Colorectal cancer (CRC) represents the third most commonly diagnosed cancer in males and the second in females, causing 1.4 million cases and 693 900 deaths in 2012 worldwide . CRC is also the fifth leading cause of cancer death accounting for 180 000 deaths per year in China, demonstrating a rapidly growing health burden due to the aging of population and a host of unhealthy habits . Despite this, current screening tools targeting at CRC like colonoscopy have limitations, including morbidity, expense and poor patient compliance [3,4].
With the escalating incidence and tumor-related mortality of CRC over the past decade, the prediction of cancer survival contributes a lot to the guidelines, proper treatment and surveillance strategies [1,2]. By far, many prognosis-related factors have been identified, guiding treatment decisions and the evaluation of its efficacy . Despite the existing prognostic factors, overall survival (OS) of CRC remains unsatisfactory, which may be associated with the reason that these prognostic biomarkers mainly depend on some clinicopathological characteristics such as tumor stage . However, the succedent tumor progression may be not identical to each other even with the same stage . Thus, there are still pending biomarkers applied as new efficient prognostic factors of CRC.
Evidence shows that inflammation plays a pivotal role in the progression of cancer [7,8]. Moreover, tumor-related inflammation, manifested by inflammatory cytokines including TNF, IL-6, IL-11, IL-17, IL-21, IL-22 and IL-23 and limited by TGFβ and IL-10, has shown to drive cancer development in the gut, indicating the fundamental role of inflammation in CRC [9,10]. Monocyte is identified as the major inflammatory component in most solid tumors, and its recruitment and activation are primarily regulated by tumor-derived signals such as chemokines, cytokines and endogenous signals . It is reported that peripheral monocyte displayed tumor-promoting roles like angiogenesis and invasion . Also, inflammatory monocytes from the bone marrow are recruited to sites of inflammation where they infiltrate into tissues and differentiate into macrophages, which were regarded as the critical regulators in the tumor microenvironment (TME) [12,13]. Previous studies indicated high circulating monocyte counts or some factors that were related to monocyte counts were associated with poor outcome in subdividing cancers such as melanoma and hepatocellular carcinoma [14,15]. However, the prognostic value of absolute monocyte count (AMC) in CRC patients remains controversial. Based on several studies, AMC was found to show significance as an independent prognostic biomarker [16,17], whereas others reported opposite results [18,19].
Therefore, it was necessary and timely to analyze the prognostic significance of peripheral AMC to clarify the pending issue and fill the gap of lacking potential circulating biomarker in CRC. In the present study, a meta-analysis integrating the valid results from conditional homogeneous studies was conducted to quantitatively analyze the effect of high AMC on the survival of CRC patients.
Material and methods
According to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we performed a comprehensive literature search in several databases which were lastly updated to 23 December 2018, including EMBASE, Web of Science and PubMed. We used following keywords in combination as search terms: ‘Colonic Neoplasms [MeSH Terms]’, ‘Colorectal Neoplasms [MeSH Terms]’, ‘colon cancer’, ‘rectal cancer’, ‘monocyte count’, ‘absolute monocyte count’, ‘AMC’. Moreover, all references in retrieved articles were also manually reviewed to identify other potentially eligible studies. Two authors independently searched and reviewed these studies, and disagreements were resolved by the third author or by discussion.
Inclusion and exclusion criteria
Studies were included if they met the following criteria: (1) patients with CRC were pathologically confirmed; (2) the prognostic role of peripheral AMC on OS, disease-free survival (DFS), progression-free survival (PFS) and cancer-specific survival (CSS) in CRC was investigated; (3) the hazard ratio with the corresponding 95% confidence interval (CI) could be extracted in Cox hazard model, or could be estimated by Parmar’ method ; and (4) studies evaluated AMC as a dichotomous cutoff. Studies were excluded if they met the following criteria: (1) case reports, reviews, reference abstracts, animal studies, conference report or meta-analysis; (2) duplicated publications or studies based on overlapping patients; (3) data with insufficient data; (4) studies on AMC as a continuous variable; and (5) articles written in non-English or non-Chinese languages. Besides, study with the largest sample size and with more information was included if there were studies with overlapped cases.
