Patients with colorectal liver-only metastases (CRLM) eligible for local treatment (resection/ablation) do not always receive this potentially curative treatment due to the lack of clear resectability criteria and expertise in centres not performing liver surgery. We evaluated the potential value of a liver expert panel in daily practice.

All patients with CRLM starting with systemic treatment in centres not performing liver surgery between 2016 and 2020 were identified in the Netherlands Cancer Registry. A panel of liver surgeons retrospectively re-evaluated patients' imaging for resectability before and two-monthly during systemic treatment.

Sixty-three patients were included from 24 hospitals requiring a total of 544 resectability assessments by individual panel surgeons. The panel considered 18 (29 %) patients to have resectable CRLM before starting systemic treatment, which increased to 43 (68 %) after up to three evaluations. Eighteen (29 %) patients considered resectable by the panel at any time received no local treatment of whom 9 (50 %) were not referred to a liver surgeon.

In non-liver-surgery centres, over a quarter of patients technically eligible for local treatment of initially unresectable CRLM, sometimes mistakenly categorised as such, did not receive this. This stresses the need for liver expert panels in daily practice to increase local treatment rates.

For patients with resectable colorectal liver metastases (CRLM), the efficacy of adjuvant chemotherapy remains a subject of debate. Several studies have concluded that postoperative circulating tumor DNA (ctDNA) is a marker of minimal residual disease (MRD) and is a useful prognostic factor in patients with nonmetastatic colorectal cancer. However, few studies have explored its application in cases involving metastases. This was an observational study that included CRLM patients who underwent primary and liver tumor resection. By examining targeted sequencing of 50 genes commonly mutated in CRC, we identified at least one somatic mutation in each patient's metastatic liver tumor. Blood samples were obtained before and 1-month after surgery. Fifty-three patients were included, and recurrence was diagnosed in 39 patients. Of those, 13 patients experienced early relapse. ctDNA was detected in 45 patients before surgery and 11 after. All MRD-positive patients experienced recurrence. Among them, nine had early recurrence. MRD-positive patients had poorer recurrence free survival (RFS, p < 0.0001) and overall survival (OS, p < 0.0005). Nine of 13 patients with early recurrence had MRD; however, two of 40 patients without early recurrence also had MRD (p < 0.0001). Among 42 MRD-negative patients, adjuvant chemotherapy had no impact of RFS (p = 0.84) or OS (p = 0.54). MRD proved valuable in predicting the risk of postoperative recurrence in patients with CRLM, particularly because MRD positivity emerged as a significant risk factor for early recurrence. Furthermore, it appears that adjuvant chemotherapy may not effectively improve the prognosis for MRD-negative patients.

There is no consensus on the optimal surveillance interval for patients undergoing resection of colorectal liver metastases (CRLM). We sought to assess the timing and intensity of recurrence following curative-intent resection of CRLM utilizing a recurrence-free survival (RFS) hazard function analysis.

Patients with CRLM who underwent curative-intent resection were identified from a multi-institutional database. The RFS hazard function was used to plot hazard rates and identify the peak of recurrence over time.

Among 1804 patients, the median RFS was 19.9 months. In the analytic cohort, the RFS hazard curve peaked at 5.9 months (peak hazard rate: 0.054) and gradually declined, indicative of early recurrence. In subgroup analyses, patients with high and medium tumor burden scores (TBS) had RFS hazard peaks at 4.9 months (peak hazard rate: 0.060) and 5.8 months (peak hazard rate: 0.054), respectively. In contrast, patients with low TBS had a later peak at 7.5 months, with the lowest peak hazard rate of 0.047.

The recurrence peak for CRLM patients occurred approximately 6 months postsurgery, highlighting the need for intensified early postoperative surveillance. Patients with high TBS experienced earlier recurrence, underscoring the importance of close monitoring, particularly during the first 6 months after surgery.

Surgical removal of metastasized paraaortic lymph nodes (PALNs) can prolong the survival of certain patients with colorectal cancer (CRC). However, the role of postoperative chemotherapy in such patients remains unknown.

This multicenter retrospective study examined 97 patients with PALN metastasis from CRC who underwent surgical resection at 36 centers in Japan between 2010 and 2015. On the basis of adjuvant chemotherapy (AC) after the lymphadenectomy, patients were classified into non-AC and AC groups (27 and 70 patients, respectively). After the exclusion of patients receiving irinotecan, the latter group was further categorized into 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) subgroups (14 and 52 patients, respectively) according to the use of L-OHP. Background characteristics and postoperative survival were compared among the groups.

Marked differences were not seen in background characteristics, except for neoadjuvant treatment, between the non-AC and AC groups. The AC group exhibited better recurrence-free survival (RFS; p = 0.009) and overall survival (OS; p = 0.040 by the Wilcoxon test) than the non-AC group. However, RFS and OS of the 5-FU group did not differ from those of the L-OHP group (p = 0.73 and p = 0.92 by the Wilcoxon test, respectively).

