The Surgical Outcome and Prognostic Factors for Solitary Colorectal Liver Metastasis

doi:10.21203/rs.3.rs-3250405/v1

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The Surgical Outcome and Prognostic Factors for Solitary Colorectal Liver Metastasis

https://doi.org/10.21203/rs.3.rs-3250405/v1

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Background:

The study focused on patients who had surgery for solitary liver metastasis of colorectal cancer (CRLM) and experienced relapse. Its main objective was to analyze the factors that independently contribute to recurrence and long-term overall survival.

Methods:

We retrospectively analyzed 230 solitary CRLM patients who received liver resection between 2010 and 2019. Factors prognostic of disease recurrence and overall survival were investigated and nomograms were developed to predict patient outcome after liver resection.

Results:

For these patients, the 3-year-overall survival (OS) rate was 72.3% and 59.8% for 5-years. For the recurrence-free survival (RFS) rate, it was 40.0% for 3-years and 27.1% for 5-years. The multivariate analysis showed that age ≥ 70, resection margin width < 10 mm, initial N2 stage, hypoalbuminemia before liver resection, and neutrophil-lymphocyte ratio (NLR) ≥ 3 after liver resection were independent prognostic factors for OS. For RFS, the multivariate analysis showed that initial N2 stage, hypoalbuminemia before liver resection, NLR ≥ 3 after liver resection, abnormal Carcinoembryonic antigen (CEA) after liver resection, and CEA ratio (after/before liver resection) < 0.3 were independent prognostic factors.

Conclusions:

The study found that several factors significantly impact both the recurrence and overall survival rates of patients who had surgery for solitary liver metastasis of colorectal cancer. The most important risk factors identified were the initial N2 stage, a neutrophil-lymphocyte ratio of 3 or higher after liver resection, and hypoalbuminemia (albumin levels below 3.5 g/dL) before liver resection.

Colorectal cancer

liver metastasis

solitary

prognosis

hepatectomy

Colorectal cancer has consistently been recognized as a significant form of cancer. According to the latest available data from the 2022 cancer statistics in the United States, colorectal cancer stands as the third most frequently detected cancer among newly diagnosed cases. Similarly, it ranks third in terms of mortality attributed to cancer. (1) Following the diagnosis of colorectal cancer (CRC), it is estimated that approximately 25–50% of individuals within this patient cohort will develop liver metastases, and a significant proportion of them, approximately 90%, succumb to the metastatic disease.(2, 3) Surgical resection of colorectal liver metastasis (CRLM) remains the therapeutic intervention associated with 5-year survival rates of up to 50%. Moreover, it presents an opportunity for a potential cure, as approximately 25% of patients achieve disease-free survival at 5 years. However, only a minority, specifically 25% of these patients, meet the criteria for surgical resection. (4, 5)

In order to attain the potential benefits of surgery, patients with multiple metastases require meticulous screening. Generally, the presence of liver metastases should be confined to a limited and surgically resectable extent, ensuring the preservation of an adequate volume of liver tissue. Additionally, patients should demonstrate favorable liver function and the ability to tolerate the surgical procedure. It is essential that patients are in good overall health, and the surgical intervention should result in tangible clinical advantages. According to previous research findings, patients with multiple liver metastases who undergo surgery have a five-year disease-free survival rate of 18.1%.(6) Conversely, for patients with solitary liver metastasis who undergo surgical intervention, the five-year disease-free survival rate reaches 30 ~ 38.9%.(2, 7) A comprehensive review of the existing literature reveals the presence of numerous clinical risk scores designed for patients with colorectal liver metastases. Many of these risk scores consider the number of metastases as a significant factor in determining the surgical benefit. As such, the outcomes of surgical intervention for patients with multiple metastases may not be as favorable compared to those with solitary metastasis.(8–11)

Despite the relatively improved prognosis associated with solitary liver metastasis compared to multiple metastases, a considerable number of patients still experience relapse within one year following treatment. Currently, there is a limited number of articles available on CRLM with solitary liver metastasis. Most of the literature covers medical records from a relatively long time ago as well. (7, 12, 13) However, the latest article also considers lung metastasis as a potential risk factor in this context. (7) The advantage of our study is that we focus specifically on CRLM with solitary liver metastasis without any other metastases. Additionally, the patient data recorded in this study are all treated according to the treatment trends of the past decade.

