Effects of preoperative recombinant Interleukin 2-based immunomodulation on outcome after gastrointestinal cancer surgery: a systematic review and meta-analysis

Effects of preoperative recombinant Interleukin 2-based immunomodulation on outcome after gastrointestinal cancer surgery: a systematic review and meta-analysis

  • International Surgical Outcomes Study Group. Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries. Br J Anaesth. 2016;117:601–9.

    Article 

    Google Scholar
     

  • Fortun J, Martin-Davila P, Pascual J, Cervera C, Moreno A, Gavalda J, et al. Immunosuppressive therapy and infection after kidney transplantation. Transpl Infect Dis. 2010;12:397–405.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van Kooten RT, Bahadoer RR, Peeters K, Hoeksema JHL, Steyerberg EW, Hartgrink HH, et al. Preoperative risk factors for major postoperative complications after complex gastrointestinal cancer surgery: a systematic review. Eur J Surg Oncol. 2021;47:3049–58.

    Article 
    PubMed 

    Google Scholar
     

  • Paun BC, Cassie S, MacLean AR, Dixon E, Buie WD. Postoperative complications following surgery for rectal cancer. Ann Surg. 2010;251:807–18.

    Article 
    PubMed 

    Google Scholar
     

  • Kurita N, Miyata H, Gotoh M, Shimada M, Imura S, Kimura W, et al. Risk model for distal gastrectomy when treating gastric cancer on the basis of data from 33,917 Japanese patients collected using a nationwide web-based data entry system. Ann Surg. 2015;262:295–303.

    Article 
    PubMed 

    Google Scholar
     

  • Smits FJ, Verweij ME, Daamen LA, van Werkhoven CH, Goense L, Besselink MG, et al. Impact of complications after pancreatoduodenectomy on mortality, organ failure, hospital stay, and readmission: analysis of a nationwide audit. Ann Surg. 2022;275:e222–e8.

    Article 
    PubMed 

    Google Scholar
     

  • Baiocchi GL, Giacopuzzi S, Reim D, Piessen G, Costa PMD, Reynolds JV, et al. Incidence and grading of complications after gastrectomy for cancer using the GASTRODATA registry: a European retrospective observational study. Ann Surg. 2020;272:807–13.

    Article 
    PubMed 

    Google Scholar
     

  • WHO. Guidelines for Safe Surgery 2009: Safe Surgery Saves Lives. Geneva; 2009.

  • Bakos O, Lawson C, Rouleau S, Tai LH. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J Immunother Cancer. 2018;6:86.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andersson R, Andersson B, Andersson E, Eckerwall G, Norden M, Tingstedt B. Immunomodulation in surgical practice. HPB (Oxf). 2006;8:116–23.

    Article 
    CAS 

    Google Scholar
     

  • Adiamah A, Skorepa P, Weimann A, Lobo DN. The impact of preoperative immune modulating nutrition on outcomes in patients undergoing surgery for gastrointestinal cancer: a systematic review and meta-analysis. Ann Surg. 2019;270:247–56.

    Article 
    PubMed 

    Google Scholar
     

  • Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hernandez R, Poder J, LaPorte KM, Malek TR. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol. 2022;22:614–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21:3127–32.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dafni U, Michielin O, Lluesma SM, Tsourti Z, Polydoropoulou V, Karlis D, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol. 2019;30:1902–13.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142.

    PubMed 

    Google Scholar
     

  • Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • National Institute for Health and Care Excellence. NICE guidance “Conditions and diseases” United Kingdom 2025 [cited 31 January 2025]. Available from: https://www.nice.org.uk/guidance/conditions-and-diseases.

  • US Department of Health and Human Services NIoH, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5. 2017, November 27. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 [cited 20th February 2025].

  • Higgins JPT, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.cochrane.org/handbook.

  • Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guyatt GH, Oxman AD, Montori V, Vist G, Kunz R, Brozek J, et al. GRADE guidelines: 5. Rating the quality of evidence-publication bias. J Clin Epidemiol. 2011;64:1277–82.