The data were extracted independently by two reviewers with a standard extraction table. A consensus was reached by discussion or by consulting the third reviewer. The following information was extracted: publication year, first author’s name, country, ethnicity of patients, source of sample, sample size, mean age, gender, cancer type, study design, characteristics of cancer (status of distant metastasis, TNM stage), testing time of AMC, follow-up period, cutoff value, cancer therapy, hazard ratio with corresponding 95% CI for cancer outcomes (OS, DFS, CSS and PFS).
Two independent investigators assessed the quality of the included studies according to the Newcastle-Ottawa quality assessment scale (NOS) , and a third investigator would participate in the discussion of conflicting judgments until they reached a consensus. NOS is a 9-point scoring system, and quality assessment included three broad domains: selection (up to four stars), comparability (up to two stars), and outcome (up to three stars). An NOS score above six was considered as the standard of high-quality studies.
The meta-analysis was performed by Stata 14.0 (STATA Corporation, College Station, Texas, USA). Hazard ratios evaluated the role of peripheral AMC on cancer prognosiss with 95% CIs, which were directly extracted from published aggregate data or estimated from Kaplan–Meier curves. Additionally, only outcomes with multivariate analysis would be extracted if univariate and multivariate analysis data were both available in one study. Cochran’s Q test and Higgins’ I2 test were used to assess the interstudy heterogeneity, and a P value less than 0.1 and I2 more than 50% indicated significant heterogeneity. The pooled hazard ratio was calculated as the summary effect measure. When there was no statistically significant heterogeneity, we used the random-effects model for pooling the results; otherwise, the fixed-effect model was applied. All statistical tests were two sided, and the P value threshold for statistical significance was set at 0.5 in data synthesis.
What’s more, the subgroup analyses stratified by status, ethnicity, the test time of monocytes, sample size, cutoff value, cancer therapy, survival analysis method and study quality were performed. Begg’s and Egger’s tests were also used to evaluate publication bias.
Literature search and study selection procedure
The literature search of electronic databases identified a total of 1827 studies through the primary filtration. Two investigators reviewed titles and abstracts independently and thoroughly, excluded 1321 studies and retrieved the full texts of remaining 41 articles artificially for further identification. Finally, we included 15 articles comprising 3826 patients in our study for analysis [16–19,22–32]. The flow diagram of the selection procedure was shown in Fig. 1.
Characteristics of included studies
A total of 15 articles involving 16 studies included in the systemic review, four studies recruited Caucasian patients, while 12 studies recruited Asian patients, and four studies recruited patients with primary CRC or with metastatic cancer, five studies investigated only primary cancer patients and seven studies examined only metastatic cancer patients. Among these studies, 10 studies focused on preoperative AMC, three studies explored pretreatment AMC and three studies remained unknown based on the test time of blood. Moreover, AMC cutoff values ranged from 300 to 900/mm3, and the cutoff values were principally obtained from receiver operating characteristic curves. In addition, 14 studies were evaluating OS, five studies for DFS, four studies for CSS and four for PFS. The NOS scores of eight studies were higher than or equal to 7. The major characteristics of the included studies were shown in Table 1. The detailed extracted data were presented in Supplementary Table S1, Supplemental digital content 1, http://links.lww.com/EJGH/A459, and individual NOS scores of each included study were presented in Supplementary Table S2, Supplemental digital content 2, http://links.lww.com/EJGH/A460.
A total of 14 studies of CRC patients comprising 3612 patients investigated the association between AMC and OS. The results were shown in Table 2. In the pooled analysis, we found that elevated AMC was significantly associated with the adverse OS of patients with CRC (hazard ratio = 1.708, 95% CI: 1.480–1.971, P < 0.001) with small heterogeneity (I2= 14.90%, P = 0.290) (Fig. 2). No heterogeneity existed in studies with large sample size, cutoff values ranging from 400 to 500/mm3 and low-quality subgroup. The similar association also existed when stratified with ethnicity, status of distant metastasis, test time of AMC, cancer therapy, analysis method and study quality. There was reduced heterogeneity existed when stratified with status of distant metastasis (I2= 9.90%, P= 0.350) (Fig. 3), also in subgroup with univariate analysis ((I2= 6.00%, P = 0.384). As to the difference of cutoff values, higher effect on OS was found in studies with cutoff values >500/mm3 (hazard ratio = 1.852, 95% CI: 1.521–2.255, P < 0.001). In addition, nine studies involving 2498 patients reported the hazard ratios of preoperative AMC for OS, and the pooled adjusted hazard ratio was 1.759 (95% CI: 1.404–2.203, P < 0.001) with low heterogeneity (I2= 17.40%, P = 0.288). The estimated hazard ratio was 1.830 (95% CI: 1.465–2.286, P< 0.001) in the surgery subgroup and 1.625 (95% CI: 1.355–1.950, P < 0.001) in nonsurgery subgroup (Fig. 3).
