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Postoperative serum interleukin-6 levels correlate with survival in stage I-III colorectal cancer

BMC Gastroenterology volume 23, Article number: 156 (2023) Cite this article

Abstract

Aims

The preoperative serum levels of inflammatory mediators, including C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), have been demonstrated to be correlated with patient outcomes in colorectal cancer (CRC); however, the prognostic role of these levels has been less well-studied in postoperative settings.

Materials and methods

A total of 122 stage I-III CRC patients were retrospectively enrolled. Serum levels of CRP, PCT and IL-6 were measured after surgery, and their prognostic value was evaluated. Kaplan-Meier analysis was used to determine the differences in disease-free survival (DFS) and overall survival (OS) between patients with different levels of these mediators, and the Cox proportional hazards model was used to estimate the risk factors.

Results

In contrast to CRP and PCT, only the level of IL-6 was significant in predicting DFS (P = 0.01) but not OS (P = 0.07). A total of 66.39% (81/122) of patients were assigned to the low IL-6 group and no significant differences were found in the collected clinicopathological parameters among the low or high IL-6 subgroups. The level of IL-6 was negatively correlated with postoperative (1 w) (R=-0.24, P = 0.02) absolute lymphocyte counts. Patients with low levels of IL-6 had better DFS (log rank = 6.10, P = 0.01) but not OS (log rank = 2.28, P = 0.13). Finally, the level of IL-6 was an independent risk factor for DFS (HR: 1.81, 95% CI: 1.03–3.15, P = 0.04).

Conclusions

Compared to CRP and PCT, the level of IL-6 was observed to be the only significant factor in predicting the prognosis of stage I-III CRC patients after surgery, and a low level of IL-6 was associated with good DFS.

Peer Review reports

Introduction

It has long been established that inflammation plays a critical role in cancer development, such as by facilitating the proliferation and survival of malignant cells and by promoting important biological processes such as angiogenesis and migration [1, 2]. Colorectal cancer (CRC), which exhibits increased mobility and mortality rates according to the latest statistics [3], is still a serious health problem worldwide. Previously, a substantial number of studies have indicated that inflammation-related mediators, such as C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), play an important role in the prediction of CRC prognosis.

Interestingly, most previous studies have explored the prognostic value of CRP, PCT and IL-6 levels individually for CRC in the preoperative setting [4, 5] and have yielded inconsistent results when considered together. For example, the study by Groblewska et al. indicated that CRP was the only independent risk factor for survival when compared to IL-6 [6]; in contrast, the study by Lee et al. suggested that IL-6 but not CRP, was an independent risk factor for disease-free survival (DFS) in stage III patients [7]. In addition, the study by Kwon et al. work suggested that both CRP and IL-6 were not independent risk factors for DFS or overall survival (OS) [8]. In recent years, a group of new CRC prognostic markers based on inflammatory cells have been identified; these examples include the neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ratio (LMR), and longitudinal measurements of these markers have suggested that they may be more meaningful when they were analyzed in postoperative settings [9, 10]. For CRP, PCT and IL-6, it is notable that many factors can cause changes in their levels during tumor removal, including surgical stress [11,12,13] and anesthesia [14, 15]. However, only a few studies have investigated their prognostic role concurrently in postoperative scenarios. For example, Hermunen et al. conducted a post hoc analysis for 147 patients (stages II-IV) in the phase III LIPSYT study and found that both postoperative CRP and IL-6 were significant for survival (CRP was a risk factor for DFS but not OS, and IL-6 showed opposite results) but with a low sensitivity (CRP: 20%, IL-6: 28% for DFS) [16]. Hua et al. performed a study with 306 stage II-III patients and found that IL-6 was the most promising prognostic marker in contrast with CRP [17]. Nonetheless, reports that concurrently explore the prognostic value of postoperative CRP, PCT and IL-6 levels in CRC are still lacking.

Based on this background, we aimed to concurrently examine the usefulness of postoperative CRP, PCT and IL-6 levels in determining the prognosis of stage I-III CRC.

Methods

Patient enrollment

Patients who underwent radical resection of colorectal adenocarcinoma from December 2012 to October 2020 at Hainan Hospital of PLA General Hospital were retrospectively enrolled. Patients who met any of the following criteria were not included: (1) accepted neoadjuvant therapies; (2) lacked any of the results of CRP, PCT and IL-6 levels within 7 days (d) (median 1 d; range:1–7 d) after surgery or routine blood tests in the subsequent 7 d and 2 weeks (w) to 3 months (m); (3) lacked any pathological TNM information or stage IV according to the 7th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual; and (4) lost to follow-up. Other clinicopathological parameters were registered as described previously [18, 19]. The study was carried out in accordance with the principles stated in the Declaration of Helsinki and was approved by the ethics committee of Hainan Hospital of PLA General Hospital and the requirement for written informed consent was waived due to its retrospective nature.