AC may be associated with improved prognosis of patients after the removal of PALN metastasis from CRC, but L-OHP did not offer additional survival benefits. Prospective studies comparing non-AC with 5-FU- and L-OHP-based AC are needed to confirm these findings.

Repeat liver resection is a well-established treatment option for patients with recurrent colorectal liver metastases (CLM). However, the risk of recurrence following the second and third CLM resections was not assessed.

Data of patients undergoing first, second, and third CLM resection between 2005 and 2018 were obtained from a prospectively maintained database.

Of the 695 patients, 486, 159, and 50 underwent first, second, and third CLM resections, respectively. The changing risks of recurrence in patients undergoing first, second, and third CLM resection, and the cumulative recurrence curve after a given interval without recurrence in patients undergoing first and second CLM resection were relatively similar. Time to recurrence after the first CLM resection ≤12 months (HR 2.09, 95% CI 1.35-3.23, P = 0.001) and number of CLM (HR 1.07, 95% CI 1.02-1.12, P = 0.003) were significant risk factors for recurrence in patients undergoing second CLM resection.

Patients undergoing second and third CLM resection did not have a lower risk of recurrence than those undergoing first CLM resection. The surveillance strategy after the second and third CLM resections should be similar to that after the first CLM resection.

Colorectal cancer most commonly metastasizes to the liver. While various treatment strategies have been developed, surgical management of these patients has vital implications on the prognosis and survival of this group of patients. There remains a need for a consensus guideline regarding the surgical evaluation and management of patients with colorectal liver metastases (CRLM).

This review article is a consensus guideline established by the members of the AHPBA Professional Standards Committee, as an amalgamation of existent literature and a guide to surgeons managing this complex disease.

These guidelines reports the benefits and shortcomings of various diagnostic modalities including imaging and next-generation sequencing in the management of patients with CRLM. While surgery has established survival benefits in patients with resectable disease, this report notes the importance of treatment sequencing with non-surgical modalities as well as between colon and liver resection. Finally, the guidelines address the various treatment modalities for patients with unresectable disease, that may have significant impact on survival.

CRLM is a complex diagnosis which warrants multidisciplinary approach with early surgical involvement in both assessment and management of the disease, to optimize patient outcomes and survival.

Colorectal cancer (CRC) frequently metastasizes to the liver and lungs, leading to poor prognosis. Advances in chemotherapy, minimally invasive surgery, and perioperative care have expanded adjuvant chemotherapy (AC) regimens and eligibility for AC. However, the impact of AC after curative resection of distant metastases on recurrence and prognosis remains uncertain. This study evaluated the role of AC in CRC liver and lung metastases, focusing on cases with curative resection based on the latest studies published in the past five years.

This systematic review followed PRISMA guidelines. Literature searches of Medline and Cochrane Library (2019-2023) identified studies on AC or observation after curative resection of CRC metastases, reporting outcomes such as overall survival (OS) and disease-free survival (DFS). Data analysis was performed using Review Manager and R software, with results expressed as hazard ratios (HR) and 95% confidence intervals (CI).

Seven studies met the eligibility criteria, including one randomized controlled trial and six retrospective studies, encompassing 1580 patients who underwent curative resection (R0) for CRC metastases. This meta-analysis showed a positive trend in OS for the AC group compared to that for the surgery-alone group (HR 0.86, 95% CI: 0.73-1.01; p = 0.06), but the difference was insignificant. AC significantly improved DFS (HR 0.81, 95% CI: 0.66-0.99; p = 0.04). Subgroup analysis indicated that AC significantly improved DFS and tended to improve OS for liver metastasis. In contrast, AC did not improve OS in cases of lung metastasis.

This meta-analysis suggests that AC demonstrated significant positive effects on DFS. Moreover, AC could contribute to improvements in OS. These findings, supported by the latest research, reinforce the recommendation of AC as a valuable strategy for improving both recurrence and survival outcomes in patients with curatively resected distant CRC metastases.

The benefit of resection of liver metastases depends on primary diseases. Neuroendocrine tumors are associated with favorable prognosis after resection of liver metastases. Gastric cancer has worse tumor biology, and resection of gastric liver metastases should be performed in selected patients. A multidisciplinary approach is well established for colorectal liver metastases (CLMs). Resection remains the only curative treatment of CLM. Chemotherapy and molecular-targeted therapy have improved survival in unresectable metastatic colorectal cancer. Understanding of the following two strategies, conversion therapy and two-stage hepatectomy, are important to make this patient group to be candidates for curative-intent surgery.

