Epidural anesthesia and cancer outcomes in bladder cancer patients: is it the technique or the medication? A matched-cohort analysis from a tertiary referral center

The perioperative period is a critical period which may impact long-term cancer outcomes. A complex state of inflammation, immunosuppression, angiogenesis, and high adrenergic state has been shown to potentially facilitate growth of residual disease and promote seeding of circulating tumor cells [1‐3]. Thus, tumor surveillance and eradication are strongly dependent on an adequate immune response to these potentially influencing tumor biology [4‐6].

Radical cystectomy (RC) with pelvic lymph node dissection is the mainstay treatment for muscle invasive bladder cancer. A greater survival advantage has been shown at 2 years or more following RC as opposed to bladder-sparing modalities [7]. However, the surgical stress response might initiate a cascade of cellular, hormonal, and neuronal perturbations that leave patients susceptible to the pro-metastatic effects of tumor manipulation [4‐6]. In addition, the choice of anesthetic technique may influence cancer outcomes in two ways. First, the immosuppressive effects of opioids, has been proposed to possibly influence immunogenicity during surgery in several solid organ malignancies thereby influencing cancer recurrence [8, 9]. Secondly, regional anesthesia such as epidural anesthesia may blunt the pro metastatic effect of surgical stress [10, 11].

If one can attenuate these perioperative pro-metastatic processes, the immediate postoperative period could become a window of opportunity to improve long-term oncologic control for surgical oncology patients. Given the paucity of studies in the urological and anesthetic literature, we aim to evaluate cancer outcomes in a matched cohort of patients undergoing RC at our institution. Our hypothesis was that tumor recurrence may be associated with the use of epidural opioids.

Patients who received epidural analgesia sustained a decreased time to disease recurrence. Interestingly the log rank p-values (Fig. 4) did not show a statistical difference for RFS and CSS between groups, however the univariate Cox proportional hazard regression showed a statistical difference in RFS between the epidural and GA group. This is mostly likely due to the use of competing risk methods that was used in the RFS analysis. Since epidural sufentanil is such a potent opioid translating to a large ivMEQ, we believe the immunosuppressive effects of increased systemic opioids led to the poor recurrence and survival outcomes seen in our epidural cohort of patients [14].

The perioperative period is a fragile state for patients undergoing cancer surgery and is characterized by various pro-metastatic processes such as release of tumor cells, increased levels of pro-angiogenic growth factors, and numerous hormonal and autonomic alterations caused by the surgery-induced stress response [15]. Thus, it is the synchronization of these detrimental processes that may render a patient susceptible to poor oncologic outcomes. Given that anesthesia and analgesia play an integral role in perioperative recovery and pain control, our study is significant in describing an association between anesthetic technique and cancer outcomes for bladder cancer patients.

Surgery induces a stress response that can affect the host’s cytotoxic T-cell and natural killer (NK) cellular function, increase pro-angiogenic factors that promote tumor growth, and reduce circulating concentrations of tumor-related anti-angiogenic factors [16‐19] In addition, systemic opioids used during hospital course can affect both humoral and cellular immunity by inhibiting antibody production, NK cell activity, cytokine expression, and phagocytic activity [14, 20‐22].

One previous study of over 1000 prostatectomy patients reported intravenous sufentanil administration associated with increased risk of biochemical recurrence [8]. Interestingly, 97% of patients received sufentanil (epidural and intravenous) introducing a risk of type 1 error. Patients receiving intravenous sufentanil had a significant reduced survival rate (HR 7.8). The authors did not compare the dosage of sufentanil given through the epidural versus intravenously so we are unable to tell if the dosage was equal in both groups. If the intravenous sufentanil group received a higher ivMEQ, this would confirm previous observations that synthetic lipophilic opioids can negatively impact cancer-related outcomes. Given that our epidural cohort did not receive the opioid-sparing effect that is normally seen with hydrophilic opioid-based regional analgesia, our study adds support for decreased use of systemic opioids for patients recovering from cancer surgeries. Due to the inhibitory effects of opioids on not only NK cell function but also immunological pathways involving monocytes, secretion of immunoglobulins, cytokines and cell proliferation [8, 23], the increased systemic absorption caused by lipophilic, potent analgesics such as sufentanil may be detrimental for our cystectomy patients.

The issue of opioid use in the perioperative period has been increasingly recognized in the literature. The role of the mμ opioid receptor (MOR), which has been shown expressed in cancer cells such lung adenocarcinoma and breast cancer, has been postulated as a mechanism of cancer progression due its interactions with angiogenesis, epithelial-mesenchymal transition, and the mammalian target of rapamycin signaling pathways [24‐26]. These findings have been substantiated by retrospective data suggesting worse outcomes in patients with cancer who are exposed to systemic opioids and high levels of MOR expression [24, 27, 28]. Although our study adds more evidence on the detrimental effect of synthetic opioids, our findings require further translational studies which may help further characterize the pathophysiological basis of MOR inhibition and identify potential targets for future therapeutic strategies.

Several important limitations are inherent in this study including a limited sample size and the retrospective, observational design. Although we used propensity score matching to reduce selection bias, the effects of unmeasured confounding variables cannot be excluded. Our results relate to only sufentanil epidural anesthesia and do not translate to other neuraxial anesthetic techniques. Additionally, any association between anesthetic techniques and oncologic outcomes among patients with bladder cancer will need to be better characterized from a pathophysiological standpoint for our results to have not only epidemiological but therapeutic implications.

Worse oncologic outcomes may be associated with sufentanil based epidural anesthesia during radical cystectomy. This may have been due to the larger amount of opioids used with epidural sufentanil. Although limited by its retrospective design, our study suggests that further investigation in the clinical setting evaluating the effects of opioid-based epidural analgesia and bladder cancer progression is warranted.