Routine blood tests and measurements of the target indicators

Routine laboratory tests and the method to measure blood cell fractions were performed as described previously [19, 20]. The CRP (reference: 0-0.5 mg/dl) was measured by using turbidimetric inhibition immunoassay with the CRPL3 kit (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer’s manual with the automatic analysis system (Cobas e 501, Roche, Switzerland). In addition, PCT (reference: <0.05 ng/ml) and IL-6 (reference: 0–7 pg/ml) were measured via chemiluminescence with the Elecsys BRAHMS PCT kit and Elecsys IL-6 kit (Roche Diagnostics GmbH, Mannheim, Germany) according to the manufacturer’s manual with the automatic analysis system (Cobas e 601 and Cobas e 801, Roche, Switzerland, respectively). The NLR and LMR were calculated as described previously [21].

Endpoints

The follow-up was started immediately after resection according to the procedure described previously [19]. DFS and OS were set as the endpoints for the current study, and DFS was estimated from the time of operation to the time of any recurrence or metastasis or death from any cause; in addition, OS was estimated from the time of operation to the time of death from any cause. The latest follow-up point ended in December 2021.

Statistical analysis

The significance of CRP, PCT and IL-6 in predicting survival was determined by using the receiver operating characteristic curve (ROC), and patients were then divided into low or high subgroups based on the optimal discriminator points when it was statistically significant. Differences in the collected clinicopathological parameters among these subgroups were analyzed via χ2-test or Student’s t test. Correlations of the levels of markers with the ALCs were estimated by using the Pearson or Spearman (when any of the parameters did not meet the Gaussian distribution) correlation coefficients. Moreover, differences in DFS and OS among these subgroups were calculated via Kaplan-Meier analysis. Risk factors for DFS and OS were determined by using the Cox proportional hazards model (with the iterative forward LR method). The statistical analyses were performed by using SPSS 20.0 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA, USA). Two-sided P < 0.05 was regarded to be statistically significant.

Results

General features of the study cohort and the prognostic significance of CRP, PCT and IL-6

A total of 122 patients were enrolled in the study. There were 44 female and 78 male patients, with a median age of 64 years (y) (range: 26–86 y) and a median follow-up of 44 m (1-108 m). At the end of the follow-up, 52 events were observed with 39 deaths (1 stage I patient, 12 stage II patients and 26 stage III patients). As shown in Fig. 1, in contrast to CRP and PCT, only the level of IL-6 was found to be significant in predicting DFS (area under the curve [AUC] = 0.62, 95% CI: 0.52–0.73, P = 0.02) but not OS (AUC = 0.60, 95% CI: 0.49–0.71, P = 0.07). The optimal discriminator point for IL-6 in predicting DFS was 70.27 pg/ml, and 66.39% (81/122) of patients were then assigned to the low IL-6 group (< 70.27 pg/ml) and 33.61% (41/122) of patients were assigned to the high IL-6 group (≥ 70.27 pg/ml). In addition, no differences were found for the collected clinicopathological parameters among the low or high IL-6 subgroups (Table 1).

Fig. 1
figure 1

ROC results of CRP, PCT and IL-6 in predicting DFS (A) and OS (B)

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Table 1 Comparison of the clinicopathological features among low or high level IL-6 subgroups
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Correlation of IL-6 with ALCs

By using the Spearman correlation analysis (Fig. 2), no significant correlations were observed for the level of IL-6 with the ALCs both preoperatively (R=-0.13, P = 0.15) and postoperatively at 2 w-3 m (R=-0.06, P = 0.49); however, a significant correlation was found for the level of IL-6 with the ALCs postoperatively (1 w) (R=-0.21, P = 0.02). Furthermore, significant positive correlations were observed between the levels of IL-6 and CRP (R = 0.52, P < 0.01) and PCT (R = 0.47, P < 0.01).

Fig. 2
figure 2

Correlation of postoperative IL-6 level with preoperative (A), postoperative (1 w) (B), (2 w-3 m) (C) absolute lymphocyte counts

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Survival differences among low or high IL-6 subgroups

According to the Kaplan-Meier analysis (Fig. 3), patients in the low level IL-6 group had significantly superior DFS (log rank = 6.10, P = 0.01) compared with the high level group; however, no such difference was found in OS (log rank = 2.28, P = 0.13).

Fig. 3
figure 3

Survival differences for DFS (A) and OS (B) among low- or high-level IL-6 subgroups

Full size image

Risk factors determined by univariate and multivariate tests

By using the univariate tests, parameters including type of operation, N stage and TNM stage were demonstrated to be risk factors for both DFS and OS, whereas gender, history of drinking and IL-6 level were found to be additional risk factors for DFS (Table 2). Furthermore, when these factors were entered into the multivariate tests, the IL-6 level was found to be an independent risk factor for DFS (HR = 2.24, 95% CI: 1.19–4.21, P = 0.01) but not OS (Table 3).

