Spinal Anesthesia is Associated with Lower Recurrence Rates after Resection of Nonmuscle Invasive Bladder Cancer

Spinal Anesthesia is Associated with Lower Recurrence Rates after Resection of Nonmuscle Invasive Bladder Cancer Yuri Koumpan, Melanie Jaeger,* Glenio Bitencourt Mizubuti, Rob Tanzola, Kunal Jain, Gregory Hosier, Wilma Hopman and D. Robert Siemens From the Departments of Anesthesiology and Perioperative Medicine (YK, MJ, GBM, RT) and Urology (KJ, GH, DRS), Kingston General Hospital Research Institute and Departments of Public Health Sciences (WH) and Oncology (DRS), Queen’s University, Kingston, Ontario, Canada

Abbreviations and Acronyms ASAÒ ¼ American Society of AnesthesiologistsÒ BCG ¼ bacillus Calmette-Guerin GA ¼ general anesthesia NK ¼ natural killer NMIBC ¼ nonmuscle invasive bladder cancer POCT ¼ postoperative chemotherapy SA ¼ spinal anesthesia TURBT ¼ transurethral bladder tumor resection Accepted for publication November 6, 2017. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. * Correspondence: Victory 2, Kingston General Hospital, 76 Stuart St., Kingston, Ontario K7L 2V7, Canada (telephone: 613-548-7827; FAX: 613-548-1375; e-mail: [email protected]).

Purpose: We sought to determine whether anesthetic type (general vs spinal) would influence cancer recurrence following transurethral resection of bladder tumors. Materials and Methods: With institutional ethics board approval we examined the electronic medical records of all patients who underwent transurethral bladder tumor resection for nonmuscle invasive urothelial bladder cancer between 2011 and 2013 at a single tertiary care center. Followup information was gathered on all patients in December 2016. The time to first cancer recurrence and the incidence of cancer recurrence were the main outcome measures. Results: A total of 231 patients underwent 1 or more transurethral bladder tumor resections between 2011 and 2013. Of the 231 patients 135 received spinal anesthesia and 96 received general anesthesia. On univariable analysis the 135 patients who received spinal anesthesia had a longer median time to recurrence than the 96 who received general anesthesia (42.1 vs 17.2 months, p ¼ 0.014). As anticipated, adjuvant therapies and risk category were associated with recurrence rates (p ¼ 0.003 and 0.042, respectively). On multivariable analyses incorporating a priori variables of nonmuscle invasive bladder cancer risk stratification and postoperative therapies the patients who received general anesthesia had a higher incidence of recurrence (OR 2.06, 95% CI 1.14e3.74, p ¼ 0.017) and an earlier time to recurrence (HR 1.57, 95% CI 1.13e2.19, p ¼ 0.008) than those who received spinal anesthesia. Anesthetic type was not associated with cancer progression or overall mortality. Conclusions: Patients who received spinal anesthesia had a lower incidence of recurrence and a delayed time to recurrence following transurethral bladder tumor resection for nonmuscle invasive bladder cancer. These findings should prompt large-scale prospective studies to confirm this association. Key Words: urinary bladder neoplasms; anesthesia, spinal; anesthesia, general; neoplasm recurrence, local; margins of excision THE potential association between surgical oncology outcomes and perioperative management has been an intriguing area of investigation in the last decade. Despite progress in preoperative imaging and surgical techniques as well as other advances in

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precision oncology, at most surgical cancer sites postoperative recurrence and metastases remain universal and represent the basis of subsequent morbidity and mortality.1 Increasing evidence suggests a role of invasive procedures themselves leading to

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https://doi.org/10.1016/j.juro.2017.11.064 Vol. 199, 940-946, April 2018 Printed in U.S.A.

