Abstract
Background: Several immune-inflammatory markers are associated with cancer progression. The purpose of the present study was to clarify the influence of the preoperative C-reactive protein-to-albumin ratio (CRP/ALB ratio) on survival of patients with esophageal cancer and recurrence after curative resection. Patients and Methods: The preoperative CRP/ALB ratio was evaluated in 122 patients who underwent radical resection for esophageal cancer from 2005 to 2018. The correlations between the CRP/ALB ratio and cancer-specific overall (OS), recurrence-free (RFS) survival and the clinicopathological status were analyzed. Results: The optimal cut-off value of the CRP/ALB ratio determined using receiver operating characteristic curve analysis was 0.04. Patients were divided into two groups based on this cut-off value: the low CRP/ALB group (n=59) and the high CRP/ALB group (n=50). The OS rate at 5 years after surgery was significantly lower in the group with high CRP/ALB at 40.5% whilst it was 63.5% in the low CRP/ALB group (p=0.005). The corresponding RFS rates at 5 years after surgery were 32.5% and 48.3%, respectively, which was a statistically significant difference (p=0.007). A multivariate analysis showed that a high CRP/ALB ratio was a significant independent risk factor for poorer cancer-specific OS and RFS. Conclusion: The preoperative CRP/ALB ratio was a strong prognostic marker for patients with esophageal cancer. The surgical strategy, including procedure and perioperative care should be carefully planned for patients with a high CRP/ALB ratio.
Esophageal cancer is the seventh most common type of cancer and the sixth most common cause of cancer death in the world (1). The combination of neoadjuvant chemoradiotherapy and complete surgical resection has become the standard treatment for advanced esophageal cancer (2). However, although the resection rate has increased gradually, patients with esophageal cancer often develop tumor recurrence. The prognosis of patients after curative resection remains poor, with 3- and 5-year overall survival (OS) rates of 44% and 26%, respectively (3). Therefore, it is important to identify reliable predictive factors for patients with a high risk of recurrence.
The systemic inflammatory response plays an important role in carcinogenesis and tumor progression and has a poor prognostic effect in various types of cancer (4-6). Several inflammation-based prognostic scores, including the Glasgow Prognostic Score, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio have been reported to have prognostic significance in many types of malignant disease (7, 8).
In 2009, Fairclough et al. reported a simple and easy system for prediction of complications using the preoperative C-reactive protein-to-albumin ratio (CRP/ALB ratio), and found that the simple score based on this was also an independent prognostic marker (9). Recently, the preoperative CRP/ALB ratio was also reported as an independent prognostic marker in patients with various cancer types (10-19), on emergency admission (20), and in acute coronary syndrome (21). However, the prognostic value of the CRP/ALB ratio in patients with esophageal cancer is still unclear. The purpose of this study was to investigate the prognostic value of the preoperative CRP/ALB ratio in a retrospective cohort analysis.
Patients and Methods
Patient data. Patients were identified from a database of cases with primary esophageal cancer who underwent surgical treatment at Yokohama City University from January 2005 to September 2018. Patients who had undergone palliative or non-curative surgery were excluded. All patients were pathologically diagnosed with squamous cell carcinoma in clinical stage IB to III (excluding T4).
Surgical procedure. Conventional open transthoracic esophagectomy via right thoracotomy or video-assisted surgery with two- or three-field lymphadenectomy was performed, with reconstruction through the retrosternal route or posterior mediastinal route and cervical or intrathoracic anastomosis. A feeding tube was routinely placed at the stomach or duodenum. A jejunostomy catheter was routinely placed for postoperative enteral nutrition.
Perioperative care. All of the patients received the same perioperative management. Antibiotics were administered 30 min before surgical incision and every 3 h during the operation, as well as on postoperative day (POD) 2. On POD 1, enteral nutrition and ambulation training were started. On POD 5, oral intake with water and gelatinous foods was initiated and solid food was started on POD 10.
