C-Reactive Protein/Albumin Ratio Is an Independent Risk Factor for Recurrence and Survival Following Curative Resection of Stage I–III Colorectal Cancer in Older Patients

Background The number of older patients with cancer has increased, and colorectal cancer is expected to be affected by this trend. This study aimed to compare prognostic factors, including nutritional and inflammation-based indices, between patients aged ≥ 70 and < 70 years following curative resection of stage I–III colorectal cancer. Patients and Methods This study included 560 patients with stage I–III colorectal cancer who underwent curative resection between May 2010 and June 2018. A retrospective analysis was performed to identify prognosis-associated variables in patients aged ≥ 70 and < 70 years. Results Preoperative low body mass index, high C-reactive protein/albumin ratio, and comorbidities were mainly associated with poor prognosis in patients aged ≥ 70 years. Tumor factors were associated with a poor prognosis in patients aged < 70 years. The C-reactive protein/albumin ratio was independently associated with poor overall survival and recurrence-free survival in those aged ≥ 70 years. The time-dependent area under the curve for the C-reactive protein/albumin ratio was superior to those of other nutritional and inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years. Conclusions Tumor factors were associated with a poor prognosis in patients aged < 70 years. In addition to lymph node metastasis, preoperative statuses were associated with poor prognosis in patients aged ≥ 70 years. Specifically, the preoperative C-reactive protein/albumin ratio was independently associated with long-term prognosis in patients aged ≥ 70 years with stage I–III colorectal cancer after curative resection. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-024-14961-2.

C-Reactive Protein/Albumin Ratio Is an … for older patients and selecting appropriate treatment strategies, including the implementation of postoperative adjuvant chemotherapy, are extremely important.
The central role of systemic inflammatory responses in cancer progression has been reported, 7 and influences tumor prognosis by providing a suitable environment for tumor progression. 80][11][12][13] One of these factors, the C-reactive protein/ albumin ratio (CAR), can sensitively detect systemic inflammation because it is calculated from serum CRP and Alb levels, which are influenced by liver synthesis in the presence of inflammation. 14CAR is affected by age and tends to be higher in older people. 12,15,16However, a few studies have reported the effect of CAR on the prognosis of older patients with CRC. 17 This retrospective study investigated prognostic factors, including preoperative nutritional and inflammation-based indices, and compared factors that affect long-term prognosis between patients aged < 70 and ≥ 70 years who underwent curative resection for stage I-III CRC.

Study Population
This retrospective study evaluated 609 patients with stage I-III CRC who underwent R0 resection between May 2010 and June 2018 at the Hiroshima University Hospital.Patients with other primary malignancies in the same period, heterochronic CRC within 5 years, or coexisting colon and rectal cancers were excluded.Finally, 560 patients who underwent R0 resection were enrolled in this study (Fig 1).
This study was conducted in accordance with the guidelines of the Declaration of Helsinki (Fortaleza, Brazil, October 2013) and approved by the Institutional Review Board of Hiroshima University Hospital (Approval No. E-744-4).

Definition of Nutritional and Inflammation-Based Indices
Nutritional and inflammation-based indices were calculated by preoperative blood examinations.CAR was calculated as the serum CRP level (mg/dL)/serum Alb level (g/ dL).Neutrophil/lymphocyte ratio (NLR) was calculated as relative neutrophil (%)/relative lymphocyte (%).Platelet/ lymphocyte ratio (PLR) was calculated as the absolute number of platelets/lymphocytes.Prognostic nutritional index (PNI) was calculated as 10 × Alb level (g/dL) + 0.005 × total lymphocyte count (per mm 3 ). 18eatment and Follow-Up Follow-up blood examinations to identify tumor markers were performed every 3-6 months 5 years after surgery.Simple or enhanced abdominal computed tomography was performed to rule out recurrence in 6-12 months, and colonoscopy was performed in the first, third, and fifth years after surgery.Patients with high-risk stage II or III CRC underwent postoperative adjuvant chemotherapy (ACT).Postoperative ACT for older patients or those with severe comorbidities was performed at the discretion of the primary surgeon on the basis of their general condition.

Statistical Analysis
Continuous variables are presented as medians and ranges.Nominal variables are expressed as numbers (%).Nonparametric quantitative data were analyzed using the Mann-Whitney U-test.The chi-squared test or Fisher's exact test were performed to determine the relationships among nominal variables.The cutoff values for nutritional and inflammation-based indices were set using receiver operating characteristic (ROC) curve analysis.The Kaplan-Meier method was used to analyze overall survival (OS) and recurrence-free survival (RFS), and the log-rank test was used to compare different groups.Multivariate analyses were performed to assess the factors influencing OS and RFS using the Cox regression model.
To overcome the bias caused by different distributions of covariates among patients from the high and low-CAR groups, propensity score-matched (PSM) analysis was performed using a multiple logistic regression model based on the clinicopathological variables.PSM analysis was performed according to baseline characteristics, such as age, American Society of Anesthesiologists Physical Status (ASA-PS), tumor markers, nutritional or inflammationbased indices, surgery-related factors, and tumor depth, FIG. 1 Flowchart of the study design which were variables that differed significantly (P values < 0.05).The prognostic capabilities of the CAR, PNI, NLR, and PLR were compared using time-dependent ROC curves and the area under the curve (AUC).Harrell's concordance index (C-index) was calculated for each model to determine which index had a predictive association with the endpoints.Bootstrapping method was used to calculate 95% confidence intervals (CI).P values < 0.05 were considered statistically significant.Calculations were performed using JMP v17 (SAS Institute, Cary, NC, USA) and EZR Ver 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). 19