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microvascular seeding and dissemination of cancer cells.2 Various perioperative factors such as surgical inflammation, volatile anesthetic agents, opioids, hypothermia and blood transfusions have been implicated in cancer recurrences secondary to cancer promoting effects, including immunosuppression.3e6 Regional anesthesia, potentially by minimizing the use of volatile anesthesia and opioids, is associated with a reduction in perioperative immunosuppression and maintenance of the functionality of anticancer immune cells.3,4,7 Several studies have investigated the effect of regional anesthesia on recurrence and survival in different oncologic surgical populations.8e12 A recent meta-analysis suggested that regional anesthesia/analgesia improves overall survival after oncologic surgery, although a definitive effect on cancer recurrence was not confirmed.8 These studies hint that surgical intervention, particularly when performed with the patient under GA, may contribute to some degree of cancer immune escape.13 Although these analyses are intriguing, they are far from definitive as they have generally been limited by heterogeneous, retrospective studies with small study populations. In the urological literature 1 observational study in patients undergoing radical prostatectomy failed to demonstrate any effect on recurrence for SA alone compared to GA.14 Bladder cancer is the seventh most common cancer in men and the seventeenth most common cancer in women.15 Most presenting cases are NMIBC and, given the high recurrence rates and the generally intensive local therapies, NMIBC represents a highly prevalent and expensive cancer to manage.15 The frequency of recurrence associated with NMIBC has led to significant investments, including enhanced cystoscopic technologies and novel neoadjuvant therapies, to optimize the care of these patients.16 Although different anesthetic techniques are commonly used at the time of TURBT, to our knowledge no previous report has linked the type of anesthesia to NMIBC recurrence. Although 1 previous small, retrospective study suggested a potential benefit of regional anesthesia on 5-year survival in patients after TURBT, no effect on cancer recurrence was identified.17 Our primary objective in this retrospective, single center study was to determine whether anesthetic type (general vs spinal) would influence cancer recurrence after TURBT.

who underwent TURBT for NMIBC at a single academic center between 2011 and 2013. Patient records were accessed through an institutional electronic medical record system. All NMIBC cases in the time frame were identified. Patients were initially captured if TURBT represented the first presentation of bladder cancer. If they had had infrequent recurrences of NMIBC, they were included if data on the incident TURBT was fully captured in our electronic medical records. The electronic record was used to identify dates of all patient procedures, including TURBTs and office biopsies. The perioperative data collected included anesthetic type (general vs spinal), patient age and ASAÒ classification. Other variables collected were those factors determined a priori to be strong predictors of NMIBC recurrence such as stage, grade, size and number of tumors. These individual variables as well as a previous history of NMIBC diagnosis prior to 2011 were used to assign the case to a risk category.18 Finally we recorded the use of adjuvant anticancer therapies, including POCT and BCG. Study exclusion criteria included patients in whom a previous history of NMIBC was uncertain or followup data were unavailable as well as those who continued elsewhere or in whom the primary pathology was not consistent with NMIBC, specifically muscle invasive disease. Patients with a history of initial TURBT not captured in our electronic medical record system were excluded due to incomplete data on pathology findings, risk category or adjuvant therapies. Patients in whom SA failed or was inadequate and who were converted to GA were also excluded. The Pearson chi-square test and the independent samples t-test were performed to test for associations between patient characteristics and the incidence of recurrence, progression and overall mortality. KaplanMeier estimates were performed for time to first recurrence, progression and mortality. Time to first recurrence was defined as the time in months from pathological confirmation of NMIBC at TURBT to the date of the subsequent pathology result identifying urothelial bladder cancer recurrence. Progression was defined as the date of pathology indicating muscle invasive bladder cancer (pT2 or greater). Surviving patients who had no recurrence or progression were censored as of December 1, 2016. Multivariable logistic regression and a Cox proportional hazards regression model were used to explore the association of anesthetic type with recurrence and time to recurrence, respectively. Covariates that demonstrated a potential association (p <0.15) with outcomes on univariable analyses were controlled in the models. No adjustments were made for multiple comparisons and p <0.05 was considered statistically significant. Analyses were performed with IBMÒ SPSSÒ, version 24.0 for WindowsÒ.

MATERIALS AND METHODS

RESULTS

Following Queen’s University research ethics board approval this observational study identified all patients

A total of 238 patients underwent TURBT between January 2011 and December 2013, and met study

