Regional Analgesia Does Not Reduce Cancer Recurrence. Case closed

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Rod J. Nault Quinton Riter Daniel I. Sessler


Cancer is the second-leading cause of death worldwide. The initial treatment for nearly all solid cancers is surgical resection of a primary tumor. While tumors can usually be grossly removed, surgical interventions release tumor cells into the lymphatics and vascular beds1. Whether circulating tumor cells develop into clinical metastases depends largely on host defense, mostly natural killer cell function2,3.

Surgery and opioids have the potential to shift the disease-patient relationship towards cancers via at least three major avenues. One is the surgical intervention itself that depresses cell-mediated immunity, reduces concentrations of anti-angiogenic factors, and increases pro-angiogenic factors and release of growth factors that stimulate cancer cells1,3-8. Another factor is general anesthesia, which impairs the function of several immune cells important for anti-metastatic immune activity9. A third factor is the use of opioids for pain management which inhibit cellular and humoral immunity, and might even promote angiogenesis and tumor growth10-12.

Regional anesthesia and analgesia techniques attenuate perioperative tumor-promoting effects by blocking afferent signaling to the central nervous system. Thus, regional techniques might reduce the neuroendocrine response to surgery more effectively than general anesthesia. Furthermore, regional analgesia decreases the need for volatile anesthetics and opioids. Regional analgesia might thus help maintain perioperative anti-cancer immune function, notably natural killer cell activity, and thus reduce the risk of circulating tumor cells developing into clinical metastases13-16.

Potential benefit of regional analgesia for cancer recurrence is supported by animal investigations. For example, a study in rats compared halothane alone combined with either systemic morphine or with spinal block using bupivacaine with morphine. General anesthesia alone increased tumor retention in the lungs by up to 17-fold.  Additionally, natural killer cell activity was depressed by general anesthesia7. Another study compared general anesthesia with sevoflurane alone versus spinal blocks combining bupivacaine and morphine. Addition of the spinal block to general anesthesia attenuated suppression of tumoricidal liver mononuclear cells and consequently reduced promotion of tumor metastasis17. Animal evidence is thus largely consistent in suggesting benefit from regional analgesia and from reducing volatile anesthesia and opioid use.

Subsequent retrospective analyses in humans were encouraging. One compared combined general anesthesia with paravertebral analgesia versus general with morphine analgesia for breast cancer and reported that paravertebral analgesia reduced cancer recurrence18.  Another retrospective analysis reported that epidural analgesia reduced biochemical recurrence of prostate cancer by 57%19. However, many other retrospective analyses found no association between regional anesthesia and cancer outcomes20-23, leaving the overall record mixed.

Because purpose-designed trials of cancer recurrence naturally take a long time, investigators initially re-purposed previous randomized trials that were conducted for other purposes. For example, a team re-evaluated patients who participated in the MASTER trial.24 They identified 503 patients who had surgery for cancer and were able to obtain long-term follow-up information in 446 of them. Two other re-analyses evaluated 99 patients who had prostatectomies for prostate cancer comparing general to general plus epidural analgesia and 132 patients who had intra-abdominal surgery via midline or bilateral subcostal incisions for non-benign cancer resection comparing general anesthesia with epidural blocks versus with fentanyl analgesia followed by continuous subcutaneous morphine. None of these trials demonstrated notable differences in cancer-associated outcomes25,26. The only exception was a re-analysis that compared survival in patients randomized to general anesthesia with and without epidural supplementation for colon cancer surgery. A post hoc subgroup analysis implausibly found enhanced survival in the epidural group only in patients without metastasis before 1.5 years27. Analyses of trials conducted for other purposes thus provide little support for a benefit of regional analgesia for reducing cancer recurrence.

There have been three major trials of regional analgesia on cancer recurrence. The first randomized 2,132 patients having potentially curative primary breast cancer surgery to paravertebral analgesia or conventional opioid analgesia. Cancer recurrence was similar in each group after a median follow-up time of 36 months (hazard ratio 0.97, 95% CI 0.74–1.28; p=0.84). The authors noted that breast surgery causes less operative stress and pain than major abdominal and thoracic surgery, and postulated that regional analgesia might yet be beneficial for such cases.28

The next trial therefore compared overall survival and cancer-free survival in patients randomized to combined general-epidural anesthesia versus general anesthesia alone for major abdominal cancer resections. In a total of 1,712 patients with a median follow-up duration of 66 months, there were no differences in terms of mortality (adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408) or recurrence-free survival (adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692)29.

