Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Perioperative events influence cancer recurrence risk after surgery

Key Points

  • Surgery remains the primary treatment for patients with solid tumours, yet postoperative locoregional recurrence and distant metastasis occur frequently and confer high risks of morbidity and mortality

  • Deleterious effects of surgery include the initiation of local and/or systemic inflammation, increased catecholamine levels, immunosuppression, a prothrombotic state, and exposure to anaesthetic agents; these processes overlap with cancer-promoting signalling pathways

  • Cancer cells that escape resection are subject to perioperative physiological changes and might disseminate and colonize distant organs, thus contributing to postoperative cancer recurrence

  • Perioperative use of β-adrenoceptor antagonists, anti-inflammatory drugs, intravenous anaesthetics, and antithrombotic agents is linked with improved survival outcomes in patients with cancer

  • >60% of patients with cancer are treated with surgery; therefore, offsetting the deleterious effects of surgery by use of affordable and readily available therapies might rapidly improve the postoperative survival of patients with cancer

Abstract

Surgery is a mainstay treatment for patients with solid tumours. However, despite surgical resection with a curative intent and numerous advances in the effectiveness of (neo)adjuvant therapies, metastatic disease remains common and carries a high risk of mortality. The biological perturbations that accompany the surgical stress response and the pharmacological effects of anaesthetic drugs, paradoxically, might also promote disease recurrence or the progression of metastatic disease. When cancer cells persist after surgery, either locally or at undiagnosed distant sites, neuroendocrine, immune, and metabolic pathways activated in response to surgery and/or anaesthesia might promote their survival and proliferation. A consequence of this effect is that minimal residual disease might then escape equilibrium and progress to metastatic disease. Herein, we discuss the most promising proposals for the refinement of perioperative care that might address these challenges. We outline the rationale and early evidence for the adaptation of anaesthetic techniques and the strategic use of anti-adrenergic, anti-inflammatory, and/or antithrombotic therapies. Many of these strategies are currently under evaluation in large-cohort trials and hold promise as affordable, readily available interventions that will improve the postoperative recurrence-free survival of patients with cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The effects of surgery and perioperative stress on cancer recurrence.
Figure 2: Putative mechanisms of postoperative cancer recurrence and metastasis.

Similar content being viewed by others

References

  1. Mehlen, P. & Puisieux, A. Metastasis: a question of life or death. Nat. Rev. Cancer 6, 449–458 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Murthy, B. L. et al. Postoperative wound complications and systemic recurrence in breast cancer. Br. J. Cancer 97, 1211–1217 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Beecher, S. M., O'Leary, D. P., McLaughlin, R., Sweeney, K. J. & Kerin, M. J. Influence of complications following immediate breast reconstruction on breast cancer recurrence rates. Br. J. Surg. 103, 391–398 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Lu, Z. R., Rajendran, N., Lynch, A. C., Heriot, A. G. & Warrier, S. K. Anastomotic leaks after restorative resections for rectal cancer compromise cancer outcomes and survival. Dis. Colon Rectum 59, 236–244 (2016).

    Article  PubMed  Google Scholar 

  5. Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  6. Brown, D. C., Purushotham, A. D., Birnie, G. D. & George, W. D. Detection of intraoperative tumor cell dissemination in patients with breast cancer by use of reverse transcription and polymerase chain reaction. Surgery 117, 95–101 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Hashimoto, M. et al. Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. Interact. Cardiovasc. Thorac. Surg. 18, 775–783 (2014).

    Article  PubMed  Google Scholar 

  8. 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 102, 1327–1334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hiratsuka, S., Watanabe, A., Aburatani, H. & Maru, Y. Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis. Nat. Cell Biol. 8, 1369–1375 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Kurosawa, S. & Kato, M. Anesthetics, immune cells, and immune responses. J. Anesth. 22, 263–277 (2008).