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inclusion criteria. Two patients with a remote history of bladder cancer and 5 previously diagnosed with upper tract urothelial cell cancer were excluded from study. The 231 remaining patients who were identified had complete clinical data to assess the incident (initial) TURBT, including 135 (58%) who had received SA and 96 (42%) who had received GA. Supplementary table 1 (http://jurology. com/) lists patient and cancer characteristics by anesthetic technique. Patients who received SA were significantly older than those with GA (mean age 71.72  10.57 vs 65.45  10.86 years, p <0.001) and they had more comorbidities as defined by ASA score. The overall cohort included 64 patients (27.7%) with low risk disease and 141 (61.0%) with NMIBC defined as high risk. There was no significant difference in cancer characteristics between the investigational groups. Although there was no difference in the use of BCG induction therapy between the groups, there was a numerically higher rate of POCT for lower risk disease in those who received general anesthesia (22 patients or 22.9% vs 15 or 11.1%). Surgical time was assessed in 96 patients (42%) on whom accurate data were captured in a dedicated electronic operating room charting system initiated in April 2012. There was no significant difference in surgical skin to skin time between the 53 patients in the SA group and the 43 in the GA group (mean 26.2  13.7 vs 27.1  14.48 minutes, p ¼ 0.642). Table 1 shows the univariable analysis of NMIBC recurrence. The observed recurrence rate in the entire cohort was 63.2%. Anticipated cancer specific variables, which have been well described to be associated with recurrence, were generally consistent in this cohort, particularly the presence of carcinoma in situ. Stage and grade did not reach statistical significance, perhaps mitigated by adjuvant therapies in 70.5% of the entire cohort. However, the assigned low, intermediate or high risk stratification was significantly associated with recurrence. As expected, adjuvant intravesical therapy was associated with the recurrence rate (p ¼ 0.003). Those who did not receive any adjuvant therapy experienced a higher number of recurrences compared to those with adjuvant therapy (39 patients or 57.4% vs 29 or 42.6%). On this univariable analysis the higher recurrence rate in those who received BCG is consistent with confounding by indication since these patients presented with higher risk NMIBC. Interestingly those who underwent TURBT under SA had a significantly lower incidence of recurrence (57.8% vs 70.8%, p ¼ 0.043). On Kaplan-Meier analysis of anesthetic type and time to recurrence patients who received SA had a

Table 1. Univariable analysis of recurrence No Recurrence No. pts Mean  SD age Mean  SD body mass index (kg/m2) No. male (%) ASA classification (%): 1 2 3 4 No. smoking status (%): Current Nonsmoker Former No. anesthesia (%): Spinal General No. adjuvant chemotherapy (%): None Postop BCG No. tumor grade (%): 1 or 2 3 No. tumor stage (%): Ta T1 No. Ca in situ (%): None Yes No. risk category (%): Low Intermediate High

Recurrence

p Value

85 70.52  11.79 29.10  5.94

146 68.32  10.65 29.16  6.50

e 0.147 0.946

68 (36.6)

118 (63.4)

0.879

(16.7) (32.9) (40.6) (20.0)

5 (83.3) 49 (67.1) 82 (59.4) 8 (80)

0.309

24 (39.3) 28 (37.8) 33 (35.1)

37 (60.7) 46 (62.2) 61 (64.9)

0.857

57 (42.2) 28 (29.2)

78 (57.8) 68 (70.8)

0.043

29 (42.6) 21 (56.8) 35 (27.8)

39 (57.4) 16 (43.2) 91 (72.2)

0.003

43 (39.8) 42 (34.1)

65 (60.2) 81 (65.9)

0.373

61 (40.4) 24 (30.0)

90 (59.6) 56 (70.0)

0.119

76 (41.5) 9 (18.8)

107 (58.5) 39 (81.3)

0.004

29 (45.3) 13 (50.0) 43 (30.5)

35 (54.7) 13 (50.0) 98 (69.5)

0.042

1 24 56 2

longer median time to recurrence (42.1 vs 17.2 months, p ¼ 0.014, part A of figure). On univariable analysis for other NMIBC outcomes grade (p ¼ 0.009), stage (p ¼ 0.02) and risk category (p ¼ 0.007) were associated with progression (supplementary table 2, http://jurology.com/). ASA classification and age were significantly associated with overall mortality (p ¼ 0.007 and 0.042, respectively, supplementary table 3, http:// jurology.com/). Anesthetic type was not associated with cancer progression or overall mortality (parts B and C of figure). On multivariable analyses incorporating key a priori variables, including NMIBC risk stratification as well as adjuvant therapies, patients who underwent TURBT under GA had a higher incidence of recurrence (OR 2.06, 95% CI 1.14e3.74, p ¼ 0.017) and earlier time to recurrence (HR 1.57, 95% CI 1.13e2.19, p ¼ 0.008) compared to those who received SA (table 2). Although there was a trend toward an association of risk category with recurrence on multivariable analysis, it did not reach statistical significance, possibly due to collinearity with the use of adjuvant intravesical therapies. POCT of lower risk NMIBC demonstrated an

