Effects of propofol/remifentanil-based total intravenous anesthesia versus sevoflurane-based inhalational anesthesia on the release of VEGF-C and TGF-β and prognosis after breast cancer surgery: a prospective, randomized and controlled study

Breast cancer is one of the most common malignant tumors and remains a leading cause of cancer mortality among women [1]. Surgical excision is the principle treatment of such solid tumors. However, it has been widely recognized that both surgical manipulation and anesthetic techniques can alter immunologic function to potentially influence cancer recurrence and metastasis [2, 3]. Sevoflurane can suppress cell-mediated immunity (CMI) and induce T lymphocyte apoptosis, and it has also been shown to increase proliferation, mitigation and invasion of breast cancer cells [4‐6]. In contrast, propofol predominantly exhibited anti-tumor effects and was conducive to maintain anti-tumor immunity through promoting the activation and differentiation of T helper lymphocytes [7‐9]. The effects of opioids on tumor growth and metastasis appeared to be more complex and controversial, depending on drug concentration or exposure duration, or even type of cancer [10‐12]. Furthermore, perioperative administration of opioids attenuated surgery-induced stress response, thereby modulating tumor promoting effects of surgery [13, 14].

The previous studies suggested that propofol/paravertebral anesthesia was associated with unchanged serum concentration of vascular endothelial growth factor (VEGF) after breast cancer surgery and greater inhibition of tumor cell proliferation compared with sevoflurane/opioids anesthesia [2, 15]. However, paravertebral block is usually performed under ultrasound guidance which may not be available in some hospitals, and thus limits the favorable results to be generalized to most of breast cancer patients. Conventional method of propofol based anesthesia typically consists of remifentanil and fentanyl, which could further confound the effects of propofol on immune function. Nonetheless, propofol/opioids-based total intravenous anesthesia (TIVA) has been proven to be associated with reduced risk of recurrence after modified radical mastectomy (MRM) in a retrospective study, but where perioperative angiogenic factors were not measured [3]. Moreover, whether propofol/opioids-based TIVA could still render anti-tumor properties for the patients receiving breast conserving surgery (BCS), a surgical procedure inducing less stress response than MRM, has not been evaluated.

Therefore, we conducted the present study to investigate the influences of two commonly used anesthetic methods, propofol/opioids-based TIVA and sevoflurane-based inhalational anesthesia, on the release of angiogenic factors including VEGF and transforming growth factor-β(TGF-β) which play a crucial role in tumor progression [16‐18], and on the recurrence-free survival (RFS) and overall survival (OS) rates in the patients undergoing MRM or BCS.

Our study showed that propofol/remifentanil-based TIVA can effectively inhibit the increase of VEGF-C serum concentration induced by breast cancer surgery compared with sevoflurane-based inhalational anesthesia, especially for the patients receiving modified radical mastectomy. These two anesthetic methods had a comparable impact on the release of VEGF-C and TGF-β in the patients undergoing breast conserving cancer surgery. Furthermore, the short-term recurrence rates of breast cancer were similar between the two anesthetic groups.

It is plausible that surgery-induced activation of sympathetic nervous system and anesthetics related cell-mediated immunosuppression may promote angiogenesis through increasing the release of soluble factors such as VEGF and hypoxia-inducible factor1α [19, 20]. VEGF-C has been demonstrated to be overexpressed in the breast cancer [21] and increase metastatic potential of tumor cells by stimulating blood vessel growth [17]. TGF-β is also a potent angiogenic factor, but it can represent either tumorigenic or anti-tumor effect, depending on the presence and concentrations of other cytokines as well as its own concentration [2, 18].

