Revisiting the two-stage hepatectomy and hepatic arterial infusion chemotherapy for colorectal liver metastases: insights and long-term outcomes from a large cohort

Complete resection of all colorectal liver metastasis (CRLM) is associated with improved survival. However, achieving a complete resection in patients with extensive disease, while preserving sufficient residual functional liver parenchyma, remains challenging and, in many cases, not feasible. Since it was first described over two decades ago (1), the two-staged hepatectomy (TSH) has been further refined and has become a cornerstone surgical approach for patients with extensive CRLM deemed unresectable in a single procedure. Advancements in perioperative management focused on optimizing the future liver remnant (e.g., portal vein embolization), and improvements in systemic chemotherapy regimens have further expanded the number of patients eligible for this potentially curative procedure. Nevertheless, disease progression during the inter-stage interval remains a major limitation of the TSH, which often leads to inferior outcomes and could render patients ineligible for the second procedure (2,3).

Recently, Boerner et al. published a large retrospective single-center series from the Memorial Sloan Kettering Cancer Center (MSKCC) reporting on the long-term outcomes of 183 patients who underwent a TSH with perioperative systemic chemotherapy, furthermore, 85% of included cases received hepatic arterial infusion of chemotherapy (HAIC) before or after the first procedure (4). Successful completion of a TSH, achieved in nearly 70% of patients, resulted in a median overall survival of 65 months, compared to only 21 months in patients who failed to undergo the second procedure (4). This translated into a predicted 5-year overall survival of 53% among patients completing both procedures (4). Furthermore, the authors reported acceptable morbidity and mortality rates (4).

Importantly, beyond reporting oncological outcomes, this study also identified clinical parameters predictive of treatment failure. On multivariate analysis, the presence of large CRLM (>5 cm) and extrahepatic disease were both independently associated with an increased risk of failure to complete the TSH (4). In contrast, a maximum pathological tumor response of ≥70% to preoperative chemotherapy was independently associated with successful completion of the TSH (4). These findings emphasize the crucial importance of not only technical feasibility but also tumor biology in determining long-term outcomes. Moreover, these results highlight that extrahepatic disease should be regarded as a negative prognostic indicator when considering TSH, but they also suggest that a favorable response to perioperative chemotherapy may justify TSH in patients with extensive disease (4,5).

The use of HAIC in this series is of particular importance. HAIC was developed several decades ago by Dr. Nancy Kemeny at MSKCC as a treatment for CRLM (6-8). HAIC is most commonly used in an attempt to reduce the tumor burden and downstage a patient with unresectable CRLM to resection, or provide durable disease control (9-11). Despite the encouraging data, HAIC has not been widely accepted and several limitations must be acknowledged. HAIC requires surgical pump implantation and specialized expertise. Furthermore, there are significant concerns regarding chemotherapy-associated hepatotoxicity, however, Boerner et al. reported low rates of postoperative liver failure and low mortality rates, indicating that their regimen is both feasible and safe when performed in specialized centers (4,6). In recent years, several centers in North America and Europe have started HAIC programs (9-11). In this series, HAIC was used in 67% of patients after the first surgery. In 25% of patients HAIC was commenced prior to the first procedure due to initial unresectability, and a small proportion of patients did not receive HAIC due to medical reasons, patient preference, or logistical reasons. The routine use of HAIC in this cohort may partly explain the favorable survival outcomes and high R0 resection rates observed after the second procedure (4). However, given the limited evidence on HAIC outside major referral centers, the generalizability of these results should be interpreted with caution. In addition, the benefit of HAIC in patients with systemic or extrahepatic disease, present in 1/4 patients of the MSKCC cohort, remains uncertain and raises questions whether HAIC in these patients is ontologically justified (4).

It should also be noted that 56% of patients in the MSKCC cohort received a portal vein embolization, suggesting that a large proportion of the cohort might have had adequate liver function. This further questions whether all included cases truly required a two-staged approach. Furthermore, 34% of patients in the MSKCC cohort underwent simultaneous colorectal resection during the first procedure. Whether this reflects logistical factors or a planned approach was not specified but may have influenced timing and outcome. Lastly, this study did not detail the duration and number of HAIC cycles administered, making it difficult to assess the true contribution of HAIC (4).

Despite the favorable outcomes following complete TSH, nearly 90% of patients developed a recurrence within the first 5 years (4). Most recurrences were extrahepatic, luckily, the majority of these patients were eligible for salvage therapy (4,12). These findings reinforce the importance of a structured long-term follow-up and timely initiation of additional treatment.