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Kaplan-Meier curves of anesthetic type and time to cancer recurrence (A), progression (B) and death (C ). Mantel-Cox log rank test p ¼ 0.014.

overall decrease in recurrence (OR 0.417, 95% CI 0.176e0.988), although time to recurrence was not statistically significant. Sensitivity analysis of patients stratified by risk category indicated that the effect of anesthetic type on recurrence was driven by those with high risk NMIBC. In the 64 patients at low risk the anesthetic type was not associated with recurrence (OR 1.38, 95% CI 0.45e4.25, p ¼ 0.58 and HR 1.54, 95% CI 0.77e3.06, p ¼ 0.22). However, the association of anesthesia and recurrence appeared to be strongly driven by those in the high risk group (OR 3.00, 95% CI 1.28e7.02, p ¼ 0.011 and HR 1.68, 95% CI 1.12e2.53, p ¼ 0.012). As expected, BCG induction therapy was associated with a decreased rate of recurrence in the high risk cohort.

DISCUSSION The main findings of this retrospective study suggest that patients who received spinal anesthesia for TURBT showed a decreased incidence of recurrent NMIBC as well as increased time to the first recurrence compared to patients who received general anesthesia. Although the choice between these 2 anesthetic techniques is generally determined by patient factors and preference, multivariable analysis controlling for cancer risk categories and adjuvant therapies revealed a persistent effect on recurrence. Our findings support emerging evidence that regional anesthesia techniques, perhaps through mitigation of a perioperative cancer promoting microenvironment, may be an important consideration in surgical oncology cases.

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Table 2. Multivariable analysis of incidence and time to recurrence Incidence*

Adjuvant chemotherapy: None Postop BCG Anesthesia: Spinal General Risk category: Low Intermediate High

Time to Recurrence†

OR (95% CI)

p Value

HR (95% CI)

p Value

Referent 0.42 (0.18e0.98) 1.51 (0.75e3.06)

0.047 0.248

Referent 0.61 (0.34e1.11) 1.24 (0.78e1.96)

e 0.108 0.372

Referent 2.06 (1.14e3.74)

0.017

Referent 1.57 (1.13e2.19)

e 0.008

Referent 0.79 (0.30e2.00) 1.45 (0.73e2.91)

0.584 0.299

Referent 0.83 (0.44e1.58) 1.41 (0.88e2.26)

e 0.574 0.150

* Logistic regression. † Cox regression.

Volatile agents used for general anesthesia have been implicated in dose and time dependent suppressive effects on immune cells, including NK cells and T lymphocytes, while inducing mitogenesis, angiogenesis and metastasis in tumors.6 Volatile anesthetic agents have also been shown to stimulate the rapid production of hypoxia-inducible factor-1 with subsequent activation of cancer cell proliferation.19 Reducing the requirement for these agents using regional anesthetic techniques was shown to have a measureable effect on cancer cell proliferation in human studies.20 Cancer immune escape is a well recognized feature of malignant neoplasms and a focus of intense investigation for therapeutic intervention.21 Regional anesthesia attenuates perioperative activation of the hypothalamic-pituitary-adrenal axis and subsequent stress induced immunosuppression. Hypothalamic-pituitary-adrenal activation suppresses NK, T cell and macrophage activity, and the significant sympathetic output with surgical interventions leads to decreased local perfusion and inhibition of immune activity through catecholamine binding to effector cells.22 The local anesthesia administered in regional techniques may also reduce cancer recurrence through more direct effects on cancer cells since lidocaine and ropivacaine have been shown to have antiproliferative effects on cancer cells in vitro.23 Another purported benefit of regional anesthesia is the decrease in opioid use, which was demonstrated to have suppressive effects on NK, B and T cells as well as pro-angiogenic effects.3e6,24,25 Although we were unable to collect complete data on perioperative pain management in our cohort, it is unlikely that variability in opioid use contributed significantly to our results as perioperative pain and subsequent opioid requirements after TURBT were low. Cancer progression and overall survival were not significantly influenced by the anesthetic technique

