In recent decades, perioperative management has been identified as a factor that could impact cancer outcomes by altering the microenvironment and it has been receiving more clinical attention 10. All tissue trauma, including the sterile dissection carried out by surgeons, and inflammation have been associated with tumor progression 2. This study demonstrated the hypothetical benefits of perioperative EA for long-term cancer control and survival in patients following RCC resection. To the best of our knowledge, the current study is the largest comparative epidural study to date which has investigated the association between EA and long-term outcomes after RCC surgery.
The current study had several strengths, including a relatively large sample size, and the fact that we took more prognostic and pathologic factors into account. We also used sound analytical approaches such as IPTW and other regression-based sensitivity analyses to ensure the consistency of the estimated results 9. Charlson comorbidity index was also used to control for the potential influence of comorbidity severity on the outcomes of interest in the analysis 11. All these efforts were used to try and provide more precise and reliable estimated results to determine the actual association between EA and RFS or OS after curative surgery for RCC.
Although opioids are widely used to control postoperative pain, they are believed to have negative effects on the immune system 8. The evidence from clinical observational studies indicates that opioids suppress cellular and humoral immunity, promote angiogenesis, and enhance progression of metastatic disease 2. Overexpression of µ-opioid receptors on cancer cells is observed and associated with angiogenesis and oncogenic signaling 4. Perioperative EA is administered near the nerve roots to block sensory and sympathetic nerves. It attenuates the neuroendocrine stress responses of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system activation 4 and minimizes volatile agent and opioid consumption 7,9. Therefore, it has been suggested that EA preserves immune function and prevents cancer recurrence after curative surgery but previous studies have reported inconsistent results 7,10. Zimmitti et al. reported improved RFS but not OS in patients receiving general anesthesia with EA compared to those without after hepatic resection for colorectal liver metastases 12. However, the study did not take pre-existing medical conditions, perioperative blood transfusion or pathological features into account. Myles et al. found no significant difference in RFS or OS between the EA and non-EA groups following abdominal cancer surgeries in a post hoc review of randomized control trials 13. A systemic review and meta-analysis revealed a lower risk of OS but not cancer recurrence among patients with perioperative regional anesthesia and analgesia 9. A recent study compared perioperative systemic analgesia (SA group) with perioperative EA in addition to systemic analgesia (EA group) following surgical resection of localized RCC, which suggested that EA usage was associated with a significantly improved OS but did not significantly impact cancer-specific survival 8. Accordingly, more prospective studies are needed to elucidate the associations between EA and long-term outcomes after curative cancer surgeries.
During cancer development, circulating tumor cells may leave the primary tumor and form clinically undetectable metastatic foci 2. Micrometastases remain in an immunologic equilibrium between tumor cell proliferation and host immunity 4. However, a cascade of local, systemic cellular and humoral inflammation events may reduce the ability of the host immune system to detect and eradicate cancer cells and could help to disseminated cancer cells which survive the host’s defensive mechanisms 2,10. Clinical evidence shows that tissue trauma caused during surgery can accelerate subsequent neoplastic disease 2,6. Moreover, an experimental trial reported that the more extensive the surgery is, the more potential there is for postoperative inflammation and complications, which further increase the recurrence rate 14. Some studies have suggested that open cancer surgery was associated with shorter disease-free survival compared with minimally invasive surgery, which limited surgical trauma 2,15, however our investigation did not support the beneficial effects of minimally invasive surgery and partial nephrectomy compared with open surgery and radical nephrectomy, respectively. Notice that similar findings were also noted in another two studies which investigated oncological outcomes in patients undergoing minimally invasive surgery compared with open surgery for clinical T2 RCC and locally advanced RCC, respectively 16,17. Similar findings were also noted in another study comparing partial or radical nephrectomy for clear cell RCC larger than 7cm 18.
Interestingly, we also noted that a longer anesthesia time was associated with worse RFS and OS in the stepwise regression analysis. Singh et al. had similar findings in an analysis of minimally-invasive surgeries for endometrial cancer 19. In their study, longer operative time was also associated with increased medical, surgical and overall complication rates. In fact, longer anesthesia time, as a surrogate for longer surgical time, may reflect the underlying aggressiveness of the disease or the complexity and difficulty of the surgery, or both. Since we have taken miscellaneous surgical and oncological factors into consideration to reduce confounding effects, anesthesia time is highly suspected as an independent risk factor of cancer recurrence and mortality in patients receiving RCC surgery.
Still, there are other factors which may have an effect on long-term cancer outcomes, including the use of steroids 10, nonsteroidal anti-inflammatory drugs 4,14,15 and systemic lidocaine 4,10, hypothermia 2,10,14, postoperative infections 2, blood transfusions 2,10, etc. Red blood cells (RBC) are commonly given to cancer patients before, during or after major surgery for a number of different reasons. Although the value of blood transfusions for saving lives is indisputable 20, blood-component therapy can induce negative effects on the recipients’ immune system 21, a condition called “transfusion-related immunomodulation” 21,22. The detrimental effects of immunomodulation are thought to have an association with systemic inflammation 22,23 and various immunologic changes, including inhibition of cytotoxic cell activity, and immunosuppressive prostaglandin release 22. In the sensitivity analysis, we observed that perioperative packed RBC transfusion was associated with a worse RFS in the multivariable regression analysis. Abu-Ghanem et al. also reported that transfusion reduced RFS, cancer-specific survival, and OS in patients undergoing nephrectomy for RCC 24. Tsivian et al. found that perioperative blood transfusion was independently associated with worse oncological outcomes for localized RCC after curative surgery and that the recipients were associated with roughly a 2-fold increase in metastatic progression, all-cause and RCC-specific mortality 25. Moreover, negative clinical outcomes were also observed in colon 22,23 and esophageal 26 cancer patients who received transfusion during curative-intent surgeries. Based on these findings, it has been suggested that blood transfusion can influence the different stages of tumor development including initiation, promotion, malignant conversion, invasion and metastasis 20. To reduce the potential confounding of perioperative blood transfusion on the outcomes of interest, the IPTW methodology was used to balance the exposure of transfusion in both the EA and non-EA groups.
The current study had several limitations. First, patients were not randomized to either group, they instead received EA depending on the preference of the patient, the surgeon or the anesthesiologist. Second, the influence of unmeasured covariates such as opioid dose and nonsteroidal anti-inflammatory drugs use on cancer outcomes cannot be evaluated due to a lack of available data. Third, the clinical outcomes of loss to follow-up patients are unknown and the last observed censoring time was used in the analysis, which may have affected the results.
In conclusion, we demonstrated an association between perioperative EA use and better RFS and OS in patients undergoing curative surgery for RCC. Future prospective studies and randomized clinical trials with careful design are needed to confirm this relationship between EA and cancer outcomes after curative surgery for RCC and to elucidate the underlying mechanisms.