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:

Exploiting the critical perioperative period to improve long-term cancer outcomes

Nature Reviews Clinical Oncology volume 12, pages 213–226 (2015)Cite this article

Subjects

Key Points

  • The perioperative timeframe—days before and after tumour excision—is pivotal in determining long-term cancer outcomes, disproportionally to its short duration

  • Potential metastasis-promoting aspects of the perioperative period and of surgery include anxiety and stress, specific anaesthetics and analgesics, hypothermia, blood transfusion, tissue damage, specific sex hormones, nociception and pain

  • Deleterious processes include excess and maladaptive perioperative responses at the paracrine, endocrine, and immune-system levels

  • Potential novel interventions include specified modifications to surgical procedures, stress-reducing and anti-inflammatory approaches, such as perioperative administration of non-selective β-adrenergic blockers and COX2 inhibitors, and perioperative immune stimulation

  • These interventions could transform the perioperative timeframe from being a prominent facilitator of metastatic progression, to a yet unexplored opportunity for arresting and/or eliminating residual disease

Abstract

Evidence suggests that the perioperative period and the excision of the primary tumour can promote the development of metastases—the main cause of cancer-related mortality. This Review first presents the assertion that the perioperative timeframe is pivotal in determining long-term cancer outcomes, disproportionally to its short duration (days to weeks). We then analyse the various aspects of surgery, and their consequent paracrine and neuroendocrine responses, which could facilitate the metastatic process by directly affecting malignant tissues, and/or through indirect pathways, such as immunological perturbations. We address the influences of surgery-related anxiety and stress, nutritional status, anaesthetics and analgesics, hypothermia, blood transfusion, tissue damage, and levels of sex hormones, and point at some as probable deleterious factors. Through understanding these processes and reviewing empirical evidence, we provide suggestions for potential new perioperative approaches and interventions aimed at attenuating deleterious processes and ultimately improving treatment outcomes. Specifically, we highlight excess perioperative release of catecholamines and prostaglandins as key deleterious mediators of surgery, and we recommend blockade of these responses during the perioperative period, as well as other low-risk, low-cost interventions. The measures described in this Review could transform the perioperative timeframe from a prominent facilitator of metastatic progression, to a window of opportunity for arresting and/or eliminating residual disease, potentially improving long-term survival rates in patients with cancer.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: A schematic presentation of major perioperative risk factors for tumour progression, and some of the neuroendocrine, paracrine, immunological, and angiogenic perturbations they elicit.

Similar content being viewed by others

References

  1. Neeman, E., Zmora, O. & Ben-Eliyahu, S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. Clin. Cancer Res. 18, 4895–4902 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Neeman, E. & Ben-Eliyahu, S. Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. Brain Behav. Immun. 30 (Suppl.), S32–S40 (2013).

    PubMed  Google Scholar 

  3. Snyder, G. L. & Greenberg, S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br. J. Anaesth. 105, 106–115 (2010).

    CAS  PubMed  Google Scholar 

  4. Yamaguchi, K., Takagi, Y., Aoki, S., Futamura, M. & Saji, S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann. Surg. 232, 58–65 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Fisher, B., Gunduz, N., Coyle, J., Rudock, C. & Saffer, E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res. 49, 1996–2001 (1989).

    CAS  PubMed  Google Scholar 

  6. O'Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Armaiz-Pena, G. N., Cole, S. W., Lutgendorf, S. K. & Sood, A. K. Neuroendocrine influences on cancer progression. Brain Behav. Immun. 30 (Suppl.), S19–S25 (2013).

    CAS  PubMed  Google Scholar 

  9. Gullino, P. M. Prostaglandins and gangliosides of tumor microenvironment: their role in angiogenesis. Acta Oncol. 34, 439–441 (1995).

    CAS  PubMed  Google Scholar 

  10. Kim, R., Emi, M., Tanabe, K. & Arihiro, K. Tumor-driven evolution of immunosuppressive networks during malignant progression. Cancer Res. 66, 5527–5536 (2006).

    CAS  PubMed  Google Scholar 

  11. Badwe, R. et al. Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. J. Clin. Oncol. 29, 2845–2851 (2011).

    CAS  PubMed  Google Scholar 

  12. Biki, B. et al. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 109, 180–187 (2008).

    PubMed  Google Scholar 

  13. Exadaktylos, A. K., Buggy, D. J., Moriarty, D. C., Mascha, E. & Sessler, D. I. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105, 660–664 (2006).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Shakhar, G. & Ben-Eliyahu, S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann. Surg. Oncol. 10, 972–992 (2003).

    PubMed  Google Scholar 

  16. Buvanendran, A. et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 104, 403–410 (2006).

    CAS  PubMed  Google Scholar 

  17. Traynor, C. & Hall, G. M. Endocrine and metabolic changes during surgery: anaesthetic implications. Br. J. Anaesth. 53, 153–160 (1981).

    CAS  PubMed  Google Scholar 

  18. Bartal, I. et al. Immune perturbations in patients along the perioperative period: alterations in cell surface markers and leukocyte subtypes before and after surgery. Brain Behav. Immun. 24, 376–386 (2010).

    CAS  PubMed  Google Scholar 

  19. Rosenne, E. et al. In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins. Brain Behav. Immun. 37, 207–219 (2014).

    CAS  PubMed  Google Scholar 

  20. Perez-Sayans, M. et al. β-adrenergic receptors in cancer: therapeutic implications. Oncol. Res. 19, 45–54 (2010).

    CAS  PubMed  Google Scholar 

  21. Wu, W. K., Sung, J. J., Lee, C. W., Yu, J. & Cho, C. H. Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. Cancer Lett. 295, 7–16 (2010).

