Introduction
Pancreatic cancer ranks as the 12th most commonly diagnosed cancer and seventh leading cause of cancer death; there are an estimated 337,900 new cases and 330,400 deaths occurring in 2012 worldwide [
1]. Most patients are diagnosed at an advanced stage and have a rapid clinical decline, culminating in death within less than 1 year after diagnosis. The high mortality is associated with a limited chance of curative resection at the time of diagnosis, as surgical resection offers the only prospect of long-term survival or cure. Moreover, one study showed that the median survival in patients with curative resection was 14.9 months longer than in those with an advanced stage (19.1 vs 4.2 months). Similarly, the 5-year survival rates were higher in the operable patients (19.3 vs 0.8 %) [
2]. Although surgical resection has improved the prognosis of pancreatic cancer patients, it continues to have a poor prognosis.
Currently, although continuous advances in modern diagnostic imaging have been achieved, most established prognostic factors continue to rely on surgical exploration, such as the tumor size, histologic grade, and vascular and nodal involvement. Many patients at an advanced stage also undergo a morbid operative procedure during the course of pancreatic lesion evaluation. Therefore, it is important to identify some easily obtainable and reliable prognostic factors for better risk stratification and optimal treatment plans. With the increasing number of studies suggesting that tumor-elicited inflammation plays a key role in malignant transform and tumor progression [
3‐
6], some inflammation-based prognostic factors have been explored in many cancers during the course from bench to bedside. These factors are all easily available from peripheral blood samples, including the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), white cell count and C-reactive protein (CRP) combined into the prognostic index (PI), albumin and lymphocyte count in the prognostic nutritional index (PNI), and CRP- and albumin-based factors of the modified Glasgow prognostic score (mGPS) and C-reactive protein/albumin (CRP/Alb) ratio [
7‐
12]. Among these indicators, the CRP/Alb ratio has been reported as a novel reliable marker in different cancers such as lung, liver, gastric, and esophageal cancer [
8,
13‐
16]. However, the role of the CRP/Alb ratio in patients with advanced pancreatic cancer has not previously been elucidated.
In this retrospective study, we examined the prognostic value of the CRP/Alb ratio and compared it to other established inflammation-based prognostic scores.
Discussion
Despite recent improvements in the validated benefit of chemotherapy and spread of multidisciplinary therapy for patients in the advanced stage, pancreatic cancer remains a devastating disease with an extremely poor prognosis. Optimal responses will be achieved only if the treatment plan is tailored for individuals based on accurate and stable prediction of potential survival. However, tumor-related parameters such as the pathological stage and resectability of the primary tumor primarily play a role in evaluating disease and predicting the outcome.
Therefore, an increasing number of thorough studies have identified some easily available predictors for substituting the traditional surgical method. A diverse set of observations offers evidence supporting the correlation between inflammation and cancer. While early studies were devoted to elucidating the link between pre-existing inflammation and consequent tumor initiation, more recent studies tend to add new insight into tumor-associated inflammation and the host response to oncogenic change in the intrinsic pathway. For the intrinsic pathway, inflammation and tumor growth are driven by genetic mutations that cause the activation of transcription factors, release of inflammatory mediators (chemokines, cytokines, and prostaglandins), and subsequent infiltration of inflammatory cells and angiogenesis [
5]. This inflammatory condition further promotes the malignant progression of tumors, enhances local immunosuppression, induces invasion and metastatic spread, and influences the treatment response [
5,
22,
23].
Among the many inflammatory mediators, interleukin-6 (IL-6) is a notable inflammatory cytokine secreted by innate immune cells that regulates the levels of C-reactive protein (CRP), an acute-phase protein [
24]. Recently, it was reported that elevated pretreatment serum IL-6 and CRP levels showed a significant relationship with a poor outcome [
25‐
28]. Additionally, the serum albumin level is not only a reflection of nutritional state but also it is, to a larger degree, a consequence of the inflammatory state. Plausible explanations are as follows. When considered with tumor-related systematic inflammation, the ability of the liver to produce albumin decreases as a result of increased acute-phase protein synthesis [
29,
30]. Alternatively, the release of cytokines from inflammatory cells increases the microvascular permeability, increasing the flow of serum albumin towards the extravascular compartment [
31]. Therefore, the link between hypoalbuminemia and inflammation is also quite strong [
32]. Meanwhile, the role of the pretreatment serum albumin levels as an independent predictor of the OS has been demonstrated in various cancers, including PC [
33‐
35].
These achievements greatly piqued our interest in combining CRP and albumin into a noble potential inflammatory prognostic indicator in advanced PC and identifying its predictive value. In addition, some recent studies have demonstrated that the CRP/Alb ratio is a promising inflammation-associated prognostic factor in cancer, including liver, lung, gastric, and esophageal cancer [
8,
13‐
17]. In our study, we assessed and compared the prognostic value of the NLR, PLR, mGPS, and CRP/Alb ratio in advanced PC by retrospectively analyzing the pretreatment laboratory data of 233 eligible patients. According to statistical analysis, there was a significant association between the CRP/Alb ratio and other inflammatory indexes (excluding PLR), which might suggest that comprehensive evaluation of these inflammatory parameters could provide a more advisable prognostic estimate. In accordance with the result of the chi-square test of the CRP/Alb ratio versus disease stage, the CRP/Alb ratio remained a significant prognostic parameter regardless of the stage of advanced PC in subgroup analyses. After excluding the confounding factors from the multivariate analyses, the CRP/Alb ratio remained the only significant inflammation-related prognostic index. To the best of our knowledge, this is the first study to explore the role of the CRP/Alb ratio as a predictor of prognosis in advanced PC.
As the mGPS and CRP/Alb ratio both include the CRP and albumin levels, comparison of the two factors was performed. Because the CRP/Alb ratios of patients with mGPS scores of 0 were all less than 0.54, dichotomizing patients with mGPS scores of 1 and 2 on the basis of the CRP/Alb ratio was conducted. Kaplan–Meier tests showed that patients with an mGPS score of 1 and CRP/Alb ratio < 0.54 and an mGPS score of 2 and CRP/Alb ratio < 0.54 had comparable longer OS. Similarly, those in the groups with an mGPS score of 1 and CRP/Alb ratio ≥ 0.54 and an mGPS score of 2 and CRP/Alb ratio ≥ 0.54 had parallel poor outcome. The results exposed defects in the mGPS prognostic ability for patients with scores of 1 and 2 because they did not have significant differences in OS; by contrast, they could be distinguished according to the CRP/Alb ratio. This disadvantage arises from its nature as a categorized variable that fails to accurately reflect the disease condition of every patient. In conclusion, the CRP/Alb ratio is superior to the other inflammation-related prognostic factors. Our findings may have practical value in the therapy of advanced PC patients. Patients with a high CRP/Alb ratio may require more active adjuvant chemotherapy.
The generalizability of the conclusions is limited by the threatened independence of the variables. As a retrospective and single-center study, the limitations of the current research lie in its intrinsic features. To narrow down the inevitable selection bias, we enrolled consecutive patients and included a relatively large sample size. Meanwhile, we explored the prognostic significance of the CRP/Alb ratio in a multi-faceted approach, including validation of the value at the level of all patients and patient subgroups based on disease stage. However, a multicenter prospective validation study with a larger scale sample is needed to confirm our findings.
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