Maximizing the “toolbox” for patients with initially unresectable colorectal liver metastases: have liver mets “met” their match?

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second most common cause of cancer related deaths (1). Up to 50% of patients with CRC will develop colorectal liver metastases (CRLM) during their disease course, for which the only opportunity for cure is resection or ablation (2,3). Unfortunately, many patients with CRLM are not surgical candidates due to a variety of factors, including concomitant distant metastases, burden of liver disease, vascular involvement, or functional status. In recent years, increased interest in a multidisciplinary approach to these patients and the utilization of a variety of systemic and locoregional therapies have grown. The goal of these multimodal therapies is to control disease systemically and locally, potentially increasing the number of initially unresectable patients who are downstaged and able to undergo curative intent surgery. The indications for surgery, which was previously reserved for those with low volume, oligometastatic liver disease, has expanded to patients with large volume liver disease (>10 liver metastases), who previously may have only been considered for palliative therapies. However, as the so-called “toolbox” of therapies is growing, there remains no consensus on the optimal sequence, combination, or patient selection for these different approaches and certainly no strong evidence to guide which cases to pursue aggressive surgical resection or ablation for high volume CRLM.

We commend the authors Lu et al. for their work “Survival of hepatectomy in colorectal cancer patients with ten or more liver metastases: a retrospective cohort study of multidisciplinary treatment” for their contributions to addressing this question (4). The authors performed a retrospective cohort study to identify patients with 10 or more liver metastases who were initially considered unresectable and received systemic therapy between 2010 and 2022 at a single institution. These patients were further split into three groups based on additional therapies: (I) hepatic surgery with/without radiofrequency ablation (RFA) and systemic therapy (n=118); (II) RFA with systemic therapy but without hepatectomy (n=106); and (III) systemic treatment alone (n=149). The main outcomes were overall survival (OS) and progression-free survival (PFS). Significant survival differences were found among the groups with 3-year OS rates of 39.2% for the surgery ± RFA and systemic group compared to 18.6% in the RFA + systemic therapy group and 8.2% for the systemic therapy alone group. A nomogram was developed, which identified six independent risk factors for survival: primary tumor location (left colon/rectum vs. right colon), KRAS/NRAS/BRAF mutational status, duration of conversion therapy (<4 vs. ≥4 months), early tumor shrinkage (ETS), treatment response based on RECIST (partial response, stable disease/progressive disease), and therapy regimen. From this nomogram, the authors developed three risk groups (low, middle, high) and found significant survival differences between the groups (P<0.001).

When evaluating the population of this study, there are a few points that might prevent the generalizability of the results. Although a large cohort (n=373), the population is exclusively Asian/Pacific Islander. These patients likely have different risk factors for background liver disease and liver reserve than the Western population, in which metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to 40% of adults in the United States, possibly impacting their ability to tolerate aggressive liver resections, especially after chemotherapy (5). Given the retrospective nature of the study, performance status in the form of Eastern Cooperative Oncology Group (ECOG) performance status, American Society of Anesthesiologists (ASA) score, or another surrogate for baseline function would be helpful to include in the multivariable analysis to account for its non-negligible impact on the selection of those who were offered a hepatectomy. It is also important to acknowledge the influence of tumor biology on survival, which confounds the conclusions. The study found that patients who converted to resectability within four months had better survival compared to those with longer duration of therapy, which indicates that more favorable and responsive tumor biology likely also influences survival in addition to surgical resection. Conceptually, we agree with Lu et al. that there is likely a survival benefit of a hepatectomy in these patients as it represents the most durable option for cure, however the question remains what is the most beneficial locoregional therapy [RFA, hepatic artery infusion with chemotherapy (HAI-C), etc.] to downstage those initially deemed unresectable.

Other promising locoregional therapies have been shown to be effective in patients with CRLM in recent years, such as ablation and HAI-C. The recent COLLISION trial randomized patients with 1–10 small (<3 cm) CRLM to surgical resection or open, laparoscopic, or percutaneous ablation and found the OS for patients who underwent ablation was non-inferior to resection with fewer adverse events, shorter hospital stay, and non-inferior local control (6). The study by Lu et al. included patients with more extensive disease burden (>10 lesions), and patients who underwent RFA + systemic therapy had worse survival than those who underwent resection. This is not entirely surprising, as there was likely a logistical, pathophysiological, or functional reason why those patients did not undergo resection, and it is unclear the aggressiveness or completeness of the ablations in this study, as >10 metastases may require an exhaustive effort. Despite the findings of the COLLISION trial, the study by Lu et al. shows that surgery combined with RFA could be a more appropriate modality than RFA alone in the setting of more extensive liver metastatic burden.

