The role of anaesthetics in cancer outcomes: do we need more clinical trials?

Cancer persists as a significant global health challenge, responsible for nearly 10 million deaths annually, representing one-sixth of all deaths [1]. Gastrointestinal cancers, including colorectal, liver, stomach, oesophagus and pancreas, account for approximately 34% of these fatalities [1]. Despite the development of screening programmes, adjuvant therapies and significant advancements in surgical techniques [2], nearly 20% of patients still experience local or distant recurrence, with 80% occurring within the first three years after surgery [3]. Given this, identifying interventions that can reduce cancer recurrence and prolong disease-free survival continues to be a major focus of research, with anaesthetic technique being one of interest (Fig. 1). Two recently published studies have examined whether maintenance of anaesthesia with propofol-based total intravenous anaesthesia (TIVA) compared with inhalational anaesthesia, was associated with improved oncological outcomes after liver and colorectal surgeries. The first study by Kwon et al., involved 536 patients undergoing elective hepatectomy for hepatocellular carcinoma who were assigned randomly to either propofol-based TIVA or sevoflurane-based inhalation anaesthesia [4]. Patients were followed for one year to assess overall and recurrence-free survival. No relevant clinical differences were observed between the groups. However, a post-hoc subgroup analysis revealed that patients undergoing open hepatectomy who received propofol-based TIVA had a lower hazard of tumour recurrence or death (hazard ratio 0.49, 95%CI 0.25–0.95, p = 0.034). In the study by Kwon et al., we find the use of thiopental for induction of anaesthesia in patients allocated to the inhalational anaesthesia group particularly interesting, as this is a major difference in anaesthesia care compared with other studies. Although animal studies suggest that thiopental impairs immunity and promotes metastatic cancer growth [5], we do not think that the difference in recurrence and death in the sub-group analysis was related to a single dose barbiturate. In fact, this finding should be interpreted with caution. While Kwon et al. suggest that the observed effects might be due to a greater immunomodulatory effect of propofol in patients having open surgery, previous randomised trials in patients undergoing open abdominal surgery have not shown significant differences in the inflammatory response between groups [6, 7]. Circulating tumour cells does not appear to explain these findings as Hovaguimian et al. found no significant differences between groups in postoperative circulating tumour cells in patients undergoing breast cancer surgery (rate ratio 1.27, 95%CI 0.95–1.71) [8]. A strength of the work by Kwon et al. was its design and focus on a single cancer type. This approach was not considered in previous studies, such as the one by Cao et al., who, despite similar findings, included patients with multiple cancers [9]. The CAN breast cancer study also compared propofol-based TIVA vs. inhalational anaesthesia [10] and, in agreement with Kwon et al., did not show differences in survival. A limitation of the study by Kwon et al. is the limited follow-up (one year). However, the authors have indicated that patients will be monitored for three years. While we wait for the results of this extended follow-up, previous randomised clinical trials and large registry studies have shown no evidence suggesting that a longer follow-up period would reveal differences in survival between groups [10-12]. The second study was conducted by Enlund et al. and analysed data from the Swedish Colorectal Cancer Registry and the Swedish Peri-Operative Registry [13]. The study examines overall and disease-free survival outcomes in patients with stage 1–3 colorectal cancer who underwent curative surgery between 2014 and 2019. While the findings before propensity-score matching suggested that patients with colon cancer who received propofol-based TIVA had better overall and disease-free survival rates than those receiving inhalational anaesthesia, after 1:2 matching no significant differences were observed among the groups. Similarly, no differences were noted in patients with rectal cancer in either the matched groups or the unmatched groups. One of the key strengths of the study is the large sample size (n = 11,598) and the inclusion of variables known to impact colorectal cancer, such as tumour staging. Furthermore, the researchers analysed colon and rectal cancers separately, a methodology we believe is crucial for studies of this nature, as rectal cancers exhibit varying levels of aggressiveness and recurrence patterns compared with their colonic counterparts. Unfortunately, nearly 22% of the initial study population was excluded from the overall survival analysis due to missing information, but they remained in the disease-free survival zone. The authors did not report how missing values were replaced for disease-free survival analysis, which is a critical statistical consideration. Ongoing multicentre randomised clinical trials are expected to provide a further understanding of the complex relationship between maintenance anaesthesia and cancer outcomes. A clinical trial based in China (NCT02660411) involves 1228 patients and aims to examine the 5-year survival rate, recurrence-free survival, quality of life and cognitive function in older adults who have undergone surgery for primary malignant tumours without previous chemotherapy and/or radiation treatment. Another study based in the USA (NCT0303409) involving 1804 patients is assessing all-cause survival, recurrence and length of postoperative stay in adults who have had major cancer surgeries such as lung, pancreatic and liver. A Swedish study (NCT01975064) is aiming to recruit 8000 patients to look specifically at all-cause survival at one and five years after breast or colorectal cancer surgery. Finally, an Australian trial (NCT04316013 trial) expects to enrol 5736 patients and employs factorial design to evaluate disease-free survival, overall survival and postoperative outcomes in patients with colorectal and non-small-cell lung cancer, while also exploring the potential role of a lidocaine infusion. While we await the results of these and other large studies such as the VITAL trial [14], the pressing question is whether more randomised controlled trials are needed to evaluate whether the type of anaesthesia impacts cancer outcomes; our answer is no. Instead, we believe future research should focus on other interventions with stronger biological plausibility. For example, administering a single drug or combining multiple drugs with well-established anti-cancer efficacy for a longer duration peri-operatively. Anaesthetists and surgeons should recognise the peri-operative period as a critical window of opportunity, during which only a limited number of interventions are available [15]. Therefore, there is a need for trials designed to target known mechanisms of cancer progression [16]. For example, the co-administration of non-steroidal anti-inflammatory drugs and non-selective beta-blockers (DRKS00014054) [16] or the use of peripheral mu-opioid receptor antagonists (NCT06162377) before and immediately after surgery may help mitigate cancer progression and improve peri-operative outcomes. These interventions were conceived based on prior preclinical and clinical evidence suggesting that modulation of their effect target peri-operatively may impact cancer outcomes. In the case of beta-blockers, previous randomised trials show that their use during the window-of-opportunity period reduce tumour biomarkers [17] and significantly reduce postoperative inflammatory markers [18]. Due to their ability to simulate the tumour environment [19] more accurately, future potential interventions could utilise novel experimental paradigms such as tumour organoids to identify the most promising candidates and optimise the duration of the intervention [20, 21]. In summary, although numerous in vitro and in vivo experiments and some retrospective studies have suggested that propofol may have anti-cancer effects, it is unlikely that brief exposure to this or other anaesthetics during surgery could significantly influence long-term cancer outcomes. Whilst we await the results of ongoing clinical trials, anaesthetists should focus on ensuring they implement interventions that optimise postoperative recovery to enable patients to receive adjuvant oncological therapies in a timely manner [22]. How patients recover from an anaesthetic may turn out to be a more important peri-operative metric than the type of anaesthetic delivered. No competing interests declared.