Five studies involving 1409 patients with CRC reported hazard ratios for DFS. A combined analysis demonstrated that high AMC was significantly associated with worse DFS (hazard ratio = 1.817, 95% CI: 1.289–2.560, P = 0.001) with not significant heterogeneity (I2= 30.50%, P = 0.218) (Fig. 4). There was no heterogeneity when stratified by sample size, cutoff value, metastasis status and analysis method. The results were shown in Table 2.
Data on the association between AMC and CSS were derived from four studies involving 632 patients with CRC. Overall, elevated monocyte counts predicted decreased CSS in CRC patients (hazard ratio = 1.551, 95% CI: 1.187–2.027, P = 0.001) with small heterogeneity (I2= 12.00%, P = 0.333) (Fig. 4). Exploratory subgroup analyses stratified by sample size and status of distant metastasis, and the poor prognostic impact of higher AMC in CRC patients were also observed in all subgroups. Pooled hazard ratios for DFS according to ethnicity, cutoff value, test time and quality and the CSS rates were significantly worse in studies concerning on Caucasian subgroup, high cutoff values, preoperative subgroup, surgery subgroup and high-quality subgroup. The results were also shown in Table 2.
Four studies provided the data for PFS with 1094 CRC patients. When pooling the hazard ratios for PFS, the result showed a significant poor prognostic effect on PFS in CRC patients with high AMC (hazard ratio = 1.487, 95% CI: 1.259–1.756, P < 0.001) with no heterogeneity between these studies (I2 = 0%, P = 0.667) (Fig. 4). No heterogeneity was found in all subgroups (Table 2).
Publication bias and sensitivity analysis
The publication bias of our study was investigated. No publication bias was detected in Begg’s test (Pr > |z| = 0.743) and Egger’s test (P > |t| = 0.940) and the reliability was suggested in our meta-analysis (Fig. 5). In addition, we found no significant changes in our results which further proved the stability of our meta-analysis, after dropping each included study.
The association between peripheral AMC and clinical outcome of CRC has been inconsistent in the previous literature, and the magnitude of the studies has been relatively moderate. This systematic review with meta-analysis involving 3826 patients from 16 studies provided compelling evidence that elevated monocyte counts might be suggestive of a more adverse outcome of OS, DFS, CSS and PFS in CRC patients. Subgroup analyses were conducted according to ethnicity, cancer status, the test time of AMC, sample size, cutoff value, cancer therapy and study design method, further validating the strong association between peripheral monocyte counts and CRC patients. Therefore, enhanced AMC may be a robust indicator of poor survival in CRC patients.
Increasing evidence suggested that inflammatory cells had an impact on CRC prognosis . The mechanism of the inflammatory cells, as prognostic factors, was related to TME. The cancer and the surrounding microenvironment had a close relation and interacted constantly [34,35]. In TME, macrophages arising from monocytes served as a major inflammatory component of the stroma and directly affected many aspects of the neoplastic tissue, including tumorigenesis, tumor progression and metastasis, with inflammatory mediators interacting with vascular permeability and cancer cell infiltrating [36–38]. Monocytes mainly differentiate into M1 and M2 phenotypes after recruitment into tumor tissue, and M1 macrophages possess antitumor activity, whereas M2 macrophages are responsible for cancer invasion, metastasis, angiogenesis and immunosuppression [39,40]. Previous studies reported that tumor-associated macrophages (TAMs) within the TME were associated with a shorter long-term outcome of cancer because of the M2-like phenotype of TAM . The close relationship between monocytes and TAM is critical for the better understanding of the pathway of the escape of tumor cells from immune surveillance. Monocyte was also an essential source of cytokines and chemokines. It was known that inflammation was caused not only by the systemic reaction of the host to the tumor but also caused by inflammatory cytokines and chemokines , so that monocyte could promote tumor metastasis and progression and was also an important part of TME .