    Article 
    PubMed 

    Google Scholar
     

  • Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26:53–77.

    Article 
    PubMed 

    Google Scholar
     

  • J. Sweeting M, J. Sutton A, C. Lambert P. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351–75.

    Article 

    Google Scholar
     

  • Angelini C, Bovo G, Muselli P, Mussi C, Crippa S, Caprotti R, et al. Preoperative interleukin-2 immunotherapy in pancreatic cancer: preliminary results. Hepato Gastroenterol. 2006;53:141–4.

    CAS 

    Google Scholar
     

  • Brivio F, Fumagalli L, Lissoni P, Nardone A, Nespoli L, Fattori L, et al. Pre-operative immunoprophylaxis with interleukin-2 may improve prognosis in radical surgery for colorectal cancer stage B-C. Anticancer Res. 2006;26:599–603.

    CAS 
    PubMed 

    Google Scholar
     

  • Brivio F, Lissoni P, Alderi G, Barni S, Lavorato F, Fumagalli L. Preoperative interleukin-2 subcutaneous immunotherapy may prolong the survival time in advanced colorectal cancer patients. Oncology. 1996;53:263–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brivio F, Lissoni P, Gilardi R, Ferrante R, Vigore L, Curzi L, et al. Abrogation of surgery-induced decline in circulating dendritic cells by subcutaneous preoperative administration of IL-2 in operable cancer patients. J Biol Regul Homeost Agents. 2000;14:200–3.

    CAS 
    PubMed 

    Google Scholar
     

  • Brivio F, Lissoni P, Tisi E, Erba L, Barni S, Tancini G, et al. Effects of a preoperative therapy with interleukin-2 on surgery-induced lymphocytopenia in cancer patients. Oncology. 1992;49:215–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brivio F, Lissoni P, Perego MS, Lissoni A, Fumagalli L. Abrogation of surgery-induced IL-6 hypersecretion by presurgical immunotherapy with IL-2 and its importance in the prevention of postoperative complications. J Biol Regul Homeost Agents. 2001;15:370–4.

    CAS 
    PubMed 

    Google Scholar
     

  • Cesana GC, Romano F, Piacentini G, Scotti M, Brenna A, Bovo G, et al. Low-dose interleukin-2 administered pre-operatively to patients with gastric cancer activates peripheral and peritumoral lymphocytes but does not affect prognosis. Ann Surg Oncol. 2007;14:1295–304.

    Article 
    PubMed 

    Google Scholar
     

  • Deehan DJ, Heys SD, Ashby J, Eremin O. Interleukin-2 (IL-2) augments host cellular immune reactivity in the perioperative period in patients with malignant disease. Eur J Surg Oncol. 1995;21:16–22.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lissoni P, Brivio F, Brivio O, Fumagalli L, Gramazio F, Rossi M, et al. Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients. J Biol Regul Homeost Agents. 1995;9:31–3.

    CAS 
    PubMed 

    Google Scholar
     

  • Nichols PH, Ramsden CW, Ward U, Sedman PC, Primrose JN. Perioperative immunotherapy with recombinant interleukin 2 in patients undergoing surgery for colorectal cancer. Cancer Res. 1992;52:5765–9.

    CAS 
    PubMed 

    Google Scholar
     

  • Romano F, Cesana G, Caprotti R, Bovo G, Uggeri F, Piacentini MG, et al. Preoperative IL-2 immunotherapy enhances tumor infiltrating lymphocytes (TILs) in gastric cancer patients. Hepato Gastroenterol. 2006;53:634–8.

    CAS 

    Google Scholar
     

  • Romano F, Cesana G, Berselli M, Gaia Piacentini M, Caprotti R, Bovo G, et al. Biological, histological, and clinical impact of preoperative IL-2 administration in radically operable gastric cancer patients. J Surg Oncol. 2004;88:240–7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Uggeri F, Caprotti R, De Grate L, Crippa S, Nobili C, Penati C, et al. Short-term preoperative IL-2 immunotherapy in operable pancreatic cancer: a randomized study. Hepato Gastroenterol. 2009;56:861–5.