    CAS  PubMed  Google Scholar 

  22. Mathew, B. et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth. Analg. 112, 558–567 (2011).

    CAS  PubMed  Google Scholar 

  23. Bernabe, D. G., Tamae, A. C., Biasoli, E. R. & Oliveira, S. H. Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells. Brain Behav. Immun. 25, 574–583 (2011).

    CAS  PubMed  Google Scholar 

  24. van der Bij, G. J. et al. The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer. Ann. Surg. 249, 727–734 (2009).

    PubMed  Google Scholar 

  25. 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 

  26. Kerros, C., Brood, I., Sola, B., Jauzac, P. & Allouche, S. Reduction of cell proliferation and potentiation of Fas-induced apoptosis by the selective kappa-opioid receptor agonist U50 488 in the multiple myeloma LP-1 cells. J. Neuroimmunol. 220, 69–78 (2010).

    CAS  PubMed  Google Scholar 

  27. Roche-Nagle, G., Connolly, E. M., Eng, M., Bouchier-Hayes, D. J. & Harmey, J. H. Antimetastatic activity of a cyclooxygenase-2 inhibitor. Br. J. Cancer 91, 359–365 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sood, A. K. et al. Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J. Clin. Invest. 120, 1515–1523 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. Wei, D. et al. Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 64, 2030–2038 (2004).

    CAS  PubMed  Google Scholar 

  31. Yang, E. V. et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav. Immun. 23, 267–275 (2009).

    CAS  PubMed  Google Scholar 

  32. Inbar, S. et al. Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity. PLoS ONE 6, e19246 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kalinski, P. Regulation of immune responses by prostaglandin E2 . J. Immunol. 188, 21–28 (2012).

    CAS  PubMed  Google Scholar 

  34. 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).

    PubMed  Google Scholar 

  35. 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).

    PubMed  Google Scholar 

  36. 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).

    CAS  PubMed  Google Scholar 

  37. Greenfeld, K. et al. Immune suppression while awaiting surgery and following it: dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity. Brain Behav. Immun. 21, 503–513 (2007).

    CAS  PubMed  Google Scholar 

  38. Smyth, M. J. et al. Activation of NK cell cytotoxicity. Mol. Immunol. 42, 501–510 (2005).

    CAS  PubMed  Google Scholar 

  39. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).

    CAS  PubMed  Google Scholar 

  40. Hodgson, D. M. & Knott, B. Potentiation of tumor metastasis in adulthood by neonatal endotoxin exposure: sex differences. Psychoneuroendocrinology 27, 791–804 (2002).

    CAS  PubMed  Google Scholar 

  41. Dewan, M. Z. et al. Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo. Breast Cancer Res. Treat. 104, 267–275 (2007).

    CAS  PubMed  Google Scholar 

  42. Ben-Eliyahu, S., Page, G. G., Yirmiya, R. & Taylor, A. N. Acute alcohol intoxication suppresses natural killer cell activity and promotes tumor metastasis. Nat. Med. 2, 457–460 (1996).

    CAS  PubMed  Google Scholar 

  43. Goldfarb, Y. et al. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann. Surg. 253, 798–810 (2011).

    PubMed  Google Scholar 

  44. Shakhar, G. & Ben-Eliyahu, S. In vivo β-adrenergic stimulation suppresses natural killer activity and compromises resistance to tumor metastasis in rats. J. Immunol. 160, 3251–3258 (1998).

    CAS  PubMed  Google Scholar 

  45. Landmann, R. β-adrenergic receptors in human leukocyte subpopulations. Eur. J. Clin. Invest. 22 (Suppl. 1), 30–36 (1992).

    PubMed  Google Scholar 

  46. Uotila, P. The role of cyclic AMP and oxygen intermediates in the inhibition of cellular immunity in cancer. Cancer Immunol. Immunother. 43, 1–9 (1996).

    CAS  PubMed  Google Scholar 

  47. Ben-Eliyahu, S., Shakhar, G., Page, G. G., Stefanski, V. & Shakhar, K. Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and β-adrenoceptors. Neuroimmunomodulation 8, 154–164 (2000).

    CAS  PubMed  Google Scholar 

  48. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  49. McCoy, J. L., Rucker, R. & Petros, J. A. Cell-mediated immunity to tumor-associated antigens is a better predictor of survival in early stage breast cancer than stage, grade or lymph node status. Breast Cancer Res. Treat. 60, 227–234 (2000).

    CAS  PubMed  Google Scholar 

  50. Detry, O., Honore, P., Meurisse, M. & Jacquet, N. Cancer in transplant recipients. Transplant. Proc. 32, 127 (2000).

    CAS  PubMed  Google Scholar 

  51. Decaens, T. et al. Role of immunosuppression and tumor differentiation in predicting recurrence after liver transplantation for hepatocellular carcinoma: a multicenter study of 412 patients. World J. Gastroenterol. 12, 7319–7325 (2006).

    PubMed  PubMed Central  Google Scholar 

  52. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    CAS  PubMed  Google Scholar 

  53. Postow, M., Callahan, M. K. & Wolchok, J. D. Beyond cancer vaccines: a reason for future optimism with immunomodulatory therapy. Cancer J. 17, 372–378 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim, J. W. & Eder, J. P. Prospects for Targeting PD-1 and PD-L1 in Various Tumor Types. Oncology 28 (Suppl. 3), pii:202332 (2014).