in the current analysis. However, there are multiple studies of the relationship between anesthetic technique and these cancer outcomes. A recent meta-analysis indicated a potential association between neuraxial anesthesia and improved overall survival, particularly in patients with colorectal cancer.26 Importantly there were no bladder cancer studies in that analysis. A recent study examined the potential benefit of adding neuraxial analgesia (single dose intrathecal opioid) in patients undergoing radical cystectomy for muscle invasive bladder cancer under GA and yet revealed no improvement in cancer recurrence or mortality.27 Similarly in a population level analysis Doiron et al did not find an effect of thoracic epidural analgesia on short-term or long-term outcomes in patients treated with radical cystectomy.28 However, these studies varied significantly in the definitions of regional vs general anesthesia. Patients in the regional cohort usually received GA for the surgical procedure in conjunction with regional analgesia postoperatively and they were compared to a cohort that received GA followed by an opioid based analgesic regimen. Variability in the efficacy of the postoperative analgesic technique could have affected the ability of these investigators to measure any effect of regional techniques on cancer outcomes. Using NMIBC and TURBT procedures as a model allowed us to have a clearly defined cohort who only received one or the other technique. Furthermore, this cohort of patients had a measurable and clinically relevant end point, given the high recurrence of NMIBC. The abundance of strong preclinical evidence and multiple retrospective studies outlining the beneficial effect of regional anesthesia on cancer outcomes has led to ongoing randomized, controlled trials in various cancer populations.29,30 Limitations of the current study include those inherent to its retrospective nature. Detailed data were lacking on components of the clinical history, including comorbid conditions other than those described by ASA score, the individual anesthetic agents used, including opioid equivalents, and patient willingness to undergo certain therapies, such as maintenance BCG. Although there was complete pathological reporting in this cohort, there was no secondary centralized review of NMIBC cases. During this time the 1973 WHO and 2004 AJCC (American Joint Committee on Cancer) NMIBC grading schemes were reported for this cohort. Although we used the 2 systems in our analysis with the 2004 AJCC system applied to assign risk category, variability in NMIBC grading is common. Also, this cohort included patients with infrequent recurrences as well as those with a primary diagnosis in the study time frame. However, we do

SPINAL ANESTHESIA AND BLADDER CANCER RECURRENCE

not believe that there were significant temporal changes in surgical or anesthetic technique that would have influenced the results. The choice of anesthetic technique at most centers is generally based on patient variables and preference compared to tumor factors. Indeed, those who received general anesthesia were younger and healthier, factors that would potentially be associated with better cancer outcomes in contradistinction to our findings. Beyond any possible selection bias it is possible that different anesthetic techniques may produce better surgical conditions to facilitate optimal TURBT, thus, lowering the risk of recurrence. Although this current study was unable to control for such surgical conditions, we were able to confirm that surgical times in patients treated while under SA or GA were remarkably equivalent.

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Lastly, given the observational nature of the current study, it is possible that unmeasured confounders remained despite controlling for well described variables associated with NMIBC recurrence.

CONCLUSIONS In this retrospective, observational study patients who received spinal anesthesia had a lower incidence of recurrence and increased time to recurrence following TURBT for NMIBC. Given previous retrospective clinical and correlative study evidence of the beneficial effect of regional anesthesia, these findings should prompt largescale multicenter studies to further delineate this association.

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tumour recurrence. Cochrane Database Syst Rev 2014; CD008877.

effects of anesthetic agents. Int J Cancer 2012; 130: 1237.

2. Demicheli R, Retsky MW, Hrushesky WJ et al: The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008; 19: 1821.

12. Biki B, Mascha E, Moriarty DC et al: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008; 109: 180.

20. Deegan CA, Murray D, Doran P et al: Effect of anaesthetic technique on oestrogen receptornegative breast cancer cell function in vitro. Br J Anaesth 2009; 103: 685.

13. Wada H, Seki S, Takahashi T et al: Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology 2007; 106: 499.

21. Ren R, Koti M, Hamilton T et al: A primer on tumour immunology and prostate cancer immunotherapy. Can Urol Assoc J 2016; 10: 60.

