Advanced approaches to loco-regional and surgical management for hepatocellular carcinoma

We commend the authors Yan et al. for their work “Trans-arterial chemo-emobilization (TACE) combined with laparoscopic portal vein ligation and terminal branches portal vein embolization for hepatocellular carcinoma: a novel conversion strategy” (1). Yan et al. describe a novel and somewhat heroic strategy to provide safe resection for patients with hepatocellular carcinoma (HCC), primarily in patients with limitations in the proposed functional liver remnant (FLR) that preclude traditional resection. Such surgical innovation is critical to the ongoing improvement of our collective ability to provide potential cure for patients with advanced and complicated liver disease. Our aim is to highlight some critical developments from this manuscript as well as discuss some limitations and alternative considerations for surgeons in various clinical contexts.

First, the simultaneous single-staged performance of the laparoscopic portal-vein ligation and portal vein embolization (PVE) is novel with its performance in a hybrid operating room. This undoubtedly poses clinical and logistical challenges, and we applaud this ingenuity. Such ingenuity mimics that of Baimas-George in 2019 who described associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as a strategy for FLR augmentation prior to ex vivo hepatectomy, turning tumors that are un-resectable to operable cases (2,3). However, the Charlotte experience is now teaching us that even extreme liver surgery can be preceded by FLR-augmentation using hepatic venous deprivation (HVD), which has also been demonstrated in large studies to significantly improve FLR-augmentation and can be effectively followed by major hepatectomy (4,5). Indeed, Kobayashi and others have emphasized how HVD may preclude the need for ALPPS in many cases, thus sparing the patient the need for two operations (6,7). ALPPS represented an advancement of PVE by obliteration of blood flow across Cantlie’s line, which is also the mechanism for PVE + segment-4 embolization (8-10). This study seems to describe only portal vein ligation (PVL) plus PVE without liver partitioning, which essentially makes the approach similar mechanistically to HVD, which improves PVE by preventing hepatic venous back-bleeding. The potential clinical impacts of this are emphasized by recent evidence showing that prolonged operative time is associated with reduced outcomes, thus highlighting strategies that prevent the need for long and complex operations may improve outcomes (11). We pose the question to Yan et al. how they might integrate HVD in their practice moving forward, particularly given their groups’ clear expertise in advanced hepatic embolization techniques and their employment of this mechanism in the described group.

The authors highlight a first-staged laparoscopic approach. However, they do not specifically address whether stage II of this approach is performed using any minimally invasive techniques. We would be curious if they indeed have been able to use either laparoscopic or robotic approaches to improve stage II outcomes, with studies demonstrating that minimally invasive (MIS) hepatectomy improves outcomes in patients with early-stage cirrhosis (12). There are good data to suggest that robotic approach may aid with both technical operative success in MIS major hepatectomy (13,14). The previously described Japanese Difficulty Score (JDS) has now been re-applied in laparoscopic hepatectomy and may help guide centers as they begin their robotic hepatectomy experience, particularly in these complex multi-stage cases (15). Are the authors incorporating MIS hepatectomy into stage II and, if so, how is the robotic approach (if at all) factoring into their practice?

We also note that many patients in this study (92%, 12/13) had cirrhotic background liver at time of resection. The authors do not make mention of liver transplantation in this study. We are curious how selection for advanced multi-stage liver resection is considered versus liver transplantation, particularly given that only HCC was included in this series. Based on our review of the features in Tab. 2, a subset of patients were within Milan criteria (n=2), UCSF (n=5), 5-5-500 (n=3), up-to-seven (n=6) and Metroticket2.0 (n=2). Recent evidence suggests that expended criteria for transplantation do not harm post-transplant outcomes, indicating that perhaps up to half of these patients were optimal transplant candidates (16,17). Further, this assessment is before any neo-adjuvant/down-staging therapy, which has been shown to be very effective even in extremely advanced HCC, and patients with good response may be optimal transplant candidates after down-staging (18-23). While we acknowledge that avoiding transplantation is of independent value to the patients, particularly given long-term complications of immunosuppression even in patients with positive early outcomes (24). However, most included patients still have underlying cirrhosis that has not been treated, indicating that transplant may have been a reasonable approach for this cohort as well. The authors begin the discussion with the statement “…surgical resection is the only curative method”, which we feel is not representative of the option afforded by liver transplantation. With the ongoing improvement in graft availability in transplantation coinciding with the rise of machine perfusion, in the US the graft shortage is somewhat lessened of late, which may help expand access to single-staged therapy to address both HCC and underlying cirrhosis (25,26).

Finally, we are curious as to the pre- and post-operative management of these patients, and how trans-arterial chemotherapy (TACE) is selected versus other therapies. Long-term downstaging data does certainly support utility in TACE, though outcomes are suggested to be better with trans-arterial radiotherapy [trans-arterial radioembolization (TARE), Y90] and even now with immunotherapy (17,20,23,27). Both are mentioned by the authors in limitations, however we felt it was important to emphasize these options as they continue to emerge. The ischemic pre-conditioning referenced by the authors has only a weak scientific background at best, particularly with the timeline of 4–6 weeks between TACE and PVE/PVL, emphasizing that the most oncologically effective locoregional therapy (LRT) should be performed. Even less studied modalities such as histotripsy have also been suggested and are even included as down-staging options by the United Network for Organ Sharing (UNOS), and may even further reduce the need for multiple invasive therapies, though certainly no definitive statement may yet be made on this topic (28,29). We are curious why TACE is specifically selected versus Y90, stereotactic radiation (SBRT) and other techniques, and additionally if there were any complications of TACE such as hepatic abscess. Finally, the authors do not discuss advanced methods of patient selection or down-staging guidance, such as circulating tumor DNA (ctDNA), which has been suggested as a method to guide treatment response and as a method of surveillance after resection of HCC (19,30). Indeed, ctDNA is even being theorized as a method of guiding transplant selection and is combined with radiomic biomarkers to guide optimal timing of transplantation in colorectal liver metastasis (31-33). Of course, we acknowledge that this is a particular interest of group, and that its’ inclusion of the study was not mandatory, however we are curious how such technologies are being considered by the authors in their advanced experience.

Finally, it is important to note that the presented cohort is entirely cirrhotic, though early-stage, and many cirrhotic liver simply never regenerate despite in- and/or out-flow occlusion. Our opinion is that the greatest scientific question remains knowing how much to push liver molding strategies and in which patients, rather than needing new techniques for the actual occlusion themselves. This is of course a different focus to the current article, but we simply emphasize that this is an ongoing area of clinical need.

We again thank Yan et al. for their work furthering the field of oncologic liver resection and are curious how their experience will continue to grow along with the entire field as we collectively learn more about approaches to these challenging cases. We look forward to their response on these topics and admire their commitment to advancing the surgical fields.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2024-879/coif). A.S. reports that he received consulting fees from BridgetoLife. D.C.H.K. reports that he served as a Medtronics Advisory Consultant. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy of integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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