Patient Characteristics of Patients with CRC Aged ≥ 70 and < 70 Years
Table 1 summarizes the preoperative characteristics of patients aged ≥ 70 and < 70 years with stage I-III CRC who underwent R0 resection.Overall, 231 (41.3%) patients were ≥ 70 years old and 329 (58.7%) were < 70 years old.Compared with patients aged < 70 years, those aged ≥ 70 years included more patients with ASA-PS ≥ 3 (P = 0.0001) and more patients with hypertension (HTN; P < 0.0001), diabetes mellitus (DM; P = 0.0022), and cardiovascular disease (P < 0.0001), and more frequently used antiplatelet or coagulation agents (P < 0.0001).Among the nutritional and inflammation-based indices, CAR was higher in patients aged ≥ 70 years (P = 0.0036) than in those aged < 70 years.PNI was lower (P < 0.0001) and operative time was shorter in patients aged ≥ 70 years (P = 0.0004).In patients aged ≥ 70 years, the proportion of patients who underwent laparoscopic or robot-assisted surgery (P = 0.0471) and the implementation of postoperative ACT (P < 0.0001) were lower.
Tumor localization was less frequent in the rectum (P < 0.0001).No significant differences were observed in tumor factors or postoperative complications between patients aged ≥ 70 years and aged < 70 years groups.A total of 447 patients were assessed for budding grades.The number of patients with budding grade > 1 was 118 (45.2%) in those aged < 70 years and 76 (40.9%) in those aged ≥ 70 years.Moreover, 281, 237, and 274 patients were screened for the presence of RAS, BRAF, and microsatellite instability (MSI) mutations, respectively.Of these patients, 122 (43.4%) had RAS mutations, 14 (5.9%) had BRAF mutations, and 25 (9.1%) had MSI-high.No differences in biological markers according to age were noted.

Comparison of Backgrounds by Preoperative CAR Value
Table 4 summarizes the characteristics of patients in the high and low-CAR groups.Compared with the low-CAR group, the high-CAR group included older patients (P = 0.0047), more patients with ASA-PS ≥ 3 (P = 0.0045), and more patients who underwent open surgery (P < 0.0001).Intraoperative blood loss (P < 0.0001), intraoperative blood transfusion (P = 0.0401), and the number of patients with pT ≥ 4 (P = 0.0001) were higher in the high-CAR group than in the low-CAR group.Tumor marker levels were higher in the high-CAR group than in the low-CAR group (CEA: P < 0.0001, CA19-9: P = 0.0006).Among the nutritional and inflammation-based indices, the PNI (P < 0.0001), NLR (P < 0.0001), and PLR (P < 0.0001) were significantly different between the two groups.After PSM analysis, no significant differences were found between the two groups.Figure 4 summarizes the Kaplan-Meier analysis showing the OS and RFS in patients aged ≥ 70 years after PSM using CAR.A high CAR was associated with a poor OS (P = 0.0423, log-rank test; Fig. 4a).Although not significant, a high CAR tended to show poor RFS (P = 0.0855, log-rank test; Fig. 4b).