CRP/ALB ratio. The CRP/ALB ratio was calculated as the serum level of CRP divided by the serum albumin level. A CRP/ALB ratio of 0.04 was regarded as the optimum critical point of classification based on a receiver operating characteristics curve analysis (95% confidence interval=0.559-0.776; area under the curve=0.668; p=0.004; Figure 1).
Follow-up. All patients were followed-up for 5 years after surgical curative resection. The serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels were measured and computed tomography was performed at least every 3 months for 5 years at outpatient clinics. Disease recurrence was diagnosed based on tumor marker levels and radiographic evidence of a new suspicious low-density mass.
Evaluations and statistical analyses. The significance of the associations between the CRP/ALB ratio and clinicopathological parameters was determined using the chi-squared test or Fisher's exact test. OS was defined as the period from surgery until death. Recurrence-free survival (RFS) was defined as the period from surgery until recurrence or death. The OS and RFS curves were plotted according to the Kaplan–Meier method, and a log-rank test was performed to identify statistical differences between different groups. Independent prognostic factors were identified by a Cox proportional hazards regression model. Values of p<0.05 were considered to indicate statistical significance. All statistical analyses were performed using the SPSS software program (version 23.0; IBM, Armonk, NY, USA). This study was approved by the Institutional Review Board (IRB) Committee of Yokohama City University (IRB number: B191100037). Informed consent for use of the clinical data without identifying personal data was obtained in all cases.
Results
Patient characteristics. One hundred and twenty-two patients underwent esophagectomy for esophageal cancer between October 2005 and September 2018 and the preoperative albumin and CRP levels were measured in 109 cases. The patients' ages ranged from 40 to 82 years (median=68 years); 94 patients were male, and 15 were female. The median follow-up period was 72.5 months (range=13.9-125.2 months). Fifty-nine patients were classified into the low CRP/ALB group and 50 were classified into the high CRP/ALB group.
A receiver operating characteristic curve analysis of the C-reactive protein to albumin ratio in patients who underwent potentially curative surgery for esophageal cancer. Area under the curve=0.668, 95% confidence interval=0.559-0.776; p=0.004.
Clinicopathological features. Table I summarizes the background characteristics of the patients in the low and high CRP/ALB groups in the present study. There were significant differences between the two groups in sex, pathological T factor, stage and smoking habit. In the cases with low CRP/ALB ratio, the percentage of female patients was lower and the depth of invasion was greater.
Survival analyses. The cancer-specific OS rate at 5 years after surgery was 40.5% in the high CRP/ALB group and 63.5% in the group with low CRP/ALB (p=0.005). The cancer-specific OS curves are shown in Figure 2. Univariate analyses for cancer-specific OS showed that the CRP/ALB ratio was a significant prognostic factor, as were age and depth of tumor invasion (Table II). The CRP/ALB ratio was selected for the final model to be analyzed by a multivariate analysis.
The RFS rate at 5 years after surgery was 32.5% in the group with high CRP/ALB and 48.3% in that with low CRP/ALB, which was a statistically significant difference (p=0.007). The RFS curves are shown in Figure 3. The univariate analysis of factors associated with RFS showed that the CRP/ALB ratio was a significant prognostic factor, as were age and depth of tumor invasion (Table III). The CRP/ALB ratio was selected for the final model to be analyzed by a multivariate analysis.
Comparison between the C-reactive protein-to-albumin (CRP/ALB) ratio and clinicopathological factors.
Discussion
The present study examined whether or not the CRP/ALB ratio was associated with poorer cancer-specific OS in patients who underwent radical esophagectomy for esophageal cancer. Our major findings clearly indicated that the CRP/ALB ratio was an independent risk factor for cancer-specific OS and RFS in patients with esophageal cancer. Thus, our results suggest that the measurement of the preoperative CRP/ALB ratio had a clinical influence and that it should be considered in treatment strategies for esophageal cancer.
Inflammation has become widely recognized to contribute to cancer progression and metastasis (22, 23). Inflammatory cells may change the tumor microenvironment and 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.