The third major trial randomized 400 patients having video-assisted thoracoscopic lung cancer resection to general anesthesia alone or general anesthesia combined with thoracic epidural analgesia. At a median follow-up duration of 32 months, epidural analgesia did not reduce recurrence-free (adjusted hazard ratio, 0.90; 95% CI, 0.60 to 1.35; P = 0.608), overall (adjusted hazard ratio, 1.12; 95% CI, 0.64 to 1.96; P = 0.697), or cancer-specific survival (adjusted hazard ratio, 1.08; 95% CI, 0.61 to 1.91; P = 0.802).30 Thus, even when restricting analysis to patients experiencing high surgical stress and considerable postoperative pain, regional techniques failed to reduce cancer recurrence.

While regional anesthetic techniques have many benefits, three robust trials which randomized a total of 4,244 patients conclusively demonstrate that regional analgesia does not reduce recurrence of breast, abdominal, and lung cancer (Figure). Given the quality and diversity of evidence, further investigations into regional analgesia are unlikely to prove fertile. Case closed. Instead, perioperative investigators might better focus on comparisons between volatile and intravenous anesthesia31-33, and on adjuncts such as COX-2 inhibitors34,35 and lidocaine36.






























Figure legend: Forest plot of hazard ratios for cancer recurrence and recurrence-free survival from three major trials of regional analgesia in patients having cancer surgery. There was no evidence of benefit in any of the trials.




Corresponding author

Daniel I. Sessler, MD,

Michael Cudahy Professor and Chair,

Department of Outcomes Research,

Anesthesiology Institute, Cleveland Clinic,

9500 Euclid Ave

Ave — L1-407, Cleveland, OH 44195, USA.

Tel: 216-870-2620,

Email: [email protected]



Conflict of Interest Statement

None of the authors reports relevant conflicts.


Funding Statement

Internal resources only.





Keywords: Regional Analgesia, Cancer Recurrence, Analgesia, Cancer

Article Details

How to Cite
NAULT, Rod J.; RITER, Quinton; SESSLER, Daniel I.. Regional Analgesia Does Not Reduce Cancer Recurrence. Case closed. Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 29 mar. 2023. doi:


