This retrospective analysis of 1513 HCC patients with PVTT evaluates long-term OS, RFS and several short-term postoperative adverse events in surgical patients receiving INHA using sevoflurane and TIVA using propofol. We identify that patients receiving INHA had a lower 5-year OS and RFS rate than that of patients receiving TIVA. On multivariable Cox regression analysis, INHA is an independent risk factor for mortality and cancer recurrence in 5-year after surgery. In subgroup analysis, patients accepted INHA, compare with those who accepted TIVA, have worse survival rates when there are in severe liver cancer statues. No significant differences in postoperative adverse events and 30-day mortality are found between the two groups in this study.
Clinical Evidence of anesthesia type on surgical outcomes
Recently, several clinical studies with large sample sizes have been investigated for anesthesia type on postoperative outcomes in elective cancer patients. In a retrospective analysis based on 2,838 patients with breast, rectal, and colon cancer, Enlund et al. firstly reported that overall survival for patients receiving propofol anesthesia is 4.7% higher at 1-yr and 5.6% at 5-yr than those receiving sevoflurane. But after balance for confounders, this diﬀerences are not significant. In another study, Wigmore et al. analyzed 7,030 patients who underwent elective cancer surgery over a 3-yr period, They reported a worse outcome in patients receiving volatile anesthesia, with a HR of 1.46 (95% CI, 1.29 to 1.66) for death, compare with TIVA. In addition, Yan et al. designed a randomized controlled trail in 80 breast cancer patients and identified that total intravenous anesthesia can inhibit the release of VEGF-C induced by breast surgery, yet with no significant benefice in the short-term recurrence rate of breast cancer. Importantly, a recent meta-analysis with 9 retrospective studies and 1 RCT concluded that, the use of TIVA was associated with improved RFS in all cancer types and improved OS in several certain types of cancers. These studies have achieved consistent results that TIVA anesthesia has a better long-term prognosis for patients undergoing tumor resection compared with INHA, nevertheless, the population they enrolled varies a lot. As such, meaningful conclusions on whether TIVA is superior to INHA for all cancer patients or just for certain types of cancer are difficult to define. To this end, the current study sort to compare long-term survival rate in TIVA and INHA in HCC patients with PVTT.
Laboratory evidence of anesthetics on tumors metastasis and recurrence
Over the years, numerous animal and laboratory studies have been investigated for the mechanism of anesthetic agents on primary tumors metastasis and recurrence. Cellular immune system and tumor proliferation-associated factors are considered to play a key role in it. Of note, 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]. Specifically, T lymphocytes and NK cells are two major cytotoxic effector cells that participate in cell-mediated immune responses. Meanwhile, researches also proved 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 anesthetic agents 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. according to their description, this change could be beneficial for liver function, as HIF-1α governs the transcription of genes controlling proliferation and metastasis of tumor cells[17, 18]. Additionally, previous researches already demonstrate that isoflurane administration could result in an up-regulation of HIF-1α in tumor. However, there have no solid evidence to prove those theory in human body, while the molecular mechanisms of the different outcomes of the two anesthetic methods remains to be determined yet.
HCC with PVTT
HCC ranges as the fifth most common malignancy tumor. Indeed, even worse prognosis is reported in HCC patients with 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, surgery is recommended as one of the beneficial multidisciplinary treatments for PVTT. Moreover, 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]. Meanwhile, 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 for postoperative mortality, cancer recurrence and other side events of HCC patients with PVTT still remains insufficient. Our result provides with extra evidence that anesthesia type might be a risk factor for surgical outcomes of HCC patients with PVTT.
Several methodological discrepancies and limitations of this study should be discussed. First, there might be inclusion bias exist in our cohort, as more than a thousand patients were excluded with only 471 enrolled. Meanwhile, the majority of included patients are male, with ASA score of II, Child-Pugh score of A, and large tumor size over 10cm. Second, 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 intermittently. In this study all patients accepted at least one of remifentanil or sufentanil treatment in standard dose. Besides, since this is a retrospective analysis based clinical records and follow up data, the reason for the choice of anesthesia type at that time point, as well as potential factors affecting this choice, are not recorded or balanced. Thus, prospective researches with rigorous study design and large sample size on this field are in urgent need.
In conclusion, this retrospective analysis of long-term outcomes identifies that INHA is associated with worse survival rate compare with TIVA, and the choice of anesthesia type might be an independent risk factor for survival of HCC patients with PVTT. Future prospective researches are urgent to verify this difference and figure out underlying causes of it.