In patients with colorectal cancer and unresectable liver-only metastases (CRLM), treatment with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) plus irinotecan (FOLFOXIRI) and bevacizumab vs FOLFOX/folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab increased progression-free survival, response, and R0/R1 resection/ablation rates, as well as toxic effects in RAS/BRAFV600E-variant and/or right-sided tumors. FOLFOX/FOLFIRI-panitumumab vs FOLFOX/FOLFIRI-bevacizumab increased response at the cost of more toxic effects in RAS/BRAFV600E wild-type, left-sided tumors.

To present long-term outcomes of treatment with FOLFOXIRI plus bevacizumab vs FOLFOX/FOLFIRI plus bevacizumab and FOLFOX/FOLFIRI plus panitumumab vs FOLFOX/FOLFIRI + bevacizumab.

The randomized phase 3 CAIRO5 trial included patients with initially unresectable CRLM in 46 Dutch centers and 1 Belgian center between November 2014 and January 2022. A liver expert panel repeatedly evaluated resectability.

Patients with RAS/BRAFV600E-variant and/or right-sided tumors randomly received FOLFOX/FOLFIRI-bevacizumab (group 1) or FOLFOXIRI-bevacizumab (group 2), and those with RAS/BRAFV600E wild-type, left-sided tumors received FOLFOX/FOLFIRI-bevacizumab (group 3) or FOLFOX/FOLFIRI-panitumumab (group 4). Adjuvant chemotherapy (ACT) after complete local treatment was recommended but not standard.

Overall survival (OS) was analyzed as a secondary outcome. Other outcomes were post hoc analyses.

A total of 530 patients (327 male [62%] and 203 female individuals [38%]; median age, 62 [IQR, 54-69] years) were randomized: 148 in group 1, 146 in group 2, 118 in group 3, and 118 in group 4. The median OS in group 1 was 23.6 (95% CI, 20.1-27.5) vs 24.1 (95% CI, 21.0-30.9) months in group 2 (hazard ratio [HR], 0.90; 95% CI, 0.70-1.17; P = .44), and 39.9 (95% CI, 30.7-44.6) in group 3 vs 38.3 (95% CI, 35.3-51.3) months in group 4 (HR, 0.95; 95% CI, 0.68-1.32; P = .75). OS was longest after complete local treatment without early (≤6 months) recurrence (64.3 months; 95% CI, 57.6 to not reached) and salvage local treatment options after early recurrence (58.9; 95% CI, 47.3 to not reached), followed by patients without salvage local treatment after early recurrence (30.5; 95% CI, 24.4-33.4) and with incomplete local treatment (28.7; 95% CI, 25.9-38.3), and worst in patients with continued unresectability (18.3; 95% CI, 15.7-20.0). After confounder adjustment, ACT was associated with longer OS (HR, 0.66; 95% CI, 0.44-0.98) and relapse-free survival (HR, 0.65; 95% CI, 0.48-0.88) and less early recurrence without salvage local treatment (odds ratio, 0.46; 95% CI, 0.25-0.85).

These results support using FOLFOX/FOLFIRI-bevacizumab for patients with initially unresectable CRLM irrespective of RAS/BRAFV600E status and tumor sidedness. Patients with complete local liver treatment with salvage local treatment in case of early recurrence had the longest OS. ACT might be considered for these patients.

ClinicalTrials.gov NCT02162563.

The Joint Committee for Nationwide Survey on colorectal liver metastasis (CRLM) was established to improve treatment outcomes in patients with CRLM. The aim of this study was to evaluate the transition in the characteristics and treatment strategies of patients with CRLM and to analyze the prognostic factors. The data of 5085 patients newly diagnosed between 2013 and 2017 were compared with those of 3820 patients from 2005 and 2007. In patients who underwent hepatectomy (n = 2759 and 2163), the number of CRLMs was significantly higher and in the 2013-2017 data than in the 2005-2007 data (median 2 vs. 1; p = .005). Overall survival (OS) rates after diagnosis of CRLM after hepatectomy were better in the 2013-2017 data than that in the 2005-2007 data (5-year OS, 62.4% vs. 56.7%, p < .001). Recurrence-free survival (RFS) after hepatectomy was comparable between the groups (5-year RFS, 30.5% vs. 30.7%; p = .068). Multivariate analyses identified age at diagnosis of CRLM ≥70 years, lymph node metastasis of primary lesion, preoperative carbohydrate antigen (CA) 19-9 value >100 U/mL, number of CRLM 2-4, and R2 resection as independent predictors of OS. Synchronous CRLM, concomitant extrahepatic metastasis, lymphatic invasion, lymph node metastasis of primary lesion, preoperative CA19-9 value >100 U/mL, number of CRLM 5-, and nonlaparoscopic approach were selected as that of RFS. Despite having a higher prevalence of advanced stage CRLM in the 2013-2017 patient population compared to the 2005-2007 cohort, prognostic outcomes demonstrably improved in the later period.