DISCUSSION
This retrospective study investigated and compared prognostic factors affecting long-term prognosis in patients aged < 70 and ≥ 70 years who underwent curative resection for stage I-III CRC.Interestingly, tumor factors, such as tumor markers and lymph node metastasis, were associated with poor long-term prognosis in younger patients.In addition to lymph node metastasis, preoperative factors, such as CAR, an inflammation-based marker, and comorbidities, were associated with poor long-term prognosis in older patients.Recently, the number of older patients with cancer has been increasing; in one study, 56.3% of patients with CRC were ≥ 70 years of age. 20The 231 patients in this study were ≥ 70 years old, accounting for 41.3% of the total patients.Generally, older patients have various comorbidities, malnutrition, and age-related declines in organ function and immunity. 3,4In recent years, frailty, which is defined as a state of reduced physiological reserve from pathological or iatrogenic stressors owing to age-related impairments, 21 has received increasing attention.3][24] In older patients, the preoperative evaluation of health-related priorities, realistic assessments of surgical risks, and individualized optimization strategies are important.In this study, statistical analysis revealed that high preoperative CAR was associated with poor OS and RFS in patients aged ≥ 70 years following curative resection of stage I-III CRC, and a high preoperative CAR was an independent poor prognostic factor for OS and RFS.Furthermore, a high preoperative CAR was found to be a better predictor of prognosis than other markers in a timedependent ROC curve for OS.Recent studies have reported the association between systemic inflammation and various carcinomas. 7,8These indicators can be easily calculated and are expected to be useful for predicting preoperative prognosis in older patients.
In this study, CAR was a useful prognostic indicator for older patients following curative resection of stage I-III CRC.CAR was initially reported as an inflammation-based index to identify patients with serious illness. 25CAR is calculated on the basis of serum CRP and Alb levels, which are synthesized in hepatocytes.During the acute inflammatory phase, the serum concentration of CRP increases, whereas that of Alb is suppressed through the activation of inflammatory cytokines.Despite the weak correlation between nutritional intake and serum Alb levels, hypoalbuminemia has been reported to be associated with inflammation. 26In addition, inflammatory responses influence tumor development and prognosis by providing a suitable environment for tumors. 8On the basis of the above, CAR, calculated from two factors that exhibit antithetical responses during inflammation, can be considered a highly sensitive prognostic indicator of malignant tumors.This study showed that the CAR was affected by age and tumor factors, which is consistent with previous studies. 15,17In addition, the time-dependent ROC curve for CAR was superior to those for other inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years.][30][31] However, some studies have shown that CAR is not associated with poor prognosis in CRC. 32In this study, preoperative CAR, in addition to tumor factors and general conditions, was associated with a poor prognosis of CRC after curative resection in older patients.However, only tumor factors were associated with poor prognosis of CRC following curative resection in younger patients.CRP elevation and hypoalbuminemia, which are indicators of chronic inflammation in older people, have been suggested as candidate biomarkers for frailty. 33Frailty has recently been reported as a prognostic factor affecting the postoperative outcomes of stage I-III CRC. 5 In older patients, CAR values calculated from CRP and Alb levels may reflect tumor-induced inflammation and the state of reduced physiological reserve, which was considered the reason why CAR was a sensitive biomarker for the poor prognosis of CRC following curative resection in older patients.CAR reflects low preoperative nutritional status and the immune system, which is the leading cause of poor prognosis after curative resection, and older patients with high CAR on preoperative examination must be identified to provide them with appropriate therapeutic interventions.
Although high CAR levels have been identified as a poor prognostic factor in various carcinomas, appropriate therapeutic interventions to improve CAR levels remain unknown.In older patients, the selection of multidisciplinary treatments, such as nutritional support and aggressive rehabilitation, and avoidance of overly invasive treatments are extremely important.Despite the importance of carefully selecting treatment for older patients, a situation leading to a poor prognosis should be avoided by choosing a treatment strategy that differs from that of younger patients because of age.Yasui et al. reported that the normalization of CAR before and after surgery improved the prognosis of patients with CRC. 30 Recently, antiinflammatory drug therapy using non-steroidal antiinflammatory drugs, aspirin, histamine-2-receptor agonists, and statins has been shown to suppress host-related inflammatory responses and prevent cancer recurrence. 8,34A prospective study would thus be desirable to determine whether CAR reflects the suppression of the inflammatory response by these therapeutic interventions and can be used as a therapeutic indicator.
This study had several limitations.This was a retrospective study, and data were gathered from single centers, which had a limited sample size, particularly for biological markers such as RAS, BRAF, and MSI.More analyses are needed to confirm whether the results are similar to those of the present study after accumulating more cases of these biological markers.

CONCLUSIONS
High preoperative CAR was found to be independently associated with poor prognosis in patients aged ≥ 70 years with stage I-III CRC after curative resection.Preoperative CAR may be a useful assessment tool for predicting the prognosis of older patients who underwent curative resection of nonmetastatic CRC.Further studies investigating treatments to improve CAR are desirable.

Figure 5 FIG. 3 a
Figure 5 summarizes the comparison of each nutritional and inflammation-based index for OS in patients aged ≥ 70 years.Figure 5a shows a comparison of the

FIG. 4 aFIG. 5
FIG. 4 a, b Kaplan-Meier curves for overall survival and recurrence-free survival in patients aged ≥ 70 years after propensity score-matched analysis used to compare the high and low-CAR groups

TABLE 2
Univariate and multivariate analyses of prognostic factor for overall survival in patients aged ≥ 70 yearsThe variables in bold are statistically significant (P < 0.05).

TABLE 4
Characteristics of patients according to CAR value in the whole study series and the propensity score-matched studyThe variables in bold are statistically significant (P < 0.05).Continuous variables are expressed as medians (ranges).Qualitative variables are expressed as numbers (%).M male, F female, BMI body mass index, ASA-PS, American Society of Anesthesiologists Physical Status, HTN hypertension, DM diabetes mellitus, DL dyslipidemia, CEA carcinoembryonic antigen, CA19-9 carbohydrate antigen 19-9, PNI prognostic nutrition index, CAR C-reactive protein/albumin ratio, NLR neutrophil/lymphocyte ratio, PLR platelet/lymphocyte ratio, CD Clavien-Dindo