    Google Scholar 

  55. Hegde, S., Fox, L., Wang, X. & Gumperz, J. E. Autoreactive natural killer T cells: promoting immune protection and immune tolerance through varied interactions with myeloid antigen-presenting cells. Immunology 130, 471–483 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Melamed, R. et al. Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a β-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav. Immun. 19, 114–126 (2005).

    CAS  PubMed  Google Scholar 

  57. Melamed, R. et al. The marginating-pulmonary immune compartment in rats: characteristics of continuous inflammation and activated NK cells. J. Immunother. 33, 16–29 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Luo, D. Z. et al. On the cell biology of pit cells, the liver-specific NK cells. World J. Gastroenterol. 6, 1–11 (2000).

    PubMed  PubMed Central  Google Scholar 

  59. Macleod, A. S. & Havran, W. L. Functions of skin-resident γδ T cells. Cell Mol. Life Sci. 68, 2399–2408 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Larmonier, N., Fraszczak, J., Lakomy, D., Bonnotte, B. & Katsanis, E. Killer dendritic cells and their potential for cancer immunotherapy. Cancer Immunol. Immunother. 59, 1–11 (2010).

    PubMed  Google Scholar 

  61. Goldfarb, Y., Levi, B., Sorski, L., Frenkel, D. & Ben-Eliyahu, S. CpG-C immunotherapeutic efficacy is jeopardized by ongoing exposure to stress: potential implications for clinical use. Brain Behav. Immun. 25, 67–76 (2011).

    CAS  PubMed  Google Scholar 

  62. Levi, B. et al. Continuous stress disrupts immunostimulatory effects of IL-12. Brain Behav. Immun. 25, 727–735 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Prigione, I. et al. Reciprocal interactions between human mesenchymal stem cells and γδ T cells or invariant natural killer T cells. Stem Cells 27, 693–702 (2009).

    CAS  PubMed  Google Scholar 

  64. Martinet, L., Poupot, R. & Fournie, J. J. Pitfalls on the roadmap to γδ T cell-based cancer immunotherapies. Immunol. Lett. 124, 1–8 (2009).

    CAS  PubMed  Google Scholar 

  65. Bodey, B., Bodey, B. Jr, Siegel, S. E. & Kaiser, H. E. Failure of cancer vaccines: the significant limitations of this approach to immunotherapy. Anticancer Res. 20, 2665–2676 (1999).

    Google Scholar 

  66. Azrad, M. & Demark-Wahnefried, W. The association between adiposity and breast cancer recurrence and survival: a review of the recent literature. Curr. Nutr. Rep. 3, 9–15 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chlebowski, R. T. Nutrition and physical activity influence on breast cancer incidence and outcome. Breast 22 (Suppl. 2), S30–S37 (2013).

    PubMed  Google Scholar 

  68. Heaney, A. & Buggy, D. J. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br. J. Anaesth. 109 (Suppl. 1), i17–i28 (2012).

    PubMed  Google Scholar 

  69. Schlagenhauff, B. et al. Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma. Melanoma Res. 10, 165–169 (2000).

    CAS  PubMed  Google Scholar 

  70. Myles, P. S. et al. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 342, d1491 (2011).

    PubMed  Google Scholar 

  71. Gottschalk, A. et al. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 113, 27–34 (2010).

    PubMed  Google Scholar 

  72. Tsui, B. C. et al. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can. J. Anaesth. 57, 107–112 (2010).

    PubMed  Google Scholar 

  73. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  74. US National Library of Medicine. ClinicalTrials.gov [online], (2013).

  75. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  76. Deegan, C. A. et al. Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro. Br. J. Anaesth. 103, 685–690 (2009).

    CAS  PubMed  Google Scholar 

  77. Page, G. G., Ben Eliyahu, S., Yirmiya, R. & Liebeskind, J. C. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 54, 21–28 (1993).

    CAS  PubMed  Google Scholar 

  78. Shavit, Y., Ben-Eliyahu, S., Zeidel, A. & Beilin, B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation 11, 255–260 (2004).

    CAS  PubMed  Google Scholar 

  79. Afsharimani, B., Doornebal, C. W., Cabot, P. J., Hollmann, M. W. & Parat, M. O. Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis. Br. J. Pharmacol. http://dx.doi.org/10.1111/bph.12589 (2014).

  80. Bayer, B. M., Daussin, S., Hernandez, M. & Irvin, L. Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. Neuropharmacology 29, 369–374 (1990).

    CAS  PubMed  Google Scholar 

  81. Yeager, M. P. et al. Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 83, 500–508 (1995).

    CAS  PubMed  Google Scholar 

  82. Page, G. G., Ben-Eliyahu, S., Yirmiya, R. & Liebeskind, J. C. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 54, 21–28 (1993).

    CAS  PubMed  Google Scholar 

  83. Gaspani, L., Bianchi, M., Limiroli, E., Panerai, A. E. & Sacerdote, P. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J. Neuroimmunol. 129, 18–24 (2002).

    CAS  PubMed  Google Scholar 

  84. 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).

    CAS  PubMed  Google Scholar 

  85. Ben-Eliyahu, S., Shakhar, G., Rosenne, E., Levinson, Y. & Beilin, B. Hypothermia in barbiturate-anesthetized rats suppresses natural killer cell activity and compromises resistance to tumor metastasis: a role for adrenergic mechanisms. Anesthesiology 91, 732–740 (1999).

    CAS  PubMed  Google Scholar 

  86. Gupta, A., Bjornsson, A., Fredriksson, M., Hallbook, O. & Eintrei, C. Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden. Br. J. Anaesth. 107, 164–170 (2011).