The survival benefit of adjuvant chemotherapy after curative hepatectomy for colorectal cancer (CRC) liver metastases remains controversial. This retrospective study aimed to evaluate the efficacy of adjuvant chemotherapy in improving recurrence-free survival (RFS) and overall survival (OS) in patients who underwent curative hepatectomy for CRC liver metastases at a tertiary medical center.

We retrospectively analyzed clinicopathological factors in 89 patients (surgery alone, n = 63; adjuvant chemotherapy, n = 26) who underwent curative hepatectomy for CRC liver metastases from January 2010 to December 2022. Patients who received neoadjuvant therapy or prior hepatectomy were excluded to minimize patient heterogeneity. Multivariate analysis using Cox proportional hazards regression was conducted to assess the independent effect of adjuvant therapy on RFS and OS.

The 3-year RFS rates were 22.6% in the surgery alone group and 29.6% in the adjuvant chemotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.43-1.21; p = 0.102). The 3-year OS rates were 72.3% in the surgery alone group and 88.5% in the adjuvant chemotherapy group (hazard ratio, 0.59; 95% confidence interval, 0.29-1.25; p = 0.17). Univariate analyses showed that the number of liver metastases (> 2) was significantly associated with poorer OS (hazard ratio, 2.44; 95% confidence interval, 1.11-5.37; p = 0.027). Additionally, multivariate analyses showed that the addition of adjuvant chemotherapy was significantly associated with improved OS (hazard ratio, 0.23; 95% confidence interval, 0.07-0.81; p = 0.021).

Adjuvant chemotherapy may improve OS after curative hepatectomy for CRC liver metastases, though it did not significantly impact RFS. Larger-scale multicenter prospective studies with stratified analyses are needed to confirm these findings.

The risk factors for residual liver recurrence after resection of colorectal cancer liver metastases were analyzed separately for synchronous and metachronous metastases.

This retrospective study included 236 patients (139 with synchronous and 97 with metachronous lesions) who underwent initial surgery for colorectal cancer liver metastases from April 2010 to December 2021 at the Fujita Health University Hospital. We performed univariate and multivariate analyses of risk factors for recurrence based on clinical background.

Univariate analysis of synchronous liver metastases identified three risk factors: positive lymph nodes (p = 0.018, HR = 2.067), ≥3 liver metastases (p < 0.001, HR = 2.382), and use of adjuvant chemotherapy (p = 0.013, HR = 0.560). Multivariate analysis identified the same three factors. For metachronous liver metastases, univariate and multivariate analysis identified ≥3 liver metastases as a risk factor (p = 0.002, HR = 2.988); however, use of adjuvant chemotherapy after hepatic resection was not associated with a lower risk of recurrence for metachronous lesions. Inverse probability of treatment weighting analysis of patients with these lesions with or without adjuvant chemotherapy after primary resection showed that patients with metachronous liver metastases who did not receive this treatment had fewer recurrences when adjuvant therapy was administered after subsequent liver resection, although the difference was not significant. Patients who received adjuvant chemotherapy after hepatic resection had less recurrence but less benefit from this treatment.

Risk factors for liver recurrence after resection of synchronous liver metastases were positive lymph nodes, ≥3 liver metastases, and no postoperative adjuvant chemotherapy. Adjuvant chemotherapy is recommended after hepatic resection of synchronous liver metastases.

The prognostic role of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear.

Patients with CLM without extrahepatic disease from the GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number, and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing (mPCR-NGS) assay. ctDNA-based MRD status was evaluated 2-10 weeks after curative surgery, before the start of ACT.

Among 6061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 months (1-48 months). ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT [33.3% versus not reached, adjusted hazard ratio (HR): 0.07, P < 0.0001]; whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% versus 62.2%, adjusted HR: 0.68, P = 0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P = 0.031) was prognostic of DFS in the MRD-positive group. In the MRD-negative group, however, none of the clinicopathological factors were prognostic of DFS.

Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk stratification could be potentially incorporated in future clinical trials for CLM.

Accurate prediction of patients at risk for early recurrence (ER) among patients with colorectal liver metastases (CRLM) following preoperative chemotherapy and hepatectomy remains limited.

Patients with CRLM who received chemotherapy prior to undergoing curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Multivariable Cox regression analysis was used to assess clinicopathological factors associated with ER, and an online calculator was developed and validated.

