Propofol-based total intravenous anesthesia and recurrence-free survival after hepatectomy—does it improve outcomes?

Surgical resection of liver cancer, along with events during the post-operative period, can create a window of biological vulnerability to cancer regrowth or spread. Surgical manipulation of a tumor can disseminate tumor cells, tissue trauma can create inflammatory responses, perioperative stress and immunosuppression may facilitate residual or disseminated tumor cells to survive, and remote tissue site changes may also facilitate establishment of metastasis (1). The study by Kwon et al. (2) is timely and provides results from a single-center randomized controlled trial (RCT) on whether a simple decision between anesthesia types [total intravenous anesthesia (TIVA) versus inhalational anesthesia] would affect recurrence-free survival after hepatectomy.

Given the anesthetic effects on the immune system, stress response and directly on cancer cells, the choice of anesthetic technique during cancer surgery could be a modifiable factor with long-term consequences for recurrence and survival. Volatile anesthetics and propofol both have been shown to have effects on cancer cells both directly or indirectly by modulating the body’s stress response or immune system. Pre-clinical studies have shown that direct anesthetic effects on cancer cells can be variable, but overall, propofol has antitumor effects, whereas volatile anesthetics have pro-tumor effects (3). Volatile anesthetics overall may exert a bigger stress response and more immunosuppression compared to propofol (4).

Clinical studies, in which the majority have been retrospective designs, have been mixed in determining if there are indeed differences in oncologic outcomes across anesthetics. In glioma and glioblastoma surgery, for example, retrospective analyses comparing propofol to sevoflurane (5) or between propofol and different volatile anesthetics (6) have not demonstrated clear differences in survival or recurrence. In oral cancer surgery, one retrospective study comparing propofol and sevoflurane reported no difference in overall or recurrence-free survival associated with sevoflurane and propofol (7). In breast cancer surgery, there was also no difference in effect on recurrence associated with propofol compared to volatile anesthetics (8). In colorectal surgery, one large retrospective study showed no difference in survival (9), whereas another showed propofol was associated with improved survival (10). In open liver cancer surgery, propofol was associated with improved survival compared with desflurane (11) or sevoflurane (12). A similar improved survival was seen with propofol compared with volatile anesthesia after esophagectomies (13). Meta-analyses and systematic reviews have suggested propofol associated with less or later recurrence, or better survival (4,14,15).

Retrospective analyses, even those involving large cohorts, inherently have risk of residual confounding. There are currently few large RCTs that measure cancer outcomes and additional prospective clinical trials are very much needed to determine whether anesthetic effects meaningfully influence outcomes. One multicenter RCT on different cancers showed no difference in overall survival in propofol vs. sevoflurane anesthesia at 3-year follow-up (16). A multicenter RCT involving breast cancer surgery showed no difference between patients who received sevoflurane or propofol in recurrence (17), though patients who received propofol did so as an adjunct to regional anesthesia and not at general anesthetic doses. Another large multicenter RCT also showed no difference in survival at 5-year follow-up after receiving sevoflurane and propofol anesthesia for breast cancer surgery (18).

Overall, there is currently no clear evidence to guide clinical decision-making based on retrospective studies; thus, the results of a RCT presented by Kwon et al. (2) add valuable insight. The study by Kwon et al. adds valuable insight. The authors investigated patients undergoing resection for hepatocellular carcinoma, excluding those with cholangiocarcinoma or distant metastasis. Participants were randomized to receive either propofol-based total intravenous anesthesia or sevoflurane-based volatile anesthesia. Outcomes were assessed at 1 year following surgery. The authors report that anesthetic choice did not significantly affect the recurrence-free survival or overall survival. Although the trial was originally designed with 3-year follow-up, the study currently only has 1-year outcomes are available. The longer-term results will be important to determine whether late differences in recurrence or survival emerge over time.

It has been previously suggested that the magnitude of surgical trauma itself may be a critical modifier of any anesthetic effect. Prior work also suggests that the extent of surgery may influence the impact of anesthetic technique (19). Major surgery is pro-inflammatory and immunosuppressive, and greater tissue injury may amplify differences in host response. In the present trial, subgroup analyses suggested potential differences between open and laparoscopic hepatectomy, with propofol associated with lower recurrence at 1 year among patients undergoing open surgery. Open procedures are typically associated with greater surgical stress and immune perturbation than minimally invasive approaches. Open procedures are also often performed in patients with more advanced or complex disease. However, more than 80% of the procedures in this study were laparoscopic, and the study was not powered to detect this outcome measure. Despite being an interesting signal in the data, this finding needs to be further validated in a dedicated RCT. In the context of these data, it would be potentially practice-changing to address the question of what effects on outcomes do volatile anesthetics versus propofol have on patients undergoing large cancer resection surgeries and what type of surgeries would make such a difference appear.

There are also other unknowns to be investigated in terms of patient or surgical factors that influence effect of anesthetic type on oncologic outcomes. Patients with more advanced and larger tumors may be more suited for and thus receive open instead of minimally invasive surgery. More advanced or larger tumors may have different metastatic or regrowth potential compared with smaller tumors. Larger surgeries also necessitate longer duration of general anesthesia and greater exposure to anesthetic agents, making duration of surgery a potential factor to measure in future trials and studies.

The question of whether anesthetic technique affects cancer recurrence and survival remains unclear. The possibility exists that anesthetic effects on cancer cells, the systemic stress response or immune system seen in laboratory studies do not translate into meaningful differences in outcomes after cancer surgery. Currently however, systematic reviews of retrospective clinical studies point to positive effect of using propofol to maintain a general anesthetic in patients undergoing cancer surgery improving cancer outcomes. Despite no clear evidence so far, there is a need for further large RCTs with long term follow up, especially on cancer surgery of either significant duration where anesthetic exposure is greater, or large, open surgeries where there is greater perturbation of systemic stress response, immune changes, and for different cancer types which have different metastatic or regrowth potential. Current evidence—including the current RCT by Kwon et al.—suggests that propofol and sevoflurane do not differ in short-term oncologic outcomes following hepatocellular carcinoma resection, although intriguing signals exist in specific subgroups such as open surgery, which deserves to be further investigated. If anesthetic choice were shown to influence recurrence or survival in certain types of cancers or surgery types, it would represent an easily modifiable factor during cancer surgeries with profound implications for millions of patients worldwide.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0037/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0037/coif). The authors have no conflicts of interest to declare.

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