Table 2 Risk factor determination by univariate analysis for DFS or OS
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Table 3 Risk factor determination by multivariate analysis for DFS or OS
Full size table

Discussion

In this study, we demonstrated that only the postoperative level of IL-6 was a useful prognostic marker in CRC in contrast to CRP and PCT. Patients with a relatively low level of IL-6 had significantly superior survival to those with a high level, and IL-6 was an independent risk factor for DFS. To the best of our knowledge, this is the first report to concurrently compare the prognostic value of CRP, PCT and IL-6 in CRC.

Previously, the prognostic values of CRP, PCT and IL-6 have been individually explored in CRC in preoperative settings; however, only a few studies have been conducted in postoperative settings [22,23,24,25,26,27]. For example, McSorley et al. conducted a study with 377 stage 0-III patients and found that postoperative CRP > 150 mg/L at 4 d was independently associated with poor DFS [22]; in addition, other studies have also indicated that postoperative CRP could be useful in predicting DFS [23,24,25] or OS [26]. In addition, Bae et al. performed a study with 248 stage I-IV patients and found that postoperative PCT was a risk factor for OS; however, it was not an independent factor [27]. Notably, no reports to date have explored the role of postoperative IL-6 alone. Interestingly, two reports have concurrently explored these markers (CRP and IL-6), as mentioned previously [16, 17], but with several limitations. One study included stage IV patients [16], who exhibited different survival rates than others [28], and the other study included patients who received additional treatments (such as radiation and chemotherapy) except for surgery [17]. In our study, we included stage I-III patients who underwent surgery alone and concurrently compared the prognostic value of CRP, PCT and IL-6. The results indicated that IL-6 was significant in predicting DFS, which was partially consistent with these reports [16, 17]. Furthermore, we did not identify any significant differences in the collected clinicopathological parameters, including gender, history of smoking, and BMI, among the low or high level IL-6 subgroups, which was also partially consistent with the results of a previous study [17].

It was notable that the prognostic efficacy of CRP and PCT in CRC was inferior to that of IL-6 in the postoperative scenario in our study. In fact, although previous studies have indicated that CRP and PCT were correlated with the outcome either preoperatively [4, 29,30,31] or postoperatively [23,24,25,26,27] in CRC, there have also been studies suggesting that these factors would be more useful in predicting infective complications [12, 32,33,34] and may not be associated with disease recurrence [33] or outcome [7, 34,35,36,37]. Moreover, one study indicated that IL-6 was the only independent risk factor for survival in contrast to CRP [7]. Additionally, although it was observed that CRP and IL-6 increased within 4 and 24 h, respectively, after the operation [38], CRP normalized within 10 d, but IL-6 did not, which was particularly evident in patients with significantly high preoperative levels [39]. These studies may support the notion that IL-6 would be more robust in predicting survival in CRC to some extent.

Generally, circulating IL-6 levels were found to correlate with systemic inflammatory responses in CRC patients undergoing surgery [40], and it has broad functions in CRC development, such as in promoting tumor growth [41], spreading [42], and angiogenesis [43], as well as in regulating treatment resistance [44, 45]. In recent years, cancer dissemination was found to occur at the very beginning of the disease in CRC [46]. These detached cells, which are also known as circulating tumor cells (CTCs), play a pivotal role in disease recurrence and treatment failure [47, 48]. Interestingly, systemic inflammation can contribute to the metastatic colonization of CTCs [49]. Based on these facts, it is plausible that patients with a surge in IL-6 after surgery are at high risk of cancer metastasis, and these patients can exhibit poor outcomes. Additionally, cancer stem cells (CSCs) were identified as the “true bad seeds” in CRC [50] and are considered to be the source of cancer initiation, recurrence and treatment resistance [51]. Notably, some studies have indicated that a proportion of CTCs are actually CSCs [52, 53], and IL-6 was found to be involved in the expansion [54, 55], promotion [56] and support [57] of these cells. Thus, we speculate that high levels of IL-6 can contribute to the evolution of these CSCs and can also result in poor patient survival. In addition, it was observed that lymphocyte counts as well as T-cell subset counts significantly decline in CRC patients after surgery [38]; additionally, some subsets, such as CD8 + cytotoxic T-lymphocytes, are important in recognizing CSCs [58] and are closely correlated with prognosis [59]. Interestingly, it was also reported that inflammatory conditions not only resulted in a decreased proportion of circulating lymphocytes (although not reported in CRC) [60, 61] but also impaired the anticancer function induced by these cytokines [62]. In our study, the level of IL-6 was observed to be negatively correlated with the ALCs, and although such a correlation seems temporary, it would also partially support its role in survival. Additionally, numerous studies have validated the prognostic value of preoperative inflammation-related markers such as the NLR and LMR in CRC, and it has been generally suggested that a high NLR or a low LMR correlates with poor survival in patients [63,64,65,66]. Interestingly, an increasing number of reports have also postoperatively explored the prognostic value of these markers. For example, in a study with 176 stage II cases, Hayama et al. found that postoperative (7 d after surgery) high NLR is a significant independent indicator for shortened relapse-free survival (RFS) [10]; furthermore, in a study with 568 stage III cases, Yasui et al. found that postoperative NLR and LMR were more accurate in predicting RFS or OS in contrast to preoperative factors [9]. In our study, no prognostic value was observed for either NLR or LMR (both preoperatively and postoperatively), which is possibly due to the small sample size, as in previous studies [67,68,69]. Furthermore, we also demonstrated no correlation of the postoperative IL-6 level with the NLR or LMR (data not shown); thus, its role in prognosis cannot be explained by these markers. We advocate that a larger sample study should be conducted to validate these findings in the future.