Among 768 patients undergoing preoperative chemotherapy and curative-intent resection, 128 (16.7 %) patients had ER. Multivariable Cox analysis demonstrated that Eastern Cooperative Oncology Group Performance status ≥1 (HR 2.09, 95%CI 1.46-2.98), rectal cancer (HR 1.95, 95%CI 1.35-2.83), lymph node metastases (HR 2.39, 95%CI 1.60-3.56), mutated Kirsten rat sarcoma oncogene status (HR 1.95, 95%CI 1.25-3.02), increase in tumor burden score during chemotherapy (HR 1.51, 95%CI 1.03-2.24), and bilateral metastases (HR 1.94, 95%CI 1.35-2.79) were independent predictors of ER in the preoperative setting. In the postoperative model, in addition to the aforementioned factors, tumor regression grade was associated with higher hazards of ER (HR 1.91, 95%CI 1.32-2.75), while receipt of adjuvant chemotherapy was associated with lower likelihood of ER (HR 0.44, 95%CI 0.30-0.63). The discriminative accuracy of the preoperative (training: c-index: 0.77, 95%CI 0.72-0.81; internal validation: c-index: 0.79, 95%CI 0.75-0.82) and postoperative (training: c-index: 0.79, 95%CI 0.75-0.83; internal validation: c-index: 0.81, 95%CI 0.77-0.84) models was favorable (https://junkawashima.shinyapps.io/CRLMfollwingchemotherapy/).

Patient-, tumor- and treatment-related characteristics in the preoperative and postoperative setting were utilized to develop an online, easy-to-use risk calculator for ER following resection of CRLM.

The survival benefit of adjuvant chemotherapy after surgical resection of oligometastases from colorectal cancer (CRC) remains unclear. The prognostic role of circulating-tumor DNA (ctDNA) was reported recently and a risk stratification strategy based on monitoring minimal/molecular residual disease (MRD) has been proposed, however, which drug regimen is most effective for ctDNA-positive patients is unknown.

Oligometastatic CRC patients planning to undergo surgery were registered in this study. After metastasectomy, the registered patients were enrolled in the treatment arm, in which 8 courses of modified-FOLFOXIRI (mFOLFOXIRI; irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, l-leucovorin (l-LV) 200 mg/m2, and 46-h continuous infusion of 5-fluorouracil (5-FU) 2400 mg/m2 every 2 weeks) followed by 4 courses of 5-FU/l-LV are administered. The patients who did not meet the eligibility criteria for the treatment arm or did not consent to mFOLFOXIRI enrolled in the observation arm in which standard of care treatment is provided. Prospective blood collections for retrospective ctDNA analysis are scheduled pre-surgery, and at 28 days, 4 and 7 months after surgery. The primary endpoint is treatment compliance at 8 courses of mFOLFOXIRI and the key secondary endpoints are the ctDNA-positivity rate and survival outcomes in ctDNA-positive and -negative groups. A total of 85 patients will be enrolled from 11 institutions. First patient-in was on July 2020. Accrual completed in February 2024.

This study will potentially identify a better treatment strategy for patients with resectable oligometastatic CRC having postsurgical ctDNA positivity, compared to the current standard of care approaches.

The high recurrence rate of colorectal cancer liver metastasis (CRCLM) after surgery remains a crucial problem. However, adjuvant chemotherapy after hepatectomy for CRCLM has not yet been established. This study evaluated the efficacy of adjuvant therapy with S-1 and oxaliplatin (SOX).

In a multicenter, randomized, phase II study, patients undergoing curative resection of CRCLM were randomly enrolled in a 1:1 ratio to either the low- or high-dose group. S-1 and oxaliplatin were administered from days 1 to 14 of a 3-week cycle as a 2-h infusion every 3 weeks. The dose of S-1 was fixed at 80 mg/m2. The doses in the low- and high-dose oxaliplatin groups were 100 mg/m2 (low-dose group) and 130 mg/m2 (high-dose group), respectively. This treatment was repeated eight times. The primary endpoint was the rate of discontinuation owing to toxicity. The secondary endpoints were the relapse-free survival (RFS) and frequency of adverse events (AEs).

Between August 2010 and March 2015, 44 patients (low-dose group: 31 patients and high-dose group: 13 patients) were enrolled in the study. Of these, one patient was excluded from the efficacy analysis. In the high-dose group, five of nine patients were unable to continue the study due to toxicity in February 2013. At that time, recruitment to the high-dose group was stopped from the protocol. The relative dose intensity (RDI) for S-1 in the low- and high-dose groups were 49.8 and 48.7% (p = 0.712), and that for oxaliplatin was 75.9 and 73.0% (p = 0.528), respectively. The rates of discontinuation due to toxicity were 60 and 53.8% in the low- and high-dose groups, respectively, with no marked difference noted between the groups (p = 0.747). The frequency of grade ≥ 3 common adverse events was neutropenia (23.3%/23.1%), diarrhea (13.3%/15.4%), and peripheral sensory neuropathy (6.7%/7.7%). The disease-free survival (DFS) at 3 years was 52.9% in the low-dose group, which was not significantly different from that in the high-dose group (46.2%; p = 0.705).

SOX regimens as adjuvant therapy after hepatectomy for CRCLM had high rates of discontinuation due to toxicity in both groups. In particular, the RDI of S-1 was < 50%. Therefore, the SOX regimen is not recommended as adjuvant chemotherapy after hepatectomy for CRCLM.

