Tom Wall and Donal J. Buggy
Cancer caused nearly 10 million deaths in 2018 and incidence rates are increasing rapidly worldwide.1 Surgery is potentially curative for many cancers. Unfortunately, postoperative metastatic cancer recurrence remains common and is the most frequent cause of death in cancer patients. In recent years a greater understanding has evolved of how perioperative factors influence recurrence risk.2 Malignant cells dispersed during surgery may potentially seed distant organs and progress to clinically significant metastases. The immune system acts to identify and eliminate such tumour cells; however, perioperative conditions (including the surgical stress response, inflammation, blood transfusion, and anaesthesia) might impair immune function or promote cancer cell survival.3 Therefore, conditions induced by the surgical procedure aiming to eliminate the cancer may paradoxically facilitate cancer cell dispersion, survival, and proliferation.
Anaesthesia is suspected of influencing recurrence risk, and laboratory research has produced signals that certain agents have potentially pro-cancer or anti-cancer effects.4Over a decade ago a number of retrospective studies were published suggesting that use of regional anaesthesia (RA) reduced post-operative recurrence risk following prostate cancer and breast cancer surgery.5,6This led to numerous similar retrospective studies reporting varied, often contradictory, results. A recent Cochrane review concluded that current evidence for a benefit of RA on cancer recurrence remains inadequate.7Intriguingly, evidence has emerged from pre-clinical studies suggesting that amide local anaesthetic (LA) agents may possess systemic anti-tumour capabilities independent of their sodium channel blocking effect.8,9
Propofol has been found in laboratory studies to have anti-inflammatory and immune-stimulating properties, whereas volatile anaesthetic agents have largely been associated with cancer-promoting effects including angiogenesis and inflammation.10,11 Retrospective analyses of cancer patients and anaesthetic technique have detected reduced recurrence risk or improved survival in many (but not all) studies comparing propofol anaesthesia versus inhalational agents.12Analgesic agents have also been studied, with pre-clinical evidence that opioids may cause immunosuppression and stimulate cancer growth and therefore potentially increase recurrence risk.13 Conversely, NSAIDs appear to possess beneficial anti-cancer effects from in vitroand epidemiological research, but again clinical trial evidence of postoperative cancer outcome benefits remains inconclusive.14
In summary, signals from laboratory and retrospective clinical data suggest beneficial anti-cancer and anti-metastasis effects with propofol, regional anaesthesia, and NSAIDs, whereas volatile anaesthesia and opioids may have detrimental effects. However, these inferences are not supported by good quality clinical evidence – to produce such evidence requires prospective randomised controlled trial (RCT) data. Such RCTs are difficult to perform, requiring long follow-up periods and large enrolments to be adequately powered. The first such RCT (NCT00418457) studying cancer outcomes after breast cancer surgery comparing propofol-regional versus volatile-opioid techniques will report early in 2019. Other RCTs are also planned or ongoing, including evaluation of the effect of systemic lidocaine on recurrence.15 Until they are completed, there is insufficient evidence to recommend a change in current anaesthetic practice in order to minimise postoperative cancer recurrence risk.16
- Pilleron S, Sarfati D, Janssen-Heijnen M, et al. Int J Cancer2019;144(1):49-58.
- Duff S, Connolly C, Buggy DJ. Int Anesthesiol Clin2016;54:48-57.
- Hiller JG, Perry NJ, Poulogiannis G, et al. Nat Rev Clin Oncol2018;15:205-18.
- Heaney A, Buggy DJ. Br J Anaesth2012;109 Suppl 1:i17-28.
- Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Anesthesiology2006;105:660-4.
- Biki B, Mascha E, Moriarty DC, et al. Anesthesiology2008;109:180-7.
- Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Cochrane Database Syst Rev2014:Cd008877.
- Piegeler T, Votta-Velis EG, Liu G, et al. Anesthesiology2012;117:548-59.
- Johnson MZ, Crowley PD, Foley AG, et al. Br J Anaesth2018;121:76-85.
- Jiang S, Liu Y, Huang L, Zhang F, Kang R. Eur J Pharmacol2018;831:46-51.
- Buckley A, McQuaid S, Johnson P, Buggy DJ. Br J Anaesth2014;113 Suppl 1:i56-62.
- Wigmore TJ, Mohammed K, Jhanji S. Anesthesiology2016;124:69-79.
- Wigmore T, Farquhar-Smith P. Curr Opin Support Palliat Care2016;10:109-18.
- Cata JP, Guerra CE, Chang GJ, et al. Br J Anaesth2017;119:750-64.
- B R. Volatile Anaesthesia and Perioperative Outcomes Related to Cancer (VAPOR-C): A Feasibility Study. 2017. Available from https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373249
- Buggy DJ, Borgeat A, Cata J, et al. Br J Anaesth. 2015;114(1):2-3.