    CAS  PubMed  Google Scholar 

  87. Lin, L. et al. Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. Br. J. Anaesth. 106, 814–822 (2011).

    CAS  PubMed  Google Scholar 

  88. Cata, J. P., Gottumukkala, V. & Sessler, D. I. How regional analgesia might reduce postoperative cancer recurrence. Eur. J. Pain Suppl. 5, 345–355 (2011).

    CAS  Google Scholar 

  89. Kao, K. J. Mechanisms and new approaches for the allogeneic blood transfusion-induced immunomodulatory effects. Transfus. Med. Rev. 14, 12–22 (2000).

    CAS  PubMed  Google Scholar 

  90. Lenhard, V., Maassen, G. & Opelz, G. Transfusion-induced enhancement of prostaglandin and thromboxane release in prospective kidney graft recipients. Proc. Eur. Dial. Transplant. Assoc. Eur. Ren. Assoc. 21, 923–927 (1985).

    CAS  PubMed  Google Scholar 

  91. Jensen, L. S. et al. Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. Br. J. Surg. 79, 513–516 (1992).

    CAS  PubMed  Google Scholar 

  92. Blumberg, N. & Heal, J. M. Effects of transfusion on immune function. Cancer recurrence and infection. Arch. Pathol. Lab. Med. 118, 371–379 (1994).

    CAS  PubMed  Google Scholar 

  93. Schriemer, P. A., Longnecker, D. E. & Mintz, P. D. The possible immunosuppressive effects of perioperative blood transfusion in cancer patients. Anesthesiology 68, 422–428 (1988).

    CAS  PubMed  Google Scholar 

  94. Landers, D. F., Hill, G. E., Wong, K. C. & Fox, I. J. Blood transfusion-induced immunomodulation. Anesth. Analg. 82, 187–204 (1996).

    CAS  PubMed  Google Scholar 

  95. Acheson, A. G., Brookes, M. J. & Spahn, D. R. Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis. Ann. Surg. 256, 235–244 (2012).

    PubMed  Google Scholar 

  96. Amato, A. & Pescatori, M. Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD005033. http://dx.doi.org/10.1002/14651858.CD005033.pub2.

  97. Rosenberg, S. A., Seipp, C. A., White, D. E. & Wesley, R. Perioperative blood transfusions are associated with increased rates of recurrence and decreased survival in patients with high-grade soft-tissue sarcomas of the extremities. J. Clin. Oncol. 3, 698–709 (1985).

    CAS  PubMed  Google Scholar 

  98. Johnson, J. T., Taylor, F. H. & Thearle, P. B. Blood transfusion and outcome in stage III head and neck carcinoma. Arch. Otolaryngol. Head Neck Surg. 113, 307–310 (1987).

    CAS  PubMed  Google Scholar 

  99. Atzil, S. et al. Blood transfusion promotes cancer progression: a critical role for aged erythrocytes. Anesthesiology 109, 989–997 (2008).

    PubMed  Google Scholar 

  100. Gohel, M. S., Bulbulia, R. A., Slim, F. J., Poskitt, K. R. & Whyman, M. R. How to approach major surgery where patients refuse blood transfusion (including Jehovah's Witnesses). Ann. R. Coll. Surg. Engl. 87, 3–14 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Martyn, V. et al. The theory and practice of bloodless surgery. Transfus. Apher. Sci. 27, 29–43 (2002).

    PubMed  Google Scholar 

  102. Kurz, A., Sessler, D. I. & Lenhardt, R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N. Engl. J. Med. 334, 1209–1215 (1996).

    CAS  PubMed  Google Scholar 

  103. Beilin, B. et al. Effects of mild perioperative hypothermia on cellular immune responses. Anesthesiology 89, 1133–1140 (1998).

    CAS  PubMed  Google Scholar 

  104. Frank, S. M. et al. The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia. A randomized clinical trial. Anesthesiology 82, 83–93 (1995).

    CAS  PubMed  Google Scholar 

  105. Rajagopalan, S., Mascha, E., Na, J. & Sessler, D. I. The effects of mild perioperative hypothermia on blood loss and transfusion requirement. Anesthesiology 108, 71–77 (2008).

    PubMed  Google Scholar 

  106. Kurz, A., Sessler, D. I. & Lenhardt, R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N. Engl. J. Med. 334, 1209–1215 (1996).

    CAS  PubMed  Google Scholar 

  107. Nduka, C. C. et al. Intraperitoneal hypothermia during surgery enhances postoperative tumor growth. Surg. Endosc. 16, 611–615 (2002).

    CAS  PubMed  Google Scholar 

  108. Walker, J. L. et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J. Clin. Oncol. 27, 5331–5336 (2009).

    PubMed  PubMed Central  Google Scholar 

  109. van der Pas, M. H. et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol. 14, 210–218 (2013).

    PubMed  Google Scholar 

  110. Breukink, S., Pierie, J. & Wiggers, T. Laparoscopic versus open total mesorectal excision for rectal cancer. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD005200. http://dx.doi.org/10.1002/14651858.CD005200.pub3.

  111. Schwenk, W., Haase, O., Neudecker, J. & Muller, J. M. Short term benefits for laparoscopic colorectal resection. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD003145. http://dx.doi.org/10.1002/14651858.CD003145.pub2.

  112. Wu, F. P. et al. Systemic and peritoneal inflammatory response after laparoscopic or conventional colon resection in cancer patients: a prospective, randomized trial. Dis. Colon Rectum 46, 147–155 (2003).