    Article  PubMed  Google Scholar 

  12. Zhou, L. et al. Propranolol attenuates surgical stress-induced elevation of the regulatory T cell response in patients undergoing radical mastectomy. J. Immunol. 196, 3460–3469 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Demicheli, R., Retsky, M. W., Hrushesky, W. J. M. & Baum, M. Tumor dormancy and surgery-driven interruption of dormancy in breast cancer: learning from failures. Nat. Clin. Pract. Oncol. 4, 699–710 (2007).

    Article  PubMed  Google Scholar 

  14. Retsky, M. et al. Reduction of breast cancer relapses with perioperative non-steroidal anti-inflammatory drugs: new findings and a review. Curr. Med. Chem. 20, 4163–4176 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee, J.-W. et al. Surgical stress promotes tumor growth in ovarian carcinoma. Clin. Cancer Res. 15, 2695–2702 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kelsey, C. R. et al. Metastasis dynamics for non-small-cell lung cancer: effect of patient and tumor-related factors. Clin. Lung Cancer 14, 425–432 (2013).

    Article  PubMed  Google Scholar 

  17. Oosterling, S. J., van der Bij, G. J., van Egmond, M. & van der Sijp, J. R. M. Surgical trauma and peritoneal recurrence of colorectal carcinoma. Eur. J. Surg. Oncol. 31, 29–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Dillekås, H. et al. The recurrence pattern following delayed breast reconstruction after mastectomy for breast cancer suggests a systemic effect of surgery on occult dormant micrometastases. Breast Cancer Res. Treat. 158, 169–178 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Isern, A. E. et al. Risk of recurrence following delayed large flap reconstruction after mastectomy for breast cancer. Br. J. Surg. 98, 659–666 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Mirnezami, A. et al. Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann. Surg. 253, 890–899 (2011).

    Article  PubMed  Google Scholar 

  21. Wigmore, T. J., Mohammed, K. & Jhanji, S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: a retrospective analysis. Anesthesiology 124, 69–79 (2016).

    Article  CAS  PubMed  Google Scholar 

  22. Enlund, M. et al. The choice of anaesthetic — sevoflurane or propofol — and outcome from cancer surgery: a retrospective analysis. Ups. J. Med. Sci. 119, 251–261 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Alkire, B. C. et al. Global access to surgical care: a modelling study. Lancet Glob. Health 3, e316–e323 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sullivan, R. et al. Delivering affordable cancer care in high-income countries. Lancet Oncol. 12, 933–980 (2011).

    Article  PubMed  Google Scholar 

  25. Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Klein, C. A. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9, 302–312 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Schmidt-Kittler, O. et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc. Natl Acad. Sci. USA 100, 7737–7742 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hosseini, H. et al. Early dissemination seeds metastasis in breast cancer. Nature 540, 552–558 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rahbari, N. N. et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology 138, 1714–1726 (2010).

    Article  PubMed  Google Scholar 

  32. Hardingham, J. E. et al. Detection and clinical significance of circulating tumor cells in colorectal cancer — 20 years of progress. Mol. Med. 21 (Suppl. 1), S25–S31 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martin, O. A., Anderson, R. L., Narayan, K. & MacManus, M. P. Does the mobilization of circulating tumour cells during cancer therapy cause metastasis? Nat. Rev. Clin. Oncol. 14, 32–44 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Hayashi, K. et al. Real-time imaging of tumor-cell shedding and trafficking in lymphatic channels. Cancer Res. 67, 8223–8228 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Tvedskov, T. F., Jensen, M.-B., Kroman, N. & Balslev, E. Iatrogenic displacement of tumor cells to the sentinel node after surgical excision in primary breast cancer. Breast Cancer Res. Treat. 131, 223–229 (2012).

    Article  PubMed  Google Scholar 

  36. Greco, K. V., Lara, P. F., Oliveira-Filho, R. M., Greco, R. V. & Sudo-Hayashi, L. S. Lymphatic regeneration across an incisional wound: inhibition by dexamethasone and aspirin, and acceleration by a micronized purified flavonoid fraction. Eur. J. Pharmacol. 551, 131–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Swartz, M. A. & Lund, A. W. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nat. Rev. Cancer 12, 210–219 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Hirakawa, S. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201, 1089–1099 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cao, R. et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6, 333–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Carpinteri, S. et al. Peritoneal tumorigenesis and inflammation are ameliorated by humidified-warm carbon dioxide insufflation in the mouse. Ann. Surg. Oncol. 22 (Suppl. 3), S1540–S1547 (2015).

