Rationale and Design of the CAN Study: an RCT of Survival after Propofol- or Sevoflurane-based Anesthesia for Cancer Surgery

Author(s): Mats Enlund*, Anna Enlund, Anders Berglund, Leif Bergkvist

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 28 , 2019


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Abstract:

Background: Based on animal data only, some clinicians have adopted propofol-based anesthesia for cancer surgery with the aim of increased survival.

Objective: Our objective is to verify or refute the hypothesis that survival increases after cancer surgery with propofol compared with sevoflurane for anesthesia maintenance. This aim deserves a large-scale randomized study. The primary hypothesis is an absolute increase of minimum 5%-units in 1- and 5-year survival with propofol- based anesthesia for breast or colorectal cancer after radical surgery, compared with sevoflurane-based anesthesia.

Method: Ethics and medical agency approvals were received and pre-study registrations at clinicaltrial.gov and EudraCT were made for our now ongoing prospective, randomized, open-label, multicenter study. A power analysis based on a retrospective study, including a safety margin for drop outs, resulted in a total requirement of 8,000 patients. The initial inclusion period constituted a feasibility phase with an emphasis on the functionality of the infrastructure at the contributing centers and at the monitoring organization, as well as on protocol adherence.

Conclusion: The infrastructure and organization work smoothly at the different contributing centers. Protocol adherence is good, and the monitors are satisfied. We expect this trial to be able to either verify or refute that propofol is better than sevoflurane for cancer surgery.

Keywords: Anesthetics/intravenous/inhalational, epidemiology, neoplasm recurrence, surgery, survival, inclusion period.

