Colorectal cancer (CRC) is known as the third common cancer and contributes the second most to cancer death (1,2). The current standard treatment for non-metastatic rectal cancer is total mesorectal excision (TME) or combination treatments, such as surgery with chemo/radiotherapy (3). However, the survival outcomes after surgery vary in different patients, which makes it essential to stratify patients by different risk of recurrence and death to avoid overtreatment or insufficient therapy. The period immediately around surgery for tumors has been supposed to be a critical time that facilitates tumor growth and metastasis (4,5). Therefore, great efforts have been made to develop predictive markers for long-term outcomes by using clinicopathological variables collected from perioperative care in rectal cancer patients.
It has been suggested that inflammation plays a vital role in tumorigenesis and development of CRC (6,7). In this context, some models based on markers representing the systemic inflammation status in perioperative period, such as platelet-to-lymphocyte ratio (PLR), have been proposed to predict prognosis of CRC patients in multiple studies (8-10). However, their prognostic values remain controversial with high variability and limited reproducibility (10,11), suggesting a dramatic heterogeneity among cancer populations, and the current inflammation marker panels need to be improved by combining other markers.
Calcium signaling has been recognized as a crucial role in tumor immune regulation and inflammatory promotion. The emerging data have shown that not only changes of calcium ions level can remodel channels in inflammation cells which play an important role in the perioperative immune system, but alterations of calcium levels are associated with several tumor-related proinflammatory cytokines (12-14). There has been evidence from cohort studies suggesting an association of elevated serum calcium with low-level chronic inflammation in populations (15). Previous studies have shown the prognostic value of serum calcium in multiple cancers, including prostate, breast, and lung cancers (16-19). Furthermore, a study demonstrated that serum calcium could contribute to an inflammation-based modified Glasgow Prognostic Score (mGPS) model for survival prediction in multiple cancers (20).
On the basis of the aforementioned association of serum calcium with inflammation and cancer progression, we aimed to explore the prognostic value of serum calcium and investigate whether the model that combines serum calcium and systemic inflammation markers could improve survival prediction. We speculated that this comprehensive inflammation panel might achieve a considerable improvement in predicting prognosis for patients with rectal cancer. We present the following article in accordance with the TRIPOD reporting checklist (available at http://dx.doi.org/10.21037/jgo-20-479).
We retrospectively studied the patients that were prospectively and consecutively enrolled in the institutional database program of colorectal disease (IDPCD) as previously described (21,22). Patients were included if they were pathologically diagnosed with stage I to III rectal cancer. The patients with familial adenomatous polyposis (FAP), multiple primary cancers, inflammatory bowel disease, hepatic or renal insufficiency, end-stage lung diseases and thyroid disease were excluded. Rectal cancer was staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) staging system (23). Staging procedures included contrast-enhanced computed tomography (CT) scans of the thorax, abdomen, and pelvis, pelvic MRIs and colonoscopy.
Measurement of inflammation-associated markers
Serum calcium was measured photometrically by the clinical laboratory in our institute, on a PRISMA multichannel autoanalyzer (Clinicon AB, Bromma, Sweden). According to the IDPCD protocols in our institution, the enrolled patients were consented to test preoperative serum calcium levels and blood cell counts within the 24 hours after admission to the hospital. Since total calcium changes with albumin concentration, it was corrected by serum albumin level to obtain the corrected serum calcium (cCa): cCa = total calcium +[0.8×(4.0− serum albumin)] (24). PLR was defined as the absolute platelet count divided by the absolute lymphocyte count, and a cut-off value of 150 was adopted to discriminate patients with low versus high PLR as previously described (25-27).
Treatment, follow-up and study endpoints
Patients were treated and followed up according to NCCN guidelines-based protocols in our institute (28,29). Briefly, all patients underwent TME, and 13.1% patients received neoadjuvant chemo/radiotherapy. Surgical approaches included low anterior resections, abdominoperineal resections, and Parks procedure. Postoperative assessment of TME quality was performed in all surgical specimens. According to physicians’ suggestions and patients’ decisions, 5-fluorouracil-based chemotherapy was given after operation. Patients were followed up every three months for the first two years and every six months thereafter. Each visit consisted of pertinent medical history, physical examination, including rectal examination, and measurement of serum carcinoembryonic antigen (CEA) levels. Colonoscopy and radiological examinations consisting of chest radiography, abdominopelvic CT and ultrasonography were scheduled every six months for the first three years and annually thereafter. Cancer recurrence was detected by CEA >5 ng/mL and/or a sequential computerized tomography scan with evidence of the disease followed by histopathological confirmation. The primary endpoint was disease-free survival (DFS), which was defined as the time from the surgery until recurrence or death from any cause.