    Article  PubMed  Google Scholar 

  41. Schott, A. et al. Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker. Ann. Surg. 227, 372–379 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Green, B. L. et al. Long-term follow-up of the Medical Research Council CLASICC trial of conventional versus laparoscopically assisted resection in colorectal cancer. Br. J. Surg. 100, 75–82 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Kadar, N. Port-site recurrences following laparoscopic operations for gynaecological malignancies. Br. J. Obstet. Gynaecol. 104, 1308–1313 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Song, J. et al. Port site metastasis after surgery for renal cell carcinoma: harbinger of future metastasis. J. Urol. 192, 364–368 (2014).

    Article  PubMed  Google Scholar 

  45. Downey, R. J., McCormack, P. & LoCicero, J. Dissemination of malignant tumors after video-assisted thoracic surgery: a report of twenty-one cases. The Video-Assisted Thoracic Surgery Study Group. J. Thorac. Cardiovasc. Surg. 111, 954–960 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Berger-Richardson, D. et al. Trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer: a systematic review. Surgery 161, 618–627 (2017).

    Article  PubMed  Google Scholar 

  47. Chang, H. Y. et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc. Natl Acad. Sci. USA 102, 3738–3743 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  49. Murdoch, C., Muthana, M., Coffelt, S. B. & Lewis, C. E. The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Zhao, H., Feng, Y., Wang, Y., Yang, B. & Xing, Z. Comparison of different loading dose of celecoxib on postoperative anti-inflammation and analgesia in patients undergoing endoscopic nasal surgery-200 mg is equivalent to 400 mg. Pain Med. 12, 1267–1275 (2011).

    Article  PubMed  Google Scholar 

  52. Wang, D. & DuBois, R. N. Eicosanoids and cancer. Nat. Rev. Cancer 10, 181–193 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ruan, D. & So, S.-P. Prostaglandin E2 produced by inducible COX-2 and mPGES-1 promoting cancer cell proliferation in vitro and in vivo. Life Sci. 116, 43–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Chang, N., Goodson, W. H., Gottrup, F. & Hunt, T. K. Direct measurement of wound and tissue oxygen tension in postoperative patients. Ann. Surg. 197, 470–478 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hong, W. X. et al. The role of hypoxia-inducible factor in wound healing. Adv. Wound Care 3, 390–399 (2014).

    Article  Google Scholar 

  56. Nakazawa, M. S., Keith, B. & Simon, M. C. Oxygen availability and metabolic adaptations. Nat. Rev. Cancer 16, 663–673 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hayashi, T. et al. Impact of infectious complications on gastric cancer recurrence. Gastr. Cancer 18, 368–374 (2015).

    Article  Google Scholar 

  58. Murthy, S. M. et al. The influence of surgical trauma on experimental metastasis. Cancer 64, 2035–2044 (1989).

    Article  CAS  PubMed  Google Scholar 

  59. Stanczyk, M., Olszewski, W. L., Gewartowska, M. & Maruszynski, M. Cancer seeding contributes to intestinal anastomotic dehiscence. World J. Surg. Oncol. 11, 302 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Abramovitch, R., Marikovsky, M., Meir, G. & Neeman, M. Stimulation of tumour angiogenesis by proximal wounds: spatial and temporal analysis by MRI. Br. J. Cancer 77, 440–447 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Abramovitch, R., Marikovsky, M., Meir, G. & Neeman, M. Stimulation of tumour growth by wound-derived growth factors. Br. J. Cancer 79, 1392–1398 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Antonio, N. et al. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. EMBO J. 34, 2219–2236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsuchiya, Y. et al. Increased surgical stress promotes tumor metastasis. Surgery 133, 547–555 (2003).

