Relationship between survival outcomes in patients with colorectal liver metastasis undergoing hepatectomy and significance of fibrotic markers for liver injury assessment

Introduction

Background

In the field of hepatic surgery for colorectal liver metastasis (CLM), improvements in multiple anticancer chemotherapy regimens provide opportunities for surgical interventions, even for multiple or large tumors (1). However, steatohepatitis or sinusoidal endothelial impairment with dilatation or some levels of liver dysfunction often occurs due to multi-drug or long-term chemotherapy (2,3). Chemotherapy remains one of the primary treatment modalities for various malignancies. However, the systemic nature of anti-cancer drugs often leads to adverse effects on non-cancerous tissues, including the liver, which is a critical organ for drug metabolism and detoxification. The liver is particularly vulnerable to chemotherapy-induced damage due to its extensive role in processing cytotoxic agents. Chemotherapeutic agents can cause both direct hepatotoxicity and indirect injury through immune-mediated mechanisms, oxidative stress, and inflammatory responses (2,3). Liver parenchymal damage may manifest as steatosis, fibrosis, cholestasis, or veno-occlusive disease, depending on the drug and dosage used. Additionally, impaired liver function can compromise the body’s ability to clear chemotherapeutic agents, creating a vicious cycle of toxicity. Hepatotoxicity not only limits the therapeutic efficacy of chemotherapy but also poses significant clinical challenges in patient management, particularly in those with pre-existing liver conditions. Understanding the mechanisms of liver injury associated with chemotherapy is crucial for improving therapeutic outcomes and minimizing treatment-related morbidity (4). These alterations are crucial for maintaining functional liver reserve. Some patients demonstrate severe hepatic impairment beyond scheduled operative indications. These parenchymal changes may decrease functional liver volume, and the resected permitted volume would be slightly reduced compared with the basic volume to reduce operative risk (5). Compared with chronic hepatitis caused by viral hepatitis, metabolic diseases, and long-term alcohol consumption, more rapid liver injury in patients with CLM may occur during chemotherapy, which is a different mechanism for background liver impairments or conditions (6). However, distinguishing between these hepatic pathogeneses using conventional liver function parameters is difficult (7).

Rationale and knowledge gap

Concerning evaluating liver injury degree, increased intrahepatic fibrosis is a significant potential factor of impaired functional causes for liver injury (8). Unlike needle biopsy or resected specimens, representative direct liver fibrosis-associated surrogate markers in serum samples (9-12), and Mac-2 binding protein glycosylation isomer (M2BPGi) have been investigated (13,14). In other non-invasive scoring systems based on liver functional parameters, a decreased platelet count (15,16), an increased aspartate aminotransferase-to-platelet ratio index, and the Fib-4 index are often used to evaluate hepatic fibrosis or injury at this stage (17). Type IV collagen level is a classical fibrotic marker of the liver, and serum hyaluronic acid (HA) level is a well-known marker of both hepatic fibrosis and sinusoidal endothelial dysfunction (11,12). Additionally, M2BPGi level is a novel marker among the abovementioned markers for assessing hepatic fibrosis, inducing inflammatory cytokines and increasing extracellular collagen or fibronectin levels (14). Hepatic stellate cells are a source of M2BPGi, reflecting their activation during liver fibrosis (15). Our pilot study showed that M2BPGi levels before hepatectomy were closely related to post-hepatectomy complications (18). To the best of our knowledge, the relationship between these fibrosis markers and preoperative liver dysfunction levels, short-term surgical outcomes, and long-term prognosis in patients with CLM undergoing hepatectomy remains unclear.

Objective

We aimed to clarify the recently improved surgical results of hepatectomy for CLM and to identify four representative fibrotic markers related to liver injury by multi-drug chemotherapy for primary colorectal carcinomas or patient survival. We collected data on fibrotic parameters, followed up on the long-term outcomes of patients with CLM, and retrospectively investigated the relationship between serum marker levels and clinicopathological factors, tumor recurrence, and patient survival in 45 consecutive patients with CLM undergoing hepatectomy at a single academic cancer institute in the last eight years. This manuscript is written following an observation retrospective cohort of consecutive patients. It is necessary to investigate the association between fibrotic markers indicative of liver damage and patient demographics, as well as their impact on prognosis in patients with CLM who have received multi-agent chemotherapy following hepatectomy. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1138/rc).

