Anesthesia in Combination with Propofol Increases Disease-Free Survival in Bladder Cancer Patients Who Undergo Radical Tumor Cystectomy as Compared to Inhalational Anesthetics and Opiate-Based Analgesia - Beyond the Abstract
Recurrence is a major concern for oncologic patients. However, a solution has not yet been found to this problem. There is cumulative evidence that anesthesia and analgesia techniques may influence outcomes after cancer surgery. This effect is mediated by induced changes in the immune system and by other mechanisms including the mitigation of surgical stress response.
A prospective study was conducted in patients with infiltrating bladder cancer, who underwent radical cystectomy and received combined anesthesia with propofol as hypnotic and a local anesthetic for analgesia. A comparison was performed of disease-free survival (in days) associated with combined anesthesia versus opioid-based analgesia.
A range of retrospective studies have been published on the influence of the anesthetic technique and cancer outcomes.4-8 A relationship has been suggested between anesthesia and impaired anti-tumor immune cell function as it is the case of NK cells, lymphocytes, and macrophages. The use of opioids and the stimulation of the mu opioid (mu) receptor have been associated with an increased risk for recurrence, as these agents reduce cellular and humoral immunity.9,10
Regional anesthesia seems to improve anti-tumor immunity through lower use of volatile anesthetics and opioids, the reduction of a surgical stress response, and an anti-inflammatory effect mediated by a direct local anesthetic. The anesthetic agent with the strongest association with cancer outcomes is non-muscle invasive bladder cancer (NMIBC), with regional anesthesia being associated with lower recurrence rates and higher disease-free survival.11,12
Pain management with local anesthetics instead of opioids has also been associated with an anti-tumor effect. The use of neuraxial anesthesia stimulates NK function and hinders tumor dissemination. The mechanism by which local anesthetics and neuraxial anesthesia reduce the risk for recurrence and increase disease-free survival may be a reduction of surgical stress response, a lower use of opioids, and its effect on endogenous endorphins.
Pain suppresses NK cell activity. Adequate management of postoperative pain has been documented to preserve the anti-tumor activity of NK cells in animals. Pain activates the hypothalamic-pituitary-adrenal axis (HPA) and activates the sympathetic nerve system, thereby favoring immunosuppression via beta-adrenergic receptors. The sympathetic system blockade attenuates surgery-induced immunosuppression. Therefore, spinal anesthesia preserves NK and TH1 / TH2 cell function.13
As to hypnotics, volatile anesthetics seem to favor mechanisms such as mitogenesis and angiogenesis, which favors the development of metastasis and tumors.15 Isoflurane has been suggested to stimulate tumor proliferation and oncologic angiogenesis, as compared to propofol as a hypnotic. One of the mechanisms by which halogenated agents exert protective effects is the increase in hypoxia-inducible factors (HIFs), which stimulates tumor dissemination.16
Written by: Aida Raigon-Ponferrada, MD, Institute of Biomedical Research in Malaga [IBIMA], Malaga, Spain and Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga, Spain; Alfredo Malo Manso, MD, Institute of Biomedical Research in Malaga [IBIMA], Malaga, Spain and Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga, Spain; Jose Luis Guerrero Orriach, MD, Institute of Biomedical Research in Malaga [IBIMA], Malaga, Spain and Department of Anaesthesiology, Virgen de la Victoria University Hospital, Malaga, Spain, Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, Malaga, Spain, Member of COST Action 15204
References:
1. Kurosawa, Shin. "Anesthesia in patients with cancer disorders." Current Opinion in Anesthesiology 25, no. 3 (2012): 376-384.
2. Hussain, Muzammal, Aqeel Javeed, Muhammad Ashraf, Nuha Al-Zaubai, Alastair Stewart, and Muhammad Mahmood Mukhtar. "Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy." Pharmacological research 66, no. 1 (2012): 7-18.
3. Cassinello, Fernando, Isabel Prieto, Mercedes del Olmo, Sonia Rivas, and Gary R. Strichartz. "Cancer surgery: how may anesthesia influence outcome?." Journal of clinical anesthesia 27, no. 3 (2015): 262-272.