    CAS  PubMed  Google Scholar 

  113. Sammour, T., Kahokehr, A., Chan, S., Booth, R. J. & Hill, A. G. The humoral response after laparoscopic versus open colorectal surgery: a meta-analysis. J. Surg. Res. 164, 28–37 (2010).

    PubMed  Google Scholar 

  114. Torres, A., Torres, K., Paszkowski, T., Staskiewicz, G. J. & Maciejewski, R. Cytokine response in the postoperative period after surgical treatment of benign adnexal masses: comparison between laparoscopy and laparotomy. Surg. Endosc. 21, 1841–1848 (2007).

    CAS  PubMed  Google Scholar 

  115. Sammour, T., Kahokehr, A., Zargar-Shoshtari, K. & Hill, A. G. A prospective case-control study of the local and systemic cytokine response after laparoscopic versus open colonic surgery. J. Surg. Res. 173, 278–285 (2012).

    CAS  PubMed  Google Scholar 

  116. Wichmann, M. W. et al. Immunological effects of laparoscopic vs open colorectal surgery: a prospective clinical study. Arch. Surg. 140, 692–697 (2005).

    PubMed  Google Scholar 

  117. Landman, J. et al. Prospective comparison of the immunological and stress response following laparoscopic and open surgery for localized renal cell carcinoma. J. Urol. 171, 1456–1460 (2004).

    PubMed  Google Scholar 

  118. Hu, J. K. et al. Comparative evaluation of immune response after laparoscopical and open total mesorectal excisions with anal sphincter preservation in patients with rectal cancer. World J. Gastroenterol. 9, 2690–2694 (2003).

    PubMed  PubMed Central  Google Scholar 

  119. Solomon, M. J., Young, C. J., Eyers, A. A. & Roberts, R. A. Randomized clinical trial of laparoscopic versus open abdominal rectopexy for rectal prolapse. Br. J. Surg. 89, 35–39 (2002).

    CAS  PubMed  Google Scholar 

  120. Lacy, A. M. et al. Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: a randomised trial. Lancet 359, 2224–2229 (2002).

    PubMed  Google Scholar 

  121. Kuhry, E., Schwenk, W. F., Gaupset, R., Romild, U. & Bonjer, H. J. Long-term results of laparoscopic colorectal cancer resection. Cochrane Database of Systematic Review, Issue 2. Art. No.: CD003432. http://dx.doi.org/10.1002/14651858.CD003432.pub2.

  122. Galaal, K. et al. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database of Systematic Review, Issue 9. Art. No.: CD006655. http://dx.doi.org/10.1002/14651858.CD006655.pub2.

  123. Lawrie, T. A. et al. Laparoscopy versus laparotomy for FIGO stage I ovarian cancer. Cochrane Database of Systematic Review, Issue 2. Art. No.: CD005344. http://dx.doi.org/10.1002/14651858.CD005344.pub3.

  124. Sorski, L. et al. The impact of surgical extent and sex on the hepatic metastasis of colon cancer. Surg. Today 44, 1925–1934 (2014).

    PubMed  Google Scholar 

  125. Sorski, L. et al. Do minimally-invasive surgical procedures reduce colorectal cancer progression? A severity-independent need for arresting surgically-induced stress responses using β-adrenergic blockers and COX2 inhibitors. Brain Behav. Immun. 25, S200 (2011).

    Google Scholar 

  126. Hrushesky, W. J., Bluming, A. Z., Gruber, S. A. & Sothern, R. B. Menstrual influence on surgical cure of breast cancer. Lancet 2, 949–952 (1989).

    CAS  PubMed  Google Scholar 

  127. Badwe, R. A. et al. Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. Lancet 337, 1261–1264 (1991).

    CAS  PubMed  Google Scholar 

  128. Lemon, H. M. & Rodriguez-Sierra, J. F. Timing of breast cancer surgery during the luteal menstrual phase may improve prognosis. Nebr. Med. J. 81, 73–78 (1996).

    CAS  PubMed  Google Scholar 

  129. Samuel, M., Wai, K. L., Brennan, V. K. & Yong, W. S. Timing of breast surgery in premenopausal breast cancer patients. Cochrane Database of Systematic Review, Issue 5. Art. No.: CD003720. http://dx.doi.org/10.1002/14651858.CD003720.pub2.

  130. Ben-Eliyahu, S., Page, G. G., Shakhar, G. & Taylor, A. N. Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: possible role of oestradiol and natural killer cells. Br. J. Cancer 74, 1900–1907 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ben-Eliyahu, S., Shakhar, G., Shakhar, K. & Melamed, R. Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis: possible clinical implications. Br. J. Cancer 83, 1747–1754 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Shakhar, K., Shakhar, G., Rosenne, E. & Ben-Eliyahu, S. Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity. Br. J. Cancer 83, 1630–1636 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Page, G. G. & Ben-Eliyahu, S. Increased surgery-induced metastasis and suppressed natural killer cell activity during proestrus/estrus in rats. Breast Cancer Res. Treat. 45, 159–167 (1997).

    CAS  PubMed  Google Scholar 

  134. Wheeldon, N. M. et al. Influence of sex-steroid hormones on the regulation of lymphocyte β2-adrenoceptors during the menstrual cycle. Br. J. Clin. Pharmacol. 37, 583–588 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Grant, C. S. et al. Menstrual cycle and surgical treatment of breast cancer: findings from the NCCTG N9431 study. J. Clin. Oncol. 27, 3620–3626 (2009).