Methods

Patients

This study included 45 consecutive patients with CLM who were scheduled for surgery and admitted to the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, the University of Miyazaki Faculty of Medicine, Miyazaki, Japan, between 2015 and 2022. Patients with distant metastases or double cancer during surgery were excluded from the study. A radical hepatectomy was performed, and the hepatic tumors were completely resected without macroscopic exposure of the amputated sections to the remaining liver tissue. Before and after primary treatment, serum carcinoembryonic antigen (CEA) levels were measured as tumor markers every three months, and enhanced computed tomography of the liver was performed every six months after hepatectomy to monitor tumor recurrence. The minimum follow-up period after hepatic resection in patients who survived was 24 months (14–83 months). This study adhered to the Declaration of Helsinki’s statement (as revised in 2013) on the ethical principles for medical research involving human participants, including research on identifiable human materials and data. The Human Ethics Review Board of the University of Miyazaki Faculty of Medicine approved all the study protocols (O-1469; December 22, 2023). An opt-out procedure obtained patient consent for study participation for 1 month on the website and in the outpatient clinic of our institution. Anesthesia and patient data were retrieved from the database of the University of Miyazaki Faculty of Medicine. The study was a retrospective cohort observation study. This study showed potential sources of bias due to the retrospective cohort.

Measurement of tumor markers and histological findings

Patient clinicopathological data were retrieved from our institute’s archives. In the University of Miyazaki Faculty of Medicine, the normal CEA and CA19-9 levels in patients are <5 and <37 U/mL, respectively, and levels exceeding the normal levels are considered elevated at our institutional standard. Tumor-related factors were compared with the histopathological findings of the resected specimen. For the clinicopathological assessment of biliary tract carcinomas, we used the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma (19).

Measurement of fibrotic markers

Peripheral blood samples were collected from each patient preoperatively. The blood samples were centrifuged at 3,000 rpm for 15 min, and the obtained serum was stored at −80 °C. HA was assayed using the sandwich binding protein assay by SRL Inc. (Tokyo, Japan) (11). The normal serum HA level reported by SRL Inc. is <50 ng/mL. M2BPGi levels were measured using a chemiluminescent enzyme immunoassay with anti-Wisteria floribunda agglutinin and anti-M2BP antibodies using a fully automated HSCL-2000i Immunoanalyzer (Sysmecs Co., Hyogo, Japan) (18). According to the company data, the cutoff value was set at <1 of the cutoff index (COI). Serum 7S collagen concentration was measured using a type IV collagen 7S domain RIA kit (Diaiatron Co., Tokyo, Japan), which uses a polyclonal antibody against the 7S domain of type IV collagen isolated from the human placenta. According to the company data, the normal value was set at <8.0 ng/mL (13). These quantitative variables were defined based on our institutional standard levels.

Statistical analysis

Differences in continuous data between groups were evaluated using the Mann-Whitney test. The correlation analysis was examined using Pearson’s correlation analysis, and the correlation coefficient is a statistical measure that quantifies the strength and direction of the relationship between two variables. It is represented by a value ranging from −1 to 1. A correlation coefficient of 1 indicates a perfect positive relationship, meaning that as one variable increases, the other also increases proportionally. A correlation coefficient of −1 indicates a perfect negative relationship. A correlation coefficient of 0 suggests no linear relationship between the two variables. Disease-free and overall survival periods and rates were calculated using the Kaplan-Meier method, and differences between groups were tested for significance using the log-rank test. A two-tailed P value of <0.05 was considered significant. Statistical analyses were performed using the SPSS version 23 (IBM Corp., Armonk, NY, USA). Missing data were considered by the deletion of the follow-up examination.