The intergroup comparisons of clinicopathologic variables were performed using the analysis of variance and Kruskal-Wallis tests for continuous variables depending on their distributions, and the chi-square and two-tailed Fisher’s exact tests were used for categorical variables. According to the optimum cutoff point determined by maximally selected rank statistics, the cohort was divided into high and low cCa group. The Cox proportional hazard model was applied to generate the CaPLR score. According to CaPLR score, patients were divided into three groups, including high score group (HS, score =0.745), intermediate score group (IS, score =0.397 or 0.348), and low score group (LS, score =0). The Kaplan-Meier method was used to estimate the long-term survival. A univariate screen of potential predictors of mortality by Cox proportional hazard model for each candidate variable was performed, and the selected predictors with statistical significance were included in the multivariate Cox model to examine their independently predictive value. The comparison between predictive models was assessed using likelihood ratio (LR) and Akaike information criterion (AIC), as previously described (30,31), in competing models including or not including cCa or CaPLR score. In general, the model with a lower AIC and a higher LR were considered a better one. The predictive nomogram was developed based on the results of multivariate Cox regression analysis. The Harrell’s concordance index (C-index) of the nomogram was calculated using the bootstrap method to evaluate the discriminative ability of the nomogram. Data analyses were performed using SPSS version 22.0 for Windows (SPSS, Inc., Chicago, IL) and R version 3.5.1 (R-project, Institute for Statistics and Mathematics, Vienna, Austria). A two-side P value <0.05 was considered statistically significant.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University (No. 2017ZSLYEC-006) and informed consent was taken from all the patients.
Between June 2007 and June 2011, a total of 795 patients with pathologically confirmed rectal cancer received curative surgery. In this cohort, 508 patients matched the inclusion and exclusion criteria and were included (Figure 1). Among them, 26.7% (136/508) patients reached recurrence after curative surgery. The demographics and clinicopathological features were shown in Table 1. There were 296 male and 212 female patients, with a median age of 59 years (21–89 years). The AJCC staging among patients was distributed as 26.2%, 31.3% and 42.5% for stages I, II and III, respectively. Patients were grouped by preoperative cCa based on the optimal cutoff value determined by maximally selected rank statistics (Figure 2A). The low and high cCa group had 137 and 371 patients respectively. There was no significant difference in baseline characteristics between two groups (Table 1).
Predicting value of serum calcium for survival outcome in rectal cancer
We performed a screen for prognostic markers by using univariate Cox analysis, in which the high cCa was found to be significantly associated with worse DFS (HR =1.486, 95% CI, 1.018–2.171; P=0.040; Table 2). In the Kaplan-Meier curve, significantly worse survival was observed in patients with high cCa compared to those with low cCa (P=0.038; Figure 2B). In addition, high PLR, representing a high systemic inflammation status, was also found to predict worse DFS in this cohort (HR =1.452, 95% CI, 1.059–1.991; P=0.021; Figure 2C, Table 2). The other markers that were significantly associated with DFS in the univariate Cox analysis included age, TNM stage, differentiation degree, lymphovascular invasion, perineural invasion, preoperative CEA, and distance from anal verge (Table 2).
Serum calcium adds values to current prognostic makers
Considering the aforementioned association of serum calcium with inflammation, we applied LR test and AIC to explore how cCa could improve current systemic inflammation marker in predicting survival outcome. As shown in Table 3, the model 3 including both PLR and cCa had a lower AIC and a higher LR in comparison to the model 1 or model 2 that only included PLR or cCa (AIC: 1,704.83 vs. 1,707.14 vs. 1,707.15; LR: 8.68 vs. 4.37 vs. 4.36; P=0.037; Table 3). This result showed that the model combined PLR and cCa may perform better in DFS prediction. We therefore constructed a CaPLR score model for further survival analysis by using Cox proportional hazard model with their grouping information (1 for high cCa or PLR group, and 0 for low cCa or PLR group) and coefficients in the regression: CaPLR score = cCa ×0.348+ PLR ×0.397.
