|Ahead of print publication
Prognostic significance of the preoperative C-reactive protein-to-albumin ratio in patients with colorectal cancer
Hiroshi Tamagawa1, Toru Aoyama1, Masakatsu Numata1, Yukio Maezawa1, Keisuke Kazama1, Yosuke Astumi1, Kentaro Hara1, Kazuki Kano1, Norio Yukawa1, Hiroyuki Saeki2, Tenii Godai3, Takashi Oshima1, Motohiko Goda1, Yasushi Rino1, Munetaka Masuda1
1 Department of Surgery, Yokohama City University, Yokohama, Japan
2 Department of Surgery, Yokohama Minamikyousai Hospital, Yokohama, Japan
3 Department of Surgery, Fujisawa Shonandai Hospital, Fujisawa, Japan
|Date of Submission||22-May-2019|
|Date of Decision||10-Aug-2019|
|Date of Acceptance||26-Nov-2019|
|Date of Web Publication||03-Nov-2020|
Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa, Yokohama 236-0004
Source of Support: None, Conflict of Interest: None
Background: The aim of the present study was to determine the utility of the C-reactive protein-to-albumin ratio (CAR) for predicting the overall survival (OS) in locally advanced colorectal cancer (CRC) patients.
Patients and Methods: This retrospective multicenter study was performed using data from a prospectively maintained database of pathological Stage II or III patients undergoing CRC surgery at the Yokohama City University, Department of Surgery, and its affiliated institutions between April 2000 and March 2016. The risk factors for the OS were identified.
Results: A CAR of 0.03 was considered to be the optimal cutoff point for classification based on the 1-, 3-, and 5-year survival rates and receiver operating characteristic curve. The OS rates at 3 and 5 years after surgery were 92.4% and 85.7% in the CAR-low group, respectively, and 86.7% and 81.1% in the CAR-high group. A multivariate analysis showed that the CAR was a significant independent risk factor for the OS. When comparing the patients' demographic and clinical characteristics between the CAR ≤0.03 and >0.03 groups, the incidence of patients who received adjuvant chemotherapy and the incidence of postoperative complications were significantly different between the two groups.
Conclusion: The present study showed that the preoperative CAR was a risk factor for the OS in patients who underwent surgery for CRC. To improve the patients' survival, CAR might be a useful tool for devising treatment strategies.
Keywords: Colorectal cancer, C-reactive protein/albumin ratio, prognostic factor
|How to cite this URL:|
Tamagawa H, Aoyama T, Numata M, Maezawa Y, Kazama K, Astumi Y, Hara K, Kano K, Yukawa N, Saeki H, Godai T, Oshima T, Goda M, Rino Y, Masuda M. Prognostic significance of the preoperative C-reactive protein-to-albumin ratio in patients with colorectal cancer. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 2]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299886
| > Introduction|| |
Colorectal cancer (CRC) is the third-most frequent cause of mortality and cancer-related death worldwide. Complete resection is essential for obtaining a cure for CRC. Stage I CRC rarely recurs and such patients have an excellent prognosis. In contrast, Stage IV CRC is unresectable, and these patients have a poor prognosis. Patients with Stage II/III CRC often develop tumor recurrence even after complete curative resection. Patients with Stage II/III CRC have about 50% of recurrent diseases, such as local and distant metastasis, recurrence, and the 5-year survival is still about 70%–76%. Recently, adjuvant treatment was introduced for Stage II/III CRC and improved the patient's survival.,, Therefore, it is important to identify the prognostic factors for patients with Stage II/III CRC to select patients for more aggressive treatment.
The systemic inflammatory response plays a major role in carcinogenesis and tumor progression, and the systemic inflammatory response has a poor prognostic effect on various types of cancer.,, Several scoring models have been reported to be useful for predicting the survival. However, the previously reported models, such as the Glasgow Prognostic Score (GPS), modified GPS, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio require complex calculations using numerous perioperative elements, rendering them difficult to implement in daily clinical practice.,
In 2009, Fairclough et al. proposed a simple and easy complication prediction system using the preoperative C-reactive protein-to-albumin ratio (CAR), and they found that the simple score based on the preoperative CAR was also an independent prognostic marker. Since then, the CAR has been adopted as a prognostic and/or predictive marker for various cancers.,,,,,,, However, the clinical influence of the CAR has not been fully evaluated in locally advanced CRC patients.
The aim of the present study was to determine the utility of the CAR for predicting the overall survival (OS) in locally advanced CRC patients.
| > Patients and Methods|| |
This retrospective multicenter study was performed using data from a prospectively maintained database of pathological Stage II or III patients undergoing CRC surgery at the Yokohama City University, Department of Surgery, and its affiliated institutions between April 2000 and March 2016. In this study, all preoperative inflammatory comorbidities were included.