    Article  PubMed  Google Scholar 

  64. Choi, J. E. et al. Perioperative neutrophil:lymphocyte ratio and postoperative NSAID use as predictors of survival after lung cancer surgery: a retrospective study. Cancer Med. 4, 825–833 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. McSorley, S. T., Watt, D. G., Horgan, P. G. & McMillan, D. C. Postoperative systemic inflammatory response, complication severity, and survival following surgery for colorectal cancer. Ann. Surg. Oncol. 23, 2832–2840 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Desborough, J. P. The stress response to trauma and surgery. Br. J. Anaesth. 85, 109–117 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Sloan, E. K. et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 70, 7042–7052 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Le, C. P. et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat. Commun. 7, 10634 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim-Fuchs, C. et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 40, 40–47 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thaker, P. H. et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 12, 939–944 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Masur, K., Niggemann, B., Zanker, K. S. & Entschladen, F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by β-blockers. Cancer Res. 61, 2866–2869 (2001).

    CAS  PubMed  Google Scholar 

  72. Wolter, J. K. et al. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma. Oncotarget 5, 161–172 (2014).

    Article  PubMed  Google Scholar 

  73. Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).

    Article  PubMed  Google Scholar 

  74. Hassan, S. et al. Behavioral stress accelerates prostate cancer development in mice. J. Clin. Invest. 123, 874–886 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Moretti, S. et al. β-Adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines. Lab. Invest. 93, 279–290 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Chang, A. et al. β2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav. Immun. 57, 106–115 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pon, C. K., Lane, J. R., Sloan, E. K. & Halls, M. L. The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. FASEB J. 30, 1144–1154 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Creed, S. J. et al. β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Res. 17, 145 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Kim, T.-H. et al. Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling. J. Cell. Sci. 129, 4563–4575 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McGeown, J. G. Splanchnic nerve stimulation increases the lymphocyte output in mesenteric efferent lymph. Pflugers Arch. 422, 558–563 (1993).

    Article  CAS  PubMed  Google Scholar 

  81. Hiller, J. G. et al. Neuraxial anesthesia reduces lymphatic flow: proof-of-concept in first in-human study. Anesth. Analg. 123, 1325–1327 (2016).

    Article  CAS  PubMed  Google Scholar 

  82. Koltun, W. A. et al. Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response. Am. J. Surg. 171, 68–72 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Elefteriou, F. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Campbell, J. P. et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 10, e1001363 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chiang, S. P. H., Cabrera, R. M. & Segall, J. E. Tumor cell intravasation. Am. J. Physiol., Cell Physiol. 311, C1–C14 (2016).

    Article  Google Scholar 

  86. Lee, S. W., Whelan, R. L., Southall, J. C. & Bessler, M. Abdominal wound tumor recurrence after open and laparoscopic-assisted splenectomy in a murine model. Dis. Colon Rectum 41, 824–831 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Stone, R. L. et al. Paraneoplastic thrombocytosis in ovarian cancer. N. Engl. J. Med. 366, 610–618 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Paramanathan, A., Saxena, A. & Morris, D. L. A systematic review and meta-analysis on the impact of pre-operative neutrophil lymphocyte ratio on long term outcomes after curative intent resection of solid tumours. Surg. Oncol. 23, 31–39 (2014).

    Article  PubMed  Google Scholar 

  89. Konstantopoulos, K. & McIntire, L. V. Effects of fluid dynamic forces on vascular cell adhesion. J. Clin. Invest. 98, 2661–2665 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Im, J. H. et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res. 64, 8613–8619 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Benish, M. et al. The marginating-pulmonary immune compartment in mice exhibits increased NK cytotoxicity and unique cellular characteristics. Immunol. Res. 58, 28–39 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gil-Bernabé, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).

    Article  PubMed  CAS  Google Scholar 

  93. Hu, L., Lee, M., Campbell, W., Perez-Soler, R. & Karpatkin, S. Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 104, 2746–2751 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Terraube, V., Marx, I. & Denis, C. V. Role of von Willebrand factor in tumor metastasis. Thromb. Res. 120 (Suppl. 2), S64–S70 (2007).