Results

Perioperative parameters

The patients included 34 (76%) men and 11 (24%) women with a mean age of 64.4±12.4 years (± standard deviation; range, 24–84 years) at the time of surgery. Primary colorectal carcinoma was located in the cecum in 2 patients (4%), ascending colon in 5 (11%), transverse colon in 7 (16%), descending colon in 7 (16%), sigmoid colon in 11 (24%), and rectum in 13 (29%). Lymph node metastases were observed in 33 patients (88%). The tumor factors were T1 in 1 (2%), T2 in 1, T3 in 24 (53%), and T4 in 23 (29%) patients. Of 45 patients, 36 (80%) underwent adjuvant chemotherapy after the primary surgery. The mean CEA level before hepatectomy was 7,204±12.4 ng/mL, and 30 patients demonstrated abnormally higher CEA levels of >5 ng/mL. The chemotherapy regimen before hepatectomy, including adjuvant chemotherapy for primary cancer, was a FOLFOX-based regimen in 11 patients (24%), a FOLFIRI-based regimen in 10 (22%), S-1 in 2 (4%), UFT in 2 (4%), and XELOX in 11 (24%). Surgical procedures for CLM included hepatic segmentectomy or sectionectomy in 13 patients (29%) and partial resection in 32 patients. Liver metastases were synchronous with the primary lesions in 16 patients (36%). The H-classification was H1 in 36 patients (80%) and H2 in 9, and the H-grading was A in 17 patients (37%), B in 26 (58%), and C in 2 (4%). The distribution of CLM was in the right liver in 22 patients (49%), left liver in 8 (18%), both livers in 12 (27%), caudate lobe in 2 (4%), and hilar bile duct in 1 (2%). Multiple CLM were observed in 13 patients (29%), and the mean tumor size was 35±31 mm (range, 5–200 mm). The mean surgical margin was 4.9±4.8 mm, and a 0-mm margin was observed in five patients (11%). The pathological findings of CLM were well-differentiated adenocarcinoma in 7 patients (16%), moderate in 15 (33%), and necrotic change due to chemotherapy in 18 (40%). No nodal metastasis was observed in the liver hilum. CLM recurrence was observed in 22 patients (49%), and distant metastasis was observed in 21 patients (47%), including bone metastasis in 3 patients (6%), hepatic hilar lymph node metastasis in 3 (7%), lung metastasis in 7 (15%), and peritoneal metastasis in 13 (11%). The treatment modalities for cancer recurrence were re-hepatectomy in 5 patients (9%), pulmonary resection in 2 (4%), radiation therapy in 1, additional chemotherapy in 14 (31%), and no treatment in 23 (51%). The mean recurrence-free survival and median periods were 29.8±7.5 and 14.8 [(interquartile range (IQR), 2.5–53.3] months, respectively. In total, 24 patients were alive without recurrence (53%), 20 (44%) were alive with cancer recurrence, and 1 (2%) had cancer-specific death. The mean overall survival and median periods were 38.5±3.8 and 31.6 (IQR, 21.1–64.5) months, respectively.

According to the Child-Pugh classification, all patients were classified as having class A disease preoperatively. The mean serum albumin level was 3.91±0.41 g/dL, total cholesterol level was 193±60 mg/dL, lymphocyte count was 2,905±14,273 µL, total bilirubin level was 0.63±0.25 mg/dL, prothrombin activity was 95.1%±13.7%, platelet count was 23.0±8.5 ×10⁴/µL, hyaluronic acid level was 68.9±82.3 ng/mL, M2BPGi level was 0.87±0.48 ng/mL COI, and type IV collagen level was 5.74±3.76 ng/mL.

Relationship between clinicopathological parameters and each fibrotic marker

The relationships between the six types of fibrotic markers or scores and clinicopathological, surgical, and cancer recurrence after hepatectomy in 45 patients are shown in Table 1. Representative fibrotic parameters such as platelet count and levels of HA, type IV collagen, and M2BPGi were not significantly different for each preoperative chemotherapy regimen, time of liver metastasis, H classification, location of CLM, histologic differentiation, recurrence of CLM after hepatectomy, distant metastasis and its lesion, or patient prognosis. These fibrotic parameters were not significantly correlated with patient age or tumor-related factors, such as the number and size of CLM or CEA level in Table 2. Platelet count was significantly correlated with HA level (P<0.05) and tended to be correlated with M2BPGi level, but not significantly (P=0.056). HA level was significantly associated with albumin level (P<0.05). Type IV collagen 7S level was not correlated with any of these parameters.