A radical colectomy, anterior resection, and abdominoperineal resection plus lymph node resection were performed according to the tumors that were staged according to the UICC version 6 (John Wiley & Sons, Hoboken, New Jersey, USA). Handsewn anastomosis or an end-to-end anastomosis using a double-stapling technique was performed according to the tumor location.
Definition of postoperative surgical complications
Postoperative surgical complications of Grade 2–5 according to the Clavien–Dindo classification were retrospectively determined from the patient's records.
Patients were followed up at the outpatient clinics. Hematological tests and physical examinations were performed at least every 3 months for 5 years. The carcinoembryonic antigen and CA19-9 tumor marker levels were checked at least every 3 months for 5 years. Patients underwent a computed tomography (CT) examination every 6 months until 5 years after surgery.
Measurement of the C-reactive protein-to-albumin ratio
The CAR was calculated as the serum C-reactive protein (CRP) level (mg/dl)/serum albumin level (g/dl). The optimal cutoff levels for CAR were determined by the 1–5-year OS rate and receiver operating characteristic (ROC) curve analyses.
Evaluations and statistical analyses
The significance of correlations between the CAR and clinic pathological parameters was determined using Fisher's exact test or the Chi-square test. The OS was defined as the period between surgery and death. The data of the patients who did not experience an event were censored on the date of the final observation. The OS was evaluated by univariate and multivariate analyses. The OS curves were calculated using the Kaplan–Meier method and compared by the log-rank test. A Cox proportional-hazards model was used to perform the univariate and multivariate survival analyses. P<0.05 was considered to indicate statistical significance. The survival data were obtained from hospital records or from the city registry system. The SPSS software program (version 11.0 J Win; SPSS, Chicago, IL, USA) was used for all of the statistical analyses. These were added to the patients and methods section. This study was approved by the institutional review board of each institution.
| > Results|| |
We evaluated 613 patients in the present study. [Figure 1] shows the consort diagram of the present study. The patients ranged from 33 to 98 years of age (median: 73 years) and 355 patients were male, while 258 were female. The median follow-up period was 28.2 months (range: 0–173 months). A total of 613 patients received surgery, 417 received colectomy, 136 received anterior resection, and 60 received abdominoperineal resection. The median length of the operation was 89 min (range: 57–623 min). The median blood loss was 100 ml (range: 10–14,767 ml). The median number of harvested lymph nodes was 22 (range: 0–109).
The OS stratified by each clinical factor was compared by the log-rank test, and a significant difference was observed in the CAR. In the present study, we determined cutoff value considering the point which separates the survival. The OS stratified by each clinical factor was compared by the log-rank test, and a significant difference was observed in CAR. The 3-year and 5-year survival rates were clearly separated by CAR at 0.03 [Table 1]. Each clinicopathological factor was categorized as shown in [Table 2] and was analyzed for prognostic significance. The univariate analyses for the OS showed that the CAR was a significant prognostic factor. The CAR was thus selected for the final multivariate analysis model. The OS rates at 3 and 5 years after the surgery were 92.4% and 85.7% in the CAR-low group, respectively, and 86.7% and 81.1% in the CAR-high group. The OS curves are shown in [Figure 2]. When comparing the patients' demographic and clinical characteristics between the CAR ≤0.03 and >0.03 groups, the incidence of patients who received adjuvant chemotherapy and the incidence of postoperative complications were significantly different between the two groups. The incidence of patients who received adjuvant chemotherapy was 28.8% in the CAR >0.03 group and 41.1% in the CAR ≤0.03 group (P = 0.002). The incidence of postoperative complications (Grade ≥3) was 33.1% in the CAR >0.03 group and 22.4% in the CAR ≤0.03 group (P = 0.006) [Table 3].
|Table 1: Comparison of survival rates stratified by patient characteristics|
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|Table 2: Uni- and multivariate Cox-proportional hazards analysis of clinicopathological factors for 5-year overall survival|
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|Figure 2: A comparison of the overall survival in the C-reactive protein-to-albumin ratio-low group (≤0.03) and the C-reactive protein-to-albumin ratio-high group (>0.03)|
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|Table 3: Relationship of outcomes between C-reactive protein-to-albumin ratio-low group and high group|
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| > Discussion|| |
The present study examined whether or not the CAR was associated with a poor OS in patients who received radical colectomy for CRC in our affiliated institutions. Our findings clearly indicated that the CAR was an independent risk factor for the OS in CRC patients. Therefore, our results suggested that the measurement of the preoperative CAR had a clinical influence on the CRC treatment strategy.