The primary objective of this study was to examine the results of a significant patient population who underwent surgical intervention for resectable solitary colorectal liver metastases (CRLM) and to identify a subset of individuals who experienced recurrence. This subset could potentially serve as a surrogate group that could benefit from neoadjuvant chemotherapy or innovative selection strategies.

Patients

Under the approval of the Institutional Review Boards (IRB) of Chang Gung memorial hospital (CGMH), patients with CRLM who received liver resection in Linkou CGMH from 2010 to 2019 were retrospectively reviewed. A total of 511 patients were examined. Those with multiple liver metastases on preoperative imaging studies or postoperative pathological reports were excluded from further analysis. Patients were also excluded from the current study for lack of critical clinical data or image, or with concomitant extrahepatic metastasis including peritoneal metastasis. Two hundred and thirty patients with solitary CRLM were eventually enrolled into the current study.

Demographic data including age, gender, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, primary tumor locations, initial tumor stage, hemoglobin, albumin, carcinoembryonic antigen (CEA) before and after liver resections, neutrophil-to-lymphocyte ratio (NLR) before and after liver resections, molecular profiles including microsatellite instability (MSI) and k-ras mutations, size of liver tumors, locations of liver tumors, adjuvant chemotherapy, and margin width were recorded from the prospectively established database. The surgical variables, pathological factors, and oncological outcomes were also recorded. For postoperative follow-up, patients were examined and their blood was drawn for analysis at one to two months after liver resection. The tumor was staged by the 8th edition of the AJCC TNM staging system for colorectal cancer in the current study.

Definition and statistical analysis

The preoperative preparation, operative procedures, and postoperative care had been described in our previous studies. (14, 15) Major liver resection was defined as liver resection of three or more segments according to the Brisbane 2000 terminology. (16) Recurrence-free survival (RFS) was defined as the time interval from the date of liver resection to the date of first documented disease recurrence. The overall survival (OS) was defined as the time from the date of liver resection to either the date of death or the date of the last follow-up.

Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range (IQR)) whenever appropriate, and analyzed by Student’s t-test or Mann-Whitney U test. Categorical variables were described by number and frequency (%) and analyzed by Pearson chi-square test. Kaplan-Meier method and long-rank test were adopted to analyze RFS and OS. Cox regression multivariate analysis was used to identify independent variables that were associated with RFS and OS. Variables independently associated with RFS and OS were further incorporated into nomograms capable of predicting RFS or OS after liver resection. The predictive efficacy of these models was examined by the C-statistics and further validated by bootstrapping methods with 1,000 repeats. Statistical significance was defined as P value < 0.05. The statistical analysis was performed by IBM SPSS Statistics 22 (IBM Corporation, Software Group, Somers, NY, USA).

Of the 525 colon cancer patients with liver metastasis who underwent curative intent liver resection at Linkou Chang Gung Memorial Hospital from 2010 to 2019, 295 patients were excluded because of multiple liver metastases in the preoperative image study. 230 patients with solitary CRLM were included, and the median follow-up time was 39.0 months (mean: 46.85 months).

The patient demographics and tumor characteristics are listed in Table 1. The rate of people older than 70 years old was 26.1% and the rate of females was 36.5%. For the initial stage of colon cancer, the rate of N2 was 36.0%, the rate of M1 was 46.5% and the rate of the initial stage I/II/III was 3.9%/16.2%/33.2%, respectively. The histology grade for colon cancer showed 5.2% well-differentiated, 88.6% moderately-differentiated and 6.2% poorly-differentiated. The HBV infection rate was 7.8% and HCV infection rate was 3.9%. The abnormal serum CEA level was 57.5% before colon resection, 60.9% before liver resection, and 17.2% after liver resection. The rate of NLR ≥ 3 was 63.2% before colon resection, 32.2% before liver resection, and 21.5% after liver resection. The hypoalbuminemia rate was 5.5% before liver resection. The MSI-high rate was 2.9% and the rate of K-RAS mutation was 45.3%. For pathology of liver metastasis, the rate of positive margin was 1.8%, the rate of margin width < 10mm was 27.2%, and the rate of liver tumor size ≥ 2.5cm was 57.6%. There was 31.7% of surgery performed through the laparoscopic method. The rate of patients receiving adjuvant therapy was 77.8% after colon resection and 88.3% after liver resection.