    Article  PubMed  Google Scholar 

  95. Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

    Article  CAS  PubMed Central  Google Scholar 

  96. Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 76, 1367–1380 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Vlodavsky, I. et al. Heparanase, heparin and the coagulation system in cancer progression. Thromb. Res. 120 (Suppl. 2), S112–S120 (2007).

    Article  PubMed  Google Scholar 

  98. Nadir, Y. et al. Heparanase induces tissue factor expression in vascular endothelial and cancer cells. J. Thromb. Haemost. 4, 2443–2451 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Kaplan, R. N., Psaila, B. & Lyden, D. Bone marrow cells in the 'pre-metastatic niche': within bone and beyond. Cancer Metastasis Rev. 25, 521–529 (2006).

    Article  PubMed  Google Scholar 

  100. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pietra, G. et al. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res. 72, 1407–1415 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Eddy, J. L., Krukowski, K., Janusek, L. & Mathews, H. L. Glucocorticoids regulate natural killer cell function epigenetically. Cell. Immunol. 290, 120–130 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Glasner, A. et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J. Immunol. 184, 2449–2457 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Benish, M. et al. Perioperative use of β-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann. Surg. Oncol. 15, 2042–2052 (2008).

    Article  PubMed  Google Scholar 

  105. Yakar, I. et al. Prostaglandin E2 suppresses NK activity in vivo and promotes postoperative tumor metastasis in rats. Ann. Surg. Oncol. 10, 469–479 (2003).

    Article  PubMed  Google Scholar 

  106. Cata, J. P., Conrad, C. & Rezvani, K. Potential use of natural killer cell transfer therapy in the perioperative period to improve oncologic outcomes. Scientifica 2015, 732438 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Buggy, D. J. et al. Consensus statement from the BJA Workshop on Cancer and Anaesthesia. Br. J. Anaesth. 114, 2–3 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. Beta blockers and breast cancer mortality: a population- based study. J. Clin. Oncol. 29, 2635–2644 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Hiller, J. G., Hacking, M. B., Link, E. K., Wessels, K. L. & Riedel, B. J. Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery. Acta Anaesthesiol. Scand. 58, 281–290 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. De Giorgi, V. et al. β-Blocker use and reduced disease progression in patients with thick melanoma: 8 years of follow-up. Melanoma Res. 27, 268–270 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Léauté-Labrèze, C. et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N. Engl. J. Med. 372, 735–746 (2015).

    Article  PubMed  CAS  Google Scholar 

  112. Chow, W. et al. Growth attenuation of cutaneous angiosarcoma with propranolol-mediated β-blockade. JAMA Dermatol. 151, 1226–1229 (2015).

    Article  PubMed  Google Scholar 

  113. Childers, W. K., Hollenbeak, C. S. & Cheriyath, P. β-blockers reduce breast cancer recurrence and breast cancer death: a meta-analysis. Clin. Breast Cancer 15, 426–431 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Zhang, J. et al. Norepinephrine induced epithelial-mesenchymal transition in HT-29 and A549 cells in vitro. J. Cancer Res. Clin. Oncol. 142, 423–435 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Shaashua, L. et al. Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin. Cancer Res. 23, 4651–4661 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. POISE Study Group et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet 371, 1839–1847 (2008).

  117. Khadke, V. V., Khadke, S. V. & Khare, A. Oral propranolol — efficacy and comparison of two doses for peri-operative anxiolysis. J. Indian Med. Assoc. 110, 457–460 (2012).

    CAS  PubMed  Google Scholar 

  118. Day, A. R., Smith, R. V. P., Scott, M. J. P., Fawcett, W. J. & Rockall, T. A. Randomized clinical trial investigating the stress response from two different methods of analgesia after laparoscopic colorectal surgery. Br. J. Surg. 102, 1473–1479 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Gu, C.-Y., Zhang, J., Qian, Y.-N. & Tang, Q.-F. Effects of epidural anesthesia and postoperative epidural analgesia on immune function in esophageal carcinoma patients undergoing thoracic surgery. Mol. Clin. Oncol. 3, 190–196 (2015).

