Preoperative serum C-reactive protein levels and postoperative survival in patients with esophageal squamous cell carcinoma: a propensity score matching analysis

Esophageal cancer (EC) is a common cause of cancer-related deaths worldwide [1], and almost 50% of patients with EC live in China, where the most common histological type of this cancer is esophageal squamous cell carcinoma (ESCC) [2]. Complete surgical resection is the best treatment for patients with EC [3]. EC is generally diagnosed in the later stage and progresses rapidly; therefore, the overall survival (OS) rate of EC remains poor [4‐6]. Thus, it is necessary to identify the predictive factors of prognosis in EC patients. Several markers have been reported for predicting the prognosis of this disease [7‐10]; however, none has been widely used in clinical practice.

It is being increasingly acknowledged that the intrinsic properties of tumor cells and the host inflammatory response determine the spread of tumors. C-reactive protein (CRP) is one of the acute-phase nonspecific proteins synthesized by the hepatocytes and regulated by interleukin-1, interleukin-6, and tumor necrosis factor (TNF) [11, 12]. Several reports have shown that a high preoperative serum CRP level is a disease-independent prognostic factor in a variety of tumors, such as those found in gastric cancer, lung cancer, renal cancer, and ovarian cancer [13‐17]. Moreover, there are reports on a relationship between preoperative serum CRP levels and the prognosis of EC [18‐22]. However, these studies were conducted on a small number of patients, and the imbalances between the groups in these retrospective analyzes may also have affected the results, resulting in indefinite conclusions. Owing to the inconsistent results, the role of serum CRP in EC remains controversial.

Total 961 patients (749 men and 212 women; mean age, 58 years; range, 28–88 years) were enrolled. The preoperative serum CRP levels were > 5.0 mg/mL (mean, 18.92 mg/mL; median, 9.13 mg/mL; standard deviation, 31.25 mg/mL; range, 4.50–290.81 mg/mL) in 250 patients and ≤ 5 mg/mL (mean, 1.54 mg/mL; median, 1.25 mg/mL; standard deviation, 1.09 mg/mL; range, 0.06–4.48 mg/mL) in 711 patients.

The clinicopathological characteristics of the patients are shown in Table 1. Before matching, there were significant differences in the distribution of age and the pathological T stage between patients with high preoperative CRP levels (> 5.0 mg/mL) and those with low preoperative CRP levels (≤ 5.0 mg/mL). Three- and 5-year survival rates were 68 and 56%, respectively, in patients with low preoperative CRP levels and 57 and 53%, respectively, in those with high preoperative CRP levels. After PSM, 176 patients with a low CRP level and 176 patients with a high CRP level were enrolled. There were no significant differences in the distribution of the clinicopathological characteristics between patients with high preoperative CRP levels (> 5.0 mg/mL) and those with low preoperative CRP levels (≤ 5.0 mg/mL). In the matched cohort, the differences in survival between the low- and high-CRP group remained significant (p = 0.044, Fig. 1); the 3-year and 5-year survival rates were 56 and 50%, respectively, in patients with high preoperative CRP levels (> 5.0 mg/mL) and 68 and 56%, respectively, in those with low preoperative CRP levels (≤ 5.0 mg/mL).

Before matching, univariate analysis showed that age (p < 0.001), TNM stage (p = 0.001), history of alcohol consumption (p = 0.024), tumor grade (p = 0.039), and preoperative serum CRP levels (p = 0.008) were significant risk factors for postoperative survival. Survival curves were used to illustrate the differences in the OS duration between patients with high and low preoperative CRP levels (Fig. 2). After matching, the univariate analysis showed that age (p < 0.001), TNM stage (p < 0.001), tumor site (p < 0.001), and preoperative serum CRP levels (p = 0.044) were significant risk factors for postoperative survival. Moreover, surgical incision was not a significant risk factor (p = 0.140). The factors mentioned above were included in the multivariate Cox regression analysis. The result showed that the TNM stage and the preoperative CRP level were independent prognostic factors for OS (Table 2).

In China, the most common type of EC is squamous cell carcinoma. Therefore, our study focused on the prognosis of patients with this type of tumor. It has been reported that some factors may affect the prognosis of patients with EC, such as patient status; tumor biological behavior, including the number of cancer-positive lymph nodes; histopathological cell type; histological grade; cancer location, including the esophagogastric junction; genetic mutations; and surgery type. However, no preoperative markers that can predict the prognosis of esophageal squamous cell carcinoma are currently widely used in clinical practice.

CRP is a representative reactant of acute and chronic phase inflammation. A link between inflammatory reactions and cancer has been reported by Virchow in 1863 that identified leukocyte infiltration in neoplastic tissues and suggested that these sites of chronic inflammation were the origin of the cancer [25]. There have also been reports of a relationship between inflammation and cancer progression [26]. It has now been widely accepted that the elevation in the preoperative serum CRP levels is a reliable indicator of poor postoperative prognosis in patients with certain malignancies, including those of the lung, kidney, ovary, and gastrointestinal tract. Recently, Ibuki et al. showed an association of postoperative CRP levels with poorer OS and recurrence-free survival [27, 28].

