When assessing the impact of anesthesia on cancer surgery outcomes, there are various anesthetic drug classes, as well as a number of anesthetic or analgesic techniques, that need to be taken into consideration. For the most part, however, the focus is often simply comparing the effect of general anesthesia (GA) to regional anesthesia (RA) or, if RA is not possible, the type of medications used to deliver a general anesthetic. The most common anesthesia and analgesia considerations in published work is the comparison of drugs such as propofol with or without remifentanil for total intravenous anesthesia (TIVA) versus inhalational anesthesia with a volatile anesthetic such as sevoflurane. There are many preclinical studies supporting a beneficial effect of TIVA, specifically propofol, with immunological mechanisms providing a rationale for this outcome.
In addition, some in vitro and retrospective cohort studies have described a benefit of RA techniques with direct cancer cell-related effects of the amide local anesthetics with secondary, indirect effects of stress response attenuation by avoidance of a GA and decreased need for opioids. Unfortunately, despite some compelling basic science evidence in various cancer models supporting beneficial effects described above, the results of the world’s clinical literature are not clear and often contradictory.
In our review of anesthesia and urological cancer outcomes,1 we reported the lack of evidence supporting an effect of anesthesia technique on recurrence or survival in patients with prostate cancer. The main issues revolve around the retrospective nature of the studies and the inability to control for variability in anesthetic techniques and drug doses. As outlined in our paper, however, any prospective randomized controlled trial (RCT) will be challenging due to low recurrence rates, a long time period to recurrence and most importantly, the evolving standard of care with increasing use of robotic-assisted laparoscopic approaches that minimize the stress response, inflammation, and pain. One would surmise these factors will translate to a limited ability to determine a clinically significant difference due to anesthetic technique alone and make the viability of any prospective RCT unlikely.
The evidence with non-muscle invasive bladder cancer (NMIBC), however, appears to be somewhat more intriguing. Within the last few years, there have been three retrospective studies comparing GA to spinal anesthesia (SA), and all found a lower incidence and longer time to recurrence with SA.2-4 Fortunately, NMIBC is much more amenable to a prospective RCT given the high rate of recurrence, the ability to manage the entire procedure under either a GA or a SA and the absence of significant postoperative pain. Such an RCT is currently underway in Korea however the results may still be years away. The evidence for muscle-invasive disease on the other hand is less encouraging. Although there are very few studies, they do not seem to show a benefit of regional anesthesia on cancer-specific survival or overall survival (OS).5 This is not unexpected given the increased confounding inherent in these more complex procedures.
A recent meta-analysis referenced in our review highlights many of the challenges in this important issue within surgical oncology. In 2019 Yap et al compared TIVA and volatile anesthesia on recurrence-free survival (RFS) and overall survival in various types of cancer.6 The authors reviewed 9,536 articles finding 3,075 that were potentially eligible. From those, only nine retrospective and one RCT were eventually included in the analysis which underscores the quantity as well as limitations of articles that are out there on this topic. It is worth mentioning that the lone RCT was in breast cancer patients and was designed and powered for pre- and post-operative serum immunomarkers (VEGF-C and TGF-β) but not recurrence-free survival. They found that TIVA inhibited the release of VEGF-C induced by breast cancer, and although the two-year recurrence-free survival was better for the TIVA group (95% vs 78%) than the volatile group, it did not reach statistical significance (p=0.221) as it was underpowered for this outcome. The RFS was based on five retrospective and the one RCT studies, (n=7,866 patients in total) in breast, esophageal, and non-small cell lung cancer. They found TIVA was associated with improved RFS with a pooled hazard ratio [HR] of 0.79; 95% confidence interval [CI], 0.62 to 1.00; P<0.01. Analyses for OS was based on 7 retrospective and the one RCT, and consisted of 18,778 patients in total with breast, colorectal, gastric, esophageal, non-small cell lung and mixed cancer types. Improved overall survival was associated with TIVA with a pooled HR of 0.76; 95% CI, 0.63 to 0.92; P<0.01.
There is little doubt that a well-designed, prospective, randomized, controlled trial is needed to help answer some of these questions and guide management, and there are more than half a dozen currently underway in various cancer sites. Since our review, only one has been completed and published.7 This study was a multi-center RCT, enrolling patients with curative-intention primary breast cancer resections from 2007-2018. They compared TIVA with propofol and a regional block (paravertebral) for analgesia (n=1043) vs. inhalational general anesthesia with sevoflurane and opioids for analgesia (n=1065). Their primary outcome was local or metastatic recurrence. This is the only RCT published to date designed with OS or RFS as their primary outcome. The median follow-up was 36 months. Unfortunately, this study was stopped early after a preplanned futility boundary was crossed. Of their 2108 patients, there were 213 recurrences; 10% recurrence in both groups, HR 0.97, 95% CI 0.74-1.28; p=0.84. This was a disappointing result as the study was acknowledged to be well-designed, however, there were many editorials delineating flaws that could have contributed to the lack of benefit. As it was a pragmatic trial, there was minimal information on pre/post-chemotherapy or radiation treatment. And although they had a large sample, 13 sites in eight countries with few crossovers (only six), 97% follow-up for six years, and a design consistent with usual practice, it was noted that 69% of the patients enrolled were from one center in China. There was also the suggestion that there could be a volatile dose-response relationship with risk for tumor recurrence; the average surgical time was only 1.3 hours in both groups. There may be more benefits for longer procedures such as cystectomies or colon resections as well as those procedures that have a higher requirement for opioids. There were also comments that those at higher risk of recurrence within the early peak may be more amenable to benefits within the perioperative period.
As outlined above, the evidence is unclear that anesthetic technique or drugs affect the outcome in urologic cancer surgery, or indeed any other cancer site for that matter. It is certainly discouraging given the robust pre-clinical immunological mechanisms and sound theoretical foundation outlined. Upcoming RCTs may help further clarify possible benefit and effect size, but the first RCT recently published was not promising at all. At the end of the day, the absence of strong evidence does not negate the fact that opioid-sparing techniques, minimizing greenhouse gas-producing volatile anesthetics, and optimal pain management with regional anesthesia/analgesia are laudable on their own merit beyond any possible anti-cancer effects.
Written by: Melanie Jaeger, MD and D. Robert Siemens, MD, Department of Anesthesiology and Perioperative Care and Urology, Queen’s University, Kingston, Ontario, Canada
References:
- 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, vol. 37, no. 12, pp. 845-852. Elsevier, 2019.
- 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.
- 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.
- 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.
- Doiron, R. Christopher, Melanie Jaeger, Christopher M. Booth, Xuejiao Wei, and D. Robert Siemens. "Is there a measurable association of epidural use at cystectomy and postoperative outcomes? A population-based study." Canadian Urological Association Journal 10, no. 9-10 (2016): 321.
- Yap, Andrea, Maria A. Lopez-Olivo, Julia Dubowitz, Jonathan Hiller, and Bernhard Riedel. "Anesthetic technique and cancer outcomes: a meta-analysis of total intravenous versus volatile anesthesia." Canadian Journal of Anesthesia/Journal canadien d'anesthésie 66, no. 5 (2019): 546-561.
- Sessler, Daniel I., Lijian Pei, Yuguang Huang, Edith Fleischmann, Peter Marhofer, Andrea Kurz, Douglas B. Mayers et al. "Recurrence of breast cancer after regional or general anaesthesia: a randomised controlled trial." The Lancet 394, no. 10211 (2019): 1807-1815.