Table 1

Patient demographics and tumor characteristics of the study cohort (n = 230)
Variable			Variable		No (%)
Age(yr)	(Mean: 62.4 ± 11.5)		KRAS mutation
< 70		170(73.9)	No		75(54.7)
≥ 70		60(26.1)	Yes		62(45.3)
Gender			Resection margin
Male		146 (63.5)	Positive		4(1.8)
Female		84 (36.5)	Negative		224(98.2)
Colon cancer initial T stage			Margin width(mm)	(Mean:3.46 ± 2.45)
I/II/III		177 (78.0)	< 10		62(27.2)
IV		50 (22.0)	≥ 10		166(72.8)
Colon cancer initial N stage			Synchronous liver metastasis
0-I		146 (64.04)	No		121 (52.6)
II		82 (35.96)	Yes		109 (47.4)
Colon cancer initial M stage			Liver resection method
0		123 (53.5)	Conventional open		157(68.3)
I		107 (46.5)	Laparoscopic		73(31.7)
Colon cancer initial staging			Cancer differentiation
I		9 (4.0)	Well-differentiated		12(5.2)
II		38 (16.5)	Moderately-differentiated		203(88.6)
III		76 (33.0)	Poorly-differentiated		14 (6.2)
IV		107 (46.5)	Tumor size (cm)	(Mean:6.95 ± 7.21)
CEA before colon surgery			< 2.5		97(42.4)
< 5		97(42.5)	≥ 2.5		132(57.6)
≥ 5		131(57.5)	NLR before liver resection
NLR before colon surgery			< 3		145(67.8)
< 3		77(36.8)	≥ 3		69(32.2)
≥ 3		132(63.2)	Albumin before liver resection (g/dL)
HBsAg			< 3.5		11(5.5)
Positive		18(7.8)	≥ 3.5		190(94.5)
Negative		212(92.2)	CEA before liver resection
Anti-HCV Ab			< 5		67(29.1)
Positive		9(3.9)	≥ 5		163(60.9)
Negative		221(96.1)	CEA after liver resection
Adjuvant therapy after colon surgery			< 5		183(82.8)
No		51(22.2)	≥ 5		38(17.2)
Yes		179(77.8)	NLR after liver resection
Microsatellite instability			< 3		139(78.5)
High		2(2.9)	≥ 3		38(21.5)
Low		68(97.2)	Adjuvant therapy after liver resection
			No		27(11.7)
			Yes		203(88.3)

For these patients, the 3-year-overall survival rate was 72.3% and 59.8% for 5 years. For recurrence-free survival rate, it was 40.0% for 3 years and 27.1% for 5 years. Figure 1 illustrates the overall survival curve and recurrence-free survival curve. In Table 2, we present the univariate analysis of OS after liver resection. By univariate analysis, age ≥ 70, colon tumor histologic grade, margin width < 10mm, initial T4 stage, initial N2 stage, abnormal CEA after liver resection, hypoalbuminemia before and after liver resection, and NLR ≥ 3 after liver resection were significantly associated with the OS. Table 3 reveals the univariate analysis of RFS after liver resection. By univariate analysis, age ≥ 70, colon tumor histologic grade, initial T4 stage, initial N2 stage, abnormal CEA after liver resection, CEA ratio (after/before liver resection) < 0.3, hypoalbuminemia before liver resection, NLR ≥ 3 after liver resection, and adjuvant therapy after liver resection, were significantly associated with the RFS.

