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. 2025 Jun 30;9:100190. doi: 10.1016/j.esmogo.2025.100190

Systemic adjuvant and perioperative chemotherapy following curative-intent liver metastasectomy in colorectal cancer—is it justified?

RD Peixoto 1,2, JM Loree 1,2, TA Miranda 1,∗, JP Solar Vasconcelos 1,2, DJ Renouf 1,2, JM Davies 1,2, K Gill 1,2, S Gill 1,2, V Poon 1,2, C Metcalf 1,2, M Chahal 1,2, MS Bleszynski 3, M Segedi 3, PTW Kim 3, HJ Lim 1,2
PMCID: PMC12836588  PMID: 41647996

Abstract

Colorectal liver metastases (CRLM) pose a significant challenge in oncological care, with surgical resection offering the best chance for long-term survival. Despite curative-intent liver metastasectomy, recurrence rates remain high, underscoring the need for effective adjuvant therapies. While adjuvant chemotherapy (AC) improves disease-free survival (DFS), evidence supporting its overall survival (OS) benefit is limited. This manuscript critically evaluates the role of AC following CRLM resection, with a focus on patient-specific factors influencing treatment outcomes across distinct clinical scenarios. The lack of stratification by molecular biomarkers in prior trials highlights a critical gap in current evidence. Future research should integrate biomarker-driven approaches, leverage circulating tumor DNA (ctDNA) for treatment stratification, and explore novel therapies, including immunotherapies and targeted agents, in both perioperative and adjuvant settings.

Key words: colorectal cancer, liver metastases, metastasectomy, adjuvant chemotherapy, perioperative chemotherapy

Highlights

  • •

    While AC following liver metastasectomy improves DFS, evidence supporting its benefit on OS is limited.

  • •

    Perioperative chemotherapy in upfront resectable CRLM shows no OS benefit and may lead to liver damage.

  • •

    ctDNA-based MRD assessment may help to identify CRLM patients who will benefit most from AC.

  • •

    Treatment decision should be individualized, considering prior therapy, biomarkers, and metastatic burden.

Introduction

Colorectal cancer (CRC) remains a major contributor to cancer-related morbidity and mortality worldwide, with colorectal liver metastases (CRLM) representing the most frequent site of distant disease spread.1,2 Surgical resection of liver metastases offers the most favorable opportunity for long-term survival, with 5-year survival rates ranging from 40% to 60% among patients undergoing curative-intent resection.3 Despite these encouraging outcomes, the recurrence rate remains high, with ∼60%-70% of patients experiencing disease relapse within 3 years post-operatively.4,5 Recurrence commonly involves the liver but can also occur at extrahepatic sites.4,5 The high recurrence risk following resection is a primary rationale for the consideration of adjuvant chemotherapy (AC), which aims to eliminate micrometastatic disease and thereby potentially cure a subset of patients. This rationale, which has been successfully applied in stage III or high-risk stage II CRC,6 is often extrapolated to the post-metastasectomy setting, although with limited empiric support.

In patients with stage III or high-risk stage II CRC, AC—particularly with regimens such as FOLFOX [5-fluorouracil (5-FU), leucovorin, and oxaliplatin] and CAPOX (capecitabine and oxaliplatin)—is the standard of care, significantly reducing recurrence risk and improving overall survival (OS).6 However, the addition of targeted agents that have demonstrated benefit in the metastatic setting, specifically cetuximab, panitumumab, and bevacizumab, have not yielded improved outcomes in the adjuvant setting.7, 8, 9, 10, 11, 12, 13 FOLFOX and CAPOX have been widely considered for patients following liver metastasectomy, although the evidence supporting AC in this context is limited and inconsistent, rendering formal recommendations challenging. The heterogeneity of patient presentations, including prior chemotherapy exposure, timing of metastasis development, and distinctions between synchronous and metachronous disease, further complicates clinical decision making. In this manuscript, we critically review the available evidence on AC following liver metastasectomy and explore the factors that influence treatment decisions across distinct clinical scenarios.