[1]
Lundy J, Lovett EJ III, Hamilton S, Conran P. Halothane, surgery, immunosuppression and artificial pulmonary metastases. Cancer 1978; 41(3): 827-30.
[http://dx.doi.org/10.1002/1097-0142(197803)41:3<827:AID-CNCR2820410307>3.0.CO;2-#] [PMID: 638970]
[2]
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 2003; 97(5): 1331-9.
[http://dx.doi.org/10.1213/01.ANE.0000082995.44040.07] [PMID: 14570648]
[3]
Moudgil GC, Singal DP. Halothane and isoflurane enhance melanoma tumour metastasis in mice. Can J Anaesth 1997; 44: 90-4.
[http://dx.doi.org/10.1007/BF03014331]
[4]
Shapiro J, Jersky J, Katzav S, Feldman M, Segal S. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors. J Clin Invest 1981; 68(3): 678-85.
[http://dx.doi.org/10.1172/JCI110303] [PMID: 7276167]
[5]
Kushida A, Inada T, Shingu K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol Immunotoxicol 2007; 29(3-4): 477-86.
[http://dx.doi.org/10.1080/08923970701675085] [PMID: 18075859]
[6]
Mammoto T, Mukai M, Mammoto A, et al. Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett 2002; 184(2): 165-70.
[http://dx.doi.org/10.1016/S0304-3835(02)00210-0] [PMID: 12127688]
[7]
Gordon RJ. Anesthesia dogmas and shibboleths: Barriers to patient safety? Anesth Analg 2012; 114(3): 694-9.
[http://dx.doi.org/10.1213/ANE.0b013e3182455b86] [PMID: 22358052]
[8]
Enlund M, Berglund A, Andreasson K, Cicek C, Enlund A, Bergkvist L. The choice of anaesthetic--sevoflurane or propofol--and outcome from cancer surgery: A retrospective analysis. Ups J Med Sci 2014; 119(3): 251-61.
[http://dx.doi.org/10.3109/03009734.2014.922649] [PMID: 24857018]
[9]
Wigmore TJ, Mohammed K, Jhanji S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: A retrospective analysis. Anesthesiology 2016; 124(1): 69-79.
[http://dx.doi.org/10.1097/ALN.0000000000000936] [PMID: 26556730]
[10]
Lee JH, Kang SH, Kim Y, Kim HA, Kim BS. Effects of propofol-based total intravenous anesthesia on recurrence and overall survival in patients after modified radical mastectomy: A retrospective study. Korean J Anesthesiol 2016; 69(2): 126-32.
[http://dx.doi.org/10.4097/kjae.2016.69.2.126] [PMID: 27066202]
[11]
Jun IJ, Jo JY, Kim JI, et al. Impact of anesthetic agents on overall and recurrence-free survival in patients undergoing esophageal cancer surgery: A retrospective observational study. Sci Rep 2017; 7(1): 14020.
[http://dx.doi.org/10.1038/s41598-017-14147-9] [PMID: 29070852]
[12]
Zheng X, Wang Y, Dong L, et al. Effects of propofol-based total intravenous anesthesia on gastric cancer: A retrospective study. OncoTargets Ther 2018; 11: 1141-8.
[http://dx.doi.org/10.2147/OTT.S156792] [PMID: 29535538]
[13]
Oh TK, Kim K, Jheon S, et al. Long-term oncologic outcomes for patients undergoing volatile versus intravenous anesthesia for non-small cell lung cancer surgery: A retrospective propensity matching analysis. Cancer control 2018; 25(1)1073274818775360
[http://dx.doi.org/10.1177/1073274818775360]
[14]
Yoo S, Lee H-B, Han W, et al. Total intravenous anesthesia versus inhalation anesthesia for breast cancer surgery: A retrospective cohort study. Anesthesiology 2019; 130(1): 31-40.
[http://dx.doi.org/10.1097/ALN.0000000000002491]
[15]
Buggy DJ, Borgeat A, Cata J, et al. Consensus statement from the BJA Workshop on Cancer and Anaesthesia. Br J Anaesth 2015; 114(1): 2-3.
[http://dx.doi.org/10.1093/bja/aeu262] [PMID: 25104229]
[16]
Inada T, Kubo K, Kambara T, Shingu K. Propofol inhibits cyclo-oxygenase activity in human monocytic THP-1 cells. Can J Anaesth 2009; 56: 222-9.
[17]
Salo M, Pirttikangas CO, Pulkki K. Effects of propofol emulsion and thiopentone on T helper cell type-1/type-2 balance in vitro. Anaesthesia 1997; 52(4): 341-4.
[http://dx.doi.org/10.1111/j.1365-2044.1997.95-pz0084.x] [PMID: 9135186]
[18]
Matsuoka H, Kurosawa S, Horinouchi T, Kato M, Hashimoto Y. Inhalation anesthetics induce apoptosis in normal peripheral lymphocytes in vitro. Anesthesiology 2001; 95(6): 1467-72.
[http://dx.doi.org/10.1097/00000542-200112000-00028] [PMID: 11748407]
[19]