Table 2

Univariate analysis of recurrence-free survival after liver operation
Variable	Median survival	p-value	Variable	Median survival		p-value
Liver tumor size(cm)			Margin width(mm)
< 2.5	33.5	0.330	< 10	37.18		0.128
≥ 2.5	24.8		≥ 10	20.9
Synchronous or metachronous			Initial T4 stage
Synchronous	25.0	0.701	T1/2/3	33.27		0.016
Metachronous	26.87		T4	16.37
Operation method			Initial N2 stage
Conventional open	20.23	0.591	N0/1	37.23		0.004
Laparoscopic	34.0		N2	16.93
CEA level at diagnosis of colon cancer			Initial M stage
< 5	33.5	0.207	M0	32.63		0.616
≥ 5	20.23		M1	17.27
CEA level before liver resection			Age
< 5	29.13	0.436	< 70	28.77		0.012
≥ 5	24.80		≥ 70	15.67
CEA level after liver resection
< 5	33.5	0.001	Gender
≥ 5	16.37		Male	29.13		0.336
Tumor differentiation		0.049	Female	20.9
Well	92.8
Moderate	25.17		CEA ratio(After/before liver resection)
Poor	9.0		< 0.3	35.03		0.008
Mucinous tumor			≥ 0.3		17.27
No	26.87	0.250	Hemoglobin before liver resection
Yes	15.17		< 12	16.83		0.102
KRAS2 mutation status			≥ 12	33.33
Negative	20.13	0.445	NLR before liver resection
Positive	16.37		< 3	25.53		0.460
Primary tumor location		0.959	≥ 3	28.77
Right-sided	24.80		Albumin level before liver resection
Left-sided	32.37		< 3.5	5.27		0.001
Rectum	17.27		≥ 3.5	24.8
HCV infection			Hemoglobin after liver resection
Negative	24.8	0.554	< 12	24.8		0.724
Positive	59.03		≥ 12	30.0
HBV infection			NLR after liver resection
Negative	24.8	0.294	< 3	32.63		0.028
Positive	51.73		≥ 3	13.9
Liver tumor at right lobe			Albumin after liver resection
No	16.4	0.408	< 3.5	16.93		0.318
Yes	26.87		≥ 3.5	37.67
Adjuvant chemotherapy			Adjuvant chemotherapy in 30 days
No	9.6	0.009	No	22.6		0.387
Yes	26.87		Yes	26.87

Table 3

Univariate analysis of overall survival after liver operation
Variable	Median survival	p-value	Variable	Median survival	p-value
Liver tumor Size			Margin width(mm)
< 2.5cm	NA	0.053	< 10mm	106.77	0.032
≥ 2.5cm	106.77		≥ 10mm	NA
Synchronous or metachronous			Initial T4 stage
Synchronous	110.47	0.809	T1/2/3	NA	0.023
metachronous	106.77		T4	47.13
Age			Initial N2 stage
< 70	NA	0.008	N0/1	NA	0.004
≥ 70	51.1		N2	56.50
Operation method			Initial M stage
Conventional open	NA	0.142	M0	NA	0.437
Laparoscopic	110.47		M1	110.47
CEA level at diagnosis of colon cancer			Gender
< 5	106.77	0.254	Male	110.47	0.617
≥ 5	110.47		Female	NA
CEA level before liver resection
< 5	NA	0.835	CEA ratio(After/before liver resection)
≥ 5	110.47		< 0.3	NA	0.149
CEA level after liver resection			≥ 0.3	88.4
< 5	NA	0.005
≥ 5	88.24		Hemoglobin before liver resection
Tumor differentiation		0.010	< 12	88.4	0.091
Well	NA		≥ 12	NA
Moderate	NA		NLR before liver resection
Poor	38.67		< 3	NA	0.643
Mucinous tumor			≥ 3	110.47
no	NA	0.748	Albumin level before liver resection
Yes	NA		< 3.5	9.00	0.001
KRAS2 mutation status			≥ 3.5	NA
Negative	106.77	0.519	Hemoglobin after liver resection
Positive	64.77		< 12	110.47	0.073
Primary tumor location		0.167	≥ 12	NA
Right-sided	NA		NLR after liver resection
Left-sided	NA		< 3	NA	0.043
Rectum	NA		≥ 3	106.77
			Albumin after liver resection
HCV infection			< 3.5	33.13	0.041
Negative	NA	0.698	≥ 3.5	NA
Positive	NA		Adjuvant chemotherapy
HBV infection			No	NA	0.226
Negative	110.47	0.526	Yes	NA
Positive	NA
Liver tumor at right lobe			Adjuvant chemotherapy in 30 days
No	106.77	0.974	No	NA	0.929
Yes	NA		Yes	110.47