Trials evaluating adjuvant chemotherapy following CRLM resection

Several studies have examined the role of AC after curative-intent liver metastasectomy, though results have varied. The first multicenter randomized trial to assess this included 173 European patients with completely resected CRLM (R0), comparing 6 months of systemic AC with no adjuvant treatment.14 The chemotherapy regimen included intravenous bolus injections of folinic acid (200 mg/m2) and 5-FU (400 mg/m2) over 5 consecutive days, every 28 days, for six cycles. Notably, patients who had received chemotherapy within the year preceding liver surgery were excluded. The study reported that its primary endpoint, adjusted 5-year disease-free survival (DFS), was significantly higher in the AC group [33.5% versus 26.7%, odds ratio (OR) for recurrence or death = 0.66, P = 0.028]. However, the difference in 5-year OS did not reach statistical significance (51.1% versus 41.9%, OR 0.73, P = 0.13). Unfortunately, the study did not specify the percentage of patients who had received prior AC following primary tumor resection nor the specific regimens used.

Earlier studies, including two that were published as abstracts, also evaluated adjuvant 5-FU but failed to show a significant OS benefit.15,16 These trials had notable limitations, including small sample sizes (the first included only 37 patients) and premature closure due to slow accrual.15,16

A Japanese randomized trial further investigated the role of AC, comparing oral uracil-tegafur plus leucovorin (UFT + LV) for five cycles against surgery alone in 180 patients with resected CRLM.17 While the study primary endpoint of recurrence-free survival (RFS) was significantly improved with UFT/LV [hazard ratio (HR) 0.56, P = 0.003], no significant difference in 5-year OS was observed between the two groups (66.1% versus 66.8%, HR 0.80, P = 0.409). Notably, 45% of patients in this trial had synchronous disease, and subgroup analyses suggested that UFT/LV may be more effective in patients with multiple or synchronous metastases. As in the previous trial, prior AC for resected early-stage disease was allowed, although stipulated at least 3 months following the last dose, though specific data on the number of patients receiving prior treatment and the types of chemotherapy used were not provided.

A meta-analysis of trials investigating fluoropyrimidine monotherapy following radical resection of liver metastases showed no significant OS benefit in the AC group (HR 0.781, 95% confidence interval 0.593-1.030, P = 0.080).18

The potential role of irinotecan in combination with 5-FU and folinic acid was evaluated in a randomized phase III trial of 306 patients with completely resectable CRLM.19 In this trial, no significant improvement was observed in the primary endpoint of DFS. The median DFS was 21.6 months in patients receiving FOLFIRI compared with 24.7 months in those receiving 5-FU and folinic acid alone (HR 0.89, P = 0.44). Similarly, no significant differences were seen in OS. Notably, ∼37% of patients in this trial had received prior AC, and those previously treated had worse DFS outcomes, though no significant interaction between treatment arms was identified.

More recently, the JCOG0603 phase II/III trial randomized 300 patients with resected CRLM to hepatectomy alone or hepatectomy followed by 6 months of adjuvant mFOLFOX6.20 Prior AC without oxaliplatin was allowed if administered at least 3 months prior, and ∼21% of participants fell into this category. While adjuvant FOLFOX significantly improved 5-year DFS compared with surgery alone (49.8% versus 38.7%, HR 0.67, P = 0.006), no OS benefit was observed (83.1% versus 71.2%). Patients who had received prior AC had a worse prognosis, and subgroup analyses indicated that metachronous disease patients who had undergone prior AC did not benefit from additional chemotherapy. A summary of these results, along with relevant data from other cited studies, is presented in Table 1.

Table 1.

Summary of randomized trials of systemic AC and PC for resectable CRLM

Trial (first author) Number of patients Type of AC Median number of lesions Synchronous disease (%) Prior use of chemotherapy (%) 5-Year DFS (AC/PC versus no AC/PC) 5-Year OS (AC/PC versus no AC/PC)
Portier et al.14 173 5-FU/LV 1 28.2 NR 33.5% versus 26.7% (s) 51.1% versus 41.9% (ns)
Hasegawa et al.17 180 UFT/LV 3 45 NR NR 66.1% versus 66.8% (ns)
Ychou et al.19 306 FOLFIRI 1 NR 37.6 NR NR
Kanemitsu et al.20 300 FOLFOX 1-3 (median) 55.5 21 50.1% versus 37.3% (s) 71.2% versus 83.1% (ns)
Nordlinger et al.24,25 364 FOLFOX4 1 35 42 NR 51.2% versus 47.8% (ns)
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5-FU, 5-fluorouracil; AC, adjuvant chemotherapy; DFS, disease-free survival; LV, leucovorin; NR, not reported; ns, non-significant; OS, overall survival; PC, perioperative chemotherapy; s, significant; UFT, uracil-tegafur.