Our study has some clinical implications. First, when considering that the bowel is the source of the IL-6 response to surgical trauma in colorectal surgery [70], it is important to select appropriate surgical approaches for these patients. For example, laparoscopic resection is preferred in patients with right-sided lesions due to its advantages in reducing trauma and the systemic inflammatory response [71]. Second, for patients with an obviously high postoperative IL-6 level, it is important to tailor the treatment strategies due to the notorious role of IL-6 in treatment resistance [46, 47] and other functions [41,42,43]. Third, colorectal adenoma was regarded as a risk factor for CRC [72] and was detected in 7.4–52.5% of patients under colonoscopy [73]; in addition, it was also found that up to 39.4% of CRC patients can develop adenomas in postoperative surveillance [74, 75]. Interestingly, IL-6 was observed to be significantly elevated in patients with colorectal adenoma [76], and a decrease in IL-6 was negatively associated with high-risk and advanced adenoma recurrence in a previous study [77]. Based on these facts, it is important in the clinical setting to screen colorectal adenomas in CRC patients with a high postoperative level of IL-6. There were also some other limitations to our study. First, this study included a limited sample and was retrospectively conducted, and many other factors can bias the results. Second, although a long duration of high postoperative IL-6 levels was observed in CRC patients after surgery, the level of IL-6 normalized at approximately 43 d in most cases [39]. Therefore, it would be more valid to comprehensively analyze the value of these different time points in the clinical setting.

Conclusion

Overall, our results suggested that in contrast to CRP and PCT, in postoperative settings, only IL-6 was found to be a significant prognostic factor, and patients with a lower IL-6 level could have a good DFS. However, more studies with large samples are still needed to validate our findings in the future.

Data Availability

The datasets generated or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.

    Article  CAS  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–64.

    Article  PubMed  Google Scholar 

  4. Fuglestad AJ, Meltzer S, Ree AH, McMillan DC, Park JH, Kersten C. The clinical value of C-reactive protein and its association with tumour location in patients undergoing curative surgery for colorectal cancer-a ScotScan collaborative study. Acta Oncol. 2022;61(10):1248–55.

    Article  CAS  PubMed  Google Scholar 

  5. Miyake T, Iida H, Shimizu T, Ueki T, Kojima M, Ohta H, et al. The elevation in preoperative procalcitonin is associated with a poor prognosis for patients undergoing resection for colorectal cancer. Dig Surg. 2021;38(1):80–6.

    Article  CAS  PubMed  Google Scholar 

  6. Groblewska M, Mroczko B, Wereszczyńska-Siemiatkowska U, Kedra B, Lukaszewicz M, Baniukiewicz A, et al. Serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels in colorectal adenoma and cancer patients. Clin Chem Lab Med. 2008;46(10):1423–8.

    Article  CAS  PubMed  Google Scholar 

  7. Lee WS, Baek JH, You DH, Nam MJ. Prognostic value of circulating cytokines for stage III colon cancer. J Surg Res. 2013;182(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  8. Kwon KA, Kim SH, Oh SY, Lee S, Han JY, Kim KH, et al. Clinical significance of preoperative serum vascular endothelial growth factor, interleukin-6, and C-reactive protein level in colorectal cancer. BMC Cancer. 2010;10:203.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yasui K, Shida D, Nakamura Y, Ahiko Y, Tsukamoto S, Kanemitsu Y. Postoperative, but not preoperative, inflammation-based prognostic markers are prognostic factors in stage III colorectal cancer patients. Br J Cancer. 2021;124(5):933–41.

    Article  CAS  PubMed  Google Scholar 

  10. Hayama T, Hashiguchi Y, Okada Y, Ono K, Nemoto K, Shimada R, et al. Significance of the 7th postoperative day neutrophil-to-lymphocyte ratio in colorectal cancer. Int J Colorectal Dis. 2020;35(1):119–24.

    Article  PubMed  Google Scholar 

  11. Takakura Y, Hinoi T, Egi H, Shimomura M, Adachi T, Saito Y, et al. Procalcitonin as a predictive marker for surgical site infection in elective colorectal cancer surgery. Langenbecks Arch Surg. 2013;398(6):833–9.