Loop T, Dovi-Akue D, Frick M, et al. Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology 2005; 102(6): 1147-57.
[http://dx.doi.org/10.1097/00000542-200506000-00014] [PMID: 15915027]
[20]
Inada T, Yamanouchi Y, Jomura S, et al. Effect of propofol and isoflurane anaesthesia on the immune response to surgery. Anaesthesia 2004; 59(10): 954-9.
[http://dx.doi.org/10.1111/j.1365-2044.2004.03837.x] [PMID: 15488052]
[21]
Markovic SN, Knight PR, Murasko DM. Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. Anesthesiology 1993; 78(4): 700-6.
[http://dx.doi.org/10.1097/00000542-199304000-00013] [PMID: 8466070]
[22]
Woods GM, Griffiths DM. Reversible inhibition of natural killer cell activity by volatile anaesthetic agents in vitro. Br J Anaesth 1986; 58(5): 535-9.
[http://dx.doi.org/10.1093/bja/58.5.535] [PMID: 3457589]
[23]
Gilliland HE, Armstrong MA, Carabine U, McMurray TJ. The choice of anesthetic maintenance technique influences the antiinflammatory cytokine response to abdominal surgery. Anesth Analg 1997; 85(6): 1394-8.
[http://dx.doi.org/10.1213/00000539-199712000-00039] [PMID: 9390615]
[24]
Ke JJ, Zhan J, Feng XB, Wu Y, Rao Y, Wang YL. A comparison of the effect of total intravenous anaesthesia with propofol and remifentanil and inhalational anaesthesia with isoflurane on the release of pro- and anti-inflammatory cytokines in patients undergoing open cholecystectomy. Anaesth Intensive Care 2008; 36(1): 74-8.
[http://dx.doi.org/10.1177/0310057X0803600113] [PMID: 18326136]
[25]
Schneemilch CE, Bank U. Release of pro- and anti-inflammatory cytokines during different anesthesia procedures Anaesthesiol Reanim 2001; 26(1): 4-10.
[PMID: 11256129]
[26]
Schneemilch CE, Ittenson A, Ansorge S, Hachenberg T, Bank U. Effect of 2 anesthetic techniques on the postoperative proinflammatory and anti-inflammatory cytokine response and cellular immune function to minor surgery. J Clin Anesth 2005; 17(7): 517-27.
[http://dx.doi.org/10.1016/j.jclinane.2004.12.017] [PMID: 16297751]
[27]
Homburger JA, Meiler SE. Anesthesia drugs, immunity, and long-term outcome. Curr Opin Anaesthesiol 2006; 19(4): 423-8.
[http://dx.doi.org/10.1097/01.aco.0000236143.61593.14] [PMID: 16829725]
[28]
Ben-Eliyahu S, Shakhar G, Page GG, Stefanski V, Shakhar K. Suppression of NK cell activity and of resistance to metastasis by stress: A role for adrenal catecholamines and beta-adrenoceptors. Neuroimmunomodulation 2000; 8(3): 154-64.
[http://dx.doi.org/10.1159/000054276] [PMID: 11124582]
[29]
Graziola E, Elena G, Gobbo M, Mendez F, Colucci D, Puig N. Stress, hemodynamic and immunological responses to inhaled and intravenous anesthetic techniques for video-assisted laparoscopic cholecystectomy Rev Esp Anestesiol Reanim 2005; 52(4): 208-16.
[PMID: 15901026]
[30]
Jaloszyński P, Kujawski M, Wasowicz M, Szulc R, Szyfter K. Genotoxicity of inhalation anesthetics halothane and isoflurane in human lymphocytes studied in vitro using the comet assay. Mutat Res 1999; 439(2): 199-206.
[http://dx.doi.org/10.1016/S1383-5718(98)00195-8] [PMID: 10023059]
[31]
Karpiński TM, Kostrzewska-Poczekaj M, Stachecki I, Mikstacki A, Szyfter K. Genotoxicity of the volatile anaesthetic desflurane in human lymphocytes in vitro, established by comet assay. J Appl Genet 2005; 46(3): 319-24.
[PMID: 16110191]
[32]
Wiesner G, Schiewe-Langgartner F, Lindner R, Gruber M. Increased formation of sister chromatid exchanges, but not of micronuclei, in anaesthetists exposed to low levels of sevoflurane. Anaesthesia 2008; 63(8): 861-4.
[http://dx.doi.org/10.1111/j.1365-2044.2008.05498.x] [PMID: 18540930]
[33]
Krause TK, Jansen L, Scholz J, et al. Propofol anesthesia in children does not induce sister chromatid exchanges in lymphocytes. Mutat Res 2003; 542(1-2): 59-64.
[http://dx.doi.org/10.1016/j.mrgentox.2003.08.007] [PMID: 14644354]
[34]
Braz MG, Magalhães MR, Salvadori DM, et al. Evaluation of DNA damage and lipoperoxidation of propofol in patients undergoing elective surgery. Eur J Anaesthesiol 2009; 26(8): 654-60.
[http://dx.doi.org/10.1097/EJA.0b013e328329b12c] [PMID: 19593899]