The findings from these randomized trials underscore that while AC following liver resection can improve DFS, it has not consistently translated into improved OS.14, 15, 16, 17, 18, 19, 20 One hypothesis for this phenomenon is adjuvant therapy-related shortening of survival (ATRESS), where AC may induce resistance in residual tumor clones.21 Another explanation for the lack of OS benefit may be chemotherapy-induced liver injury, such as sinusoidal obstruction syndrome or steatohepatitis, which can complicate the detection of recurrent disease via imaging.22,23 Early recurrence, if undetected, may only become apparent in more advanced stages, leading to worse outcomes. Conversely, patients in the surgery-only group may have liver recurrences detected earlier and undergo repeat hepatectomy, thereby improving their OS.

Perioperative chemotherapy for CRLM

Perioperative chemotherapy is often considered a standard of care for CRLM, although the supporting scientific evidence remains as limited as that for AC. The EORTC 40983 trial explored the role of perioperative FOLFOX in patients with up to four resectable CRLMs.24,25 This pivotal trial enrolled 364 patients, randomizing them to either surgery alone or six cycles of FOLFOX both before and after liver metastasectomy. The primary endpoint of the study was progression-free survival (PFS). Among the study population, 52% of patients had only one liver metastasis, 35% presented with synchronous metastases, and 42% received prior AC following resection of their primary tumor. Notably, only 44% of patients completed all 12 cycles of chemotherapy.

The results demonstrated that perioperative FOLFOX significantly improved PFS compared with surgery alone in the per-protocol analysis (P = 0.025), although statistical significance was not reached in the intention-to-treat population (P = 0.058). After a median follow-up of 8.5 years, the 3-year PFS was 35.4% in the perioperative FOLFOX group compared with 28.1% in the surgery-alone group. However, no significant difference in OS was observed between the two arms after further follow-up.25 A subgroup analysis identified an interaction between perioperative chemotherapy and certain variables, with patients exhibiting normal carcinoembryonic antigen levels, a performance status ≥1, or obesity (body mass index ≥30) experiencing harm from perioperative chemotherapy.

The 40983 trial demonstrated a 25% reduction in tumor size; however, the clinical significance of a 25% reduction in tumor volume for hepatic disease that is already potentially resectable remains uncertain. Notably, this study revealed that patients in the surgery-only group had a 10% likelihood of being unresectable at the time of operation due to disease progression, compared with 4% in the perioperative chemotherapy group. This finding underscores the role of perioperative chemotherapy in aiding the assessment of surgical stability. However, another critical consideration is that the EORTC trial was conducted before the availability of advanced imaging technologies, such as magnetic resonance imaging (MRI) with hepatospecific paramagnetic gadolinium-based contrast agents. The integration of liver contrast-enhanced MRI with contrast-enhanced computed tomography (CT) has since been shown to improve sensitivity and can significantly impact treatment planning for patients with CRLM eligible for local therapy.26

The European Society for Medical Oncology (ESMO) guidelines advise that patients with CRLM characterized by highly favorable prognostic criteria and good technical resectability may not require perioperative chemotherapy, though it remains a standard option based on the EORTC trial’s results.27 Conversely, ESMO strongly recommends the use of the ‘best systemic treatment’ for patients with unfavorable prognostic characteristics—an approach that has yet to be evaluated in randomized trials for resectable CRLM.