It was suggested that the expression of CRP, which is an acute-phase protein, and a decrease in the level of albumin contribute to micro-metastasis, the growth of cancer cells, or recurrence through the inhibition of apoptosis and promotion of angiogenesis because of reduced cell-mediated immunity (24-26). The characteristics of studies found in literature about the relationship between esophageal cancer and the CRP/ALB ratio are presented in Table IV. All included studies were retrospective. In 12 studies, including the present study, the CRP/ALB ratio ranged from 0.03 to 0.50 and the number of patients ranged from 63 to 633. The results showed that an elevated pre-treatment CRP/ALB ratio predicted poor OS.
An important limitation that potentially affects the available data regarding the CRP/ALB ratio in all studies is the lack of consensus regarding the most appropriate cut-off point for the CRP/ALB ratio. In the present study, we set the cut-off value of CAR as 0.04 based on the results of the ROC analysis. Similarly, most past reports have set cut-off values using a ROC analysis. There are some differences between the previous studies and the present one because of the difference in sample sizes. However, five studies conducted in Japan used very similar cut-off values (of 0.03, 0.0375, 0.04, 0.042 and 0.085, respectively) (22-26).
A comparison of the cancer-specific overall survival rates in the high and low C-reactive protein to albumin ratio groups after potentially curative surgery for esophageal cancer.
A comparison of the recurrence free survival rate in the groups with high and low C-reactive reactive protein to albumin ratio after potentially curative surgery for esophageal cancer.
Univariate and multivariate Cox proportional hazards analysis of clinicopathological factors for cancer-specific overall survival.
The present study was associated with some other limitations. Firstly, it was a retrospective study with a relatively small study population; thus, the results must be confirmed in another cohort or in a prospective multicenter-study. Secondly, there was a time bias in this study, as the data were collected between 2005 and 2018. Surgical procedures, postoperative chemotherapy, and perioperative care might have changed over this period. Moreover, the test method, detection reagent, and testing time for CRP and albumin might also have differed. Finally, all studies, including the present one, only analyzed cohorts from Eastern countries.
Univariate and multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
Main characteristics of literature studies on the C-reactive protein-to-albumin (CRP/ALB) ratio.
In conclusion, the present study showed that the preoperative CRP/ALB ratio was a significant risk factor for OS and RFS in patients who underwent radical surgery for esophageal cancer. The CRP/ALB ratio is a useful biomarker that can be conveniently evaluated to identify high-risk patients with esophageal cancer.
Acknowledgements
The work was supported, in part, by the non-governmental organization Yokohama Surgical Research Group, Association of Healthcare corporation, Yoshiki Dermatology Clinic Ginza, and Social Hearth Corporation Foundation Pond Friends Association (Fukuoka Wajiro Hospital). The Authors express their sincere gratitude to Ms. Akiko Yoshida, Ms. Yuka Maruyama, Ms. Minako Igarashi and Ms. Mariko Yamauchi for their excellent data management in this study.
Footnotes
↵* These Authors contributed equally to this study.
Authors' Contributions
Hiroshi Tamagawa and Toru Aoyama made substantial contributions to the conception and design. Toru Aoyama, Kentaro Hara, Hiroshi Tamagawa, Ayako Tamagawa, Keisuke Komori, Yukio Maezawa, Kazuki Kano, Keisuke Kazama, Itaru Hasimoto, Masaaki Murakawa, Masakatsu Numata, Takashi Oshima, Norio Yukawa, Munetaka Masuda, and Yasushi Rino made substantial contributions to the acquisition of data, or the analysis and interpretation of data. Toru Aoyama, Keisuke Kazama, Yosuke Astumi, Hiroshi Tamagawa, Ayako Tamagawa, Kazuki Kano and Yasushi Rino were involved in drafting the article or revising it critically for important intellectual content. Toru Aoyama, Yukio Maezawa, Keisuke Kazama, Kentaro Hara, gave final approval of the version to be published. Each Author participated sufficiently in the work to take public responsibility for appropriate portions of the content; and agreed to be 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. All Authors read and approved the final article.
Conflicts of Interest
The Authors declare no competing interests in association with this study.
- Received February 23, 2020.
- Revision received March 7, 2020.
- Accepted March 10, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