A growing number of studies have demonstrated that neoadjuvant chemotherapy can improve the prognosis of patients with resectable colorectal liver metastases (CRLM). However, the routine use of postoperative adjuvant chemotherapy (POAC) for patients with CRLM after simultaneous resection remains controversial. This retrospective study investigated the impact of POAC on outcomes in patients with CRLM who underwent simultaneous resection of colorectal cancer tumors and liver metastases using propensity score matching (PSM) analysis.

From January 2009 to November 2020, patients with CRLM who underwent simultaneous resection were retrospectively enrolled. The confounding factors and selection bias were adjusted by 2:1 PSM. Patients were stratified into the POAC and non-POAC groups. Kaplan-Meier curves were utilized to compare overall survival (OS) and progression-free survival (PFS) between the groups. Univariate and multivariate Cox regression analyses were used to identify independent clinicopathological factors before and after PSM analysis. The utility of the model was evaluated using receiver operating characteristic (ROC) and calibration curves after PSM analysis.

In total, 478 patients with resectable CRLM were enrolled and assigned to the POAC (n = 212, 60.9%) or non-POAC group (n = 136, 39.1%). After 2:1 PSM, there was no significant bias between the groups. Kaplan-Meier survival analysis revealed a significant effect of POAC on OS (P < 0.001) but not PFS. Multivariate Cox regression analysis identified T stage (T3-T4), lymph node metastasis, radiofrequency ablation during surgery, operative time ≥ 325 min, and the receipt of postoperative adjuvant chemotherapy (hazard ratio = 0.447, 95% confidence interval = 0.312-0.638, P < 0.001) as independent prognostic factors for OS. The areas under the ROC curves for the nomogram model for predicting 1-, 3-, and 5-year survival were 0.653, 0.628, and 0.678, respectively. Subgroups analysis suggested that POAC can enhance OS in patients with resectable CRLM with either low (1-2, P < 0.001) or high clinical risk scores (3-5, P = 0.020).

Overall, this study identified POAC as a prognostic factor to predict OS in patients with CRLM undergoing simultaneous resection.

The annual postoperative disease-free survival for colorectal liver metastases can be easily estimated by weighting six preoperative clinical parameters (Beppu score). We identified three recurrence-risk stratification groups: the low (≤6 points), moderate (7-10 points), and high-risk (≥11 points). For low-, moderate-, and high-risk patients, hepatectomy alone, hepatectomy with adjuvant chemotherapy, and hepatectomy with preoperative chemotherapy are recommended, respectively. The Beppu score enables the decision on the necessity and timing of perioperative chemotherapy.

Although systemic postoperative therapy after surgery for colorectal liver metastases is generally recommended, the benefit of adjuvant chemotherapy has been debated. We used machine learning to develop a decision tree and define which patients may benefit from adjuvant chemotherapy after hepatectomy for colorectal liver metastases.

Patients who underwent curative-intent resection for colorectal liver metastases between 2000 and 2020 were identified from an international multi-institutional database. An optimal policy tree analysis was used to determine the optimal assignment of the adjuvant chemotherapy to subgroups of patients for overall survival and recurrence-free survival.

Among 1,358 patients who underwent curative-intent resection of colorectal liver metastases, 1,032 (76.0%) received adjuvant chemotherapy. After a median follow-up of 28.7 months (interquartile range 13.7-52.0), 5-year overall survival was 67.5%, and 3-year recurrence-free survival was 52.6%, respectively. Adjuvant chemotherapy was associated with better recurrence-free survival (3-year recurrence-free survival: adjuvant chemotherapy, 54.4% vs no adjuvant chemotherapy, 46.8%; P < .001) but no overall survival significant improvement (5-year overall survival: adjuvant chemotherapy, 68.1% vs no adjuvant chemotherapy, 65.7%; P = .15). Patients were randomly allocated into 2 cohorts (training data set, n = 679, testing data set, n = 679). The random forest model demonstrated good performance in predicting counterfactual probabilities of death and recurrence relative to receipt of adjuvant chemotherapy. According to the optimal policy tree, patient demographics, secondary tumor characteristics, and primary tumor characteristics defined the subpopulation that would benefit from adjuvant chemotherapy.

A novel artificial intelligence methodology based on patient, primary tumor, and treatment characteristics may help clinicians tailor adjuvant chemotherapy recommendations after colorectal liver metastases resection.

Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer-related death. Approximately 20-30% of patients will develop hepatic metastasis in the form of synchronous or metachronous disease. The treatment of colorectal liver metastasis (CRLM) has evolved into a multidisciplinary approach, with chemotherapy and a variety of locoregional treatments, such as ablation and portal vein embolization, playing a crucial role. However, resection remains a core tenet of management, serving as the gold standard for a curative-intent therapy. As such, the input of a dedicated hepatobiliary surgeon is paramount for appropriate patient selection and choice of surgical approach, as significant advances in the field have made management decisions extremely nuanced and complex. We herein aim to review the contemporary surgical management of colorectal liver metastasis with respect to both perioperative and operative considerations.