Recently, inflammation has been widely recognized to contribute to cancer progression and metastasis., Inflammatory cells may alter the tumor microenvironment, which can promote tumorigenesis by increasing the proliferation, migration, and immune escape of tumor cells. Some inflammatory markers have been investigated as prognostic factors in various malignancies. A recent study showed that CAR was useful for predicting the prognosis of several cancers.,,,,,,, However, a few reports have described the relationship between CAR and the survival of patients who underwent CRC surgery. For example, Ishizuka et al. evaluated the clinical influence of CAR in 627 patients who underwent curative surgery for CRC. In the present study, the cutoff value of the CAR was 0.038. The OS of the patients in the CAR-high group was shorter than in those in the CAR-low group (hazard ratio [HR]: 2.613; 95% confidence interval [CI]: 1.621–4.212, P < 0.001). The mean survival period was 1308 days in the CAR-low group and 935 days in the CAR-high group (P = 0.001). In addition, Shibutani et al. evaluated the prognostic influence of CAR in 99 unresectable CRC cancer patients who underwent palliative chemotherapy. In the present study, the cutoff value of the CAR was 0.183. The OS of the CAR-high group was shorter than in the CAR-low group (HR: 1.866; 95% CI: 1.057–3.295, P = 0.031). The present and previous studies suggested that CAR had some clinical influence on the CRC patients' survival.
Why did CAR affect the CRC patients' survival? One possible explanation was that the expression of acute-phase proteins, such as CRP, and a decrease in the level of albumin contribute to the growth of cancer cells, micrometastases, or recurrence through the inhibition of apoptosis, promotion of angiogenesis, and damage of DNA because of decreasing cell-mediated immunity.,, The second possible explanation was that CAR affected postoperative surgical complications. In the present study, 33.1% of the patients developed postoperative surgical complications of grade ≥2 in the CAR-high group, while 22.4% of the patients developed such postoperative surgical complications in the CAR-low group (P = 0.023). Recent studies have shown that the development of postoperative complications reduces CRC patients' survival and increases their risk of disease recurrence. We previously investigated the impact of postoperative complications on the CRC survival and recurrence after curative treatment. That study evaluated 5530 patients who underwent curative treatment for CRC. The patients were classified into a postoperative complications group (C group) and a no postoperative complications group (NC group). The recurrence-free survival (RFS) rate at 5 years after surgery was 74.8% in the C group and 82.2% in the NC group, which was significantly different (P = 0.0189). Furthermore, the OS rate at 5 years after surgery was 68.9% in the C group and 75.8% in the NC group, which was significantly different (P = 0.0189). The multivariate analysis showed that postoperative complications were significant independent risk factors for both the RFS and OS. Similar results were observed in other reports. The third possible explanation was that the CAR affected the adjuvant chemotherapy toxicity or continuation. In the present study, the incidence of patients who received adjuvant chemotherapy was significantly different between the groups, with 28.8% receiving adjuvant chemotherapy in the CAR-high group and 44.1% receiving adjuvant chemotherapy in the CAR-low group (P = 0.002). Similar results were observed in a previous study. Tominaga et al. evaluated the predictive value of the CAR for the side effects of adjuvant chemotherapy in 136 CRC patients. They set the cutoff value of the CAR as 0.1 according to the area under the curve. CAR >0.1 was found to be a significant determinant of severe side effects with adjuvant chemotherapy (HR: 7.06, 95% CI: 2.51–19.88, P < 0.01). However, the exact mechanism is unclear at present, and further studies on this point will be required.
An important limitation that potentially affects the available data regarding the CAR in all studies – including the current study – is the lack of a consensus regarding the most appropriate cutoff point for the CAR. In the present study, which included only resectable CRC patients, we set the cutoff value of CAR as 0.03 according to the ROC and 1-, 3-, and 5-year OS rates. Similarly, Ishizuka et al. set the cutoff value of CAR as 0.038 according to the ROC curve and Youden index; they also evaluated only resectable CRC patients. In contrast, however, Shibutani et al. set the cutoff value of CAR as 0.183 according to the ROC curve in their study of only unresectable CRC patients. The optimal method for evaluating the CAR and the ideal cutoff value need to be clarified before this parameter can be implemented in daily clinical practice.
Special attention is required when interpreting the current results, as there are some potential limitations associated with this study. First, this was a retrospective study. Our findings may therefore have been observed merely by chance in this series. Second, although CAR is a novel inflammatory index, concomitant inflammatory disease might influence the judgment of the prognostic value of this ratio; all preoperative inflammatory comorbidities were included and not excluded. Therefore, the cutoff value of the CAR might be affected by the concomitant inflammatory disease. In addition, we did not collect and evaluate the CAR before operation in the present study. Third, there was a time bias in this study, as the data were collected between 2008 and 2018. Surgical procedures, perioperative chemotherapy, and perioperative care might have changed over this period. Moreover, test method, detection reagent, and testing time might be different. Fourth, the present study was only analyzed the Eastern cohort. Considering these limitations, the current results should be validated by another study.
| > Conclusion|| |
The present study showed that the preoperative CAR was a risk factor for the OS in patients who underwent surgery for colorectal cancer. To improve the patients' survival, CAR might be a useful tool for devising treatment strategies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]