    PubMed  PubMed Central  Google Scholar 

  136. Lutgendorf, S., Costanzo, E. & Siegel, S. Psychosocial influences in oncology: an expanded model of biobehavioral mechanisms. Psychoneuroimmunology 4, 869–896 (2007).

    Google Scholar 

  137. Garssen, B., Boomsma, M. F. & Beelen, R. H. Psychological factors in immunomodulation induced by cancer surgery: a review. Biol. Psychol. 85, 1–13 (2010).

    PubMed  Google Scholar 

  138. Stefanski, V. & Ben-Eliyahu, S. Social confrontation and tumor metastasis in rats: defeat and β-adrenergic mechanisms. Physiol. Behav. 60, 277–282 (1996).

    CAS  PubMed  Google Scholar 

  139. Fawzy, F. I. et al. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch. Gen. Psychiatry 50, 681–689 (1993).

    CAS  PubMed  Google Scholar 

  140. Kuchler, T., Bestmann, B., Rappat, S., Henne-Bruns, D. & Wood-Dauphinee, S. Impact of psychotherapeutic support for patients with gastrointestinal cancer undergoing surgery: 10-year survival results of a randomized trial. J. Clin. Oncol. 25, 2702–2708 (2007).

    PubMed  Google Scholar 

  141. Andersen, B. L. et al. Psychologic intervention improves survival for breast cancer patients: a randomized clinical trial. Cancer 113, 3450–3458 (2008).

    PubMed  Google Scholar 

  142. Andersen, B. L. et al. Stress and immune responses after surgical treatment for regional breast cancer. J. Natl Cancer Inst. 90, 30–36 (1998).

    CAS  PubMed  Google Scholar 

  143. Koga, C. et al. Anxiety and pain suppress the natural killer cell activity in oral surgery outpatients. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 91, 654–658 (2001).

    CAS  PubMed  Google Scholar 

  144. Levy, S. M. et al. Perceived social support and tumor estrogen/progesterone receptor status as predictors of natural killer cell activity in breast cancer patients. Psychosom. Med. 52, 73–85 (1990).

    CAS  PubMed  Google Scholar 

  145. Phillips, K. M. et al. Stress management intervention reduces serum cortisol and increases relaxation during treatment for nonmetastatic breast cancer. Psychosom. Med. 70, 1044–1049 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Antoni, M. H. et al. Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics. Biol. Psychiatry 71, 366–372 (2012).

    CAS  PubMed  Google Scholar 

  147. Ross, L., Boesen, E. H., Dalton, S. O. & Johansen, C. Mind and cancer: does psychosocial intervention improve survival and psychological well-being? Eur. J. Cancer 38, 1447–1457 (2002).

    CAS  PubMed  Google Scholar 

  148. Edelman, S., Lemon, J., Bell, D. R. & Kidman, A. D. Effects of group CBT on the survival time of patients with metastatic breast cancer. Psychooncology 8, 474–481 (1999).

    CAS  PubMed  Google Scholar 

  149. Ross, L. et al. No effect on survival of home psychosocial intervention in a randomized study of Danish colorectal cancer patients. Psychooncology 18, 875–885 (2009).

    PubMed  Google Scholar 

  150. Huhmann, M. B. & August, D. A. Perioperative nutrition support in cancer patients. Nutr. Clin. Pract. 27, 586–592 (2012).

    PubMed  Google Scholar 

  151. Gupta, D. & Lis, C. G. Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutr. J. 9, 69 (2010).

    PubMed  PubMed Central  Google Scholar 

  152. Buijs, N. et al. Perioperative arginine-supplemented nutrition in malnourished patients with head and neck cancer improves long-term survival. Am. J. Clin. Nutr. 92, 1151–1156 (2010).

    CAS  PubMed  Google Scholar 

  153. Winkels, R. M. et al. The COLON study: Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that may influence colorectal tumour recurrence, survival and quality of life. BMC Cancer 14, 374 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  155. Rothwell, P. M. et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379, 1602–1612 (2012).

    CAS  PubMed  Google Scholar 

  156. 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).

    CAS  PubMed  Google Scholar 

  157. Powe, D. G. et al. β-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1, 628–638 (2010).

    PubMed  PubMed Central  Google Scholar 

  158. Watkins, J. et al. Improved outcomes with beta blocker use in epithelial ovarian cancer patients [abstract]. Gynecol. Oncol. 130, e31 (2013).

    Google Scholar 

  159. 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).

    PubMed  Google Scholar 

  160. Martin, L. A. et al. Pre-surgical study of the biological effects of the selective cyclo-oxygenase-2 inhibitor celecoxib in patients with primary breast cancer. Breast Cancer Res. Treat. 123, 829–836 (2010).

    PubMed  Google Scholar 

  161. Dhawan, D. et al. Effects of short-term celecoxib treatment in patients with invasive transitional cell carcinoma of the urinary bladder. Mol. Cancer. Ther. 9, 1371–1377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 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 

  163. Forget, P. et al. Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery. Ann. Surg. Oncol. 20 (Suppl. 3), 650–660 (2013).

    Google Scholar 

  164. Melhem-Bertrandt, A. et al. β-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 2645–2652 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Lemeshow, S. et al. β-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol. Biomarkers Prev. 20, 2273–2279 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Hazut, O. et al. The effect of β-adrenergic blockade and COX-2 inhibition on healing of colon, muscle, and skin in rats undergoing colonic anastomosis. Int. J. Clin. Pharmacol. Ther. 49, 545–554 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. US National Library of Medicine. ClinicalTrials.gov [online], (2011).