Liver injury associated with oxaliplatin (L-OHP)-based chemotherapy can significantly impact the treatment outcomes of patients with colorectal cancer liver metastases, especially when combined with surgery. To date, no definitive biomarker that can predict the risk of liver injury has been identified. This study aimed to investigate whether organoids can be used as tools to predict the risk of liver injury.

We examined the relationship between the clinical signs of L-OHP-induced liver injury and the responses of patient-derived liver organoids in vitro. Organoids were established from noncancerous liver tissues obtained from 10 patients who underwent L-OHP-based chemotherapy and hepatectomy for colorectal cancer.

Organoids cultured in a galactose differentiation medium, which can activate the mitochondria of organoids, showed sensitivity to L-OHP cytotoxicity, which was significantly related to clinical liver toxicity induced by L-OHP treatment. Organoids from patients who presented with a high-grade liver injury to the L-OHP regimen showed an obvious increase in mitochondrial superoxide levels and a significant decrease in mitochondrial membrane potential with L-OHP exposure. L-OHP-induced mitochondrial oxidative stress was not observed in the organoids from patients with low-grade liver injury.

These results suggested that L-OHP-induced liver injury may be caused by mitochondrial oxidative damage. Furthermore, patient-derived liver organoids may be used to assess susceptibility to L-OHP-induced liver injury in individual patients.

Liver is the most common site of colorectal cancer (CRC) metastases. Treatment of CRC liver metastases (CRLM) includes different strategies, prevalently based on the clinical and oncological intent. Valid approaches in liver-limited or liver-prevalent disease include surgery, percutaneous ablative procedures (radiofrequency ablation, microwave ablation), intra-arterial perfusional techniques (chemo-embolization, radio-embolization) as well as stereotactic radiotherapy. Systemic treatments, including chemotherapy, immunotherapy and other biological agents, are the only options for patients with no chance of locoregional approaches. The use of chemotherapy in other settings, such as neoadjuvant, adjuvant or conversion therapy of CRLM, is commonly accepted in the clinical practice, although data from several clinical trials have been mostly inconclusive. The optimal integration of all these strategies, when applicable and clinically indicated, should be ever considered in patients affected by CRLM based on clinical evidence and multidisciplinary experience. Here we revised in detail all the possible therapeutic approaches of CRLM focusing on the current evidences, the studies still in progress and the often contradictory data.

Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified.

The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests.

The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010).

In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

With the rapid aging of populations worldwide, the number of vulnerable patients with liver metastasis from colorectal cancer has increased. This study aimed to examine the association between vulnerability and clinical outcomes in patients with colorectal liver metastasis (CRLM).

Consecutive 101 patients undergoing upfront hepatectomy for CRLM between 2004 and 2020 were included. The preoperative vulnerability was assessed using the Clinical Frailty Scale (CFS) score ranging from one (very fit) to nine (terminally ill), and frailty was defined as a CFS score of ≥ 4. A multivariable Cox proportional hazard regression model was utilized to investigate associations of frailty with disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS).

Of the 101 patients, 12 (12%) had frailty. Associations between frailty and surgical outcomes, namely, the incidence of 90-day mortality and postoperative complications, were not statistically significant (P > 0.05). In the multivariable analyses, after adjusting for clinical risk scores calculated using six factors (timing of liver metastasis, primary tumor lymph node status, number of liver tumors, size of the largest tumor, extrahepatic metastatic disease, and carbohydrate antigen 19-9 level) to predict recurrence following hepatectomy for CRLM, preoperative frailty was found to be an independent risk factor for DFS (hazard ratio [HR]:2.37, 95% confidence interval [CI] 1.06-4.72, P = 0.036), OS (HR:4.17, 95% CI 1.43-10.89, P = 0.011), and CSS (HR:3.49, 95% CI 1.09-9.60, P = 0.036).

Preoperative frailty was associated with worse DFS, OS, and CSS after upfront hepatectomy for CRLM. Assessment and improvement of patient vulnerability may provide a favorable prognosis for patients with CRLM.

Colorectal cancer (CRC) is the third most common cancer, and nearly half of CRC patients experience metastases. Oligometastatic CRC represents a distinct clinical state characterized by limited metastatic involvement, demonstrating a less aggressive nature and potentially improved survival with multidisciplinary treatment. However, the varied clinical scenarios giving rise to oligometastases necessitate a precise definition, considering primary tumor status and oncological factors, to optimize treatment strategies. This review delineates the concepts of oligometastatic CRC, encompassing oligo-recurrence, where the primary tumor is under control, resulting in a more favorable prognosis. A comprehensive examination of multidisciplinary treatment with local treatments and systemic therapy is provided. The overarching objective in managing oligometastatic CRC is the complete eradication of metastases, offering prospects of a cure. Essential to this management approach are local treatments, with surgical resection serving as the standard of care. Percutaneous ablation and stereotactic body radiotherapy present less invasive alternatives for lesions unsuitable for surgery, demonstrating efficacy in select cases. Perioperative systemic therapy, aiming to control micrometastatic disease and enhance local treatment effectiveness, has shown improvements in progression-free survival through clinical trials. However, the extension of overall survival remains variable. The review emphasizes the need for further prospective trials to establish a cohesive definition and an optimized treatment strategy for oligometastatic CRC.

