Effects of epidural anesthesia on the prognosis of ovarian cancer—a systematic review and meta-analysis

The registration number in PROSPERO is CRD42021240831. We have refined the title of the article and expanded the range of included study types, because we were unable to find prospective randomized controlled trials. Additionally, we have modified the tool for assessing the risk of bias in the articles and instead utilized the Newcastle-Ottawa Scale (NOS) for evaluating cohort studies. A review protocol was not prepared for this study.

Ovarian cancer is a serious health concern worldwide, characterized by its aggressive nature and late-stage diagnosis. Ovarian cancer ranks as the fifth leading cause of cancer-related deaths among women worldwide [1]. In the United States, new cases of ovarian cancer were predicted to be around 19,880 in 2022, with 12,810 deaths. The overall 5-year survival rate remains dishearteningly low, with less than 50% of patients surviving beyond five years [2]. In China, the survival prospects for ovarian cancer are equally distressing. Majority of patients are diagnosed at advanced stages, resulting in poorer outcomes and limited treatment options [3]. Medical technology has progressed significantly in recent decades, but ovarian cancer remains the fatality leader among gynecological cancers. Due to the aggressiveness and ineffectiveness of treatment, ovarian cancer is rising in the incidence with a 5-year survival rate of less than 50% [4].

Primary cytoreductive surgery, followed by adjuvant chemotherapy is the standard treatment for ovarian cancer. However, surgery inhibits immune function. Retrospective investigations have revealed a link between anesthetic technique and cancer outcomes [5, 6], epidural anesthesia appears to exert an antitumorigenic action in cancer patients [7]. In fundamental research on RNA, epidural analgesia is linked to a decreased likelihood of ovarian cancer recurrence following initial cytoreductive surgery [8]. However, currently there is no systematic evaluation to validate this measure.

Accordingly, it is urgent to elucidate how anesthesia can influence the long-term outcomes of ovarian cancer. In light of these considerations, we conducted this meta-analysis to compare general anesthesia alone with general anesthesia combined with epidural anesthesia and tried to clarify the prognostic effectiveness of epidural anesthesia in patients with ovarian cancer.

The study aims to compare the effect of epidural anesthesia with general anesthesia on survival time after cytoreductive surgery in patients with ovarian cancer. We conducted this study following the 2020 PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). The protocol of this systematic review and meta-analysis was registered in PROSPERO, and the registration number is CRD42021240831. Funnel plots are the most commonly used visualizations to demonstrate publication bias. We used the funnel plot of the Review Manager (RevMan) 5.2 to observe publication bias. Sensitivity analysis was performed by excluding 1 document in turn and merging the remaining documents (n-1 documents) for meta-analysis, and assessing whether the results of the original meta-analysis were significantly altered by the influence of certain studies by observing the changes in the merged results. We performed subgroup analyses of the results depending on whether the administration of epidural anesthesia was intraoperative (EIP) or postoperative (EP) to test the stability of the results.

After the comprehensive search of the databases, we picked 8 studies [10‐17] for our complete meta-analysis after reading the full text of all potentially eligible publications, including 948 cases in the general combined with epidural anesthesia (GEA, epidural anesthesia used postoperatively and/or intraoperatively) group and 1088 cases in the general anesthesia alone (GA) group. Postoperative intravenous analgesia was implemented in GA groups in these 8 researches. Figure 1 shows the flowchart for the literature search. The basic characteristics of studies are shown in Table 1. Intervention strategies included epidural anesthesia started either intraoperatively (EIP) or immediately postoperatively (EP).

The meta-analysis showed an association between GEA and ovarian cancer patients’ overall survival. The same result was found in the subgroup analysis of EIP. Our results from the comprehensive meta-analysis coincided with most, even not all, results from recently reported studies [5, 19]. According to the COX regression analysis of included studies, the long-term prognosis of ovarian cancer patients after surgery was also related to tumor stage, whether the tumor reduction operation was complete, as showed up the outcomes part. The results of these studies are crucial in future prospective studies investigating the intriguing prospect of appropriate perioperative GEA modifying cancer recurrence.

However, the outcomes of GEA vs GA regarding TTR and EIP vs GA on TTR exhibited instability. Epidural anesthesia as an intervention shows advantages in improving overall survival (OS) in ovarian cancer patients, whereas its effect on improving TTR remains unclear, similar to the impact of combined epidural-general anesthesia on long-term survival in colorectal cancer and other kinds of cancer patients [20‐22]. The reason for this discrepancy could be attributed to the fact that overall survival has a clearly defined time point, whereas TTR depends on the timing of patient follow-up visits, making it difficult to precisely define. Moreover, the definition of TTR is not standardized. The appearance of new lesions on imaging or an increase in CA125 levels can both be used as endpoints for defining TTR. However, the magnitude of the increase in CA125 levels is uncertain, and there is also inconsistency in imaging resolution and the diagnostic proficiency of physicians. Furthermore, all articles are retrospective ones, and most studies did not perform propensity score matching when comparing two groups. Compared to randomized controlled studies, they lack strong credibility, which is also a reason for the instability of the results. Consequently, when pooling results using TTR as an outcome, the stability of the outcome becomes uncertain.