The American Society of Clinical Oncology (ASCO) guidelines for metastatic CRC suggest that surgery with or without perioperative chemotherapy should be considered for patients with resectable CRLM, although the recommendation is based on moderate-quality evidence and is assigned a weak strength of recommendation.28 ASCO guidelines further indicate that perioperative chemotherapy is more likely to be recommended in patients with a greater number of metastases or larger tumors—characteristics that were infrequent in the EORTC 40983 trial.24

Moreover, as with adjuvant therapy in earlier stages of CRC, there is no robust evidence supporting the addition of targeted biological agents to perioperative chemotherapy for resectable CRLM. The New EPOC trial examined the addition of cetuximab to perioperative chemotherapy in patients with KRAS exon 2 wild-type CRLM.29 Contrary to expectations, both PFS and OS were worse with cetuximab addition. Similarly, there is no evidence to substantiate the benefit of intensifying preoperative chemotherapy—such as utilizing FOLFOXIRI or incorporating bevacizumab—in patients with resectable CRLM.

Another concern with perioperative chemotherapy, akin to the issues with AC, is the potential for liver damage, which may complicate the detection of liver recurrences on imaging. Perioperative chemotherapy, in particular, may induce chemotherapy-associated liver injury, leading to increased post-operative morbidity.

In a retrospective cohort study conducted at the MD Anderson Cancer Center, 406 patients who underwent resection of CRLM between 1992 and 2005 had their nontumorous liver tissues examined pathologically. Of these patients, 61.1% received preoperative chemotherapy, with 15.5% receiving 5-FU alone, 23.1% receiving irinotecan combined with 5-FU, 19.5% receiving oxaliplatin combined with 5-FU, and 3% receiving other therapeutic regimens. Pathological analysis revealed that 8.9% of the cohort exhibited steatosis, 8.4% presented with steatohepatitis, and 5.4% displayed sinusoidal dilation. Oxaliplatin use was significantly associated with sinusoidal dilation, while irinotecan use was linked to the development of steatohepatitis. Importantly, patients identified with steatohepatitis demonstrated a markedly increased 90-day post-operative mortality (OR 10.5).30 Given the lack of a statistically significant OS benefit and the modest PFS gain, the clinical relevance of adding chemotherapy in the perioperative setting has been questioned, especially in light of its toxicity and resource-intensive nature.

Consideration of perioperative and adjuvant chemotherapy in a meta-analytic framework

A recent individual patient data meta-analysis of phase III trials assessing chemotherapy for resectable CRLM was presented at the 2024 ESMO Gastrointestinal Cancers meeting. This analysis included 821 patients overall, from the EORTC perioperative trial using FOLFOX,27,28 two adjuvant trials using 5-FU/LV,14,16 and one adjuvant trial using UFT/LV; the adjuvant trial using FOLFIRI was not included. Among the 457 patients who received post-operative chemotherapy, a significant improvement in DFS was observed in favor of AC (HR 0.77, P = 0.020). However, the OS benefit did not reach statistical significance (HR 0.78, P = 0.076). Similar findings were obtained when data from all trials were combined. Notably, patients with synchronous liver metastases or normal alkaline phosphatase levels experienced the greatest DFS benefit from systemic therapy compared with surgery alone.31

Role of circulating tumor DNA (ctDNA) in resectable CRLM

Circulating tumor DNA (ctDNA) has emerged as a sensitive and specific biomarker for detecting minimal residual disease (MRD) and predicting recurrence risk in CRC, similar to its role in other malignancies.32 In high-risk stage II and stage III CRC, patients with postsurgical MRD positivity, as indicated by ctDNA, derive significant benefit from AC, while ctDNA-negative patients do not.33, 34, 35 The CIRCULATE-Japan GALAXY study, an observational study, demonstrated the association of ctDNA-based MRD detection with recurrence risk and benefit from AC in resectable stage II-IV CRC.33,35

At the 2017 ASCO Annual Meeting, findings from a prospective study were presented involving 54 patients with resectable CRLM in which ctDNA was collected both preoperatively and post-operatively using the Guardant Health assay. The post-operative sensitivity of ctDNA for detecting MRD was 58%, with a specificity of 100%. In a subgroup of 43 patients who underwent complete resection of all visible disease, the presence of post-operative ctDNA was significantly associated with reduced RFS (HR 3.1, P = 0.002), with a 2-year RFS rate of 0% in ctDNA-positive patients compared with 47% in ctDNA-negative patients. Notably, ctDNA was able to detect recurrence a median of 5.1 months before radiographic evidence of recurrence.36

