Time to dial down the vaporizer?

Abstract

It is getting close to 10 years ago now that Aristomenis Exadaktylos and colleagues published a paper suggesting that choice of anaesthetic technique might influence cancer recurrence risk after breast cancer surgery. This provocative retrospective study led to a rush of similar investigations – all of them retrospective, although some investigators reanalysed data from previous randomized trials (e.g. Myles performed a re-analysis of a subset of patients enrolled in the MASTER trial – and did not show an effect of epidural use on abdominal cancer recurrence). The results of these various reports have been rather confusing,with somepapers suggesting that regional anaesthesia or adjuncts such as ketorolac are beneficial, yet others finding no outcome effects at all – at times in the same cancer type (e.g. the use of epidural analgesia in colon cancer, 5 or prostate surgery ). For the clinician, faced with clinical choices to make, this is a baffling dataset to deal with. I have previously pointed out that we have insufficient evidence to suggest changing clinical practice and this standpoint was reiterated recently in a consensus statement from a BJA Workgroup on Cancer and Anaesthesia. But that does not mean that we should not be looking for mechanisms that might explain why anaesthetic technique potentially could influence cancer surgery outcome. Unfortunately, in the basic science arena the results are also confusing and not easily interpreted.When considering how use of regional anaesthesia or adjuncts such as ketorolac might affect recurrence, one possibility that comes to mind is that these techniques would reduce opioid use. Interestingly, opioids have unexpected effects on cancer growth: they stimulate mitogenesis and angiogenesis in tumours, and in agreement, naloxone prevents tumour growth in animal models. The peripheral opioid antagonist methylnaltrexone similarly prevents lung tumour growth after injection ofmalignant cells inmice andmight be a feasible adjunct in the clinical setting. Thus, opioid reduction for a while seemed the main candidate for explaining regional anaesthetic effects on cancer recurrence. But then, concern was raised that the animal models used are not representative of the perioperative situation, and the Consensus Statement mentioned above pointed out that in possibly more relevant models protective effects of opioids may even be seen. It is indicative of the differences of opinion that one of the participants at the conference, Jonathan Moss, ‘did not sign the consensus because he and others have done cellular,molecular and animalwork suggesting that opiate antagonism may influence cancer progression in these model systems’ and is commercially developing methylnaltrexone for this purpose. Although I feel it is too early to dismiss a role for opioids completely, what other factors could play a role? Regional techniques and adjuncts also reduce required concentrations of volatile anaesthetics. Might that effect explain their suggested effect on cancer recurrence? Might it be possible that volatile anaesthetics promote cancer recurrence? Two basic science articles in this issue of BJA address this issue. Luo and colleagues in this issue, reported the effects of isoflurane (2%) on ovarian cancer cells. They found that the anaesthetic increased tumourmarkers for cell cycle progression, as well as proliferation and angiogenesis. In addition, cell migration was increased. Shi and colleagues, in this issue, in a similar study, investigated the effects of sevoflurane (2%) on glioma stem cells, and reported that it increased proliferation and markers for proliferation. These data are in agreementwith someprevious animal studies. As far back as 1997, Moudgil and colleagues. reported that 1.3 MAC hour of isoflurane or halothane increased the number of pulmonary metastases after melanoma cell injection in mice by about 2and 3-fold, respectively. Avery interesting study published in BJA in 2009 obtained serum from patients undergoing