  168. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  169. Rader, D. J. & Hobbs, H. H. in Harrisons Principles of Internal Medicine 16th edn Ch. 335 (ed. Kasper D. L.) 2286–2319 (McGraw-Hill, 2005).

    Google Scholar 

  170. Narisawa, T. et al. Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, of N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats. Jpn J. Cancer Res. 87, 798–804 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Berquin, I. M., Edwards, I. J. & Chen, Y. Q. Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett. 269, 363–377 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Liakopoulos, O. J. et al. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients. Eur. Heart J. 29, 1548–1559 (2008).

    PubMed  Google Scholar 

  173. Graaf, M. R., Richel, D. J., van Noorden, C. J. & Guchelaar, H. J. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat. Rev. 30, 609–641 (2004).

    CAS  PubMed  Google Scholar 

  174. Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 367, 1792–1802 (2012).

    CAS  PubMed  Google Scholar 

  175. Poynter, J. N. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184–2192 (2005).

    CAS  PubMed  Google Scholar 

  176. Hamilton, R. J. et al. Statin medication use and the risk of biochemical recurrence after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database. Cancer 116, 3389–3398 (2010).

    CAS  PubMed  Google Scholar 

  177. Dellavalle, R. P. et al. Statins and fibrates for preventing melanoma. Cochrane Database of Systematic Review, Issue 4. Art. No.: CD003697. http://dx.doi.org/10.1002/14651858.CD003697.pub2.

  178. Kawata, S. et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br. J. Cancer 84, 886–891 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Matar, P. et al. Inhibitory effect of lovastatin on spontaneous metastases derived from a rat lymphoma. Clin. Exp. Metastasis 17, 19–25 (1999).

    CAS  PubMed  Google Scholar 

  180. Garwood, E. R. et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res. Treat. 119, 137–144 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Pollack, A. et al. Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92–02. J. Clin. Oncol. 22, 2133–2140 (2004).

    CAS  PubMed  Google Scholar 

  182. Zhao, J. et al. TIP30/CC3 expression in breast carcinoma: relation to metastasis, clinicopathologic parameters, and p53 expression. Human Pathology 38, 293–298 (2007).

    CAS  PubMed  Google Scholar 

  183. Weiss, G. et al. Immunomodulation by perioperative administration of n-3 fatty acids. Br. J. Nutr. 87 (Suppl. 1), S89–S94 (2002).

    CAS  PubMed  Google Scholar 

  184. Ates, E. et al. Perioperative immunonutrition ameliorates the postoperative immune depression in patients with gastrointestinal system cancer (prospective clinical study in 42 patients). Acta Gastroenterol. Belg. 67, 250–254 (2004).

    CAS  PubMed  Google Scholar 

  185. Berger, M. M. et al. Three short perioperative infusions of n-3 PUFAs reduce systemic inflammation induced by cardiopulmonary bypass surgery: a randomized controlled trial. Am. J. Clin. Nutr. 97, 246–254 (2013).

    CAS  PubMed  Google Scholar 

  186. Goldfarb, Y. et al. Fish oil attenuates surgery-induced immunosuppression, limits post-operative metastatic dissemination and increases long-term recurrence-free survival in rodents inoculated with cancer cells. Clin. Nutr. 31, 396–404 (2012).

    CAS  PubMed  Google Scholar 

  187. Murphy, R. A. et al. Supplementation with fish oil increases first-line chemotherapy efficacy in patients with advanced nonsmall cell lung cancer. Cancer 117, 3774–3780 (2011).

    CAS  PubMed  Google Scholar 

  188. Hubbard, N. E., Lim, D. & Erickson, K. L. Alteration of murine mammary tumorigenesis by dietary enrichment with n-3 fatty acids in fish oil. Cancer Lett. 124, 1–7 (1998).

    CAS  PubMed  Google Scholar 

  189. Calder, P. C. n-3 fatty acids, inflammation, and immunity—relevance to postsurgical and critically ill patients. Lipids 39, 1147–1161 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Tziakas, D. N. et al. Effect of statins on collagen type I degradation in patients with coronary artery disease and atrial fibrillation. Am. J. Cardiol. 101, 199–202 (2008).

    CAS  PubMed  Google Scholar 

  191. Dernellis, J. & Panaretou, M. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation. Am. Heart J. 150, 1064 (2005).

    PubMed  Google Scholar 

  192. Hakamada-Taguchi, R. et al. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces TH1 development and promotes TH2 development. Circ. Res. 93, 948–956 (2003).

    CAS  PubMed  Google Scholar 

  193. Ikeda, U. & Shimada, K. Statins and monocytes. Lancet 353, 2070 (1999).

    CAS  PubMed  Google Scholar 

  194. Thibault, A. et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin. Cancer Res. 2, 483–491 (1996).

    CAS  PubMed  Google Scholar 

  195. Jakobisiak, M., Bruno, S., Skierski, J. S. & Darzynkiewicz, Z. Cell cycle-specific effects of lovastatin. Proc. Natl Acad. Sci. USA 88, 3628–3632 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Dimitroulakos, J. et al. Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 93, 1308–1318 (1999).

    CAS  PubMed  Google Scholar 

  197. Dimitroulakos, J. & Yeger, H. HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells. Nat. Med. 2, 326–333 (1996).

    CAS  PubMed  Google Scholar 

  198. Dimitroulakos, J. et al. Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin. Cancer Res. 7, 158–167 (2001).

    CAS  PubMed  Google Scholar 

  199. Xiao, H. & Yang, C. S. Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention. Int. J. Cancer 123, 983–990 (2008).