CaPLR model improved survival prediction in rectal cancer
Patients were categorized into three groups based on CaPLR. There were 88 patients in the HS group, 287 in the IS group, and 127 in the LS group. In the Kaplan-Meier analysis, the three groups had a significant difference in survival curve, in which the patients with higher CaPLR had significantly worse survival (P=0.005, Figure 2D). The HS and IS group had HRs of 2.418 (95% CI, 1.390–4.206; P=0.002) and 1.892 (95% CI, 1.128–3.175; P=0.016) respectively in comparison to LS group in Cox analysis (Table 2).
We further performed outcome analysis between patients grouped by CaPLR score. The total recurrence rate was 23.3% (50/215) in the whole cohort, and HS group had 18.2% higher risk of recurrence compared with LS group [30.7% (39/127) vs. 12.5% (11/88), P=0.002] (Table 4). In addition, both the local recurrence [4.6% (4/88) vs. 13.6% (17/127), P=0.031] and distant metastasis [9.2% (8/88) vs. 25.6% (32/127), P=0.003] rate were significantly higher in HS group (Table 4).
In the multivariate Cox analysis including CaPLR score and other prognostic predictors from univariate screen, the CaPLR score was further proved to be an independent predictor for DFS with adjusted HRs of 2.216 (95% CI, 1.256–3.909; P=0.006) and 1.679 (95% CI, 1.004–2.836; P=0.047) for HS and IS group respectively in comparison to LS group (Table 2). Moreover, the TNM stage, lymphovascular invasion, CEA and distance from anal verge were also independent predictors in the multivariate Cox model (Table 2).
Next, we applied LR test and AIC to explore how CaPLR could add prognostic values to current predictive panels in rectal cancer. In the comparison between models 4 and 5, after CaPLR was added to TNM stage, a dramatic improvement was observed in AIC and LR (AIC: 1,666.57 vs. 1,659.94; LR: 44.95 vs. 53.57, P=0.003; Table 3). A similar improvement was found in the comparison between models 6 and 7, in which the multivariate Cox model was improved after CaPLR was added (AIC: 1,656.56 vs. 1,650.21; LR: 60.96 vs. 69.31, P=0.003; Table 3). Thus, both the widely-used AJCC TNM staging panel and the generated Cox model in this study may get increased discriminatory ability for predicting survival outcome with CaPLR score.
We also compared the short-term outcomes between patients stratified by CaPLR score. Intriguingly, in the association analysis between CaPLR and complication incidence after surgery, high CaPLR score was significantly related to increased risk of anastomotic stenosis [14.8% (13/88) vs. 5.5% (7/127), P=0.022, Table 4].
A nomogram for prognosis evaluation in rectal cancer
A nomogram for predicting DFS outcome was generated using the variables from the multivariate Cox model, including CaPLR score, TNM stage, lymphovascular invasion, CEA, and distance from anal verge (Figure 3). The calibration curves for the nomogram were shown. The C-index of the nomogram for predicting DFS was 0.705 (95% CI, 0.620–0.789; P<0.001).
The main finding of this work is that a novel inflammation-based prognostic panel that combined PLR with cCa had significantly improved value for predicting survival outcome in rectal cancer. This improved inflammation marker panel that was first proposed in this study is supported by the analysis using prospective data from institutional database and medical records. In current study, we demonstrated that both high cCa and high PLR were significantly associated with worse survival outcomes. In model comparison by using AIC and LR test, cCa could significantly improve the performance of PLR in survival prediction. Based on this result, the CaPLR score was generated to stratify patients into three groups with sequential risk of recurrence and death, in which patients with higher CaPLR had significantly worse DFS. Furthermore, a nomogram that could well predict survival outcome was generated by using CaPLR score, TNM stage, lymphovascular invasion, CEA and distance from anal verge.