Relationship between preoperative fibrotic parameter levels and post-hepatectomy disease-free survival

As the overall survival in this series was quite good, and cancer death was observed in only one patient, the relationship between clinicopathological parameters, including fibrotic parameters, and overall survival was not examined in this series. Table 3 summarizes the cancer-free survival rates and differences between the clinicopathological parameters. Patients with H2 and H3 classifications had significantly poor cancer-free survival (P<0.01), and increased preoperative total bilirubin levels were significantly associated with poor cancer-free survival (P<0.05). Histologically, moderately differentiated adenocarcinomas tended to exhibit poor cancer-free survival, although the difference was not significant (P=0.09). None of the fibrotic parameters were significantly associated with cancer-free survival. Risk ratio was not examined in the small number of patients in this study.

Discussion

Key findings

Considering patient survival in the present study, cancer-free survival worsened owing to advanced H classification according to the Japanese criteria of the Colorectal Cancer Society, in which the usefulness of this classification was previously clarified (20). Significant factors may not have been identified before introducing multiple anticancer regimens. However, at this stage, the influence of chemotherapy or differences in the regimen was not significantly associated with cancer-free survival. Still, it might be associated with improved overall survival, as described above. According to our recent results, patients with advanced stage or H classification accompanied with increased total bilirubin level, influencing dysfunctions of bilirubin metabolism, might avoid hepatectomy if shrinkage of the size or number of CLM by systemic chemotherapy or intrahepatic arterial infusion chemotherapy is still possible. Recently, a staging system with KRAS mutations demonstrating a better ability to predict survival in patients with CLM has been reported (21). In our series, genetic mutations such as KRAS or BRAF were not always measured or examined in limited situations. We hypothesized that increased liver fibrosis and its surrogate markers were associated with cancer-free or overall survival because deterioration of hepatic or related immunological dysfunction or acceleration of cancer progression were considered. However, no fibrotic markers were associated with prognosis in this study. Fibrotic changes in non-parenchymal liver tissue were not observed in the resected specimens. Only total bilirubin level was significantly associated with prognosis among the hepatic functional parameters, as described above. Although fibrotic markers may be related to cancer progression in malignancies (22-24), they may not influence the malignant behavior of CLM.

Strengths and limitations

This study has some limitations that should be considered. First, this study was performed in a consecutive cohort comprising relatively few participants (45 patients with CLM). Second, we did not evaluate imaging analysis as an elastographic detection or the novel fibrosis analysis of the severity of hepatic fibrosis in this series (25,26), which may be a more reliable and less-invasive modality for predicting surgical outcomes (27). Third, the detailed histological mechanism of liver fibrosis by each parameter has not been clarified, as there was no significant correlation among the fibrotic serum markers. Lastly, specific genetic markers for CLM, such as KRAS mutation or BRAF in primary colorectal carcinoma, were established, and (21) were examined in only 25 patients (56%) in this series. A recent scoring system combined with KRAS mutation could be applied by the Japan Hepato-Biliary-Pancreas Association (28). Nevertheless, this study also has strengths. Regarding the malignant behavior of CLM related to cancer recurrence, the relationship between genetic markers and fibrotic markers is promising because the interaction between non-parenchymal liver cells and cancer cells is closely associated with the metastatic environment of the liver (29). In intrahepatic cholangiocarcinoma, liver fibrosis reflecting background liver injury significantly influences poorer overall survival and higher cancer recurrence of adenocarcinoma in the long term after hepatectomy (30). Nevertheless, as with adenocarcinoma and cholangiocarcinoma, the role of liver fibrosis in CLM remains unknown. Drug therapies and other modalities may also affect patients with CLM after cancer recurrence. However, at this stage, the overall survival of patients with CLM after hepatectomy was beyond our expectations, as 98% of the five-year survivors, which was satisfied with our surgical results.