    CAS  PubMed  Google Scholar 

  200. Xiao, H., Zhang, Q., Lin, Y., Reddy, B. S. & Yang, C. S. Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int. J. Cancer 122, 2115–2124 (2008).

    CAS  PubMed  Google Scholar 

  201. Zheng, X. et al. Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin. Cancer Res. 13, 5480–5487 (2007).

    CAS  PubMed  Google Scholar 

  202. Reddy, B. S. et al. Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. Cancer Res. 66, 4542–4546 (2006).

    CAS  PubMed  Google Scholar 

  203. Avraham, R. et al. Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression. Brain Behav. Immun. 24, 952–958 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Bohm, M. et al. Pretreatment with interleukin-2 modulates perioperative immunodysfunction in patients with renal cell carcinoma. Folia Biol. (Praha) 49, 63–68 (2003).

    CAS  Google Scholar 

  205. Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 (2006).

    CAS  PubMed  Google Scholar 

  206. Novakovic, S., Stegel, V., Kopitar, A., Ihan, A. & Novakovic, B. J. Preventive and therapeutic antitumor effect of tumor vaccine composed of CpG ODN class C and irradiated tumor cells is triggered through the APCs and activation of CTLs. Vaccine 25, 8241–8256 (2007).

    CAS  PubMed  Google Scholar 

  207. Kunikata, N. et al. Peritumoral CpG oligodeoxynucleotide treatment inhibits tumor growth and metastasis of B16F10 melanoma cells. J. Invest. Dermatol. 123, 395–402 (2004).

    CAS  PubMed  Google Scholar 

  208. Kuramoto, Y., Nishikawa, M., Hyoudou, K., Yamashita, F. & Hashida, M. Inhibition of peritoneal dissemination of tumor cells by single dosing of phosphodiester CpG oligonucleotide/cationic liposome complex. J. Control Release 115, 226–233 (2006).

    CAS  PubMed  Google Scholar 

  209. Goldfarb, Y. et al. CpG-C oligodeoxynucleotides limit the deleterious effects of β-adrenoceptor stimulation on NK cytotoxicity and metastatic dissemination. J. Immunother. 32, 280–291 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Lubaroff, D. M. et al. Phase I clinical trial of an adenovirus/prostate-specific antigen vaccine for prostate cancer: safety and immunologic results. Clin. Cancer Res. 15, 7375–7380 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Smith, D. A. et al. Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy [abstract]. J. Clin. Oncol. 30 (Suppl.), e18047 (2012).

    Google Scholar 

  212. Behzad, H. et al. GLA-SE, a synthetic Toll-like receptor 4 agonist, enhances T-cell responses to influenza vaccine in older adults. J. Infect. Dis. 205, 466–473 (2012).

    CAS  PubMed  Google Scholar 

  213. Matzner, P. et al. 87. The use of the newly developed synthetic TLR-4 agonistas an immuno-therapeutic agent in a cancer model. Brain Behav. Immun. 32 (Suppl.), e25 (2013).

    Google Scholar 

  214. Schwartz, Y., Avraham, R., Benish, M., Rosenne, E. & Ben-Eliyahu, S. Prophylactic IL-12 treatment reduces postoperative metastasis: mediation by increased numbers but not cytotoxicity of NK cells. Breast Cancer Res. Treat. 107, 211–223 (2008).

    CAS  PubMed  Google Scholar 

  215. Faries, M. B., Hsueh, E. C., Ye, X., Hoban, M. & Morton, D. L. Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin. Cancer Res. 15, 7029–7035 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Varadhan, K. K., Lobo, D. N. & Ljungqvist, O. Enhanced recovery after surgery: the future of improving surgical care. Crit. Care Clin. 26, 527–547 (2010).

    PubMed  Google Scholar 

  217. Gatt, M., Khan, S. & MacFie, J. In response to: Varadhan KK, Neal KR, Dejong CH, Fearon KC, Ljungqvist O, Lobo DN. The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin. Nutr. 29 434–440 (2010).

    Google Scholar 

  218. Lv, L., Shao, Y. F. & Zhou, Y. B. The enhanced recovery after surgery (ERAS) pathway for patients undergoing colorectal surgery: an update of meta-analysis of randomized controlled trials. Int. J. Colorectal Dis. 27, 1549–1554 (2012).

    PubMed  Google Scholar 

  219. Ren, L. et al. Enhanced Recovery After Surgery (ERAS) program attenuates stress and accelerates recovery in patients after radical resection for colorectal cancer: a prospective randomized controlled trial. World J. Surg. 36, 407–414 (2012).

    CAS  PubMed  Google Scholar 

  220. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Psychological Sciences, Sharet Building, Tel Aviv University, Tel Aviv, 6997801, Israel

    Maya Horowitz, Elad Neeman & Shamgar Ben-Eliyahu

  2. Department of Surgery, Rabin Medical Center, Beilinson Hospital, Petach-Tikva, 49100, Israel

    Eran Sharon

Authors
  1. Maya Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elad Neeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eran Sharon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shamgar Ben-Eliyahu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.H. and E.N. researched data for article. All authors provided substantial contribution to discussion of content, reviewed and edited the manuscript before submission. M.H., E.N. and S.B.-E. wrote the manuscript.

Corresponding author

Correspondence to Shamgar Ben-Eliyahu.

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

Horowitz, M., Neeman, E., Sharon, E. et al. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol 12, 213–226 (2015). https://doi.org/10.1038/nrclinonc.2014.224

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2014.224

This article is cited by

Search

Advanced 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