Some studies have reported a relationship between the prognosis of EC and preoperative CRP levels. However, these studies did not demonstrate a convincing relationship between these two parameters.

The 2001 study by Nozoe et al. included 262 EC patients and showed that CRP can be an independent biomarker in patients with EC [22]. Thereafter, in 2003, Ikeda et al. gave the same conclusion based on their retrospective analyzes of the clinicopathological factors in 356 patients wherein they aimed to identify factors related to prognosis [29]. Gockel et al. investigated 291 EC patients who underwent curative resection and concluded that a high level of CRP (≥ 5 mg/dL) is associated with tumor progression and poor OS [21]. The study by Wang et al. that included 123 patients showed that the pretreatment serum levels of CRP and albumin can be used to predict survival in EC patients treated with radiotherapy [30]. Furthermore, the preoperative CRP level can also play the same role in patients with small carcinoma of the esophagus or esophageal adenocarcinoma and in patients with early stage esophageal squamous cell carcinoma [19, 31, 32]. The report from Shimada et al. included patients with metastatic disease at the time of surgery and showed that the preoperative serum CRP levels could be a prognostic indicator in patients with esophageal squamous cell carcinoma [18]. A recent study from Otowa et al. showed that preoperative CRP level is a prognostic factor for cStage III EC [33]. All these studies showed that preoperative CRP level can be a significant prognostic indicator in EC patients.

However, some contradictory reports also exist. The report by Zingg et al. showed significantly better survival in patients with normal CRP compared to that in patients with raised CRP levels among those who received neoadjuvant therapy that comprised 2 cycles of 5-fluorouracil (5-FU) and cisplatin in combination with 45–54 Gy of radiotherapy [34]. Owing to the inconsistent results, the role of serum CRP in EC remains controversial.

In addition, the sample size in previous studies was generally low. For example, Shimada et al. included 150 patients in the study, and only 35 patients were grouped into the high-CRP group. Similarly, Crumley et al. analyzed 120 patients; of these, only 15 exhibited high preoperative serum CRP levels. Therefore, the statistical power of these studies was weak because of the small number of patients. Owing to the limitation presented by the relatively smaller sample size, no study has performed PSM analysis to study the prognostic effect of CRP level. In our study, we included more patients (961) than those in previous studies. Moreover, PSM was performed to reduce the potential confounders. Before matching, the patients who exhibited high preoperative serum CRP levels had worse OS than those with low preoperative serum CRP levels (p = 0.004). In the matched cohort, the survival in the low-CRP group was better than that in the high-CRP group (p = 0.044). Additionally, multivariate Cox regression analysis of the matched patients showed that the CRP level was an independent prognostic factor for OS. As per the result, we concluded that the preoperative serum CRP level was an independent prognostic factor for patients with esophageal squamous cell carcinoma, a finding that is consistent with some previous reports.

Many factors, such as age and nutrition status, can affect the preoperative serum CRP levels [35]. By using PSM, the factors that affect CRP level can be balanced between the groups to some extent. In our study, the patients were well matched for age, tumor grade, and TNM stage. Univariate analysis showed that these three cofactors were significant risk factors for postoperative survival. After PSM, the difference between the two groups disappeared. Balanced grouping confirmed the conclusion. Another advantage of PSM is that after one-to-one matching, the high- and low-CRP groups had the same sample size.

Recently, some studies focus on the prognostic value of postoperative CRP level, and got some interesting results. In 2017, Ibuki et al. draw conclusion that the high postoperative CRP level can predict bad survival of patients who received esophagectomy [27]. Furthermore, this indicator can also predict the survival of patients with other carcinomas. In patients received non-small cell lung cancer resection, the research proposed by Shinohara showed that elevated 6-week postoperative C-reactive protein were related to worse OS [36]. The study by Pastorino et al. got a conclusion that the immediately elevated CRP level (postoperative day 3, 5, and 7) were related to worse outcome after surgery [37]. Furthermore, these studies indicate the predicative potential of postoperative serum CRP level, and the combination of preoperative and postoperative CRP may improve OS prediction in esophageal cancer patients. But in our study, we don’t collect the data of the postoperative CRP level. Maybe we can pay more attention to this aspect in further research.

The present study has certain limitations. Although we attempted to offset the potential bias between the low- and high-CRP groups with PSM, the remaining bias may have affected the results.

In conclusion, after a careful comparison and a propensity score matching analysis, we found that the A high preoperative CRP level (> 5.0 mg/mL) predicts worse survival prognosis in patients who have undergone curative resection for ESCC.