[35]
Husum B. Mutagenicity of inhalation anaesthetics studied by the sister chromatid exchange test in lymphocytes of patients and operating room personnel. Dan Med Bull 1987; 34(3): 159-70.
[PMID: 3297512]
[36]
Hoerauf KH, Wiesner G, Schroegendorfer KF, et al. Waste anaesthetic gases induce sister chromatid exchanges in lymphocytes of operating room personnel. Br J Anaesth 1999; 82(5): 764-6.
[http://dx.doi.org/10.1093/bja/82.5.764] [PMID: 10536559]
[37]
Takabuchi S, Hirota K, Nishi K, et al. The intravenous anesthetic propofol inhibits hypoxia-inducible factor 1 activity in an oxygen tension-dependent manner. FEBS Lett 2004; 577(3): 434-8.
[http://dx.doi.org/10.1016/j.febslet.2004.10.042] [PMID: 15556623]
[38]
Tanaka T, Takabuchi S, Nishi K, et al. The intravenous anesthetic propofol inhibits lipopolysaccharide-induced hypoxia-inducible factor 1 activation and suppresses the glucose metabolism in macrophages. J Anesth 2010; 24(1): 54-60.
[http://dx.doi.org/10.1007/s00540-009-0829-1] [PMID: 20039079]
[39]
Tavare AN, Perry NJ, Benzonana LL, Takata M, Ma D. Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents. Int J Cancer 2012; 130: 1237-50.
[http://dx.doi.org/10.1002/ijc.26448]
[40]
Benzonana LL, Perry NJ, Watts HR, 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 2013; 119(3): 593-605.
[http://dx.doi.org/10.1097/ALN.0b013e31829e47fd] [PMID: 23774231]
[41]
Huang H, Benzonana LL, Zhao H, et al. Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br J Cancer 2014; 111(7): 1338-49.
[http://dx.doi.org/10.1038/bjc.2014.426] [PMID: 25072260]
[42]
Looney M, Doran P, Buggy DJ. Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor β in women undergoing anesthesia and surgery for breast cancer. Anesthesiology 2010; 113(5): 1118-25.
[http://dx.doi.org/10.1097/ALN.0b013e3181f79a69] [PMID: 20930611]
[43]
Koblin DD. Nitrous oxide: A cause of cancer or chemotherapeutic adjuvant? Semin Surg Oncol 1990; 6(3): 141-7.
[http://dx.doi.org/10.1002/ssu.2980060304] [PMID: 2189194]
[44]
Amos RJ, Amess JA, Hinds CJ, Mollin DL. Incidence and pathogenesis of acute megaloblastic bone-marrow change in patients receiving intensive care. Lancet 1982; 2(8303): 835-8.
[http://dx.doi.org/10.1016/S0140-6736(82)90808-X] [PMID: 6126709]
[45]
Hadzic A, Glab K, Sanborn KV, Thys DM. Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 1995; 83(4): 863-6.
[http://dx.doi.org/10.1097/00000542-199510000-00028] [PMID: 7574068]
[46]
Freier DO, Fuchs BA. A mechanism of action for morphine-induced immunosuppression: Corticosterone mediates morphine-induced suppression of natural killer cell activity. J Pharmacol Exp Ther 1994; 270(3): 1127-33.
[PMID: 7932161]
[47]
Yeager MP, Colacchio TA, Yu CT, et al. Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 1995; 83(3): 500-8.
[http://dx.doi.org/10.1097/00000542-199509000-00008] [PMID: 7661350]
[48]
Flores LR, Dretchen KL, Bayer BM. Potential role of the autonomic nervous system in the immunosuppressive effects of acute morphine administration. Eur J Pharmacol 1996; 318(2-3): 437-46.
[http://dx.doi.org/10.1016/S0014-2999(96)00788-1] [PMID: 9016936]
[49]
Yeager MP, Procopio MA, DeLeo JA, Arruda JL, Hildebrandt L, Howell AL. Intravenous fentanyl increases natural killer cell cytotoxicity and circulating CD16(+) lymphocytes in humans. Anesth Analg 2002; 94(1): 94-9.
[PMID: 11772808]
[50]
Roelen DL, Dover EL, Niimi M, Young NT, Morris PJ, Wood KJ. Semi-allogeneic (F1) versus fully allogeneic blood transfusions: Differences in their ability to induce specific immunological unresponsiveness. Eur J Immunol 1996; 26(7): 1468-74.
[http://dx.doi.org/10.1002/eji.1830260710] [PMID: 8766548]
[51]
Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): An update. Blood Rev 2007; 21(6): 327-48.
[http://dx.doi.org/10.1016/j.blre.2007.07.003] [PMID: 17804128]


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VOLUME: 25
ISSUE: 28
Year: 2019
Page: [3028 - 3033]
Pages: 6
DOI: 10.2174/1381612825666190705184218
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