    Article  PubMed  Google Scholar 

  120. Xu, F. et al. Clinicopathological and prognostic significance of COX-2 immunohistochemical expression in breast cancer: a meta-analysis. Oncotarget 8, 6003–6012 (2016).

    PubMed Central  Google Scholar 

  121. McGeown, J. G., McHale, N. G. & Thornbury, K. D. The effect of electrical stimulation of the sympathetic chain on peripheral lymph flow in the anaesthetized sheep. J. Physiol. 393, 123–133 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lennon, F. E. et al. Overexpression of the μ-opioid receptor in human non-small cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology 116, 857–867 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Page, G. G., Blakely, W. P. & Ben-Eliyahu, S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 90, 191–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  125. Weng, M. et al. The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis. Oncotarget 7, 15262–15273 (2016).

    PubMed  PubMed Central  Google Scholar 

  126. Sun, Y., Li, T. & Gan, T. J. The effects of perioperative regional anesthesia and analgesia on cancer recurrence and survival after oncology surgery: a systematic review and meta-analysis. Reg. Anesth. Pain Med. 40, 589–598 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Karnezis, T. et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 21, 181–195 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Hiller, J. G. et al. Impact of celecoxib on inflammation during cancer surgery: a randomized clinical trial. Can. J. Anaesth. 64, 497–505 (2017).

    Article  PubMed  Google Scholar 

  129. Zhu, Y., Wang, S., Wu, H. & Wu, Y. Effect of perioperative parecoxib on postoperative pain and local inflammation factors PGE2 and IL-6 for total knee arthroplasty: a randomized, double-blind, placebo-controlled study. Eur. J. Orthop. Surg. Traumatol. 24, 395–401 (2013).

    Article  PubMed  Google Scholar 

  130. Wang, L.-D. et al. Effects of preemptive analgesia with parecoxib sodium on haemodynamics and plasma stress hormones in surgical patients with thyroid carcinoma. Asian Pac. J. Cancer Prev. 16, 3977–3980 (2015).

    Article  PubMed  Google Scholar 

  131. Ma, W., Wang, K., Du, J., Luan, J. & Lou, G. Multi-dose parecoxib provides an immunoprotective effect by balancing T helper 1 (Th1), Th2, Th17 and regulatory T cytokines following laparoscopy in patients with cervical cancer. Mol. Med. Rep. 11, 2999–3008 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Shen, J.-C. et al. Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia. Int. J. Clin. Pharmacol. Ther. 52, 669–675 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Elmets, C. A. et al. Chemoprevention of nonmelanoma skin cancer with celecoxib: a randomized, double-blind, placebo-controlled trial. J. Natl Cancer Inst. 102, 1835–1844 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Mao, J. T. et al. Lung cancer chemoprevention with celecoxib in former smokers. Cancer Prev. Res. 4, 984–993 (2011).

    Article  CAS  Google Scholar 

  135. Lönnroth, C. et al. Preoperative treatment with a non-steroidal anti-inflammatory drug (NSAID) increases tumor tissue infiltration of seemingly activated immune cells in colorectal cancer. Cancer Immun. 8, 5 (2008).

    PubMed  PubMed Central  Google Scholar 

  136. Sooriakumaran, P. et al. A randomized controlled trial investigating the effects of celecoxib in patients with localized prostate cancer. Anticancer Res. 29, 1483–1488 (2009).

    CAS  PubMed  Google Scholar 

  137. Forget, P. et al. Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth. Analg. 110, 1630–1635 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Restivo, A. et al. Aspirin as a neoadjuvant agent during preoperative chemoradiation for rectal cancer. Br. J. Cancer 113, 1133–1139 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yeh, C.-C. et al. Nonsteroidal anti-inflammatory drugs are associated with reduced risk of early hepatocellular carcinoma recurrence after curative liver resection: a nationwide cohort study. Ann. Surg. 261, 521–526 (2015).