    Article  PubMed  Google Scholar 

  12. Domínguez-Comesaña E, Estevez-Fernández SM, López-Gómez V, Ballinas-Miranda J, Domínguez-Fernández R. Procalcitonin and C-reactive protein as early markers of postoperative intra-abdominal infection in patients operated on colorectal cancer. Int J Colorectal Dis. 2017;32(12):1771–4.

    Article  PubMed  Google Scholar 

  13. Galizia G, Orditura M, Romano C, Lieto E, Castellano P, Pelosio L, et al. Prognostic significance of circulating IL-10 and IL-6 serum levels in colon cancer patients undergoing surgery. Clin Immunol. 2002;102(2):169–78.

    Article  CAS  PubMed  Google Scholar 

  14. Ding S, Ma H, Wang G, Yu Z, Li K, Huang A. Effect of remifentanil combined anesthesia on cytokines and oxidative stress in patients undergoing laparoscopic surgery for colon cancer. J Coll Physicians Surg Pak. 2019;29(1):8–11.

    Article  PubMed  Google Scholar 

  15. Margarit SC, Vasian HN, Balla E, Vesa S, Ionescu DC. The influence of total intravenous anaesthesia and isoflurane anaesthesia on plasma interleukin-6 and interleukin-10 concentrations after colorectal surgery for cancer: a randomised controlled trial. Eur J Anaesthesiol. 2014;31(12):678–84.

    Article  CAS  PubMed  Google Scholar 

  16. Hermunen K, Soveri LM, Boisen MK, Mustonen HK, Dehlendorff C, Haglund CH, et al. Postoperative serum CA19-9, YKL-40, CRP and IL-6 in combination with CEA as prognostic markers for recurrence and survival in colorectal cancer. Acta Oncol. 2020;59(12):1416–23.

    Article  CAS  PubMed  Google Scholar 

  17. Hua X, Kratz M, Malen RC, Dai JY, Lindström S, Zheng Y, et al. Association between post-treatment circulating biomarkers of inflammation and survival among stage II-III colorectal cancer patients. Br J Cancer. 2021;125(6):806–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xu R, You JH, Li F, Yan B. Postoperative fasting blood glucose predicts prognosis in stage I-III colorectal cancer patients undergoing resection. Gastroenterol Res Pract. 2020;2020:2482409.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhang Y, Liu Y, Qiu X, Yan B. Concurrent comparison of the prognostic values of tumor budding, tumor stroma ratio, tumor infiltrating pattern and lymphocyte-to-monocyte ratio in colorectal cancer patients. Technol Cancer Res Treat. 2021;20:15330338211045826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang X, Huan Y, Liu L, Ye Q, Guo J, Yan B. Preoperative low absolute lymphocyte count to fibrinogen ratio correlated with poor survival in nonmetastatic colorectal cancer. World J Surg Oncol. 2022;20(1):309.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hailun Xie, Huang S, Yuan G, Tang S, Gan J. Prognostic significance of preoperative fibrinogen-to-prealbumin ratio in patients with stage I-III colorectal cancer undergoing surgical resection: a retrospective cohort study. Biomed Res Int. 2021;2021:3905353.

    Google Scholar 

  22. McSorley ST, Watt DG, Horgan PG, McMillan DC. Postoperative systemic inflammatory response, complication severity, and survival following surgery for colorectal cancer. Ann Surg Oncol. 2016;23(9):2832–40.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yamamoto M, Saito H, Uejima C, Tanio A, Takaya S, Sakamoto T, et al. Prognostic value of the combination of pre- and postoperative C-reactive protein in colorectal cancer patients. Surg Today. 2018;48(11):986–93.

    Article  CAS  PubMed  Google Scholar 

  24. Matsubara D, Arita T, Nakanishi M, Kuriu Y, Murayama Y, Kudou M, et al. The impact of postoperative inflammation on recurrence in patients with colorectal cancer. Int J Clin Oncol. 2020;25(4):602–13.

    Article  CAS  PubMed  Google Scholar 

  25. Nakamura Y, Yamaura T, Kinjo Y, Kawase M, Kanto S, Kuroda N. Impact of severe postoperative inflammatory response on recurrence after curative resection of colorectal cancer. Int J Colorectal Dis. 2022;37(11):2375–86.

    Article  PubMed  Google Scholar 

  26. Aoki S, Migita K, Ueno M, Yasuda S, Fujimoto K, Doi S, et al. Postoperative serum C-reactive protein level predicts long-term outcomes in colorectal cancer patients. Gan To Kagaku Ryoho. 2020;47(13):2113–6.

    PubMed  Google Scholar 

  27. Bae JH, Lee CS, Han SR, Park SM, Lee YS, Lee IK. Differences in the prognostic impact of post-operative systemic inflammation and infection in colorectal cancer patients: using white blood cell counts and procalcitonin levels. Surg Oncol. 2020;35:374–81.

    Article  PubMed  Google Scholar 

  28. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352(5):476–87.