Two articles included in this study, Lacassie 2013 and Tseng 2018, both mixed the two interventions of EIP and EP for statistical analysis, but the results were not consistent. Comparison of the two interventions (Table 4): epidural analgesic was 0.1–0.5% bupivacaine with or without opioids in Lacassie 2013, duration was “All epidural catheters remained in place for at least 48 h”. The article did not mention the respective proportions of epidural anesthesia and analgesia; the epidural analgesic in Tseng 2018 was 0.05% bupivacaine, with or without opioids, and most patients can receive oral analgesia, epidural analgesia was discontinued on medication for up to 14 days, and the rate of epidural anesthesia was more than epidural analgesia that of started postoperatively (89% vs 11%). Study populations were similar (Lacassie 2013: stage IIIC and IV, Tseng 2018: stage IIIB and IV). In conclusion, it appears that the reason Tseng 2018 obtained positive results is that there was a higher proportion of participants who received EIP compared to those who received EP, and the duration of epidural analgesia was longer. This result suggests that intraoperative epidural medication, which reduces intraoperative stress and intraoperative opioid consumption, may be beneficial to the survival prognosis of such patients, but not epidural analgesia. It is consistent with other studies [23, 24].

In general, epidural anesthesia has positively effect on the prognosis of ovarian cancer patients after cytoreductive surgery. We all know that both surgery and anesthetics may suppress the body’s immune system, causing cancer to grow and spread. The mechanisms might be explained as follows. Initially, the body’s immune function can be inhibited by opioid analgesics in a dose-dependent manner, and affect both cellular and humoral immunity when they act directly on immune cells, the hypothalamic-pituitary–gonadal axis and sympathetic activity [25], especially on NK cell activity. Morphine, alfentanil, remifentanil, fentanyl and sufentanil not only suppress NK cell activity, but change T cell differentiation. Opioids usually inhibit T-lymphocyte proliferation [26]. Furthermore, investigations have demonstrated that opioid analgesics can promote tumor angiogenesis, which can drive tumor growth and invasion [27]. Volatile anesthetics also affect immune response. Halothane decreases NK cell activity and increases expression of hypoxia-inducible factor 1α (HIF-1α) [28, 29], and sevoflurane induces T-lymphocyte apoptosis and upregulates HIF-1α expression [29, 30]. Isoflurane, sevoflurane, and desflurane have also been demonstrated to up-regulate vascular endothelial growth factor A (VEGF-A), matrix metalloproteinase 11(MMP11), transforming growth factor 1 (TGF-1) and chemotaxis in investigations. The role of chemokine receptor-2 (CXCR-2) and other cell signal transduction and protein expression related to tumor metastasis directly promotes the metastasis of ovarian cancer tumor cells [31]. However, local anesthetics play a positive role. For example, ropivacaine restrained ovarian cancer cell stemness and accelerated cell ferroptosis by inactivating PI3K/AKT signaling pathway [32]. Epidural anesthesia reduces the dosage of opioid drugs and inhalational anesthetics, thereby minimizing their negative effects while also exerting a beneficial effect in inhibiting tumor recurrence. In summary, these findings broadly support the association between epidural anesthesia and the longer survival of ovarian cancer patients.

Therefore, we boldly predict that whether the use of intrathecal (IT) infusion of local anesthetic, like bupivacaine, to treat patients with chronic refractory pain has fewer adverse reactions and prolongs the survival time compared with opioid drugs such as morphine alone. Dose escalation with chronic IT opiates has been a cause for concern [33]. Research has demonstrated that local anesthetics, such as bupivacaine, exhibit a synergistic interaction with opiates [34]. From a logical standpoint, it is believed that effective pain management positively contributes to extending the survival time of patients. However, at present, there is a lack of research evidence to support this claim. Further research is needed in this area.

Of course, there are different meta-analysis conclusions. Epidural anesthesia combined with general anesthesia reduces tumor recurrence and metastasis in patients with prostate cancer but not with colorectal cancer [35]. The above findings may be attributed to epidural anesthesia having different effects on different tumors, which may be related to different pathologies and metastases. Another factor that we discussed for this effect was the duration of surgery. Ovarian cancer cytoreductive surgery often requires joint operation of several departments, the operation scope is large and time-consuming. There may be a difference between patients undergoing epidural anesthesia for colorectal cancer and prostate cancer due to the longer operative time for the latter [36, 37]. Therefore, we believe that epidural anesthesia’s effect is statistically significant only for time-consuming and traumatic operations. However, large-scale clinical studies involving different cancer types are needed to investigate the potential influence of the anesthetic technique used during surgery on cancer-related outcomes.

The tumor stage in ovarian cancer patients has a significant impact on prognosis [38]. Higher stages of ovarian cancer (such as stage III and IV) are associated with a worse prognosis compared to lower stages (stage I and II). Higher stages indicate more extensive spread of the tumor beyond the ovaries, which makes treatment more challenging and increases the risk of recurrence.

Regarding the impact of residual nodules during cytoreductive surgery for ovarian cancer cells, it has been observed that smaller residual nodules are associated with longer recurrence-free intervals and improved overall survival rates [39]. This suggests that achieving complete tumor removal during surgery is crucial for better outcomes.

However, our conclusions should also be interpreted carefully, as more randomized controlled trials are needed to verify them.

The current scenario of ovarian cancer survival and treatment paints a bleak picture both globally and domestically. Late-stage diagnosis, limited surgical options, and a lack of effective therapies contribute to the grim prognosis. However, epidural anesthesia during surgery can reduce stress response and enhance survival in ovarian cancer patients, allowing the anesthesiologist to use anesthesia techniques to provide a favorable prognosis for the ovarian cancer patient.

It is difficult to encapsulate the benefit of single postoperative epidural analgesia from each research review, as compared to general anesthesia with postoperative intravenous analgesia.