A similar prospective study conducted in Australia enrolled 54 patients and employed a personalized assay to detect a single mutation in plasma samples using the Safe-SeqS assay. Of the cohort, 43% received neoadjuvant chemotherapy, while 78% underwent AC following liver metastasectomy. Overall, ctDNA was detectable in 85% of patients before any treatment and in 24% after surgery. Although neoadjuvant chemotherapy resulted in a >40-fold reduction in ctDNA mutant allele fraction, ctDNA clearance during preoperative treatment did not correlate with improved RFS. However, the presence of detectable post-operative ctDNA was significantly associated with lower RFS (HR 6.3, P < 0.001) and OS (HR 4.2, P < 0.001) compared with patients with undetectable ctDNA. Among patients with detectable ctDNA after surgery, 11 underwent serial ctDNA sampling during AC, with only 3 achieving ctDNA clearance, 2 of whom remained disease free. Conversely, all eight patients with persistent ctDNA after AC experienced disease recurrence. Notably, patients achieving undetectable ctDNA following the completion of all treatments had a significantly higher 5-year RFS (75% versus 0%, P < 0.001).37

The best available data for using ctDNA to guide AC in patients with resectable CRLM come from a subgroup analysis of the GALAXY study, which included 190 patients who had not received prior preoperative treatment.38 ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction–next-generation sequencing assay. ctDNA-based MRD status was evaluated between 2 and 10 weeks after curative surgery, before the initiation of AC.

The study reported that ctDNA positivity in the MRD window occurred in 32.1% of patients, while 25.1% of participants received AC. In ctDNA-positive patients, 2-year DFS was significantly prolonged in those who received AC compared with those who did not (33.3% versus not reached; HR 0.07, P < 0.0001). In contrast, no improvement in DFS was observed in the ctDNA-negative group (2-year DFS: 72.3% versus 62.2%; HR 0.68, P = 0.371). The study also found that ctDNA positivity was higher in patients with synchronous tumors (48.4% versus 23.8%) and those with multiple liver metastases (54% versus 46%). Among ctDNA-positive patients, larger liver lesions (HR 3.94) and the presence of RAS mutations (HR 2.91) were significantly associated with poorer DFS.

These findings suggest that ctDNA-based MRD status may help identify patients who would benefit most from AC. However, ctDNA-based MRD testing is not yet supported by level I evidence and may be associated with technical challenges, including limited sensitivity due to low tumor DNA shedding and the detection threshold.

Role of biomarkers

Molecular and genetic profiling have become essential for tailoring treatment strategies in metastatic CRC. Studies have demonstrated that tumors with either BRAF or KRAS mutations exhibit lower resectability rates compared with tumors that are wild-type for both RAS and BRAF.39 Furthermore, tumors harboring RAS and/or BRAF V600 mutations are generally associated with a poorer prognosis and an elevated risk of recurrence following liver metastasectomy. As such, patients with these mutations may potentially derive more benefit from AC, given their heightened risk of early recurrence.39

In a cohort study conducted by institutions within the International Genetic Consortium for Colorectal Liver Metastasis, 853 patients who underwent liver metastasectomy with documented RAS and BRAF mutation status were included. While the presence of either mutation was associated with poorer outcomes following liver resection, the BRAF V600 mutation emerged as the most significant prognostic factor for both DFS and OS across the cohort.40 Whether anti-BRAF therapies could provide benefit for these patients with resectable CRLM remains to be determined. The ongoing phase II NEXUS trial aims to evaluate the efficacy and safety of perioperative encorafenib, binimetinib, and cetuximab in patients with resectable, previously untreated BRAF V600E-mutant oligometastatic CRC, and may provide further insight into this question.41

In a Dutch study, patients with CRC who underwent curative-intent local therapy for metastases were analyzed based on their mismatch repair (MMR) status. Those with deficient MMR (dMMR) demonstrated improved RFS compared with patients with proficient MMR (pMMR). However, despite better RFS, patients with dMMR tumors exhibited worse OS, as this study was conducted in the pre-immunotherapy era when dMMR status was associated with a poor prognosis in the metastatic setting.42

