Hepatocellular carcinoma (HCC) continues to pose a significant public health challenge, ranking as a leading cause of cancer-related deaths worldwide in 2020. Primarily arising on a background of underlying liver diseases or cirrhosis, its staging is primarily guided by the complex interplay of tumour burden, underlying liver function and performance status assessments. The BCLC criteria, widely adopted and updated in 2022, have pioneered such a decision-making process and define stage 0 and A HCCs as eligible for curative treatments among liver transplantation (LT), liver resection (LR) and ablative therapies (AT).¹ The present issue of Liver International is publishing a study conducted by Boros et al.² It focuses on the outcomes of transplantable patients diagnosed with HCC on cirrhosis who underwent first-line multi-bipolar radiofrequency ablation (mbpRFA) and were subsequently evaluated for salvage transplantation during follow-up.

Liver transplantation is recognized as the optimal—sometimes the only—curative option, as it addresses both cancer and cirrhosis, the primary driver of liver cancer. Consequently, an indication of LT is continuously considered for BCLC 0-A patients. LT is nevertheless a limited resource constrained by a global shortage of organ donors posing socio-economical quandaries; for HCC, its indication is a balanced decision that weighs its expected benefits against the risk of dropping out from the waiting list. Hence, LR and AT are often first-line treatments considered for BCLC 0-A patients, especially with solitary lesions overall included in a strategy considering salvage LT to treat the recurrence.³ Therefore, patients' transplantability at first recurrence, for example, recurrence within Milan criteria, is a major prognostic factor. Indeed, the chances of cure for HCC patients after LR or AT do not exceed 40%⁴; their first recurrence, including local recurrence or de novo tumours, must be anticipated as part of their management.³

Compared to LR, AT, primarily performed using percutaneous monopolar radiofrequency (RFA), is now considered a standard treatment for BCLC 0 HCCs,⁵ allowing for up to 90% of complete response and 5-year recurrence-free survival (RFS) and overall survival (OS) exceeding 40% and 70%, respectively.⁶ RFA's significant advantages include its cost-effectiveness and minimal invasive nature, translating into consistently reported better short-term outcomes (vs. LR).⁷ Furthermore, it is an elegant option for patients ineligible for LR or treatment of HCC recurrences.⁸ LR is, however, still regarded as providing better and ‘anatomical’ margin control, likely to correlate with a lower risk of local recurrence, especially when tumour diameter exceeds 3 cm or in case of perivascular location,⁹ for which AT is associated with a decreased objective response rate and an increased risk of recurrence.¹⁰

The main drawback of monopolar ablative techniques (including RFA), directly correlated with tumour size, is the limited and inhomogeneous necrotic volume they induce, raising concerns regarding margins and destruction of satellite nodules. No-touch mbpRFA has recently been introduced as outperforming these limits.¹¹ It provides better sustained local tumour control with increased ablative volume, possibly performed without the direct punction of the tumour,¹¹ making it a suitable treatment even for small intra-hepatic cholangiocarcinoma.¹² This technique showed encouraging results for BCLC A patients with solitary HCCs up to 5 cm in diameter compared to LR, especially when included in salvage transplantation strategies.¹³

Boros et al.'s study² emerged from a centre with extensive expertise in first-line HCC treatment using AT, especially mbpRFA. It focuses on the long-term outcomes of a homogenous population of BCLC 0-A HCC cirrhotic patients deemed transplantable at the diagnosis with subsequent consideration of salvage LT at recurrence.

Among their cohort of 432 cirrhotic patients with HCC(s) within Milan criteria treated by mpbRFA, 172 were deemed transplantable at the initial diagnosis (i.e. age ≤70 years, social ability, no active alcohol consumption, no extra-hepatic cancer, no severe comorbidities). These patients were a mix of BCLC 0-A with a median tumour size of 22 mm, including 77% of solitary tumours, and a median MELD of 9.^6-20 After mpbRFA, they had excellent short-term outcomes (no treatment-related mortality, 3% of severe complications, 99% of complete ablations). After 87 months of median follow-up, these patients experienced 3- and 5-year OS of 75% and 61%, demonstrating favourable results of first-line mpbRFA in this setting.

The authors advocate extending the concept of salvage transplantation beyond the first recurrence, as their favourable results suggest treating isolated recurrences with repeat ablation regardless of patient transplantability. In their series, 118 patients experienced a first recurrence of HCC, with 81% within Milan criteria. The median RFS was 25 months. Seventy-seven patients (65%) received another percutaneous ablation to treat the recurrence. While 75 patients (64%) were deemed transplantable at the first recurrence, only 48 were listed during the follow-up period, including 38 for recurrence (first or subsequent). Eventually, 41 patients underwent transplantation. Five-year post-transplant OS was 72%, with only one patient experiencing HCC recurrence.

This study further supports mbpRFA as an acceptable first-line treatment for BCLC-A patients, as reflected with 5-year OS comparable to intention-to-treat analysis of HCC patients listed in Europe as well as a rate of ineligible patients for salvage transplant approaching estimated drop-out risk (approximately 20%). A significant proportion of first recurrences (and most local ones) were treated with an additional mbpRFA, resulting in favourable survivals (3- and 5-year RFS were 76% and 66% for patients with recurrence). It emphasizes that local disease control may be sustained with iterative mbpRFA, highlighting an advantage of AT regarding its minimally invasive access. By delaying LT indications with iterative local treatments, authors are likely refining the selection of LT candidates, thereby sparing liver grafts from the donor pool.

The absence of pathology, particularly regarding microvascular invasion and satellite nodules, remains a significant limitation in treating BCLC A patients with AT. These factors are well documented to correlate with the risk of recurrence.¹⁴ They are offering crucial guidance in the decision-making process, refining the indication of pre-emptive LT or immediate salvage LT (vs. iterative AT/LR) upon first recurrence.¹⁵ However, promising tools are emerging from imaging, tumour biomolecular profiling, omics and circulating DNA, likely employing deep learning and artificial intelligence.^{16, 17} This will open new avenues for accurately predicting recurrence risk without relying on surgical specimens.

As ablative modalities have evolved over two decades, so has surgery. Minimally invasive surgery (MIS) is primarily represented by conventional laparoscopy and, more recently, by robotics. MIS has been embraced by most liver surgeons worldwide. It is widely adopted, especially for small and easily accessible lesions (e.g. BCLC 0-A), as documented by various standardized difficulty scores. MIS has been reported to improve post-operative recovery and prognosis, particularly by reducing the risk of liver decompensation and enhancing the quality of care.^{18, 19} In many ways, laparoscopic and robotic approaches hold promise in combining the advantages of LR and AT, notably as the latter is feasible under surgical control. This area of research requires further investigation, as most studies comparing AT versus LR involve heterogeneous surgical populations that incorporate multiple approaches.

In clinical practice, LR, MIS and AT are likely complementary options influenced by local expertise, tumour size, number and location and specific technical challenges associated with each technique (such as vessel/surface proximity for AT or dealing with posterosuperior segments for MIS). It becomes evident that minimally invasive approaches enabling sustained local responses, such as MIS or mbpRFA, will play a predominant role in the coming years over open surgery for selected BCLC A cases, especially in the context of transplantable patients. How the advent of neoadjuvant and adjuvant therapies will influence first-line treatment and indications for transplantation is to be determined.²⁰

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

The author declares no conflict of interest.