Effect of serum lactate dehydrogenase-to-albumin ratio (LAR) on the short-term outcomes and long-term prognosis of colorectal cancer after radical surgery

Background Whether serum lactate dehydrogenase-to-albumin ratio (LAR) influenced the outcomes of colorectal cancer (CRC) patients after radical surgery remained unclear. Therefore, this study sought to examine how LAR influences the short-term and long-term outcomes of CRC patients who have undergone radical surgery. Methods This study retrospectively included CRC patients who underwent radical resection between January 2011 and January 2020. We compared short-term outcomes, as well as overall survival (OS) and disease-free survival (DFS), among various groups. Both univariate and multivariate logistic regression analyses were utilized to pinpoint independent risk factors associated with overall complications and major complications. Moreover, Cox regression analysis were conducted for OS and DFS. Odds ratio (OR) and Hazard ratio (HR) were adjusted. Results This study encompassed a cohort of 3868 patients. 3440 patients were in the low LAR group and 428 patients constituted the high LAR group. In the high LAR group, patients experienced significantly longer operative times (p < 0.01), larger intraoperative blood loss (p < 0.01), and extended postoperative hospital stays (p < 0.01). Additionally, the incidence of both overall complications (p < 0.01) and major complications (p < 0.01) was higher in the high LAR group compared to the low LAR group. Furthermore, LAR was emerged as an independent prognostic factor for overall complications [OR/95% CI: (1.555/1.237 to 1.954), p < 0.01] and major complications [OR/95% CI: (2.178/1.279 to 3.707), p < 0.01]. As for long-term survival, the high LAR group had worse OS in stage II (p < 0.01) and stage III (p < 0.01). In both stage II (p < 0.01) and stage III (p < 0.01), the high LAR group exhibited poorer DFS. Additionally, according to Cox regression analysis, LAR was identified as an independent predictor for both OS [HR/95% CI: (1.930/1.554 to 2.398), p < 0.01] and DFS [HR/95% CI: (1.750/1.427 to 2.146), p < 0.01]. Conclusion LAR emerged as an independent predictor not only for overall complications and major complications but also for both OS and DFS, highlighting its significance and deserving the attention of surgeons.


Introduction
Globally, colorectal cancer (CRC) ranked as the third most common malignant tumor and the second leading cause of cancer-related fatalities.[1][2][3].Although the surgical procedures and neoadjuvant chemoradiotherapies had become more and more mature, the prognosis of CRC was still not optimistic [4,5].It was reported that there were many biomarkers affecting prognosis in CRC patients, including lactate dehydrogenase (LDH), albumin [6].
On behalf of the key enzymes in the glycolytic pathway, LDH can convert pyruvate to lactate to support tumor cells [7,8].Some studies already revealed that high level of LDH was closely correlated with poor prognosis in many kinds of tumors, including lung cancer, pancreatic cancer, esophageal cancer and CRC [9][10][11][12][13].On the other hand, the serum albumin level could serve as an indicator of the body's the nutritional status.Previous studies had shown that abnormal albumin levels were correlated with poor prognosis of gastric cancer, and CRC [14,15].Therefore, elevated LDH and decreased albumin were indicators of poor survival.
The lactate dehydrogenase-to-albumin ratio (LAR), combining LDH and albumin, might be more effective than each alone.Some studies demonstrated that high LAR was associated with poor survival in cases of esophageal cancer, pancreatic cancer, hepatocellular carcinoma and gastric cancer [16][17][18].There were few studies on the relationship between LAR and CRC [19,20].However, none of them did a comparison for the short-term outcomes including overall complications and major complications in different LAR groups, and none of them assessed OS and DFS across various tumor stages.
For this reason, this current study sought to examine the impact of LAR on the short-term outcomes and longterm prognosis of CRC patients who underwent radical surgery.