It has been well documented that systemic inflammation plays an important role in CRC tumorigenesis, proliferation, invasion, metastasis, angiogenesis, and suppressing anti-tumor immunity (6). Several systemic inflammation-based markers, such as PLR and mGPS, have been developed and found to have independent value in predicting cancer survival outcomes (11). An elevated preoperative PLR is usually accompanied by thrombocytosis or lymphocytopenia, implying an activated inflammatory status and repressed immune response of patients. Expectedly, PLR, a marker that represents the balance between two inflammatory status, has shown prognostic values in multiple studies (8-10). In addition, elevated platelets tend to gather tumor cells by release biological factors, help stimulate the development of new vessels by interacting with PDGF, VEGF and PF4, and activate DNA-damage-promoting agents, which may promote carcinogenesis (32).
The underlying mechanism of the association between serum calcium and inflammation includes the interaction with the extracellular calcium sensing receptor that has been reported to be a crucial regulator for inflammation through multiple downstream signaling pathways (33). In addition, the TRPV1 channel, involved in calcium signaling fundamental for many cellular processes, was recently documented to be expressed on the immune cells and activated by proinflammatory cytokines, and it was also reported to be aberrantly expressed on cancer cells (12). On the other side of the association with inflammation, calcium may promote cancer in other ways. First, calcium has been shown to be involved in cell differentiation and proliferation through modulating cell signaling that can commonly initiate colorectal carcinogenesis, such as APC/β-catenin and Hedgehog pathways (34-37), and it has been proposed that hypercalcemic environment may help colon adenocarcinoma cells develop (38). Second, patients with bone metastasis are well known to be hypercalcemic (39) suggesting that patients with elevated serum calcium and worse survival might have undiagnosed metastatic disease before the curative-intent surgery. Moreover, hypercalcemia secondary to paraneoplastic lesions may contribute to the association between serum calcium and cancer survival. However, this condition frequently occurs in other cancers such as squamous cell lung cancer but rare in rectal cancer (40).
Although impressive prognostic values were found in several systemic inflammation-based markers, including PLR, mGPS, neutrophil-lymphocyte ratio, and Lymphocyte-to-monocyte ratio, their predictive abilities varied and remained controversial among published cohorts (10,11). We therefore developed additional markers to enable accurate identification of patients with high risk of recurrence and death by using inflammation-based panels. Our results showed that serum calcium could significantly improve the performance of systemic inflammation markers in survival prediction. After serum calcium was added, the CaPLR was generated and showed dramatically improved discriminability for survival outcomes. We further combined this improved inflammation-based marker with other known independent predictors to develop a nomogram that could well predict prognosis in a more comprehensive manner.
Nevertheless, limitations to our study exist. First, the results from retrospective analysis were limited by unknown confounders due to its observational nature, although multiple variables were controlled. Then, the total serum calcium varies with changes in albumin concentration and ionized calcium may be a more reliable marker, although the cCa, albumin-adjusted calcium, was analyzed instead. Since ionized calcium is not routinely measured in daily clinical practice, the value of serum calcium needs to be validated in a study that can prospectively test blood-derived ionized calcium.
Our results provided evidence that serum calcium could improve the value of systemic inflammation markers in survival prediction for patients with rectal cancer. The CaPLR qualifies as a reliable inflammation-based predictor for survival outcome in rectal cancer patients after curative resection.
Funding: This work was supported by the National Basic Research Program of China (973 Program) (No. 2015CB554001), the National Natural Science Foundation of China (No. 81972245, YL; No. 81902877, HY), the Natural Science Fund for Distinguished Young Scholars of Guangdong Province (No. 2016A030306002, YL), the Tip-top Scientific and Technical Innovative Youth Talents of Guangdong special support program (No. 2015TQ01R454, YL), Sun Yat-sen University Clinical Research 5010 Program (No. 2018026, YL), the Natural Science Foundation of Guangdong Province (No. 2018A0303130303, HY), the “Five Five” Talent Team Construction Project of the Sixth Affiliated Hospital of Sun Yat-Sen University (No. P20150227202010244; No. P20150227202010251, YL), the Program of Introducing Talents of Discipline to Universities, and National Key Clinical Discipline .
Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at http://dx.doi.org/10.21037/jgo-20-479
Data Sharing Statement: Available at http://dx.doi.org/10.21037/jgo-20-479
Peer Review File: Available at http://dx.doi.org/10.21037/jgo-20-479
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-20-479). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of the Sixth Affiliated Hospital of Sun Yat-sen University (2017ZSLYEC-006) and informed consent was taken from all the patients.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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