Radiofrequency ablation for intrahepatic cholangiocarcinoma: a tool upon the path of integrative modalities?

KEYWORDS:

• Radiofrequency ablation
• cholangiocarcinoma
• ablation
• intrahepatic cholangiocarcinoma
• biliary tract cancer

1. Introduction

The term cholangiocarcinoma (CCA) encompasses a group of aggressive and heterogeneous malignancies, including intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA) [1,2]. Although radical surgical resection and liver transplantation remain the only curative approach for iCCA, less than one third of patients are diagnosed with resectable disease, and even following radical surgery, recurrence rates still remain high [3].

More than ten years after the publication of the ABC-02 trial, the combination of cisplatin plus gemcitabine (CisGem) remains the standard first-line treatment in patients with metastatic iCCA [4]. However, the survival benefit of CisGem is limited, with poor response in the most of iCCA patients resulting in a median survival of less than a year. Novel therapies are ushering in a new era of iCCA management, as witnessed by the exploration of immune checkpoint inhibitors and targeted therapies including Fibroblast Growth Factor Receptor (FGFR) and Isocitrate Dehydrogenase (IDH) inhibitors [5]. In addition, locoregional therapies such as percutaneous thermal ablation modalities including radiofrequency ablation (RFA), microwave ablation (MWA), or cryoablation, brachytherapy, transarterial therapies such as hepatic arterial infusion chemotherapy (HAIC), transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) have emerged as important tools in patients with unresectable iCCA in the last two decades [6]. These locoregional therapies effectively control symptoms and improve patients’ quality of life, while prolong survival in selected patients.

RFA is probably the oldest and most well-known percutaneous thermal ablation modality for the management of iCCA [7]. RFA uses high-frequency electrical currents through the electrodes. The frictional heat is generated by fast electron vibration provokes cell death. RFA has been widely evaluated in several primary and secondary liver malignancies, as well as in other solid tumors. However, limited data are available on the safety and efficacy of RFA in iCCA.

This editorial provides a critical summary of available literature on the application of RFA in iCCA patients and discusses growing evidence exploring the application of RFA as part of integral modality in this setting.

2. Expert opinion

In the last ten years, several studies have assessed the role of RFA in patients with iCCA. Nonetheless, all these studies were retrospective, non-randomized, and commonly single-center studies or case series with small sample size. Therefore, these studies lack high-quality evidence, precluding any recommendation from the CCA medical community on the role of RFA in iCCA. In addition, current literature still lacks in specific information on the impact of several elements on clinical outcomes of iCCA patients receiving RFA, including minimal ablation margins, nodes positivity, superficially located tumors, and the proximity of major intrahepatic blood vessels. In fact, although some studies suggest a possible role for the factors above, these elements still required more robust validation in larger cohorts of patients.

One of the first studies specifically focused on this topic was a small, non-randomized series reporting the results of RFA in 6 patients with iCCA in 2010. According to the results of this study, all iCCAs with tumor size less than 4 cm showed complete necrosis, while residual tumor was reported in two patients with bigger lesions (5 cm and 5.8 cm in diameter) [8]. The next study was a retrospective analysis of 13 patients with 17 iCCA nodules undergone RFA [9]. Technical success for RFA was reported for 15 iCCA tumors (88%) with larger diameter of less than 5 cm, while RFA failed in two patients with larger lesions (7 cm and 8 cm). The same year, another single-center retrospective analysis reported the results of RFA in 10 patients with unresectable iCCA [10], and RFA was technically successful in iCCA lesions smaller than 3.4 cm in diameter, while it was not effective on lesions larger than 4 cm [10].

In another retrospective study conducted on a slightly larger sample size, 17 patients with 26 iCCA lesions (median diameter of 3.8 cm) showed an early success rate of 96.2% for the first RFA after 1 month [11]. More recently, in our retrospective study on 29 unresectable, nonmetastatic iCCA patients with 117 nodules, we reported a median overall survival of 27.5 months [12]. In addition, at a median follow-up of 39.9 months, the 1-year, 2-years, and 4-years OS rate were 89%, 45%, and 11%, respectively [12]. Moreover, a lower progression-free survival (PFS) was reported in case of tumor size equal or larger than 2 cm, with this number showing the potential to represent an important threshold value [12].

Reviewing these retrospective studies suggests the tumor size as a crucial factor which determines RFA effectiveness and clinical outcomes in patients with iCCA [13]. A non-negligible proportion of iCCA-related deaths are due to local and locoregional progression rather than distant metastases, something that supports the exploration of interventional treatments such as RFA. In addition, percutaneous thermal ablation modalities such as RFA have the potential to downstage the iCCA, and thus, to increase the chance of resection and to play a fundamental role in ‘conversion’ strategies [14,15].

Another important factor is that the aggressive and commonly multifocal nature of iCCA highlights the importance of utilizing a combination of different treatment approaches, including surgery, RFA, and medical therapies. In particular, the introduction of novel agents targeting specific molecules such as the recently approved FGFR inhibitor pemigatinib, paves the way toward the exploration of these treatments in combination with RFA and other locoregional therapies [16–18]. The use of locoregional oncological therapies such as RFA may potentially beneficiate an important amount of iCCA patients that are deemed ineligible for curative resection or liver transplantation. Soon, well-designed clinical trials are required to find integrated strategies to improve clinical outcomes of RFA in this rare and aggressive malignancy.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.