Patients
Patients with CRC who underwent radical surgery at a single teaching hospital between Jan 2011 and Jan 2020 were included in this retrospective analysis.This study was conducted in accordance with the principles of the Helsinki Declaration.Moreover, the study received approval from the ethical committee at our institution (The First Affiliated Hospital of Chongqing Medical University, 2022-135-2), and the informed consent forms were acquired from all participantsAt the outset, a total of 5473 CRC patients who underwent radical resection were included in the study (n = 5473) Exclusion criteria encompassed: 1, non-R0 resection (n = 25); 2, CRC patients who diagnosed in stage IV (n = 875); and 3, incomplete medical records (n = 705).In total, 3868 patients were involved in the final analysis.(Fig. 1).

Data collection
The baseline characteristics encompassed age, sex, body mass index (BMI), smoking, drinking, hypertension, type 2 diabetes mellitus (T2DM), neoadjuvant therapy, LDH, albumin, hemoglobin, LAR, tumor location, tumor node metastasis (TNM) stage, and tumor size.Short-term outcomes were assessed based on operation time, intraoperative blood loss, postoperative hospital stays, overall complications, and major complications.Long-term prognosis was evaluated through OS and DFS.Data collection involved retrieving information from the medical record system and conducting telephone interviews.

Definitions
We determined the TNM stage based on the 8th Edition of the AJCC [21].Complications were assessed using the Clavien-Dindo classification, with major complications defined as those graded ≥ III [22].OS was calculated by the time from surgery to the last follow-up, or death from Fig. 1 Flow chart of patient selection any cause.DFS was defined as the time from initiation of radical surgery to tumor recurrence or death.

Optimal cut-off value and groups
The optimal cut-off value of 12.3 was identified using X-tile software.Then, patients with LAR ≤ 12.3 were classified into the low LAR group, while those with LAR values exceeding 12.3 were assigned to the high LAR group.

Statistics
The statistical software SPSS (version 22.0) was utilized for data analysis.We represented continuous variables as mean ± standard deviation (SD) ,and categorical variables were expressed as n (%).Independent sample t-test and the Chi-square test or Fisher's exact test were adopted to compare the difference for continuous variables and categorical variables, respectively.We assessed OS and DFS using the Kaplan-Meier method for stage I-III patients, comparing the two different groups.We conducted univariate and multivariate analyses to pinpoint predictors of overall complications and major complications, while Cox regression analyses were utilized to identify predictors of both OS and DFS.And we deemed a two-tailed p-value of less than 0.05 to be statistically significant.

Patients
In this study, a total of 3868 patients were included.Based on the LAR cut-off value, 3440 patients were categorized into the low LAR group, while 428 patients comprised the high LAR group.Patients in the high LAR group had an older age (p < 0.01), a higher portion of females (p < 0.01), lower BMI (p < 0.01), smoking (p < 0.01), drinking (p < 0.01), hypertension (p = 0.018), higher levels of LDH (p < 0.01), lower levels of albumin (p < 0.01) and lower levels of hemoglobin (p < 0.01).The high LAR group also had a higher portion of colon cancer (p < 0.01), TNM stage II (p = 0.014) and tumor size > 5 cm (p < 0.01).More detailed information was shown in Table 1.

Short-term outcomes
Table 2 showed the Short-term outcomes between the two different groups.As a result, the surgery time was significantly longer in the high LAR group than in the low LAR group(p < 0.01), and the intro-operative blood loss was significantly more in the high LAR group(p < 0.01).The postoperative hospital stays were longer for the high LAR group (p < 0.01).Moreover, the high LAR group exhibited a higher incidence of overall complications (p < 0.01) and major complications (p < 0.01) compared to the low LAR group .
Univariate and multivariate analyses were conducted to find out the factors associated with overall complications.In univariate analysis, it was found that age [OR/95% CI:    6).

OS/ DFS on different tumor stages
The median follow-up time was 34(1-114) months.We conducted the Kaplan-Meier survival curve to further evaluate the impact of LAR on prognosis at the different tumor stages.In terms of OS, the high LAR group correlated with worse OS in all stages (p < 0.01), stage II (p < 0.01), and stage III (p < 0.01) than the low LAR group.No significant difference was found in stage I (p = 0.805) (Fig. 2).As for DFS, the high LAR group associated with worse DFS in all stages (p < 0.01), stage II (p < 0.01), and stage III (p < 0.01) than the low LAR group.No significant difference was found in stage I (p = 0.817) (Fig. 3).