4. Lee, Brenda M., Vinny Singh Ghotra, Jose A. Karam, Mike Hernandez, Greg Pratt, and Juan P. Cata. "Regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: a meta-analysis." Pain management 5, no. 5 (2015): 387-395.5.- -Lusty AJ, Hosier GW, Koti M, Chenard S, Mizubuti GB, Jaeger M, et al. Anesthetic technique and oncological outcomes in urology: A clinical practice review. Urol Oncol. 2019 Dec;37(12):845-852. doi: 10.1016/j.urolonc.2019.08.004.
5. Lusty, Avril J., Gregory W. Hosier, Madhuri Koti, Stephen Chenard, Glenio B. Mizubuti, Melanie Jaeger, and D. Robert Siemens. "Anesthetic technique and oncological outcomes in urology: A clinical practice review." In Urologic Oncology: Seminars and Original Investigations. Elsevier, 2019.
6. Chipollini, Juan, Brandon Alford, David C. Boulware, Patrice Forget, Scott M. Gilbert, Jorge L. Lockhart, Julio M. Pow-Sang et al. "Epidural anesthesia and cancer outcomes in bladder cancer patients: is it the technique or the medication? A matched-cohort analysis from a tertiary referral center." BMC anesthesiology 18, no. 1 (2018): 157.
7. Jang, Dale, Chae Seong Lim, Yong Sup Shin, Young Kwon Ko, Sang Il Park, Seong Hyun Song, and Bum June Kim. "A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis." BMC anesthesiology 16, no. 1 (2015): 16.
8. Choi, Woo-Jong, Seunghee Baek, Eun-Young Joo, Syn-Hae Yoon, Eunkyul Kim, Bumsik Hong, Jai-Hyun Hwang, and Young-Kug Kim. "Comparison of the effect of spinal anesthesia and general anesthesia on 5-year tumor recurrence rates after transurethral resection of bladder tumors." Oncotarget 8, no. 50 (2017): 87667.
9. Kavanagh, Trevor, and Donal J. Buggy. "Can anaesthetic technique effect postoperative outcome?." Current Opinion in Anesthesiology 25, no. 2 (2012): 185-198.
10. Gupta, Kalpna, Smita Kshirsagar, Liming Chang, Robert Schwartz, Ping-Y. Law, Doug Yee, and Robert P. Hebbel. "Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth." Cancer research 62, no. 15 (2002): 4491-4498.
11. Koumpan, Yuri, Melanie Jaeger, Glenio Bitencourt Mizubuti, Rob Tanzola, Kunal Jain, Gregory Hosier, Wilma Hopman, and D. Robert Siemens. "Spinal anesthesia is associated with lower recurrence rates after resection of nonmuscle invasive bladder cancer." The Journal of urology 199, no. 4 (2018): 940-946.
12. Lusty, Avril J., Gregory W. Hosier, Madhuri Koti, Stephen Chenard, Glenio B. Mizubuti, Melanie Jaeger, and D. Robert Siemens. "Anesthetic technique and oncological outcomes in urology: A clinical practice review." In Urologic Oncology: Seminars and Original Investigations. Elsevier, 2019.
13. Wada, Hiroki, Shuhji Seki, Tetsuya Takahashi, Nobuaki Kawarabayashi, Hideyuki Higuchi, Yoshiko Habu, Shinya Sugahara, and Tomiei Kazama. "Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance." Anesthesiology: The Journal of the American Society of Anesthesiologists 106, no. 3 (2007): 499-506.
14. Stollings, Lindsay M., Li-Jie Jia, Pei Tang, Huanyu Dou, Binfeng Lu, and Yan Xu. "Immune modulation by volatile anesthetics." Anesthesiology: The Journal of the American Society of Anesthesiologists 125, no. 2 (2016): 399-411.
15. Tavare, Aniket N., Nicholas JS Perry, Laura L. Benzonana, Masao Takata, and Daqing Ma. "Cancer recurrence after surgery: direct and indirect effects of anesthetic agents." International journal of cancer 130, no. 6 (2012): 1237-1250.
16. Müller-Edenborn, Björn, Birgit Roth-Z'graggen, Kamila Bartnicka, Alain Borgeat, Alexandra Hoos, Lubor Borsig, and Beatrice Beck-Schimmer. "Volatile anesthetics reduce invasion of colorectal cancer cells through down-regulation of matrix metalloproteinase-9." Anesthesiology 117, no. 2 (2012): 293-301.
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