	Good tolerance	Compromised tolerance
Follow-up capability	Reliable follow-up	Regular monitoring feasible

ECOG: Eastern Cooperative Oncology Group.

ROLE OF TUMOR BURDEN AND BIOLOGY

Tumor burden represents a key determinant of treatment selection and clinical outcomes in HCC, influencing both the feasibility and efficacy of locoregional therapies[42-44]. In clinical practice, tumor size, number, and spatial distribution are critical factors that guide therapeutic decision-making and stratification of patients. For patients with small, solitary tumors, synchronous TACE-MWA therapy is generally favored, as it maximizes the synergistic effects of embolization and thermal ablation within a single session[45]. This approach allows for rapid tumor eradication, minimizes the risk of residual viable tumor tissue, and reduces the need for repeated procedures. Moreover, in such cases, the relatively limited tumor burden and preserved liver function enable patients to better tolerate combined treatment.

In contrast, for patients with large or multifocal tumors, a sequential treatment strategy is often more appropriate[46,47]. Staged therapy allows for interval assessment of treatment response, adjustment of therapeutic planning, and preservation of liver function, which is particularly important in patients with compromised hepatic reserve. Additionally, sequential approaches may help reduce the risk of procedure-related complications by avoiding excessive treatment intensity in a single session.

Beyond tumor burden, tumor biology also plays a crucial role in determining treatment response and long-term outcomes[48,49]. Factors such as tumor vascularity, differentiation status, and microenvironmental characteristics can influence both the effectiveness of embolization and the extent of thermal ablation. For example, highly vascular tumors may benefit more from embolization-based strategies, whereas tumors with aggressive biological behavior may require more comprehensive and multimodal treatment approaches[50].

Taken together, these considerations highlight the importance of a stratified and individualized approach to treatment selection. Rather than adopting a uniform strategy, clinicians should integrate tumor burden, biological characteristics, and patient-specific factors to optimize the sequencing and overall effectiveness of TACE-MWA therapy.

TUMOR MICROENVIRONMENT AND IMMUNOLOGICAL EFFECTS

The tumor microenvironment plays a critical role in determining the therapeutic response and long-term outcomes of HCC, particularly in the context of locoregional therapies[51-53]. Increasing evidence suggests that the biological effects of TACE and MWA extend beyond direct tumor destruction and involve complex interactions with the surrounding microenvironment[54].

TACE induces a hypoxic microenvironment by occluding tumor-feeding arteries, which can lead to the upregulation of hypoxia-inducible factors and pro-angiogenic mediators such as vascular endothelial growth factor[55]. While this process contributes to tumor necrosis, it may also promote angiogenesis and tumor recurrence, thereby representing a double-edged sword in clinical practice.

In contrast, MWA exerts its therapeutic effect through rapid thermal coagulation, which not only causes direct tumor cell death but can also trigger immunogenic cell death[56,57]. This process facilitates the release of tumor-associated antigens and damage-associated molecular patterns, potentially enhancing antigen presentation and activating anti-tumor immune responses.

These complementary biological effects provide a strong rationale for integrating locoregional therapies with systemic immunotherapy. By modulating the tumor microenvironment, TACE-MWA may convert immunologically “cold” tumors into “hot” tumors that are more responsive to immune checkpoint inhibitors[29]. This concept has gained increasing attention in recent years and represents a promising direction for future therapeutic strategies. Taken together, a deeper understanding of the tumor microenvironment may help optimize treatment sequencing, identify patients most likely to benefit from combination therapies, and ultimately improve clinical outcomes in HCC.

LIMITATIONS OF CURRENT EVIDENCE

Several important limitations should be acknowledged when interpreting the current evidence on TACE-MWA combination therapy. First, the majority of available studies are retrospective in nature, which inherently introduces selection bias and limits the ability to establish causal relationships between treatment strategies and clinical outcomes[58]. Differences in patient selection, treatment indications, and institutional practices may further confound the observed results.