The sequence of localized and systemic treatment for colorectal liver metastases (CRLM) remains debated. Our objective is to analyze the effect of treatment sequence on overall survival (OS) in patients with CRLM using a large cancer database.

The national cancer database (NCDB) was utilized to identify patients with stage IV colorectal cancer (CRC) diagnosed between 2004 and 2016. OS was analyzed using standard univariate and multivariate methods.

We identified 72,376 patients with synchronous CRLM, of whom 43,039 had liver-only metastases. Patients with liver-only CRLM had a median OS of 18.9 months, versus those with CRLM plus extrahepatic sites (11.3 months). In patients with liver-only CRLM, resection of both the primary and metastatic site was associated with median OS 38.9 months versus 30.2 months after resection of the metastatic site alone, and resection of the primary tumor alone (22.3 months, all p < 0.001). Receipt of perioperative chemotherapy correlated with a median OS of 44.7 months versus preoperative chemotherapy only (38.4 months) or postoperative chemotherapy only (27.9 months, all p < 0.001). Patients who received chemotherapy alone had a median OS of 16.4 months versus those who underwent resection without chemotherapy (9.5 months, p < 0.001).

This study reveals a correlation between perioperative chemotherapy and superior OS in patients with liver-only CRLM, and shows that resection of the metastatic site was linked to better OS. Despite obvious cohort heterogeneity, the data can support a resection approach with additional, preferably peri- or preoperative systemic therapy for patients with CRLM.

The rate of residual liver recurrence after the resection of colorectal liver metastases is high, and most cases recur within 5 years of the initial hepatectomy. Here, we report two cases of residual liver recurrence after radical resection of colorectal liver metastases after a long recurrence-free survival period.

Case 1 involved a 62-year-old woman treated for ascending colon cancer in April 2011 who underwent right hepatectomy for synchronous colorectal liver metastasis in April 2012. However, in September 2021, computed tomography revealed residual recurrence in the lateral segment of the liver, and a lateral segmentectomy of the liver was performed. In Case 2, a 52-year-old man treated for cecal cancer in July 2002 underwent lateral segmentectomy of the liver for metachronous colorectal liver metastasis in October 2006. Subsequently, there was no recurrence; however, computed tomography showed residual liver recurrence in the right lobe of the liver in October 2021, and an expanded posterior hepatic segmentectomy was performed. Histopathological findings in both cases were consistent with colorectal liver metastases.

We encountered two cases in which residual liver recurrence was observed after a long period of recurrence-free survival. Although rare, there have been a few cases of late recurrence of liver metastases after radical resection of cancer liver metastases.

Although patients with resectable colorectal liver metastasis (CLM), a population with good prognosis, have been treated with upfront surgery, some patients have had a poor prognosis. This study aimed to investigate biologic prognostic factors in patients with resectable CLMs.

This single-center retrospective study enrolled consecutive patients who underwent liver resection for initial CLMs at the Cancer Institute Hospital between 2010 and 2020. The study defined CLMs as resectable (tumor size < 5 cm; < 4 tumors; no extrahepatic metastasis) or borderline resectable (BR). Preoperative chemotherapy was administered to patients with BR CLMs.

During the study period, 309 CLMs were classified as resectable without preoperative chemotherapy and 345 as BR with preoperative chemotherapy. For the 309 patients with resectable CLMs, the independent poor prognostic factors associated with overall survival in the multivariable analysis were high tumor marker levels (CEA ≥ 25 ng/mL and/or CA19-9 ≥ 50 U/mL; (hazard ratio [HR], 2.45; p = 0.0007), no adjuvant chemotherapy (HR, 1.69; p = 0.043), and age of 75 years or older (HR, 2.09; p = 0.012). The 5-year survival rates for the patients with high tumor marker (TM) levels (CEA ≥25 ng/mL and/or CA19-9 ≥50 U/mL) were significantly worse than for those with low TM levels (CEA < 25 ng/mL and CA19-9 < 50 U/mL) (55.3% vs. 81.1%; p <0.0001) and similar to the rate for those with BR CLMs (52.1%; p = 0.864). Postoperative adjuvant chemotherapy had an impact on prognosis only in the high-TM group (HR, 2.65; p = 0.007).

High TM levels have a prognostic impact on patients with resectable CLMs stratified by tumor number and size. Perioperative chemotherapy improves long-term outcomes for patients with CLM and high TM levels.