The multivariate analysis for OS and RFS were listed in Table 4 and Table 5. The multivariate analysis showed that age ≥ 70 (HR: 2.209, p = 0.031), resection margin width < 10 mm (HR: 2.793, p = 0.017), initial N2 stage (HR: 2.070, p = 0.022), hypoalbuminemia before liver resection (HR: 16.785, p < 0.001), and NLR ≥ 3 after liver resection (HR: 3.073, p = 0.002) were independent prognostic factors for OS (Table 4). The nomogram was constructed using these five respective variable point scales, with the sum of the five variable points defined as total points. By drawing a perpendicular line from the total point axis to the three-outcome axis, estimated 1-, estimated 3- and 5-year survival probabilities could be obtained (Fig. 2). The C-index of this novel nomogram was 0.721 and that of internal validation was 0.737.

Table 4

Multivariate analyses of prognostic factors for overall survival after liver operation
Variables	Multivariate
Variables	N(%)		HR	95% CI	p-value
Liver tumor size ≥ 2.5cm		132(57.6)	1.493	0.787–2.755		0.206
Margin width < 10 mm		62(27.2)	2.793	1.230–7.204		0.017
Initial T4 stage		50 (22.0)	1.243	0.523–2.316	0.574
Initial N2 stage		82 (35.96)	2.070	1.008–3.512	0.022
Age > 70 yr		60(26.1)	2.209	1.082–4.820	0.031
Albumin level before liver resection < 3.5		11(5.5)	16.785	3.126–27.955	<0.001
NLR after liver resection ≥ 3		38(21.5)	3.073	0.1.476–5.882	0.002
CEA level after liver resection ≥ 5		38(17.2)	1.699	0.725–4.170	0.187

Table 5

Multivariate analyses of prognostic factors for Disease free survival after liver operation
Variables	Multivariate
Variables	N(%)	HR	95% CI	p-value
Initial T4 stage	50 (22.0)	1.588	0.973–2.591		0.064
Initial N2 stage	82 (35.96)	1.573	1.016–2.434	0.043
Age < 70 yr	60(26.1)	1.343	0.807–2.237	0.257
Albumin level before liver resection < 3.5	11(5.5)	4.208	1.743–10.160	0.001
NLR after liver resection ≥ 3	38(21.5)	1.764	1.089–2.857	0.021
CEA level after liver resection ≥ 5	38(17.2)	2.266	1.316–3.902	0.003
CEA ratio ≥ 0.3	87(39.4)	1.536	1.015–2.325	0.042
No adjuvant therapy	27(11.7)	1.165	0.487–2.788	0.731

For RFS (Table 5), the multivariate analysis showed that initial N2 stage (HR: 1.573, p = 0.043), hypoalbuminemia before liver resection (HR: 4.208, p = 0.001), NLR ≥ 3 after liver resection (HR: 1.764, p = 0.021), abnormal CEA after liver resection (HR: 2.266, p = 0.003), and CEA ratio (after/before liver resection) < 0.3 (HR: 1.536, p = 0.042) were independent prognostic factors. The nomogram was constructed using these five respective variable point scales. By drawing a perpendicular line from the total point axis to the three outcome axis, estimated 1-, estimated 3- and 5-year survival probabilities could be obtained (Fig. 3). The C-index of this nomogram was 0.657 and that of internal validation was 0.662.

The findings of our study revealed that the average overall survival (OS) for the entire cohort was 46.85 months, while the average recurrence-free survival (RFS) was 36.03 months. Several independent factors were identified as significantly influencing OS, including age ≥ 70 years, initial N2 stage, neutrophil-to-lymphocyte ratio (NLR) ≥ 3 after liver resection, hypoalbuminemia before liver resection(< 3.5 g/dL), and surgical margin < 10 mm. Similarly, various independent predictive factors were associated with RFS, indicating a poorer prognosis. These factors included initial N2 stage, neutrophil-to-lymphocyte ratio (NLR) ≥ 3 after liver resection, carcinoembryonic antigen (CEA) level ≥ 5 ng/mL after liver resection, CEA ratio (after/before liver resection) < 0.3, hypoalbuminemia(< 3.5 g/dL) before liver resection.