As Lu et al. briefly mention, another treatment modality for locoregional control is HAI-C, which in the U.S. is increasingly considered in well-selected patients with initially unresectable CRLM or resectable CRLM with high risk of recurrence (7). Notably, while the patients in this study had the aforementioned indications, they did not report any patients who underwent HAI-C, and we therefore cannot contextualize the role of HAI-C in this particular study’s population or interventions. HAI-C can be especially useful in this subset of patients with greater than 10 bilobar metastases, as resection can be difficult and extensive, and depending on practice patterns, surgeons may not consider this disease burden to be resectable. The practice at some centers is to place a HAI pump and resect/debulk in appropriate candidates or try to convert to resectability in unresectable candidates. In one study of chemotherapy-naïve patients with unresectable CRLM who underwent HAI pump placement and systemic therapy (n=58), 55% converted to resection. Of those who underwent resection, 22% had a complete pathological response and 38% had a major pathological response (8). A meta-analysis found the conversion to resection rate in unresectable CRLM patients was 31% for patients who underwent HAI-C, 20% for transarterial chemoembolization with systemic therapy (TACE-S), 35% for doublet therapy [FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin), FOLFIRI (folinic acid, 5-fluorouracil, irinotecan)], and 53% for FOLFOXIRI (5-fluorouracil, folinic acid, oxaliplatin, irinotecan) triplet chemotherapy (9). However, a subgroup analysis showed that the HAI-C arm actually had comparable outcomes to the FOLFOXIRI arm with less toxicity. The ongoing EA2222/PUMP trial aims to directly compare HAI-C combined with standard of care chemotherapy to chemotherapy alone in an effort to investigate if adding HAI-C to systemic therapy upfront, instead of after chemotherapy has failed, will improve oncologic outcomes (10).

Although not the focus of this paper, liver transplantation (LT) remains a promising treatment for a similar, well-selected group of patients, in whom there is liver-only disease without progression on systemic therapy. Prior small trials have shown that in highly selected patients, 5-year OS was 60% in SECA-I (n=21) and 83% at five years with a median follow up of 38 months in SECA-II (n=15), which had a stricter selection criteria (11,12). More recently, the TransMet trial showed similar promise in a larger cohort (13). Across 20 tertiary centers in Europe, 94 patients were randomly assigned to LT + chemotherapy (n=47) or chemotherapy alone (n=47) with 36 and 38 patients undergoing their respective assigned treatments. Median follow-up was 59.3 months, and in an intention-to-treat analysis, the 5-year OS was 56.6% for the LT + chemotherapy group compared to 12.6% for the chemotherapy alone group. These studies show the potential efficacy of LT for the treatment of these patients, but others illustrate the immense importance of patient selection, particularly with a limited resource. In a study of patients (n=10) initially excluded from SECA-II (e.g., extrahepatic disease previously resected, poor response to chemotherapy, progressive disease, or less than one year from primary diagnoses) who were transplanted with extended criteria donors, the median disease-free survival and OS were only 4 and 18 months, respectively (14). The organ shortage in the U.S. and elsewhere presently limits LT from being the primary approach to this disease, and post-transplant immunosuppression complicates future consideration for immunotherapy. As more data has become available, an increased number of centers have formed dedicated transplantation oncology teams to identify donors (both living and deceased) for a highly selected group of patients (15). Since organ supply and allocation are expected to remain an issue in certain geographic regions, we believe that studies which demonstrate the effectiveness of options other than transplantation, such as that by Lu et al., are critical to continuing to improve outcomes in this patient population.

The ultimate goal of locoregional therapies in patients with unresectable CRLM is to decrease disease burden and potentially convert select patients to a resectable state. According to international guidelines by the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO), surgical resection should be considered the first-line treatment for CRLM, however for what extent of disease burden has not been clearly delineated (16,17). A multidisciplinary and individualized approach provided by a team of physicians who are well-versed in the available multimodal systemic and locoregional therapies is critical for these patients. The “toolbox” for liver-directed therapy includes modalities that have been around for decades including HAI-C, stereotactic body radiation therapy (SBRT), thermal ablation, transarterial radioembolization (TARE), and TACE, as well as new and yet to be proven technologies such as irreversible electroporation and histotripsy (18-21). Due to the sheer number of combinations and sequences of these approaches, as well as impact of tumor location and biology, definitive guidelines are not yet established. Through ongoing randomized controlled trials and further retrospective work such as that by Lu et al., the hope is that clear evidence-based guidelines will become available which utilize resources appropriately and offer this heterogeneous patient population the most individualized care and best opportunity at long term survival.

Acknowledgments

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.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0267/coif). E.S.C. reports research collaborations with Affimed GMBH, Parabilis, Haystack, Incyte, NextCure, Pfizer, and Regeneron; and consulting role in Boston Scientific, Parabilis, Roche, Seres Therapeutics, SirTex, Tatum Biosciences, and Urogen. 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 or integrity of any part of the work are appropriately investigated and resolved.

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