    Article  CAS  PubMed  Google Scholar 

  29. Li C, Xu Q, Chen L, Luo C, Ying J, Liu J. C-reactive protein (CRP) as a prognostic factor for colorectal cancer after surgical resection of pulmonary metastases. Bull Cancer. 2017;104(3):232–6.

    Article  PubMed  Google Scholar 

  30. Woo HD, Kim K, Kim J. Association between preoperative C-reactive protein level and colorectal cancer survival: a meta-analysis. Cancer Causes Control. 2015;26(11):1661–70.

    Article  PubMed  Google Scholar 

  31. Shibutani M, Maeda K, Nagahara H, Ohtani H, Sugano K, Ikeya T, et al. Elevated preoperative serum C-reactive protein levels are associated with poor survival in patients with colorectal cancer. Hepatogastroenterology. 2014;61(136):2236–40.

    PubMed  Google Scholar 

  32. Platt JJ, Ramanathan ML, Crosbie RA, Anderson JH, McKee RF, Horgan PG, et al. C-reactive protein as a predictor of postoperative infective complications after curative resection in patients with colorectal cancer. Ann Surg Oncol. 2012;19(13):4168–77.

    Article  PubMed  Google Scholar 

  33. Park BS, Cho SH, Lee SH, Son GM, Kim HS. Role of C-reactive protein, white blood cell counts, and serum glucose levels as early predictors of infectious complications after laparoscopic colorectal surgery for colorectal cancer. Am Surg. 2022:31348221135786.

  34. Keramidaris D, Koronakis N, Lagoudianakis EE, Pappas A, Koukoutsis I, Chrysikos I, et al. Procalcitonin in patients with colorectal cancer. J BUON. 2013;18(3):623–8.

    CAS  PubMed  Google Scholar 

  35. Fujii T, Yajima R, Tabe Y, Yamaguchi S, Tsutsumi S, Asao T, et al. Elevated C-reactive protein is associated with the tumor depth of invasion but not with disease recurrence in stage II and III colorectal cancer. Hepatogastroenterology. 2013;60(126):1343–7.

    CAS  PubMed  Google Scholar 

  36. Swede H, Hajduk AM, Sharma J, Rawal S, Rasool H, Vella AT. Baseline serum C-reactive protein and death from colorectal cancer in the NHANES III cohort. Int J Cancer. 2014;134(8):1862–70.

    Article  CAS  PubMed  Google Scholar 

  37. Hua X, Dai JY, Lindström S, Harrison TA, Lin Y, Alberts SR, et al. Genetically predicted circulating c-reactive protein concentration and colorectal cancer survival: a mendelian randomization consortium study. Cancer Epidemiol Biomarkers Prev. 2021;30(7):1349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mehigan BJ, Hartley JE, Drew PJ, Saleh A, Dore PC, Lee PW, et al. Changes in T cell subsets, interleukin-6 and C-reactive protein after laparoscopic and open colorectal resection for malignancy. Surg Endosc. 2001;15(11):1289–93.

    Article  CAS  PubMed  Google Scholar 

  39. Kamińska J, Kowalska MM, Nowacki MP, Chwaliński MG, Rysińska A, Fuksiewicz M. CRP, TNF-alpha, IL-1ra, IL-6, IL-8 and IL-10 in blood serum of colorectal cancer patients. Pathol Oncol Res. 2000;6(1):38–41.

    Article  PubMed  Google Scholar 

  40. Guthrie GJ, Roxburgh CS, Richards CH, Horgan PG, McMillan DC. Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer. Br J Cancer. 2013;109(1):131–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Becker C, Fantini MC, Wirtz S, Nikolaev A, Lehr HA, Galle PR, et al. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle. 2005;4(2):217–20.

    Article  CAS  PubMed  Google Scholar 

  42. Ashizawa T, Okada R, Suzuki Y, Takagi M, Yamazaki T, Sumi T, et al. Study of interleukin-6 in the spread of colorectal cancer: the diagnostic significance of IL-6. Acta Med Okayama. 2006;60(6):325–30.

    CAS  PubMed  Google Scholar 

  43. Nagasaki T, Hara M, Nakanishi H, Takahashi H, Sato M, Takeyama H. Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour-stroma interaction. Br J Cancer. 2014;110(2):469–78.

    Article  CAS  PubMed  Google Scholar 

  44. Hara M, Nagasaki T, Shiga K, Takahashi H, Takeyama H. High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab. Surg Today. 2017;47(4):483–9.

    Article  CAS  PubMed  Google Scholar 

  45. Li S, Tian J, Zhang H, Zhou S, Wang X, Zhang L, et al. Down-regulating IL-6/GP130 targets improved the anti-tumor effects of 5-fluorouracil in colon cancer. Apoptosis. 2018;23(5–6):356–74.

