Sequential treatment after transcatheter arterial chemoembolization for patients with single large hepatocellular carcinoma

Chang et al reported the prognostic factors in single large (>5 cm) hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization (TACE).¹ Their radiological responses of complete response (CR, 8.7%), partial response (PR, 24.8%), stable disease (32.9%), and progressive disease (36%) correlated to median overall survival (OS) 71.4, 44.8, 17.7, and 14.3 months respectively. Large tumor size revealed poor prognosis factors for radiological response, while worse ALBI score and unsatisfied radiological response were two additional factors for OS.

The current article shows that low tumor burden and better liver function are the key prognostic factors, with this finding being compatible to commonly used staging systems such as BCLC,² et al. HCC screening in high-risk groups³ and anti-viral treatment for patients with hepatitis B⁴ and C⁵ are essential care modalities for liver diseases; additionally, the current study also pointed out that radiological response, an on-treatment factor, was also a significant factor of OS.

In most outcome research studies, authors have focused only on initial treatment modality and included mostly non-modifiable factors. In most guidelines,^{2, 6} treatment algorithm is the same for initial or repeat treatments. Sequential treatment and on-treatment prognostic factors are sometimes mentioned. Downstaging for curative treatments such as transplantation has been reported without consistent results,^{7, 8} while TACE-failure has been discussed in this era of targeted therapy.⁹ The concept of sequential treatment was firstly documented in treatment algorithms in the latest EASL guidelines¹⁰ where recommendations for sequential treatments for BCLC stage B and C were included. The concept of sequential treatment after TACE is gaining momentum.⁹

Although TACE is recognized as non-curative treatment in most guidelines, radiologists tend to eradicate tumors. For curative modalities, treatment response should be most adequately described as CR or non-CR after two or three sessions of TACE. In the current article, OS was related to treatment response. Up to 8.8% of patients achieved CR and gained nearly 6 years of OS, especially in patients with smaller tumor size. TACE appears to play some role in the treatment of single large HCC, and whereas surgical resection is the first priority for patients with such tumors, TACE might be an alternative modality.¹¹ The current article reported that patients with smaller tumor size should have better treatment response (<10 cm) and better OS (<7 cm).

The remaining 91.2% of non-CR patients, even PR, should undergo further intervention. This means that sequential management is an issue after TACE in around 90% patients with single large HCC. The authors have stated: “If viable or residual tumors were seen at the period of surveillance, then subsequent treatment including TACE, surgery, local ablation, radiotherapy or systemic therapy was arranged based on the patient's condition and disease stage. If subsequent treatment was not suitable, the patient would receive the best supportive care.” However, details of sequential treatment after incomplete TACE were not stated in this article.

TACE has been reported as a downstage modality to meet the inclusive criteria for curative treatment. Patients beyond Milan criteria were downstaged by TACE to become candidates of transplantation.^{7, 8} Post-TACE resection extended the indication of surgical resection. Combination of TACE and radiofrequency or microwave ablation was proven to increase benefit in median-sized HCC.¹² In these situations, TACE was used as a neo-adjuvant modality of curative treatment.

In the era of targeted therapy, TACE failure is now being discussed. It has been included in several guidelines, with slightly discrepant definitions. If two or three sessions of TACE showed unsatisfactory response, patients would be advised to shift to other treatments. The recommendations of guidelines were to switch to or to add to targeted therapy at that time.⁹ Instead of TACE-failure, a new term “TACE-unsuitable” developed. It means that patients with high chance of TACE-failure should skip unnecessary TACE.¹³ Lenvatinib prior to TACE¹⁴ or ABC conversion¹⁵ have both been reported, indicating high-response rate systemic therapy is being used for downstaging to increase the chance of successful TACE.

A simple rule for treatment modality selection should be “local disease should be treated by local therapy, while systemic disease should be treated by systemic therapy.” Should patients after TACE-failure move to curative treatment as a concept of downstaging or move to systemic therapy as a concept of local therapy failure? As we know, local therapy can only treat existing intrahepatic lesion. Rapid new growth nodules and extrahepatic disease can be defined as systemic disease and cannot be treated by local therapy. Two situations are indicated in the definition of intrahepatic TACE failure in the JSH guidelines: (a) Two or more consecutive “ineffective responses” seen within the treated tumors (viable lesion >50%), even after changing the chemotherapeutic agents and/or reanalysis of feeding artery, on response evaluation CT/MRI after 1 to 3 months following adequately performed selective TACE; and (b) Two or more consecutive “progressions in the liver” (including an increase in the number of tumors compared to that before the previous TACE procedure), even after changing the chemotherapeutic agents and/or reanalysis of feeding artery, on response evaluation CT/MRI after 1 to 3 months following adequately performed selective TACE.¹⁰ The former ineffective response indicates the possibility of local therapy as successful local therapy has higher response rate, shorter treatment and is less expensive than systemic therapy; however, the latter should be treated by way of systemic therapy.

From this article,¹ focusing on patients with single large HCC treated by TACE, we learn: (a) Small tumor burden and good liver function resulted in good prognosis; (b) Good treatment response earns longer survival; and (c) 8.8% of patients achieved CR with a median survival of 6 years, while the 91.2% having incomplete response should undergo further management.

If the authors had not omitted the details of sequential treatment after TACE-failure, this article would have provided more useful real-world data. Based on this study, the literature and personal experience, we recommend these rules of treatment modality selection after TACE-failure: (a) With existing intrahepatic tumor without new growth nodules or extrahepatic metastasis, clinicians should determine the possibility of curative treatment such as surgical resection or loco reginal therapy; (b) Patients not being candidates of curative treatment should be switched to or additionally undergo systemic therapy; and (c) Patients who respond to systemic therapy might consider the possibility of curative treatment.

Since the CR rate of TACE is quite low, survival analysis based on single initial treatment appears inadequate. Sequential treatment is an important issue. Dynamic decision-making and selection of cross-stage multidisciplinary modalities might provide more survival benefit.