Given that patients with metastatic unresectable dMMR CRC show superior outcomes with immunotherapy compared with chemotherapy, it is anticipated that patients with resectable dMMR CRLM may also benefit more from immunotherapy, whether administered perioperatively or as an adjuvant strategy. While these patients represent only 5% of all patients with metastatic disease, preliminary data highlight the potential for novel treatment strategies. In a pilot trial, 24 patients with resectable CRLM received a single preoperative dose of tremelimumab and durvalumab, followed by post-operative durvalumab monotherapy. Notably, the two patients with dMMR tumors achieved a pathological complete response, highlighting this approach as a potentially effective strategy for this patient subgroup.43

A Chinese retrospective study reported comparable results, where patients with resectable metastatic dMMR CRC underwent preoperative treatment with single-agent programmed cell death protein 1 blockade. Notably, all three patients presenting with liver metastases achieved a complete response in all hepatic lesions.44

A notable limitation in the trials evaluating perioperative and/or AC for resectable CRLM is the absence of stratification based on molecular biomarkers, such as KRAS, BRAF, and MMR status. These biomarkers are now well established as critical predictors of therapy response and overall prognosis in unresectable metastatic CRC. The absence of biomarker stratification in the trials reviewed may have introduced imbalances that could affect the interpretation of outcomes. As molecular profiling becomes more prevalent, it is increasingly clear that future studies must incorporate these biomarkers to accurately define which subgroups of patients might benefit most from AC after hepatectomy for CRLM.

Understanding the differential efficacy of adjuvant chemotherapy in earlier stages versus stage IV disease

The differential efficacy of AC between earlier stages of CRC and resectable CRLM may be explained by several factors. One key factor is the greater burden of micrometastatic disease in patients with CRLM. Patients with resectable stage IV CRC have been shown to harbor higher levels of ctDNA compared with those with earlier-stage disease, even before surgery.33,35 Notably, patients with higher ctDNA concentrations before curative surgery were more likely to remain ctDNA positive 4 weeks post-operatively, regardless of stage. Moreover, patients treated with AC who had high ctDNA concentrations 4 weeks post-surgery were less likely to achieve ctDNA clearance over time, suggesting that the burden of MRD may influence AC efficacy.

Additionally, as CRC progresses from earlier stages to metastatic disease, further genetic alterations and molecular changes occur, facilitating tumor invasion and dissemination. This progression involves a combination of genetic instability, tumor evolution, and selective pressures from the tumor microenvironment.45, 46, 47 Tumor heterogeneity and the emergence of drug-resistant subclones in metastatic CRC may also contribute to the reduced effectiveness of AC in resectable stage IV disease.

Adjuvant chemotherapy summary based on clinical scenarios in resectable CRLM

In clinical practice, the management of resectable CRLM can be categorized into four primary scenarios (summarized in Figure 1):

  • 1.

    Metachronous liver metastases following oxaliplatin-based AC: these patients are unlikely to benefit from further AC after CRLM resection, as their recurrent disease likely represents tumor clones resistant to prior oxaliplatin-based chemotherapy. Notably, these patients were excluded from both the JCOG0603 and EORTC 40983 trials.20,24 Additionally, in the adjuvant FOLFIRI trial, previously treated patients had worse DFS and did not benefit from AC with FOLFIRI.19 Surveillance is potentially the best strategy for this subgroup.

  • 2.

    Metachronous liver metastases following fluoropyrimidine-only AC: this group may theoretically benefit from oxaliplatin-based chemotherapy following CRLM resection. However, the lack of benefit observed in the JCOG0603 trial for patients with metachronous disease who had received prior AC, and the superior OS outcomes seen in patients who did not receive further AC after metachronous metastases resection, suggest that surveillance may also be appropriate for this subgroup.20

  • 3.

    Metachronous liver metastases without prior AC: these patients have not been exposed to systemic treatment and, therefore, may derive greater benefit from AC. The JCOG trial demonstrated that patients without prior chemotherapy experienced the greatest DFS benefit from AC, although OS was similar between the treatment groups.20

  • 4.

