Local Anesthetics and Recurrence after Cancer Surgery-What’s New? A Narrative Review

Thank you for giving me the opportunity to review this paper. The field of onco-anesthesiology if rapidly evolving, and this is one of the major topics within the field of anesthesia.

This narrative review covers the effects of local anesthetics on the immune system and metastasis formation. It touches upon both regional anesthesia and intravenous local anesthetics. While there are other reviews published about this topic in recent years, this article summarizes the current status of research within this field of onco-anesthesia. It can appropriately supplement articles submitted to the special issue in Journal of Clinical Medicine. The paper is well structured and readable with thorough descriptions of the pathophysiologic effects of local anesthesia and cancer. I have very little to add.

The current evidence is nicely summarized. It is mainly based on observational and laboratory studies. Yet, since ongoing RCT’s are mentioned, I think it would be worth mentioning the large trial by Sessler et al (Lancet 2019) randomizing 2000 patients undergoing breast cancer surgery to either sevoflurane + opioids or TIVA + paravertebral nerve block. They did not find an effect on cancer recurrence; possibly because the surgical stress of these operations is minor compared with other types of surgery. Therefore, a discussion of these results would be of benefit for the reader.

As this is submitted to a clinical journal, I would recommend decribing implementation of intravenous anesthesia in a clinical setting. There are challenges in administration of intravenous lidocaine after surgery, that could be discussed e.g. need of continous cardiac monitoring which to some degree compromizes enhanced recovery after surgery (ERAS).

Further, there is an ongoing discussion in anesthesiology about concerns of toxicity for intravenous lidocaine. The therapeutic index is narrow with high risk of adverse events (of which one death was reported in UK), and moreover, the clinical analgesic effect seem to be quite limited (Foo et al, anesthesia 2021, Pandit et at, Anaesthesia 2021). Therefore, I find it appropriate that this paper focuses on the antimetastatic effects of local anesthesia instead of postoperative analgesia and recovery. However, since it is stated in the introduction that one purpose is to "increase acceptance of this concept among our fellow anesthesiologists", I think that these concerns should be discussed in a paper published in a clinical journal.

Lastly, the title is "local anesthesia and survival after cancer surgery…”. Since the describes the effect of local anesthetics on the process of cancer progression, would it be more appropriate to use the word “recurrence” instead of “survival”?