    Article  PubMed  Google Scholar 

  140. Shapiro, J., Jersky, J., Katzav, S., Feldman, M. & Segal, S. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors. J. Clin. Invest. 68, 678–685 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wu, L., Zhao, H., Wang, T., Pac-Soo, C. & Ma, D. Cellular signaling pathways and molecular mechanisms involving inhalational anesthetics-induced organoprotection. J. Anesth. 28, 740–758 (2014).

    Article  PubMed  Google Scholar 

  142. Tavare, A. N., Perry, N. J. S., Benzonana, L. L., Takata, M. & Ma, D. Cancer recurrence after surgery: direct and indirect effects of anesthetic agents. Int. J. Cancer 130, 1237–1250 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. Iwasaki, M. et al. Volatile anaesthetics enhance the metastasis related cellular signalling including CXCR2 of ovarian cancer cells. Oncotarget 7, 26042–26056 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Huitink, J. M. et al. Volatile anesthetics modulate gene expression in breast and brain tumor cells. Anesth. Analg. 111, 1411–1415 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Benzonana, L. L. et al. Isoflurane, a commonly used volatile anesthetic, enhances renal cancer growth and malignant potential via the hypoxia-inducible factor cellular signaling pathway in vitro. Anesthesiology 119, 593–605 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Huang, H. et al. Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br. J. Cancer 111, 1338–1349 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Luo, X. et al. Impact of isoflurane on malignant capability of ovarian cancer in vitro. Br. J. Anaesth. 114, 831–839 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Elena, G. et al. Effects of repetitive sevoflurane anaesthesia on immune response, select biochemical parameters and organ histology in mice. Lab. Anim. 37, 193–203 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Desmond, F., McCormack, J., Mulligan, N., Stokes, M. & Buggy, D. J. Effect of anaesthetic technique on immune cell infiltration in breast cancer: a follow-up pilot analysis of a prospective, randomised, investigator-masked study. Anticancer Res. 35, 1311–1319 (2015).

    PubMed  Google Scholar 

  150. Zhu, M. et al. Isoflurane enhances the malignant potential of glioblastoma stem cells by promoting their viability, mobility in vitro and migratory capacity in vivo. Br. J. Anaesth. 116, 870–877 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Pandit, J. J. et al. 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: summary of main findings and risk factors. Br. J. Anaesth. 113, 549–559 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Chen, R.-M. et al. Anti-inflammatory and antioxidative effects of propofol on lipopolysaccharide-activated macrophages. Ann. NY Acad. Sci. 1042, 262–271 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Lee, C.-J., Tai, Y.-T., Lin, Y.-L. & Chen, R.-M. Molecular mechanisms of propofol-involved suppression of no biosynthesis and inducible iNOS gene expression in LPS-stimulated macrophage-like raw 264.7 cells. Shock 33, 93–100 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Inada, T., Hirota, K. & Shingu, K. Intravenous anesthetic propofol suppresses prostaglandin E2 and cysteinyl leukotriene production and reduces edema formation in arachidonic acid-induced ear inflammation. J. Immunotoxicol. 12, 261–265 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Markovic-Bozic, J. et al. Effect of propofol and sevoflurane on the inflammatory response of patients undergoing craniotomy. BMC Anesthesiol. 16, 18 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Inada, T. et al. Effect of propofol and isoflurane anaesthesia on the immune response to surgery. Anaesthesia 59, 954–959 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Melamed, R., Bar-Yosef, S., Shakhar, G., Shakhar, K. & Ben-Eliyahu, S. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures. Anesth. Analg. 97, 1331–1339 (2003).

    Article  CAS  PubMed  Google Scholar 

  158. Wu, K.-C. et al. Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells. Anticancer Res. 32, 4833–4842 (2012).

    CAS  PubMed  Google Scholar 

  159. Mammoto, T. et al. Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett. 184, 165–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Kushida, A., Inada, T. & Shingu, K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol. Immunotoxicol. 29, 477–486 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Lee, J. H., Kang, S. H., Kim, Y., Kim, H. A. & Kim, B. S. Effects of propofol-based total intravenous anesthesia on recurrence and overall survival in patients after modified radical mastectomy: a retrospective study. Kor. J. Anesthesiol. 69, 126–132 (2016).