Based on the hypothesis that peripheral monocyte counts reflecting the presence of TAMs and associated with TAM levels [39,40], there is an amount of substantial evidence suggested the potential prognostic value of peripheral monocytes, and that pretreatment or preoperative measurements of the monocyte counts can be applied to the prediction of cancer survival to some extent . The previous study demonstrated that preoperative peripheral blood monocyte count could also be a useful predictor of postoperative prognosis in CRC patients with liver metastasis in patients . In addition, the preoperative lymphocyte-to-monocyte ratio (LMR) was also suggested to be correlated with patients’ outcome in CRC . Therefore, elevated peripheral monocyte count was responsible for a great tumor burden, in a way, was associated with the CRC cancer prognosis. What’s more, monocytes were also a primary source of dendritic cells in peripheral blood, which contributed to the prognostic role of AMC . Regulatory dendritic cells in the peripheral blood might induce and promote the proliferation of CD4+ CD25+ regulatory T cells which inhibited the proliferation and promote the activation of CD4+CD25– T or CD8+CD25− T cells which might result in immune suppression and the inhibition of an immune attack on tumor cells [45,46]. Furthermore, recent studies suggested that a portion of monocytes or TAMs expressed programmed death-ligand 1 (PD-L1) which dampened the antitumor function of T cells via binding to programmed death-1(PD-1) in solid tumors [47,48]. The relevant studies added more piece of evidence to refine the PD-1/PD-L1 blockade therapeutics .
As shown in the present study, elevated AMC may serve as an independent prognostic factor of CRC patients who underwent surgery. Thus, peripheral blood monocyte count could be applied to other therapy of cancer on the clinical setting as surgical guidance. The mechanism of monocytes also suggested that some anti-inflammation methods might be used for better prognosis of CRC patients [41–43]. Considering that monocyte count of each patient was detected precisely currently, the inflammatory response to the tumor could add some valuable information to some inflammatory score systems. In this way, doctors could assess the patients in a more systematic way and give better judgment to the prognosis of patients via these systems . For metastatic CRC (mCRC) patients, optimal prognostic biomarkers were also critical for cancer treatment decision and timely adjustment in therapeutic regimen. In the meta-analysis, AMC seems to be a reliable surrogate marker for OS, CSS and PFS of mCRC, whereas not for DFS. One of the underlying reasons may be due to the reason that the limited data were not feasible to be pooled statistically. Hence, considerable studies should be made in seeking the predictive indicators to classify mCRC further.
Besides, peripheral blood monocytes count was related to not only the prognosis of CRC but also that of other types of cancer, like hepatocellular carcinoma . Thus, further study needed to be done to demonstrate that whether monocytes count in peripheral could be a powerful prognostic factor for most cancers or not.
There were also some limitations of this study that should be acknowledged. The most important one was the sample size and scale. Some subgroups included only one or two studies which might have a difference in the result and conclusion. Thus, larger-scale studies with large sample size and high quality were necessary for the future. Besides, many potential confounding factors that might influence monocytes were not assessed in the present study, such as the specific therapy options. Limited data were also inadequate to explore the association between AMC and clinicopathological features in the study. In addition, apart from some known cancer-related factors, inflammatory response of surgery also plays a non-negligible role in cancer prognosis. However, the inflammatory response is highly variated and may be influenced by a variety of factors such as surgical approach and psychological factors of patients. Most of the included studies only concerned on the clinical significance of preoperative inflammation state and a few studies taking postoperative inflammatory status into account, regardless of the postoperative systemic inflammation that can be easily influenced by surgical procedure and postoperative management. Hence, future research on postoperative inflammation status is warranted.
In conclusion, we demonstrated that monocytes count in the peripheral blood was associated with the prognosis of patients with CRC in the current study. As an independent prognostic factor, the potential role of monocytes counts in individualized treatment was suggested. Our conclusion needed to be further confirmed in the future by studies with large scale and large sample size.
I would like to thank all authors who were involved in the study. The conception and design of the study: Ying Hu and Shu Wen; Literature search: Jin Peng, Qian Fang and Xin He; Data extraction: Jin Peng, Qian Fang and Xin He; Data analysis: Nan Chen, Shu Wen and Ling Wei; Manuscript preparation: Nan Chen, Shu Wen and Sai-fu Yin; Manuscript revision: Meng Qiu and Ying Hu. All authors reviewed and approved the manuscript prior to submission.
Conflicts of interest
There are no conflicts of interest.
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