    Article  CAS  PubMed  Google Scholar 

  46. Hu Z, Ding J, Ma Z, Sun R, Seoane JA, Scott Shaffer J, et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat Genet. 2019;51(7):1113–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peach G, Kim C, Zacharakis E, Purkayastha S, Ziprin P. Prognostic significance of circulating tumour cells following surgical resection of colorectal cancers: a systematic review. Br J Cancer. 2010;102(9):1327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Abdalla TSA, Meiners J, Riethdorf S, König A, Melling N, Gorges T, et al. Prognostic value of preoperative circulating tumor cells counts in patients with UICC stage I-IV colorectal cancer. PLoS ONE. 2021;16(6):e0252897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li YC, Zou JM, Luo C, Shu Y, Luo J, Qin J, et al. Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation. Oncotarget. 2017;8(17):28418–30.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Koren E, Fuchs Y. The bad seed: Cancer stem cells in tumor development and resistance. Drug Resist Updat. 2016;28:1–12.

    Article  PubMed  Google Scholar 

  51. Du L, Cheng Q, Zheng H, Liu J, Liu L, Chen Q. Targeting stemness of cancer stem cells to fight colorectal cancers. Semin Cancer Biol. 2022;82:150–61.

    Article  PubMed  Google Scholar 

  52. Grillet F, Bayet E, Villeronce O, Zappia L, Lagerqvist EL, Lunke S, et al. Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in ex vivo culture. Gut. 2017;66(10):1802–10.

    Article  CAS  PubMed  Google Scholar 

  53. Ning Y, Zhang W, Hanna DL, Yang D, Okazaki S, Berger MD, et al. Clinical relevance of EMT and stem-like gene expression in circulating tumor cells of metastatic colorectal cancer patients. Pharmacogenomics J. 2018;18(1):29–34.

    Article  CAS  PubMed  Google Scholar 

  54. Kim B, Seo Y, Kwon JH, Shin Y, Kim S, Park SJ, et al. IL-6 and IL-8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor. Mol Carcinog. 2021;60(3):188–200.

    Article  CAS  PubMed  Google Scholar 

  55. Di Franco S, Bianca P, Sardina DS, Turdo A, Gaggianesi M, Veschi V, et al. Adipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery. Nat Commun. 2021;12(1):5006.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wang T, Song P, Zhong T, Wang X, Xiang X, Liu Q, et al. The inflammatory cytokine IL-6 induces FRA1 deacetylation promoting colorectal cancer stem-like properties. Oncogene. 2019;38(25):4932–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Huynh PT, Beswick EJ, Coronado YA, Johnson P, O’Connell MR, Watts T, et al. CD90(+) stromal cells are the major source of IL-6, which supports cancer stem-like cells and inflammation in colorectal cancer. Int J Cancer. 2016;138(8):1971–81.

    Article  CAS  PubMed  Google Scholar 

  58. Inoda S, Hirohashi Y, Torigoe T, Morita R, Takahashi A, Asanuma H, et al. Cytotoxic T lymphocytes efficiently recognize human colon cancer stem-like cells. Am J Pathol. 2011;178(4):1805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Katayama C, Yokobori T, Ozawa N, Suga K, Shiraishi T, Okada T, et al. Low level of stromal lectin-like oxidized LDL receptor 1 and CD8 + cytotoxic T-lymphocytes indicate poor prognosis of colorectal cancer. Cancer Rep (Hoboken). 2021;4(4):e1364.

    CAS  PubMed  Google Scholar 

  60. Jewell AP, Worman CP, Giles FJ, Goldstone AH. Serum levels of TNF, IL-6 and sCD23 correlate with changes in lymphocyte count in patients with B-cell chronic lymphocytic leukaemia receiving interferon-alpha therapy. Leuk Lymphoma. 1997;24(3–4):327–33.

    Article  CAS  PubMed  Google Scholar 

  61. Yu Y, Wang S, Su N, Pan S, Tu B, Zhao J, et al. Increased circulating levels of CRP and IL-6 and decreased frequencies of T and B lymphocyte subsets are associated with immune-related adverse events during combination therapy with PD-1 inhibitors for liver cancer. Front Oncol. 2022;12:906824.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Bent EH, Millán-Barea LR, Zhuang I, Goulet DR, Fröse J, Hemann MT. Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy. Nat Commun. 2021;12(1):6218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Naszai M, Kurjan A, Maughan TS. The prognostic utility of pre-treatment neutrophil-to-lymphocyte-ratio (NLR) in colorectal cancer: a systematic review and meta-analysis. Cancer Med. 2021;10(17):5983–97.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gülben K, Berberoğlu U, Öndeş B, Uyar O, Güler OC, Turanlı S. Preoperative neutrophil-to-lymphocyte ratio as a predictive factor for survival in nonmetastatic colorectal cancer. J Cancer Res Ther. 2020;16(Supplement):189–S193.

    Article  Google Scholar 

  65. Wu Q, Hu T, Zheng E, Deng X, Wang Z. Prognostic role of the lymphocyte-to-monocyte ratio in colorectal cancer: an up-to-date meta-analysis. Med (Baltim). 2017;96(22):e7051.