Regional Analgesia Does Not Reduce Cancer Recurrence. Case closed

1. Denis MG, Lipart C, Leborgne J, et al. Detection of disseminated tumor cells in peripheral blood of colorectal cancer patients. Int J Cancer. Oct 21 1997; 74(5):540-4.
2. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. Apr 2001; 2(4):293-9. doi:10.1038/86297
3. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol. Oct 2003;10(8):972-92.
4. O'Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. Jan 24 1997;88(2):277-85. doi:10.1016/s0092-8674(00)81848-6
5. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407-24.
6. Wong IH, Lau WY, Leung T, Yeo W, Johnson PJ. Hematogenous dissemination of hepatocytes and tumor cells after surgical resection of hepatocellular carcinoma: a quantitative analysis. Clin Cancer Res. Dec 1999;5(12):4021-7.
7. Bar-Yosef S, Melamed R, Page GG, Shakhar G, Shakhar K, Ben-Eliyahu S. Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology. Jun 2001;94(6):1066-73.
8. Antoni MH, Lutgendorf SK, Cole SW, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer. Mar 2006; 6(3):240-8.
9. Brand JM, Kirchner H, Poppe C, Schmucker P. The effects of general anesthesia on human peripheral immune cell distribution and cytokine production. Clin Immunol Immunopathol. 1997; 83(2):190-4.
10. Beilin B, Shavit Y, Hart J, et al. Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg. Mar 1996;82(3):492-7.
11. Sacerdote P, Bianchi M, Gaspani L, et al. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg. Jun 2000;90(6):1411-4.
12. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. Aug 1 2002; 62(15):4491-8.
13. Chae BK, Lee HW, Sun K, Choi YH, Kim HM. The effect of combined epidural and light general anesthesia on stress hormones in open heart surgery patients. Surg Today. 1998;28(7):727-31.
14. Buggy DJ, Smith G. Epidural anaesthesia and analgesia: better outcome after major surgery?. Growing evidence suggests so. Bmj. Aug 28 1999;319(7209):530-1.
15. Hodgson PS, Liu SS. Epidural lidocaine decreases sevoflurane requirement for adequate depth of anesthesia as measured by the Bispectral Index monitor. Anesthesiology. May 2001;94(5):799-803.
16. O'Riain SC, Buggy DJ, Kerin MJ, Watson RWG, Moriarty DC. Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth Analg. Jan 2005;100(1):244-249. doi: 10.1213/01.Ane.0000143336.37946.7d
17. Wada H, Seki S, Takahashi T, et al. Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology. Mar 2007;106(3):499-506.
18. Exadaktylos Aristomenis K, Buggy Donal J, Moriarty Denis C, Mascha E, Sessler Daniel I. Can Anesthetic Technique for Primary Breast Cancer Surgery Affect Recurrence or Metastasis? Anesthesiology. 2006;105(4):660-664. doi:10.1097/00000542-200610000-00008
19. Biki B, Mascha E, Moriarty Denis C, Fitzpatrick John M, Sessler Daniel I, Buggy Donal J. Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrence: A Retrospective Analysis. Anesthesiology. 2008;109(2):180-187. doi: 10.1097/ALN.0b013e31817f5b73
20. Gottschalk A, Ford JG, Regelin CC, et al. Association between Epidural Analgesia and Cancer Recurrence after Colorectal Cancer Surgery. Anesthesiology. 2010; 113(1):27-34. doi:10.1097/ALN.0b013e3181de6d0d
21. Forget P, Tombal B, Scholtès JL, et al. Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer? Eur J Anaesthesiol. Dec 2011;28(12):830-5. doi: 10.1097/EJA.0b013e32834b7d9a
22. Day A, Smith R, Jourdan I, Fawcett W, Scott M, Rockall T. Retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer. Br J Anaesth. Aug 2012;109(2):185-90. doi: 10.1093/bja/aes106
23. Cata JP, Chavez-MacGregor M, Valero V, et al. The Impact of Paravertebral Block Analgesia on Breast Cancer Survival After Surgery. Reg Anesth Pain Med. Nov/Dec 2016;41(6):696-703. doi:10.1097/AAP.0000000000000479
24. Myles PS, Peyton P, Silbert B, et al. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ. Mar 29 2011;342:d1491. doi: 10.1136/bmj.d1491
25. Tsui BC, Rashiq S, Schopflocher D, et al. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anaesth. Feb 2010;57(2):107-12. doi: 10.1007/s12630-009-9214-7
26. Binczak M, Tournay E, Billard V, Rey A, Jayr C. Major abdominal surgery for cancer: Does epidural analgesia have a long-term effect on recurrence-free and overall survival? Annales Françaises d'Anesthésie et de Réanimation. 2013/05/01/ 2013;32(5):e81-e88.
27. Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia. Anesth Analg. Jul 2008; 107(1):325-32.
28. Sessler DI, Pei L, Huang Y, et al. Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial. Lancet. Nov 16 2019; 394(10211):1807-1815. doi:10.1016/S0140-6736(19)32313-X
29. Du Y-T, Li Y-W, Zhao B-J, et al. Long-term Survival after Combined Epidural–General Anesthesia or General Anesthesia Alone: Follow-up of a Randomized Trial. Anesthesiology. 2021;135(2):233-245.
30. Xu Z-Z, Li H-J, Li M-H, et al. Epidural Anesthesia–Analgesia and Recurrence-free Survival after Lung Cancer Surgery: A Randomized Trial. Anesthesiology. 2021;135(3):419-432. doi:10.1097/ALN.0000000000003873
31. 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. Nov 2003;97(5): 1331-1339. doi:10.1213/01.Ane.0000082995.44040.07
32. Makito K, Matsui H, Fushimi K, Yasunaga H. Volatile versus Total Intravenous Anesthesia for Cancer Prognosis in Patients Having Digestive Cancer Surgery. Anesthesiology. Oct 1 2020;133(4):764-773.
33. Lee S, Pyo DH, Sim WS, Lee WY, Park M. Early and Long-Term Outcomes after Propofol-and Sevoflurane-Based Anesthesia in Colorectal Cancer Surgery: A Retrospective Study. J Clin Med. May 8 2022;11(9) doi:10.3390/jcm11092648
34. Menter DG, Schilsky RL, DuBois RN. Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward. Clin Cancer Res. Mar 1 2010;16(5):1384-90. doi:10.1158/1078-0432.Ccr-09-0788
35. Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, et al. Low-dose Aspirin, Nonsteroidal Anti-inflammatory Drugs, Selective COX-2 Inhibitors and Breast Cancer Recurrence. Epidemiology. Jul 2016;27(4):586-93. doi:10.1097/ede.0000000000000480
36. Xing W, Chen DT, Pan JH, et al. Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo. Anesthesiology. May 2017;126(5):868-881.