Discussion
In this current study, higher LAR exhibited longer operation time, larger intro-operative blood loss, extended postoperative hospital stays, and a higher incidence of overall complications and major complications.Moreover, LAR was established as an independent risk factor for overall complications and major complications.In terms of survival, higher LAR correlated with worse OS and DFS in all stages, stage II and III.Furthermore, LAR was identified as an independent predictor for OS and DFS.
Previous studies had demonstrated that elevated LDH and decreased albumin were correlated with poor survivals in many kinds of cancers [23][24][25][26][27]. LDH, as one of the glycolytic enzymes, could convert pyruvate to lactate and create a micro-hypoxic environment, which led to tumor hypoxia, neo-angiogenesis, and poor prognosis of various tumors [28].LAR, combing LDH and albumin, was more effective than each alone.Peng et al. [29] made a nomogram based on LAR and PLR to predict survival in nasopharyngeal carcinoma and they revealed that LAR served as an independent prognostic risk factor for OS and DFS.Nakazawa et al. [30] found that LAR was correlated with the sensitivity and therapeutic resistance of Nivolumab in patients with gastric cancer, which might be helpful to the immunotherapies.As for CRC, Aday et al. [20] included 295 CRC patients who underwent curative resection and got a result that high pretreatment LAR level was an unfavorable prognosticator.Their number of cases was relatively small.Hu et al. [19] did a comparison between the LAR and the TNM staging system, and they identified that LAR could be served as a reliable prognostic factor for OS and DFS.Moreover, Wu  From what we know, this study was firstly explore the effect of LAR on the short-term outcomes including overall and major complications of CRC patients after radical resection.And our samples were by far the largest.
In our study, we defined the high LAR group as LAR > 12.3 and the low LAR group was defined as LAR ≤ 12.3 according to the X-tile software.Then, we investigated the correlation between LAR and short-term outcomes.We found that high LAR correlated with more postoperative complications.The serum albumin, as an indicator of the nutritional status of the body, was associated with system inflammation [32,33].The decreased albumin had huge influence on recovery after surgery [34,35], which might lead to severe postoperative complication [4,36,37].LDH was involved in tumor metabolism [38,39], and elevated LDH was associated with immune suppression [40].Therefore, high LDH might play an important role in promoting tumors' progression.We found that LAR was associated with long-term prognosis including OS and DFS, and finally, our Kaplan-Meier survival curve analysis confirmed that LAR served as a prognostic indicator for OS and DFS across all tumor stages, as well as in stage II and III, which might catch surgeon's attention for earlier postoperative chemoradiotherapies and more frequent follow-up reviews [41,42].
Several limitations were present in this study.First, being a single-center retrospective study, the findings may have limited generalizability beyond the specific regions covered in this investigation.Second, the sample size of patients in stage I was relatively small, which might lead to data bias.Third, the lack of information on postoperative chemoradiotherapies could potentially affect the robustness of the survival analysis, representing an additional study limitation.Here in, more detailed and multi-center prospective randomized controlled trials studies were needed for further exploration.

Conclusion
Elevated LAR was linked to increased postoperative complications, as well as poorer overall survival (OS) and disease-free survival (DFS) among CRC patients who underwent radical resection.Additionally, LAR emerged as an independent predictor for overall complications, major complications, OS, and DFS.These findings underscore the importance of surgeons giving careful consideration to LAR when making clinical decisions.

Table 1
Baseline information between the high LAR group and the low LAR group Note: Variables are expressed as the mean ± SD, n (%), a Calculated using independent sample t-test, b Calculated using the Chi-square test or Fisher's exact test, *P-value < 0.05 Abbreviations: LAR, lactate dehydrogenase-to-albumin ratio; T2DM, type 2 diabetes mellitus; BMI, body mass index

Table 4
Univariate and multivariate logistic regression analysis of the major complications

Table 5
Univariate and multivariate analysis of overall survival