Evolution of two-stage hepatectomy: 25 years of modifications and lessons learned

Boerner et al. from Memorial Sloan Kettering Cancer Center recently published an article entitled “Long-term outcomes of patients undergoing two-stage hepatectomy for extensive colorectal liver metastasis treated with perioperative hepatic artery and systemic chemotherapy” in Annals of Surgery (1). The outcomes of two-stage hepatectomy (TSH) combined with systemic chemotherapy and hepatic arterial infusion chemotherapy (HAIC) for multiple bi-lobar liver metastases in the center were examined and evaluated. Their approach to chemotherapy is unique. HAIC for intrahepatic targets, which they have been working on, was employed in addition to common systemic chemotherapies for intra- and extra-hepatic targets (2). In this editorial commentary, the article is commented with the description of backgrounds about TSH.

The concept of TSH for bi-lobar extensive colorectal liver metastasis was first introduced by Adam et al. (the Paul Brousse team) in 2000 (3) and has evolved into combinations with portal vein embolization (PVE)/portal vein ligation (PVL) and perioperative chemotherapy. Long-term outcomes after TSH for extensive colorectal liver metastasis show excellent survival in selected patients, but high drop-out rates and morbidity still remain challenges (4). The interval duration between the first- and second-hepatectomy is reported to be 32–210 days and, therefore, the main cause of drop-out from the second hepatectomy is the tumor progression during the period (5). Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure was developed for shortening the interval duration to 1–2 weeks and minimizing drop-out rate to less than 10% (6,7). However, the original ALPPS procedure was reported as its high morbidity, and several modifications, such as partial ALPPS (8), were following. Perioperative chemotherapy, including one during interval period between the first and second hepatectomy, has been also employed in combination with TSH. However, this strategy is different from ALPPS in its nature. It aims to achieve good tumor control minimizing drop-out patients during the interval period, and also good final long-term outcomes with the combination effect of surgical removal and chemotherapy (9). Since the impacts of chemotherapy on liver regeneration and/or postoperative morbidity remains controversial (10,11), the strategy of TSH with chemotherapy tends to make the duration of the treatment longer, especially when chemotherapy is applied during its interval, for the concern. And, consequently, two-stage procedures are unavoidably associated with a long chemotherapy-free interval (CFI), which may translate into impaired chemotherapy effectiveness, higher recurrence rates, and poor oncological outcomes (12). There is currently no clear evidence proposing recommendations for the peri-TSH use of chemotherapy, when, how and how long, on the basis of the data in the literature, besides the suggestion that short CFI improves oncological outcome in the patients.

The group of Memorial Sloan Kettering Cancer Center, the authors of the article, which was commented about in this editorial, had long been working on HAIC for colorectal liver metastasis (13,14). In comparison to systemic chemotherapy, the effect of HAIC is often more potent to liver lesions but limited to those. Combination therapy with HAIC and systemic chemotherapy is employed to improve the effectiveness onto liver lesions and to decrease systemic toxicity, still keeping the effect on extrahepatic lesions. In the commented article, long-term outcomes of this combination therapy applied to TSH patients were evaluated. The outcome is remarkable with the median overall survival measured from the first hepatectomy as 45 months for the entire cohort and 65.3 months for patients completed TSH. The drop-out rate is 31%, similar to the reports of TSH with/without PVE and larger than those in ALPPS, and major complication rates of 17% and 31% in first and second hepatectomy, similar to the reports of TSH with/without PVE and less than the original report of ALPPS. However, the protocol and regimen for the combination chemotherapy with systemic and hepatic arterial infusion chemotherapies have not been established and those used for the patients evaluated in the article are also various. The patients with only HAIC or systemic chemotherapy depending on the condition were included. The durations of pre- and interval-chemotherapies were long and very different in each patient. Salvage treatments, mainly chemotherapy, were applied 53% of recurrent patients after TSH. Furthermore, ablation therapy was employed for some patients at the time of hepatectomy (1). This report in the article did not describe the strictly defined and regulated treatment regimen of TSH with HAIC and systemic chemotherapy, but it shows one of the current best results of the combination treatment using all available tools, including HAIC, for extensive bi-lobar colorectal liver metastases in the real world. This is similar to the discussion around 2000–2010 that “If a greater number of chemotherapy agents, and also surgical resection after, before or during chemotherapy, can be applied, patients with advanced colorectal carcinoma, especially with extended liver metastases who cannot get cure only with surgery, can get better prognosis”.

On the basis of this aspect, however, the data for prognostic factors are still meaningful for the approach. Completing both sequential procedures of TSH is crucial and the most important factor for long-term outcome of the patients submitted to TSH (5). Boerner et al., in the article commented in this editorial, reported size of liver tumor more than 5 cm, extrahepatic metastases prior or at the time of the first hepatectomy, and a tumor response ≥70% to neoadjuvant chemotherapy were independent predictors for the completion of TSH (1). On the other hand, in patients who completed the TSH, the following factors were reported as independent prognostic predictors after TSH: presence of concomitant extrahepatic disease, more than six liver tumors, fewer than six cycles of preoperative chemotherapy, absence of postoperative chemotherapy, major complications after the second stage, absence of repeat surgery for recurrence, first recurrence occurring at multiple sites, and the presence of a RAS mutation. Both for the completion of TSH and the long-term survival after TSH, tumor burden (such as size and number), presence/absence of extrahepatic lesions, chemotherapy application and response, and salvage treatment for recurrence after TSH should be important. The pathological response to chemotherapy at the first hepatectomy, instead of RAS mutation which was not detected as a significant factor, was shown as a predictor for completion of TSH in the report by Boerner et al. Although the reports were all retrospective, including the one commented in this editorial, these factors should be paid attention and further study should be performed, in order to select optimal patients for TSH and render their prognosis better. Furthermore, recent advances such as the minimally invasive approach to TSH (15) may help to overcome some of the current limitations of TSH.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-aw-772/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-aw-772/coif). The author has no conflicts of interest to declare.

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