    CAS 

    Google Scholar
     

  • Konrad MWHG, Hersh EM, Mansell PW, Mertelsmann R, Kolitz JE, Bradley EC. Pharmacokinetics of recombinant interleukin 2 in humans. Cancer Res. 1990;50:2009–17.

    CAS 
    PubMed 

    Google Scholar
     

  • Gaffen SL, Liu KD. Overview of interleukin-2 function, production and clinical applications. Cytokine. 2004;28:109–23.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tang F, Tie Y, Tu C, Wei X. Surgical trauma-induced immunosuppression in cancer: recent advances and the potential therapies. Clin Transl Med. 2020;10:199–223.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tai LH, Tanese de Souza C, Sahi S, Zhang J, Alkayyal AA, Ananth AA, et al. A mouse tumor model of surgical stress to explore the mechanisms of postoperative immunosuppression and evaluate novel perioperative immunotherapies. J Vis Exp. 2014:e51253. https://doi.org/10.3791/51253.

  • Chiarello MM, Fransvea P, Cariati M, Adams NJ, Bianchi V, Brisinda G. Anastomotic leakage in colorectal cancer surgery. Surg Oncol. 2022;40:101708.

    Article 
    PubMed 

    Google Scholar
     

  • Tsujimoto H, Kobayashi M, Sugasawa H, Ono S, Kishi Y, Ueno H. Potential mechanisms of tumor progression associated with postoperative infectious complications. Cancer Metastasis Rev. 2021;40:285–96.

    Article 
    PubMed 

    Google Scholar
     

  • Coccolini F, Improta M, Cicuttin E, Catena F, Sartelli M, Bova R, et al. Surgical site infection prevention and management in immunocompromised patients: a systematic review of the literature. World J Emerg Surg. 2021;16:33.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stevens NE, Chapman MJ, Fraser CK, Kuchel TR, Hayball JD, Diener KR. Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes. Sci Rep. 2017;7:5850.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang Y, Rajput A, Jin N, Wang J. Mechanisms of immunosuppression in colorectal cancer. Cancers. 2020;12:3850.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bezu L, Akçal Öksüz D, Bell M, Buggy D, Diaz-Cambronero O, Enlund M, et al. Perioperative immunosuppressive factors during cancer surgery: an updated review. Cancers. 2024;16:2304.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293–301.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kazaure HS, Roman SA, Sosa JA. Association of postdischarge complications with reoperation and mortality in general surgery. Arch Surg. 2012;147:1000–7.

    Article 
    PubMed 

    Google Scholar
     

  • Selby LV, Gennarelli RL, Schnorr GC, Solomon SB, Schattner MA, Elkin EB, et al. Association of hospital costs with complications following total gastrectomy for gastric adenocarcinoma. JAMA Surg. 2017;152:953–8.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klatte T, Ittenson A, Rohl FW, Ecke M, Allhoff EP, Bohm M. Perioperative immunomodulation with interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial. Br J Cancer. 2006;95:1167–73.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Handke J, Kummer L, Weigand MA, Larmann J. Modulation of peripheral CD4(+)CD25(+)Foxp3(+) regulatory T cells ameliorates surgical stress-induced atherosclerotic plaque progression in ApoE-deficient mice. Front Cardiovasc Med. 2021;8:682458.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scholz AS, Handke J, Gillmann HJ, Zhang Q, Dehne S, Janssen H, et al. Frontline Science: low regulatory T cells predict perioperative major adverse cardiovascular and cerebrovascular events after noncardiac surgery. J Leukoc Biol. 2020;107:717–30.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davey Smith G, Egger M, Phillips AN. Meta-analysis. Beyond the grand mean? BMJ. 1997;315:1610–4.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.

    Article 
    CAS 
    PubMed 

    Google Scholar