    Synchronous disease: several guidelines and expert opinions recommend perioperative chemotherapy in patients with synchronous disease, based on the biological rationale of more aggressive disease behavior and the potential for tumor down-staging to facilitate hepatic resection. While no randomized data specifically support this approach, retrospective studies have suggested improved RFS and OS with AC in patients with synchronous CRLM.48 Due to the typically aggressive nature of synchronous disease, most institutions implement perioperative or adjuvant FOLFOX as part of the treatment strategy.

Figure 1.

Figure 1

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Adjuvant chemotherapy summary based on clinical scenarios in resectable CRLM. AC, adjuvant chemotherapy; CRLM, colorectal liver metastases; DFS, disease-free survival.

Individualized treatment approaches

Given the clinical and molecular heterogeneity of CRLM, a ‘one-size-fits-all’ approach to AC is unlikely to be effective for all patients. Individualized treatment strategies are essential, taking into account several factors, including the following:

  • •

    Tumor biology (e.g. genetic mutations, MMR status, metachronous versus synchronous disease)

  • •

    Biomarkers that predict response to chemotherapy

  • •

    Metastatic burden, in terms of both the number, location, and size of liver metastases

  • •

    Previous systemic treatment, particularly in patients with prior exposure to chemotherapy

  • •

    Patient performance status and comorbidities, which influences treatment tolerance

In some patients, particularly those with low-risk disease or who have already received extensive preoperative chemotherapy, the risks of further AC may outweigh potential benefits. Individualized decision making, informed by molecular profiling, should guide treatment choices to ensure the best possible outcomes while minimizing unnecessary toxicity. Immunotherapy as a preoperative approach for dMMR CRLM shows significant promise; however, randomized data to substantiate its efficacy remains limited. Other biomarkers such as MRD through ctDNA technology may help determine the prognosis of patients post-surgery; however, further studies are needed to determine whether adjuvant therapy changes the risk of relapse and improves survival in patients at higher risk for relapse.

Conclusions and future directions

Despite advancements in surgical techniques and post-operative care for patients with resectable CRLM, the role of systemic chemotherapy in this context remains unclear. To date, no randomized trials have demonstrated a significant improvement in OS with the use of AC, though limited sample sizes may have compromised the ability to detect such a benefit. Additionally, the majority of patients included in these trials had few and limited liver metastases, making it difficult to extrapolate the findings to real-world patients with more extensive disease.

Future research should focus on better defining the patient populations most likely to benefit from AC following liver metastasectomy. Biomarker-driven approaches, such as genetic profiling and ctDNA assessments, will be critical in refining treatment strategies. Furthermore, the role of novel therapies, including targeted agents and immunotherapies, in the adjuvant setting warrants further exploration.

Ultimately, an individualized approach to post-metastasectomy care, grounded in molecular insights, will be key to optimizing outcomes for CRC patients. This strategy should balance the potential benefits of chemotherapy with the risks, guided by tumor biology, biomarker status, and the patient’s overall clinical profile.

Acknowledgments

Funding

None declared.

Disclosure

RDP: advisory honoraria received from Taiho, Servier, Bayer, Roche, and Pfizer outside of the submitted work. JML: research funding received from Personalis, Bayer, Saga Diagnostics, FoundationOne, and Guardant Health; consulting fees received from Amgen, Merck, Pfizer, Guardant Health, Sanofi, Ipsen, and Taiho outside of the submitted work. JPS: honoraria received from Pfizer and Incyte and advisory/consultancy fees received from Astellas and Ipsen outside of the submitted work. DJR: grants and personal fees received from Roche, Bayer, Sanofi, and Ipsen outside of the submitted work. SG: advisory honoraria received from Pfizer, Amgen, Taiho, Takeda outside of the submitted work. VP: honoraria received from Merck, Bristol-Myers Squibb, Pfizer, and Sanofi outside of the submitted work. MC: honoraria received from Servier and Novocure outside of the submitted work. HJL: received honorariums from Eisai, Taiho, Roche, Astra-Zeneca, Astellas, Amgen, Varian, CDA, Merck and Bristol-Myers Squibb for consultant work outside of the submitted work. All other authors have declared no conflicts of interest.

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