Interestingly, Boerner et al. reported declining TSH completion rates over the duration of the study, likely due to broader indications and a less stringent patient selection. This observation also highlights the vulnerability of these patients to disease progression during the inter-stage interval. To mitigate this risk, alternative approaches such as the ALPPS procedure (associating liver partition and portal vein ligation) have been proposed to shorten the inter-stage interval (13,14). Although results appear promising and the ALPPS procedure seems to produce higher resection rates, whether this strategy truly translates into improved oncological outcomes remains to be established (13,14).

In conclusion, Boerner et al. provided convincing evidence that TSH in combination with systemic chemotherapy and HAIC, can achieve favorable long-term survival in a carefully selected group of patients with extensive CRLM. In addition, clinical parameters have been identified to help predict the likelihood of a successful completion of the TSH. Their findings further emphasize the importance of biologically driven patient selection, the integration of regional chemotherapy where available, and a strict postoperative surveillance to optimize outcomes. Finally, this study reminds us that the success of a TSH depends not only on surgical expertise but also on thoughtful patient selection, multidisciplinary care, and timely salvage strategies in case of recurrence.

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-2025-738/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-738/coif). The authors have no conflicts of interest to declare.

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References

1. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: A planned strategy to treat irresectable liver tumors. Ann Surg 2000;232:777-85. [Crossref] [PubMed]
2. Wicherts DA, Miller R, de Haas RJ, et al. Long-term results of two-stage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 2008;248:994-1005. [Crossref] [PubMed]
3. Turrini O, Ewald J, Viret F, et al. Two-stage hepatectomy: who will not jump over the second hurdle? Eur J Surg Oncol 2012;38:266-73. [Crossref] [PubMed]
4. Boerner T, Gagnière J, Margonis GA, et al. Long-Term Outcomes of Patients Undergoing Two-Stage Hepatectomy For Extensive Colorectal Liver Metastasis Treated With Perioperative Hepatic Artery and Systemic Chemotherapy. Ann Surg 2025; Epub ahead of print. [Crossref]
5. Narita M, Oussoultzoglou E, Jaeck D, et al. Two-stage hepatectomy for multiple bilobar colorectal liver metastases. Br J Surg 2011;98:1463-75. [Crossref] [PubMed]
6. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999;341:2039-48. [Crossref] [PubMed]
7. Creasy JM, Sadot E, Koerkamp BG, et al. Actual 10-year survival after hepatic resection of colorectal liver metastases: what factors preclude cure? Surgery 2018;163:1238-44. [Crossref] [PubMed]
8. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34. [Crossref] [PubMed]
9. Buisman FE, Grünhagen DJ, Homs MYV, et al. Adjuvant Hepatic Arterial Infusion Pump Chemotherapy After Resection of Colorectal Liver Metastases: Results of a Safety and Feasibility Study in The Netherlands. Ann Surg Oncol 2019;26:4599-607. [Crossref] [PubMed]
10. Chakedis J, Beal EW, Sun S, et al. Implementation and early outcomes for a surgeon-directed hepatic arterial infusion pump program for colorectal liver metastases. J Surg Oncol 2018;118:1065-73. [Crossref] [PubMed]
11. Creasy JM, Napier KJ, Reed SA, et al. Implementation of a Hepatic Artery Infusion Program: Initial Patient Selection and Perioperative Outcomes of Concurrent Hepatic Artery Infusion and Systemic Chemotherapy for Colorectal Liver Metastases. Ann Surg Oncol 2020;27:5086-95. [Crossref] [PubMed]
12. Cardona K, Donataccio D, Kingham TP, et al. Treatment of extensive metastatic colorectal cancer to the liver with systemic and hepatic arterial infusion chemotherapy and two-stage hepatic resection: the role of salvage therapy for recurrent disease. Ann Surg Oncol 2014;21:815-21. [Crossref] [PubMed]
13. Hasselgren K, Røsok BI, Larsen PN, et al. ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO. Ann Surg 2021;273:442-8. [Crossref] [PubMed]
14. Petrowsky H, Linecker M, Raptis DA, et al. First Long-term Oncologic Results of the ALPPS Procedure in a Large Cohort of Patients With Colorectal Liver Metastases. Ann Surg 2020;272:793-800. [Crossref] [PubMed]