In recent years, numerous studies have been conducted to explore the prognostic factors associated with outcomes following hepatic resection for colorectal liver metastases (CRLM). Despite these efforts, the reported results have exhibited substantial heterogeneity and frequently presented conflicting findings. The identification of reliable prognostic factors could greatly contribute to the selection of patients who would benefit the most from intensified follow-up or more aggressive therapeutic interventions. To ensure statistically robust outcomes, our study focused on a more homogeneous subgroup of patients who exhibited solitary CRLM without extrahepatic involvement and underwent curative (R0) resection. The absence of perioperative mortality and the observed overall survival rate collectively indicate that the surgical intervention performed in this study was a safe procedure associated with favorable long-term outcomes. In our study, we observed a 1-year, 3-year, and 5-year overall survival (OS) rate of 93.1%, 72.3%, and 59.8%, respectively, in a cohort of 230 patients with solitary colorectal liver metastasis (CRLM) who underwent curative intent surgery. Additionally, the 1-year, 3-year, and 5-year disease-free survival (DFS) rates were found to be 71.1%, 40.0%, and 27.1%, respectively. These survival rates are comparable to those reported in single-center or bi-center series focusing on patients with solitary liver metastasis who underwent hepatic resection. (7, 12, 13) Furthermore, the survival rates observed in our study align with those reported in both single-center and multicenter series that included patients with both solitary and multiple liver metastases.

Our findings indicate that three key independent factors, namely hypoalbuminemia(< 3.5 g/dL) before liver resection, initial N2 stage, and neutrophil-to-lymphocyte ratio (NLR) ≥ 3 after liver resection, exert a substantial influence on both overall survival (OS) and disease-free survival (DFS). These factors represent crucial aspects of preoperative nutrition(and liver function), postoperative immune competence, and initial tumor characteristics. Hypoalbuminemia can serve as an indicator of various underlying conditions, including liver disease, kidney disease, malnutrition, and infection. Numerous studies in the literature have consistently demonstrated that low albumin levels are associated with a poorer short-term and long-term prognosis in patients with colorectal cancer liver metastases after hepatectomy. (17, 18) Several prognostic scoring systems, including CAR (C-reactive protein/albumin ratio)(19), GPS (Glasgow Prognostic Score)(20, 21), mGPS (modified Glasgow Prognostic Score)(22), and CALLY (C-reactive protein, albumin, lymphocyte, and liver metastases count)(23), have also identified low albumin as a significant factor impacting patient outcomes in this context. In our study, albumin emerged as a robust and independent factor in multivariate analysis, exhibiting a substantial impact on both overall survival (OS) with a hazard ratio (HR) of 16.79 and disease-free survival (DFS) with an HR of 4.21. Notably, hypoalbuminemia ranked highest in the nomogram for predicting both DFS and OS outcomes. These findings emphasize the critical importance of addressing and maintaining adequate nutritional status in patients, as it directly influences prognosis and overall treatment outcomes.

Many studies reveal that a simple biomarker of pre-treatment NLR assessment could serve as a straightforward means of identifying patients with a less favorable prognosis. (24–28) These findings hold true not only for patients treated with various intervention modalities but also specifically within the hepatectomy subgroup. But these studies were all discussing the pre-operative NLR. The underlying mechanisms responsible for the correlation between elevated NLR and poorer survival outcomes are challenging to fully elucidate. However, several plausible explanations may contribute to this association. The tumor microenvironment consists of various cellular groups, including tumor cells, normal tissue cells, mesenchymal cells, and immune cells, all of which play critical roles in tumor development. (29, 30) Moreover, immune cells exhibit diverse functions within the immune response process against tumors. These complex interactions among different cell types within the tumor microenvironment likely contribute to the observed relationship between NLR and survival outcomes in cancer patients. (31)