    Article  CAS  Google Scholar 

  162. Mikami, J. et al. Antitumor effect of antiplatelet agents in gastric cancer cells: an in vivo and in vitro study. Gastr. Cancer 19, 817–826 (2016).

    Article  CAS  Google Scholar 

  163. Palumbo, J. S. et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105, 178–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Stegeman, I., Bossuyt, P. M., Yu, T., Boyd, C. & Puhan, M. A. Aspirin for primary prevention of cardiovascular disease and cancer. A benefit and harm analysis. PLoS ONE 10, e0127194 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Lou, X.-L. et al. Interaction between circulating cancer cells and platelets: clinical implication. Chin. J. Cancer Res. 27, 450–460 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Algra, A. M. & Rothwell, P. M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol. 13, 518–527 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Liu, J.-F., Jamieson, G. G., Wu, T.-C., Zhu, G.-J. & Drew, P. A. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann. Surg. Oncol. 16, 1397–1402 (2009).

    Article  PubMed  Google Scholar 

  168. Devereaux, P. J. et al. Aspirin in patients undergoing noncardiac surgery. N. Engl. J. Med. 370, 1494–1503 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Elwood, P. C. et al. Aspirin in the treatment of cancer: reductions in metastatic spread and in mortality: a systematic review and meta-analyses of published studies. PLoS ONE 11, e0152402 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Tieken, C. & Versteeg, H. H. Anticoagulants versus cancer. Thromb. Res. 140 (Suppl. 1), S148–S153 (2016).

    Article  CAS  PubMed  Google Scholar 

  171. Niers, T. M. H. et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit. Rev. Oncol. Hematol. 61, 195–207 (2007).

    Article  CAS  PubMed  Google Scholar 

  172. Taromi, S. et al. PO-33 - Heparin suppresses progression of small cell lung cancer (SCLC) in an orthotopic mouse model. Thromb. Res. 140 (Suppl. 1), S188 (2016).

    Article  PubMed  Google Scholar 

  173. Mousa, S. A. & Petersen, L. J. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thromb. Haemost. 102, 258–267 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Van Sluis, G. L. et al. A low molecular weight heparin inhibits experimental metastasis in mice independently of the endothelial glycocalyx. PLoS ONE 5, e11200 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Bonten, T. N. et al. Effect of β-blockers on platelet aggregation: a systematic review and meta-analysis. Br. J. Clin. Pharmacol. 78, 940–949 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. McSorley, S. T., Horgan, P. G. & McMillan, D. C. The impact of the type and severity of postoperative complications on long-term outcomes following surgery for colorectal cancer: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 97, 168–177 (2016).

    Article  PubMed  Google Scholar 

  177. Davis, C. et al. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009–2013. BMJ 359, j4530 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by the Australian and New Zealand College of Anaesthetists, The David and Lorelle Skewes Foundation, the Peter Mac Foundation, and the National Cancer Institute (CA160890). N.J.P is the recipient of a Cancer Research UK Clinical Research Fellowship. Work in the G.P lab is supported by the British Journal of Anaesthesia/Royal College of Anaesthetists via the National Institute of Academic Anaesthesia, Cancer Research UK Grand Challenge award (C59824/A25044), and the Institute of Cancer Research.

Author information

Authors and Affiliations

Authors

Contributions

J.G.H, N.J.P, B.R, and E.K.S researched data for the article. All authors wrote, reviewed, and edited the manuscript before submission. J.G.H and N.J.P contributed equally.

Corresponding author

Correspondence to Bernhard Riedel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hiller, J., Perry, N., Poulogiannis, G. et al. Perioperative events influence cancer recurrence risk after surgery. Nat Rev Clin Oncol 15, 205–218 (2018). https://doi.org/10.1038/nrclinonc.2017.194

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2017.194

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer