BACKGROUND: The aim of this prospective study was to evaluate the role of serum IL-6 as a potential predictive biomarker of postoperative complications (POC) in elective colorectal surgery. METHOD: A total of 115 patients underwent colorectal surgery for malignancy. IL-6 was measured on the first and third postoperative days (POD1, POD3), and C-reactive protein (CRP) was measured on the POD3. POC was analysed in subgroups according to Clavien‒Dindo (CD), antibiotic (ATB) treatment, intensive care unit (ICU) and hospital length of stay. The predictive power of variables for evaluated endpoints was analysed using receiver-operating characteristic (ROC) analysis and described by area under the curve (AUC). ROC analysis was adopted for the identification of optimal cut-offs. Histological analysis was performed to verify IL-6 production by the tumour. RESULTS: Out of 115 patients who were analysed, 42% had POC. Patients with POC had significantly higher serum levels of IL-6 on POD1 (p < 0.001) and POD3 (p < 0.001). IL-6 early on POD1 as a predictor of antibiotic treatment, ICU stay and hospital stay (AUC 0.818; 0.811; 0.771) did not significantly differ from the AUC of CRP late on POD3 (0.879; 0.838, 0.752). A cut-off IL-6 value of 113 pg/ml on POD1 and 180.5 pg/ml on POD3 in severe complications (CD > 3a) resulted in 75% and 72% sensitivity, 78.6% and 99% specificity, negative predictive value 96.4% and 97% and positive predictive value 29% and 88.9%. CONCLUSION: The serum level of interleukin-6 can predict severe (CD > 3a) POC early on POD1. On POD3, IL-6 is superior to CRP in terms of high positive predictive power of severe POC. Interestingly, the advantage of IL-6 on POD1 is early prediction of the need for antibiotic treatment, ICU stay and hospital stay, which is comparable to the CRP serum level late on the third POD.

Department of Clinical Psychology University Hospital Brno Bohunice Brno Czech Republic

Department of Dermatovernereology 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Laboratory Methods Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pathology Faculty of Medicine University Hospital Brno Masaryk University Brno Czech Republic

Department of Surgery Faculty of Medicine University Hospital Brno Bohunice Masaryk University Brno Czech Republic

Division of Clinical Biochemistry Department of Laboratory Medicine University Hospital Brno Brno Czech Republic

Faculty of Medicine Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic

Institute of Anatomy 1st Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Alves A. Postoperative mortality and morbidity in French patients undergoing colorectal surgery: results of a prospective multicenter study. Arch Surg. 2005;140(3):278. doi: 10.1001/archsurg.140.3.278. PubMed DOI

Lacina L, Brábek J, Král V, Kodet O, Smetana K. Interleukin-6: a molecule with complex biological impact in cancer. Histol Histopathol. 2019;34(2):125–136. doi: 10.14670/HH-18-033. PubMed DOI

Španko M, Strnadová K, Pavlíček AJ, et al. IL-6 in the ecosystem of head and neck cancer: possible therapeutic perspectives. Int J Mol Sci. 2021;22(20):11027. doi: 10.3390/ijms222011027. PubMed DOI PMC

Rašková M, Lacina L, Kejík Z, et al. The role of IL-6 in cancer cell invasiveness and metastasis—overview and therapeutic opportunities. Cells. 2022;11(22):3698. doi: 10.3390/cells11223698. PubMed DOI PMC

Vokurka M, Lacina L, Brábek J, Kolář M, Ng YZ, Smetana K. Cancer-associated fibroblasts influence the biological properties of malignant tumours via paracrine secretion and exosome production. Int J Mol Sci. 2022;23(2):964. doi: 10.3390/ijms23020964. PubMed DOI PMC

Kučera J, Strnadová K, Dvořánková B, et al. Serum proteomic analysis of melanoma patients with immunohistochemical profiling of primary melanomas and cultured cells: pilot study. Oncol Rep. Published online September 17, 2019. 10.3892/or.2019.7319 PubMed PMC

Łukaszewicz-Zając M, Mroczko B. Circulating biomarkers of colorectal cancer (CRC)—their utility in diagnosis and prognosis. J Clin Med. 2021;10(11):2391. doi: 10.3390/jcm10112391. PubMed DOI PMC

Brábek J, Jakubek M, Vellieux F, et al. Interleukin-6: molecule in the intersection of cancer, ageing and COVID-19. Int J Mol Sci. 2020;21(21):7937. doi: 10.3390/ijms21217937. PubMed DOI PMC

Goodla L, Xue X. The role of inflammatory mediators in colorectal cancer hepatic metastasis. Cells. 2022;11(15):2313. doi: 10.3390/cells11152313. PubMed DOI PMC

Qi XY, Liu MX, Xu K, et al. Peritoneal cytokines as early biomarkers of colorectal anastomotic leakage following surgery for colorectal cancer: a meta-analysis. Front Oncol. 2022;11:791462. doi: 10.3389/fonc.2021.791462. PubMed DOI PMC

Hogan BV, Peter MB, Shenoy HG, Horgan K, Hughes TA. Surgery induced immunosuppression. Surgeon. 2011;9(1):38–43. doi: 10.1016/j.surge.2010.07.011. PubMed DOI

Castellheim A, Brekke OL, Espevik T, Harboe M, Mollnes TE. Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol. 2009;69(6):479–491. doi: 10.1111/j.1365-3083.2009.02255.x. PubMed DOI

Meisel C, Meisel A. Suppressing immunosuppression after stroke. N Engl J Med. 2011;365(22):2134–2136. doi: 10.1056/NEJMcibr1112454. PubMed DOI

Bouras M, Roquilly A, Mahé PJ, et al. Cortisol total/CRP ratio for the prediction of hospital-acquired pneumonia and initiation of corticosteroid therapy in traumatic brain-injured patients. Crit Care. 2019;23(1):394. doi: 10.1186/s13054-019-2680-6. PubMed DOI PMC

Mokart D, Capo C, Blache JL, et al. Early postoperative compensatory anti-inflammatory response syndrome is associated with septic complications after major surgical trauma in patients with cancer. Br J Surg. 2002;89(11):1450–1456. doi: 10.1046/j.1365-2168.2002.02218.x. PubMed DOI

Rettig TCD, Verwijmeren L, Dijkstra IM, Boerma D, van de Garde EMW, Noordzij PG. Postoperative interleukin-6 level and early detection of complications after elective major abdominal surgery. Ann Surg. 2016;263(6):1207–1212. doi: 10.1097/SLA.0000000000001342. PubMed DOI

Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. 10.1245/s10434-010-0985-4 PubMed

Pox C, Aretz S, Bischoff S, et al. S3-Leitlinie Kolorektales Karzinom Version 1.0 - Juni 2013 AWMF-Registernummer: 021/007OL. Z Für Gastroenterol. 2013;51(08):753–854. doi: 10.1055/s-0033-1350264. PubMed DOI

Rectal Cancer NCCN Guidelines. National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/default.aspx#rectal

Svoboda M, Procházka V, Grolich T, Pavlík T, Mazalová M, Kala Z. Does pathological complete response after neoadjuvant therapy influence postoperative morbidity in rectal cancer after transanal total mesorectal excision? J Gastrointest Cancer. Published online May 7, 2022. 10.1007/s12029-022-00826-y PubMed

Tejedor P, Francis N, Jayne D, et al. Consensus statements on complete mesocolic excision for right-sided colon cancer—technical steps and training implications. Surg Endosc. 2022;36(8):5595–5601. doi: 10.1007/s00464-021-08395-0. PubMed DOI PMC

Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–213. doi: 10.1097/01.sla.0000133083.54934.ae. PubMed DOI PMC

Fan J, Upadhye S, Worster A. Understanding receiver operating characteristic (ROC) curves. CJEM. 2006;8(01):19–20. doi: 10.1017/S1481803500013336. PubMed DOI

Joliat GR, Schoor A, Schäfer M, Demartines N, Hübner M, Labgaa I. Postoperative decrease of albumin (ΔAlb) as early predictor of complications after gastrointestinal surgery: a systematic review. Perioper Med. 2022;11(1):7. doi: 10.1186/s13741-022-00238-3. PubMed DOI PMC

Wang H, Yang R, Xu J, Fang K, Abdelrahim M, Chang L. Sarcopenia as a predictor of postoperative risk of complications, mortality and length of stay following gastrointestinal oncological surgery. Ann R Coll Surg Engl. 2021;103(9):630–637. doi: 10.1308/rcsann.2021.0082. PubMed DOI PMC

Cazelles A, Giacca M, Monsinjon M, Hain E, Frontali A, Panis Y. Monitoring of C-reactive protein decreases length of stay after laparoscopic total mesorectal excision for cancer: a prospective case-matched study in 236 patients. Colorectal Dis. 2021;23(5):1158–1166. doi: 10.1111/codi.15573. PubMed DOI

Stephensen BD, Reid F, Shaikh S, Carroll R, Smith SR, Pockney P. C-reactive protein trajectory to PREDICT colorectal anastomotic leak: PREDICT study. Br J Surg. 2020;107(13):1832–1837. doi: 10.1002/bjs.11812. PubMed DOI

Warschkow R, Beutner U, Steffen T, et al. Safe and early discharge after colorectal surgery due to C-reactive protein: a diagnostic meta-analysis of 1832 patients. Ann Surg. 2012;256(2):245–250. doi: 10.1097/SLA.0b013e31825b60f0. PubMed DOI

El Zaher HA, Ghareeb WM, Fouad AM, et al. Role of the triad of procalcitonin, C-reactive protein, and white blood cell count in the prediction of anastomotic leak following colorectal resections. World J Surg Oncol. 2022;20(1):33. doi: 10.1186/s12957-022-02506-4. PubMed DOI PMC

Su’a BU, Mikaere HL, Rahiri JL, Bissett IB, Hill AG. Systematic review of the role of biomarkers in diagnosing anastomotic leakage following colorectal surgery. Br J Surg. 2017;104(5):503–512. doi: 10.1002/bjs.10487. PubMed DOI

Holmgren K, Jonsson P, Lundin C, et al. Preoperative biomarkers related to inflammation may identify high-risk anastomoses in colorectal cancer surgery: explorative study. BJS Open. 2022;6(3):zrac072. doi: 10.1093/bjsopen/zrac072. PubMed DOI PMC

Ellebæk MB, Baatrup G, Gjedsted J, Fristrup C, Qvist N. Cytokine response in peripheral blood indicates different pathophysiological mechanisms behind anastomotic leakage after low anterior resection: a pilot study. Tech Coloproctology. 2014;18(11):1067–1074. doi: 10.1007/s10151-014-1204-2. PubMed DOI

Alonso S, Pascual M, Salvans S, et al. Postoperative intra-abdominal infection and colorectal cancer recurrence: a prospective matched cohort study of inflammatory and angiogenic responses as mechanisms involved in this association. Eur J Surg Oncol EJSO. 2015;41(2):208–214. doi: 10.1016/j.ejso.2014.10.052. PubMed DOI

Slotwiński R, Olszewski WL, Chaber A, Slodkowski M, Zaleska M, Krasnodebski IW. The soluble tumor necrosis factor receptor I is an early predictor of local infective complications after colorectal surgery. J Clin Immunol. 2002;22(5):289–296. doi: 10.1023/a:1020022006043. PubMed DOI

Reisinger KW, Poeze M, Hulsewé KWE, et al. Accurate prediction of anastomotic leakage after colorectal surgery using plasma markers for intestinal damage and inflammation. J Am Coll Surg. 2014;219(4):744–751. doi: 10.1016/j.jamcollsurg.2014.06.011. PubMed DOI

Boersema GSA, Wu Z, Menon AG, Kleinrensink GJ, Jeekel J, Lange JF. Systemic inflammatory cytokines predict the infectious complications but not prolonged postoperative ileus after colorectal surgery. Mediators Inflamm. 2018;2018:1–9. doi: 10.1155/2018/7141342. PubMed DOI PMC

Zawadzki M, Krzystek-Korpacka M, Gamian A, Witkiewicz W. Serum cytokines in early prediction of anastomotic leakage following low anterior resection. Videosurgery Miniinvasive Tech. 2018;13(1):33–43. doi: 10.5114/wiitm.2018.72785. PubMed DOI PMC

Zielińska-Borkowska U, Dib N, Tarnowski W, Skirecki T. Monitoring of procalcitonin but not interleukin-6 is useful for the early prediction of anastomotic leakage after colorectal surgery. Clin Chem Lab Med CCLM. 2017;55(7). 10.1515/cclm-2016-0736 PubMed

Sammour T, Singh PP, Zargar-Shoshtari K, Su’a B, Hill AG. Peritoneal cytokine levels can predict anastomotic leak on the first postoperative day. Dis Colon Rectum. 2016;59(6):551–556. doi: 10.1097/DCR.0000000000000598. PubMed DOI

Xie T, Zhao C, Ding C, et al. Postoperative interleukin-6 predicts intra-abdominal septic complications at an early stage after elective intestinal operation for Crohn’s disease patients. Inflamm Bowel Dis. 2018;24(9):1992–2000. doi: 10.1093/ibd/izy090. PubMed DOI

Dolin T, Christensen I, Johansen A, et al. Pre- and perioperative inflammatory biomarkers in older patients resected for localized colorectal cancer: associations with complications and prognosis. Cancers. 2021;14(1):161. doi: 10.3390/cancers14010161. PubMed DOI PMC

Nakagoe T, Tsuji T, Sawai T, et al. Increased serum levels of interleukin-6 in malnourished patients with colorectal cancer. Cancer Lett. 2003;202(1):109–115. doi: 10.1016/j.canlet.2003.09.008. PubMed DOI

Murdaca G, Paladin F, Casciaro M, Vicario CM, Gangemi S, Martino G. Neuro-inflammaging and psychopathological distress. Biomedicines. 2022;10(9):2133. doi: 10.3390/biomedicines10092133. PubMed DOI PMC

Gonçalves RS dos SA, Maciel ÁCC, Rolland Y, Vellas B, De Souto Barreto P. Frailty biomarkers under the perspective of GeroScience: a narrative review. Ageing Res Rev. 2022;81:101737. doi: 10.1016/j.arr.2022.101737. PubMed DOI

Li H, Qiu L, Liu Q, et al. Senescent fibroblasts generate a CAF phenotype through the Stat3 pathway. Genes. 2022;13(9):1579. doi: 10.3390/genes13091579. PubMed DOI PMC

Su’a B, Milne T, Jaung R, et al. Detection of anastomotic leakage following elective colonic surgery: results of the prospective biomarkers and anastomotic leakage (BALL) study. J Surg Res. 2022;273:85–92. doi: 10.1016/j.jss.2021.12.019. PubMed DOI