The most intriguing and valuable finding derived from our study is that the neutrophil-to-lymphocyte ratio (NLR) after hepatectomy emerges as an independent factor, while it does not exhibit such significance prior to the hepatectomy procedure. Exploring the potential influence between different types of chemotherapy and the neutrophil-to-lymphocyte ratio (NLR) would be of great interest. The decrease in NLR may suggest an improved chemosensitivity in many studies. Investigating whether specific chemotherapy regimens impact the NLR or if variations in NLR influence the efficacy of different chemotherapy treatments could provide valuable insights into the relationship between these factors. According to a specific study, it was observed that preoperative chemotherapy had the capacity to normalize the neutrophil-to-lymphocyte ratio (NLR) in 68% of patients who initially exhibited elevated NLR levels. Remarkably, this particular subgroup of patients achieved comparable survival outcomes to those individuals who had normal NLR levels prior to treatment initiation. (32) Another study has corroborated our findings, indicating that although an increased NLR is associated with reduced survival following the initial hepatectomy, this impact is counteracted by the administration of neoadjuvant chemotherapy and subsequent hepatectomy for recurrent disease. (33) Therefore, the preoperative NLR in our data has less reference value compared to the postoperative NLR. This may be because, in this group of patients with solitary CRLM, the preoperative NLR has already been screened and selected through the use of chemotherapy, following the updated treatment trends of the past decade.

Previous studies have developed several clinical risk scores for patients with CRLM, considering multiple factors associated with survival outcomes. (8–11) However, discrepancies in baseline characteristics among patient groups can lead to inconsistent results, as certain risk factors may be present in one group but absent in another. Moreover, the prognostic utility of traditional scoring systems has been questioned, as these systems were based on data from all patients, without considering the variability in risk factors across different tumor numbers. In our study, we conducted a multivariable analysis and developed a clinical risk score nomogram specifically for patients with solitary liver metastasis. We designed this method to identify high-risk patients with poorer prognosis within this population. While our study does not allow speculation on whether high-risk patients would have benefited from peri-operative intervention, we propose that the high-risk profile identified by our nomogram could serve as a selection criterion for randomized trials investigating the potential role of such treatment.

Despite remarkable findings, the present study still had several limitations. First, since the current study is retrospective clinical research based on the data recorded in our cancer registry, missing data is almost always inevitable. It was difficult to retrieve data on those patients who operated a long time ago. Secondly, the limited patient population also impaired the statistical power. We believe some of the “trending statistics” should become statistically significant once the patient population is enlarged. Third, the molecular signatures of colon cancer, i.e. k-ras, EGFR, and MSI, were not universally examined in the early 2010s. It was therefore unfeasible to thoroughly investigate the influence of these prognostic molecules on the outcome of solitary CRLM after surgery. Next, the lack of external validation cohorts also made our findings and nomograms less convincing. Last but not least, the current study failed to provide a more effective treatment strategy for those patients with higher risks of tumor recurrence or death after liver resection. Further larger scale and well-documented studies comprising patients from different tertiary centers or ethnic groups are warranted to validate our findings and establish appropriate treatment suggestions.

In our study, we found that several factors are associated with poor prognosis in terms of overall survival and disease-free survival in patients with solitary liver metastasis. These factors include the initial N2 stage, neutrophil-to-lymphocyte ratio (NLR) ≥ 3 after liver resection, and hypoalbuminemia (< 3.5 g/dL) before liver resection. Based on these findings, our nomogram identifies a high-risk profile that can be used as a selection criterion for randomized trials exploring the potential efficacy of specific treatments in the future.

Acknowledgments

The author appreciates all the colorectal surgeons, oncologists, radiologists, pathologists, and nursing and medical staff of CGMH.

Author Contributions

YJH, YJC, and CWL built the study design; YLY, CKL, WST, and JFY were involved in the collection of samples; YJH, YJC, and CWL analyzed the data; YJH, YJC, YLY, CKL, WST, and CWL were involved in editing and reviewing; CWL and JFY supervised the study. All authors have read and agreed to the published version of the manuscript.

Funding

No funding or conflicts of interest to declare from

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request

Ethics approval and consent to participate

We retrieved data regarding our clinicopathologic variables from the Colorectal Section Tumor Registry of Chang Gung Memorial Hospital (CGMH). The Institutional Review Board of CGMH approved this study (IRB No. 202301077B0).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Authors’ information

1 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Guei-Shan, Tao-Yuan, Taiwan

2 Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Guei-Shan, Tao-Yuan, Taiwan

3 Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Keelung, Taiwan

4 Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Guei-Shan, Tao-Yuan, Taiwan

* Corresponding author

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No competing interests reported.

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The Surgical Outcome and Prognostic Factors for Solitary Colorectal Liver Metastasis

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