Second, follow-up durations in many studies are relatively short, often focusing on early outcomes such as short-term tumor response rather than long-term endpoints including recurrence patterns, progression-free survival, and overall survival[59]. As a result, the durability of treatment effects and the true clinical benefit of different sequencing strategies remain insufficiently characterized.

Third, substantial variability exists in treatment protocols across studies[7]. Differences in embolic agents, chemotherapeutic regimens, ablation parameters, and timing intervals between TACE and MWA make it challenging to directly compare results and draw standardized conclusions. This lack of uniformity also limits the reproducibility of findings in routine clinical practice.

In addition to these factors, many studies lack comprehensive stratification based on tumor burden, liver function, and tumor biology, further reducing their clinical applicability. Collectively, these limitations highlight the urgent need for well-designed prospective trials with standardized protocols, adequate follow-up, and robust patient stratification to better define the optimal use of TACE-MWA in HCC management.

AUTHOR’S PERSPECTIVE

In our view, the choice between synchronous and sequential TACE-MWA should not be regarded as a binary or universally applicable decision. Instead, it should be conceptualized as a dynamic and patient-centered strategy, guided by tumor burden, liver function, and overall clinical context.

We propose that synchronous TACE-MWA is most appropriate for patients with small, solitary, and hypervascular tumors, particularly in the setting of well-preserved liver function. In such cases, a single-session approach maximizes the synergistic effects of embolization and thermal ablation, facilitating rapid and complete tumor eradication while minimizing treatment delays. This strategy may also reduce the need for repeated interventions and improve patient convenience.

Conversely, sequential TACE-MWA may be more suitable for patients with larger or multifocal tumors, as well as those with borderline hepatic reserve or increased procedural risk. A staged approach allows for interval assessment of treatment response, adjustment of therapeutic planning, and better preservation of liver function. Importantly, this strategy provides greater flexibility in managing complex disease patterns and may reduce the risk of treatment-related complications.

Beyond these general principles, we emphasize that tumor biology and patient-specific factors should be integrated into treatment decision-making. Factors such as tumor vascularity, anatomical location, and underlying liver disease can significantly influence both the efficacy and safety of different sequencing strategies. Therefore, rigid treatment algorithms should be avoided in favor of a more individualized approach.

Importantly, we believe that future clinical studies should move beyond simple comparisons of synchronous vs sequential strategies and instead focus on stratified, biomarker-driven treatment frameworks. Such approaches would better reflect real-world clinical practice and provide more meaningful guidance for personalized therapy.

In summary, rather than asking which strategy is superior, a more clinically relevant question is which strategy is optimal for a given patient. Addressing this question requires a shift toward precision medicine and multidisciplinary decision-making in the management of HCC. Future studies should incorporate stratification and biomarker-driven selection[60]. Future research should aim to address the current gaps in evidence and further refine the clinical application of TACE-MWA combination therapy through a more structured and precision-oriented approach. In summary, future research should move beyond conventional comparisons of treatment modalities and instead focus on integrated, stratified, and technology-driven approaches. Such efforts will be essential for advancing precision medicine and improving outcomes for patients with HCC.

CONCLUSION

Synchronous and sequential TACE-MWA represent effective and complementary strategies in the management of HCC. However, their optimal application remains context-dependent and should be guided by a comprehensive assessment of tumor burden, liver function, and individual patient characteristics. Current evidence suggests that neither approach demonstrates clear superiority across all clinical scenarios, underscoring the importance of a personalized treatment strategy rather than a one-size-fits-all approach. The integration of tumor biology, microenvironmental factors, and patient-specific risks is essential for optimizing therapeutic outcomes. Looking forward, the advancement of high-quality prospective studies, along with the incorporation of biomarker-driven stratification, immunotherapy, and artificial intelligence-assisted decision-making, is expected to further refine treatment paradigms. Such developments will be critical in transitioning from empirical treatment selection toward a more precise and individualized approach. In conclusion, the future of TACE-MWA therapy lies not in determining a universally superior strategy, but in identifying the most appropriate approach for each patient within a multidisciplinary and precision medicine framework.