This retrospective analysis of 1513 HCC patients with PVTT evaluates long-term OS, RFS and several short term postoperative adverse events in patients receiving INHA using sevoflurane and TIVA using propofol. We identify that patients receiving INHA anesthesia had a lower 5-year OS and shorter median survival time than that of patients receiving TIVA anesthesia. Results from multivariable Cox regression analysis also show that INHA is a risk factor for survival. In subgroup analysis, significant worse outcomes were found in INHA in patients with more severe cancer diseases. No significant difference in postoperative adverse events, 30-day mortality and liver function are discovered between the two groups in this study.
Clinical Evidence of anesthesia type on surgical outcomes
In recent years, the study of anesthesia type for postoperative outcomes have attracted due attention. Several retrospective clinical studies with large sample sizes are published according to our search. Enlund et al. firstly did a retrospective analysis of 2,838 patients with breast, rectal, and colon cancer from a Swedish database. According to their results, overall survival for patients receiving propofol anesthesia is 4.7% higher at 1-yr and 5.6% at 5-yr, but after balance for confounders, the diﬀerences are not significant. Wigmore et al. analyzed 7,030 patients who had elective cancer surgery over a 3-yr period. They suggested that patients had a worse outcome if they received volatile anesthesia, with an HR of 1.46 (95% CI, 1.29 to 1.66) for death compared with TIVA. In addition, Yan et al. did a randomized controlled trail in 80 breast cancer patients and reported that total intravenous anesthesia can inhibit the release of VEGF-C induced by breast surgery, but didn't seem to be beneficial in the short-term recurrence rate of breast cancer. Yap et al. further performed a meta-analysis with 9 retrospective studies and 1 RCT, they concluded that the use of TIVA was associated with improved RFS in all cancer types and improved OS in several certain types of cancer. Although these studies have achieved consistent results that TIVA anesthesia has a better long-term prognosis for patients undergoing tumor resection compared with INHA, the population enrolled in these studies variates a lot, and it is not yet possible to conclude that whether TIVA anesthesia is more beneficial for all cancer patients or for certain types of cancer. Our study achieves a result consistent with the previous studies that TIVA is superior to INHA in the long-term survival of HCC patients with PVTT. Notably, the cause or the molecular mechanisms to the different outcomes of these two anesthetic methods remains unexplored now.
Laboratory evidence of anesthetics on tumors metastasis and recurrence
There have been a number of animal and laboratory studies investigated the mechanism of anesthetic agents on primary tumors metastasis and recurrence. Several proliferation-associated factors and cellular immune response have been repeatedly mentioned, for instance, T lymphocytes and NK cells are two major cytotoxic effector cells that participate in cell-mediated immune responses. Propofol has been demonstrated to have preservation effective on T lymphocyte activity and Th1 cytokine secretion, or even inhibits tumor growth in animal model[9-11]. Researchers also prove that sevoﬂurane could inhibit primary leukocyte integrin lymphocyte function and induced lymphocyte apoptosis through downregulation of LFA-1, thus promoting tumor recurrence and metastasis. Moreover, Studies both in vivo and in patients undergoing breast cancer surgery have reported an inhibitory effect of sevoflurane anesthesia and propofol on natural killer cell function. According to their description, this effect is probably related to the dysfunction in CD16 cell and CD107α NK receptor after exposure to sevoflurane. More recently, Bellanti et al. demonstrated that propofol, not sevoflurane, prevents mitochondrial dysfunction and oxidative stress by limiting hypoxia-inducible factor 1 alpha (HIF-1α) activation in hepatic ischemia/reperfusion injury, thus protects liver function. HIF-1 governs the transcription of genes controlling proliferation and metastasis of tumor cells[17, 18], with previous researches already demonstrate that isoflurane administration could result in an up-regulation of HIF-1α in tumor. However, currently there have no solid evidence to prove those theory in human body.
HCC with PVTT
Hepatocellular carcinoma (HCC) ranges as the fifth most common malignancy tumor . Indeed, even worse prognosis is reported in HCC patients with portal vein tumor thrombus (PVTT), with a reported rate of 20% and a reduced median survival time (MST) of around 2-4 months compared to patients without PVTT[21-24]. According to the Asia-Pacific guideline and some more recent researches, surgery is recommended as one of the beneficial multidisciplinary treatments for PVTT, as aggressive surgical resection is associated with a longer survival outcome, and even provide chances for complete cure with type I and II PVTT[25, 26]. Recent studies reported that under advanced perioperative management and skilled surgical operation, the in-hospital mortality of HCC patients with PVTT arrives an acceptable rate ranging from 3.7% to 10%[27, 28]. However, the knowledge about risk factors of postoperative mortality, cancer recurrence and other side events for HCC patients with PVTT still remains insufficient. Our result provides with extra evidence that for these patients, the application of TIVA, rather than INHA for anesthesia maintenance, might be a better choice, especially in patients with severe cancer statues.
Several methodological discrepancies and limitations of this study should be discussed. First, in our study cohort, there have more patients who are male, with an AS score of II, Child-Pugh score of A, and a large tumor size over 10cm. what’s more, certain clinical data of treatment are not collected, including perioperative chemoradiotherapy, detailed surgical techniques, and usage of opioids during surgery. Opioids have been reported to have an effect on tumor cell proliferation and angiogenesis, as well as on tumor recurrence and metastasis. However, it’s hard to accurately record and compare total amounts of opioid used in both groups during surgery as they are administered both continuously or in intermittent. In this study all patients accepted at least one of remifentanil or sufentanil treatment in standard dose.
In conclusion, this retrospective analysis of long-term overall survival demonstrates an HR (95%CI) of 1.303 (1.065, 1.595) in HCC patients with PVTT receiving INHA compared with TIVA in multivariable analysis. Future prospective researches are urgent to verify this difference and figure out underlying causes of it.