Comparison with similar research

The specific CLM tumor markers commonly used in Japan are only CEA and CA19-9 levels to evaluate tumor aggressiveness at this stage (31). The presence of RAS or BRAF mutations in primary colorectal cancer or CLM has not been examined in any patient (21). In patients with hepatocellular carcinoma (HCC) undergoing hepatectomy, not only tumor-associated markers, but also background liver dysfunction or liver functional reserve was significantly associated with poor patient prognosis (32). Our recent study has demonstrated that the fibrotic markers examined in the present study were significantly associated with postoperative complications, which were also related to cancer-specific long-term survival in patients with HCC (data submitted, but not in press). As described above, patients with CLM frequently experience liver damage because of preoperative chemotherapy for primary colorectal cancers or the existence of CLM in recent years (7); therefore, markers associated with chemotherapy-induced liver injuries are required. To date, chemotherapy for CLM-specific markers has not yet been fully clarified (33), and although the conventional liver functional reserve is commonly examined, the permitting resected volume might be decreased in patients with CLM who had undergone long-term systemic chemotherapy (5). At our institute, the permitted resected volume is reduced to 10% of the resected liver volume to prevent post-hepatectomy liver failure (unpublished data). Nagai et al. have proposed a reduced resected liver volume for major hepatectomy in cases of multiple preoperative chemotherapies for an extended period in patients with CLM (34).

Explanations of findings

We also examined fibrotic markers such as platelet count and levels of HA, type IV collagen 7S, and M2BPGi in all hepatectomies for any background liver disease. A previous study has reported that the proposed surrogate fibrotic marker was autotaxin in patients with CLM undergoing hepatectomy (35). Although these may be helpful to liver functional markers, their correlation with cancer malignant behavior remains unclear. In a limited number of 45 patients with CLM over the last eight years, our cohort study showed promising results of patient survival with or without cancer recurrence, and only one patient died of colorectal cancer relapse. No deaths from other causes were recorded in this study. However, we are uncertain why such a good course and laparoscopic hepatectomy induced in 2016 might have influenced the maintenance of better patient general status or immunological deterioration (36). Clavien-Dindo III or higher levels of post-hepatectomy complications were rare in this series, and examining their relationship with surgical records or morbidities in our study was challenging. Thus, analyzing the relationship between the fibrotic markers and prognosis in this study was difficult. Cancer relapse was observed in 49% of the patients, including 41% with distant metastases. With effective chemotherapy before hepatectomy in patients with CLM, liver cancer recurrence may be reduced. Even though cancer recurred after hepatectomy, the patients with distant metastasis survived with various effective chemotherapies for cancer relapse, as demonstrated in the present results.

Implications and actions needed

No significant relationship between candidate fibrotic markers and CLM-related parameters or tumor recurrence was identified in the present study. Only platelet count and HA level were significantly correlated regarding the relationship between fibrotic markers. Although a previous study determined a close relationship between fibrotic parameters, we did not identify any significant correlation with the present study (11). Although these are well-known fibrotic markers associated with histologic fibrotic grade in HCC (32), they may not be useful for evaluating the liver functional parameters of yellow or blue livers in patients with CLM. HA was also significantly correlated with albumin levels in this study, although a low albumin level is a useful marker of post-hepatectomy complications such as bile leakage (37). HA level is also a parameter of the hepatic sinusoidal function.

Conclusions

We conducted a retrospective and consecutive analysis of the outcomes of 45 patients with CLM who underwent curative hepatectomy, including an analysis of the relationship between four preoperative blood fibrotic markers, conventional clinicopathological parameters, and patient surgical outcomes. None of the candidates was significantly correlated with clinicopathological parameters or patient survival, and fibrotic markers were not correlated in patients with CLM, as expected. Overall patient survival was good in this series; H classification revealed the progressive status of CLM, and preoperative total bilirubin level was significantly associated with cancer-free survival, but not with all fibrotic markers, liver functions, and other tumor-related factors. Fibrotic markers indicating chemotherapy or repeated surgical liver injury were not significant predictive factors reflecting cancer malignant behaviors or patient overall survival, contrary to our hypothesis. Future studies involving more patients must clarify the cancer-associated mechanisms and increased fibrotic markers.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1138/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1138/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1138/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-1138/coif). The 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. This study adhered to the Declaration of Helsinki’s statement (as revised in 2013) on the ethical principles for medical research involving human participants, including research on identifiable human materials and data. All the study protocols were approved by the Human Ethics Review Board of the University of Miyazaki Faculty of Medicine (approval number: O-1469; December 22, 2023). Patient consent for study participation was obtained by an opt-out procedure for 1 month on the website and in the outpatient clinic of the University of Miyazaki Faculty of Medicine.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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