    Article  Google Scholar 

  66. Song W, Wang K, Zhang RJ, Zou SB. Prognostic value of the lymphocyte monocyte ratio in patients with colorectal cancer: a meta-analysis. Med (Baltim). 2016;95(49):e5540.

    Article  Google Scholar 

  67. Shinji S, Ueda Y, Yamada T, Koizumi M, Yokoyama Y, Takahashi G, Hotta M, Iwai T, Hara K, Takeda K, Okusa M, Kan H, Uchida E. Combined use of preoperative lymphocyte counts and the post/preoperative lymphocyte count ratio as a prognostic marker of recurrence after curative resection of stage II colon cancer. Oncotarget. 2017;9(2):2553–64.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Leitch EF, Chakrabarti M, Crozier JE, McKee RF, Anderson JH, Horgan PG, et al. Comparison of the prognostic value of selected markers of the systemic inflammatory response in patients with colorectal cancer. Br J Cancer. 2007;97(9):1266–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cha YJ, Park EJ, Baik SH, Lee KY, Kang J. Clinical significance of tumor-infiltrating lymphocytes and neutrophil-to-lymphocyte ratio in patients with stage III colon cancer who underwent surgery followed by FOLFOX chemotherapy. Sci Rep. 2019;9(1):11617.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Syk I, Mangell P, Bjartell A, Jeppsson B. Systemic interleukin-6 response to colorectal surgery originates from the bowel. Dig Surg. 2002;19(3):210–5.

    Article  CAS  PubMed  Google Scholar 

  71. Zhu P, Miao W, Gu F, Xing C. Changes of serum and peritoneal inflammatory mediators in laparoscopic radical resection for right colon carcinoma. J Minim Access Surg. 2018;15(2):115–8.

    Google Scholar 

  72. Click B, Pinsky PF, Hickey T, Doroudi M, Schoen RE. Association of colonoscopy adenoma findings with long-term colorectal cancer incidence. JAMA. 2018;319(19):2021–31.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Corley DA, Jensen CD, Marks AR, Zhao WK, Lee JK, Doubeni CA, et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. 2014;370(14):1298–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Marques-Antunes J, Libânio D, Gonçalves P, Dinis-Ribeiro M, Pimentel-Nunes P. Incidence and predictors of adenoma after surgery for colorectal cancer. Eur J Gastroenterol Hepatol. 2017;29(8):932–8.

    Article  PubMed  Google Scholar 

  75. Facciorusso A, Di Maso M, Serviddio G, Vendemiale G, Spada C, Costamagna G, et al. Factors associated with recurrence of advanced colorectal adenoma after endoscopic resection. Clin Gastroenterol Hepatol. 2016;14(8):1148–1154e4.

    Article  PubMed  Google Scholar 

  76. Groblewska M, Mroczko B, Wereszczyńska-Siemiatkowska U, Kedra B, Lukaszewicz M, Baniukiewicz A, Szmitkowski M. Serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels in colorectal adenoma and cancer patients. Clin Chem Lab Med. 2008;46(10):1423–8.

    Article  CAS  PubMed  Google Scholar 

  77. Bobe G, Albert PS, Sansbury LB, Lanza E, Schatzkin A, Colburn NH, Cross AJ. Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial. Cancer Prev Res (Phila). 2010;3(6):764–75.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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Funding

This work was supported by Hainan Provincial Natural Science Foundation of China (823MS164) and the Bureau of Huzhou Science and Technology (2020GY13).

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Author notes

  1. Shouhan Feng, Zeshi Li and Mei Liu contribute equally.

Authors and Affiliations

  1. Department of Oncology, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou city of Zhejiang Province, 313000, P.R. China

    Shouhan Feng

  2. Department of Critical Care Medicine, Hainan Hospital of PLA General Hospital, Sanya city of Hainan province, 572000, P.R. China

    Zeshi Li

  3. Department of Tumor Chemotherapy, Haikou People’s Hospital, Haikou city of Hainan province, 570208, P.R. China

    Mei Liu

  4. Department of Oncology, Hainan Hospital of PLA General Hospital, No. 80 of Jianglin Road, Haitang District of Sanya city, Hainan province, 572000, P.R. China

    Qianwen Ye, Tianhui Xue & Bing Yan

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Contributions

BY was responsible for the conception of the work. QY, TX and BY obtained the data. SF and BY analyzed the data. SF, ZL, ML and BY wrote the manuscript. ZL, ML and BY critically revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Bing Yan.

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The study was carried out in accordance with the principles stated in the Declaration of Helsinki and was approved by the ethics committee of Hainan Hospital of PLA General Hospital and the requirement for written informed consent was waived due to its retrospective nature.

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Feng, S., Li, Z., Liu, M. et al. Postoperative serum interleukin-6 levels correlate with survival in stage I-III colorectal cancer. BMC Gastroenterol 23, 156 (2023). https://doi.org/10.1186/s12876-023-02800-9

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Keywords

BMC Gastroenterology

ISSN: 1471-230X

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