A randomized controlled study suggested that propofol combined paravertebral block suppressed the increase in the postoperative concentrations of VEGF-C among the patients receiving breast cancer surgery compared with sevoflurane/morphine-based technique [2]. However, this result may be attributed to the combined effects of propofol, regional anesthesia and lack of opioids [22, 23]. Morphine at clinically relevant doses stimulated angiogenesis and caused an increase in breast cancer cells growth [24, 25]. Fentanyl and remifentanil decreased NK cell activity, but didn’t suppress immune resistance at low doses [10, 26, 27]. Furthermore, fentanyl has demonstrated anti-tumor property by inhibiting cancer cell migration and invasion [28].

In our study, propofol combined opioids rather than nerve block was used for breast cancer surgery because it was easily performed without nerve block associated adverse effects. Fentanyl was administrated in both groups at low doses of 2-4μg/kg, which were unlikely to impair antitumor immunity to a great extent [10]. Moreover, opioid- induced immunosuppression can be prevented by coadministration of cyclooxygase-2 (COX-2) inhibitor [29]. Propofol was shown to increase NK cell interferon-γ production and inhibit COX-2 and prostaglandin E2 function [30, 31], NASIDs was also used at the end of surgery in all patients, thereby possibly counteracting the negative impact of opioids on immunity [32]. However, Forget et al... suggested that NASIDs be given shortly before surgery to produce the antitumor effects [33]. In Looney et al’s study, propofol/paravertebral block produced lower VEGF-C concentration than sevoflurane technique [2], while out results showed the two groups had similar postoperative VEGF-C concentrations. This may be explained as that more patients in the TIVA group required postoperative fentanyl for pain relief due to remifentanil induced hyperalgesia [34] and after all, fentanyl could interfere with the anti-angiogenic effect of propofol.

In the present study, we also found propofol/remifentanil-based TIVA can effectively suppress the release of VEGF-C for both MRM and BCS. In contrast, sevoflurane technique can only reduce the expression of VEGF-C for BCS, but not for MRM. The contributory factors included that MRM caused greater stress response than BCS, hence more release of VEGF-C [35], and propofol-based TIVA can attenuate stress response more than inhalational anesthesia [36]. TGF-β concentrations remained relatively stable in all patients. Although among the patients with early stage (Tis-Stage I) tumors, the preoperative to postoperative change of TGF-β concentrations was lower in the SEV group compared with the TIVA group, the difference was too small to be clinically relevant.

We didn’t observe the beneficial effect of propofol/remifentanil-based TIVA on RFS during the two-year follow-up because the short-term RFS of breast cancer is relatively high, and a large sample size and a long-term follow-up would be required to detect a significant difference. In a prospective observational study, postoperative change in VEGF didn’t predict the disease-free survival in breast cancer over 8 years of follow-up [37].

There are some limitations worth noting in our study. First of all, propofol and fentanyl were used for anesthetic induction in both groups, especially, fentanyl was given in all patients to blunt intraoperative stress response and provide postoperative analgesia, which might serve as major confounders, making it difficult to differentiate the properties of two anesthetic methods on immune response. However, the effects of single-dose propofol used in the SEV group would have dissipated within 10 min or less as anesthesia was maintained with sevoflurane. And also, it was not substantially evidenced that small dose of fentanyl could make significant alterations on cancer related immunity. On the contrary, uses of opioids showed no clinically significant association with the recurrence of breast cancer in a large sample sized study [38]. More importantly, we aimed to compare the distinct packaged anesthetic techniques rather than attributing the results to the individual drug so as to present clinically relevant references. Moreover, the interactions of different anesthetics may further complicate the explanation for the results. Ultimately, whether our findings can be considered to indicate long-term prognosis is unknown.

We found that for the breast cancer surgery, propofol/remifentanil-based TIVA can effectively inhibit the increases of VEGF-C concentrations after surgery compared with sevoflurane-based inhalational anesthesia, whereas these two anesthetic methods produced similar effects on the release of TGF-β. The short-term recurrence rate of breast cancer didn’t show a significant difference between the two anesthetic techniques. A large-sample sized, multicenter clinical trial with longer term follow-up should be conducted to clarify the roles of anesthetics on recurrence and metastasis of breast cancer.