3. Cassinello F, Prieto I, del Olmo M et al: Cancer surgery: how may anesthesia influence outcome? J Clin Anesth 2015; 27: 262. 4. Kim R: Anesthetic technique and cancer recurrence in oncologic surgery: unraveling the puzzle. Cancer Metastasis Rev 2017; 36: 159. 5. Coussens LM and Werb Z: Inflammation and cancer. Nature 2002; 420: 860. 6. Byrne K, Levins KJ and Buggy DJ: Can anesthetic-analgesic technique during primary cancer surgery affect recurrence or metastasis? Can J Anaesth 2016; 63: 184. 7. Bar-Yosef S, Melamed R, Page GG et al: Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 2001; 94: 1066. 8. Sun Y, Li T and Gan TJ: The effects of perioperative regional anesthesia and analgesia on cancer recurrence and survival after oncology surgery: a systematic review and meta-analysis. Reg Anesth Pain Med 2015; 40: 589. 9. Cata JP, Hernandez M, Lewis VO et al: Can regional anesthesia and analgesia prolong cancer survival after orthopaedic oncologic surgery? Clin Orthop Relat Res 2014; 472: 1434. 10. Chen WK and Miao CH: The effect of anesthetic technique on survival in human cancers: a metaanalysis of retrospective and prospective studies. PLoS One 2013; 8: 1. 11. Cakmakkaya OS, Kolodzie K, Apfel CC et al: Anaesthetic techniques for risk of malignant

14. Tseng KS, Kulkarni S, Humphreys EB et al: Spinal anesthesia does not impact prostate cancer recurrence in a cohort of men undergoing radical prostatectomy: an observational study. Reg Anesth Pain Med 2014; 39: 284. 15. Babjuk M, Burger M, Zigeuner R et al: EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2013. Eur Urol 2013; 64: 639. 16. Kassouf W, Aprikian A, Black P et al: Recommendations for the improvement of bladder cancer quality of care in Canada: a consensus document reviewed and endorsed by Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA), December 2015. Can Urol Assoc J 2016; 10: E46. 17. Jang D, Lim CS, Shin YS et al: A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis. BMC Anesthesiol 2016; 16: 16. 18. Chang SS, Boorjian SA, Chou R et al: Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 2016; 196: 1021. 19. Tavare AN, Perry NJ, Benzonana LL et al: Cancer recurrence after surgery: direct and indirect

22. Ahlers O, Nachtigall I, Lenze J et al: Intraoperative thoracic epidural anaesthesia attenuates stress-induced immunosuppression in patients undergoing major abdominal surgery. Br J Anaesth 2008; 101: 781. 23. Piegeler T, Votta-Velis EG, Liu G et al: Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology 2012; 117: 548. 24. Martin-Kleiner I, Balog T and Gabrilovac J: Signal transduction induced by opioids in immune cells: a review. Neuroimmunomodulation 2006; 13: 1. 25. Gupta K, Kshirsagar S, Chang L et al: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002; 62: 4491. 26. Weng M, Chen W, Hou W et al: The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated metaanalysis. Oncotarget 2016; 7: 15262. 27. Weingarten TN, Taccolini AM, Ahle ST et al: Perioperative management and oncological outcomes following radical cystectomy for bladder cancer: a matched retrospective cohort study. Can J Anaesth 2016; 63: 584.

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28. Doiron CR, Jaeger M, Booth CM et al: Is there a measurable association of epidural use at cystectomy and postoperative outcomes? A population-based study. Can Urol Assoc J 2016; 10: 321.

29. Sessler DI: Regional Anesthesia and Breast Cancer Recurrence. ClinicalTrials.gov Identifier NCT00418457. Available at https://clinicaltrials.gov/ ct2/show/NCT00418457?term¼00418457&rank¼1. Accessed June 22, 2017.

30. Van Aken HK: Anesthesia and Cancer Recurrence in Malignant Melanoma. ClinicalTrials.gov Identifier NCT01588847. Available at https://clinicaltrials.gov/ ct2/show/NCT01588847?term¼01588847&rank¼1. Accessed June 22, 2017.

EDITORIAL COMMENT The authors looked at 231 patients who underwent TURBT for NMIBC and found that patients who received spinal vs general anesthesia were at lower risk for recurrence and had a longer time to recurrence after controlling for the receipt of any adjuvant therapies and the bladder cancer risk group. While this is not the first study to assess anesthetic type and oncologic outcomes after TURBT (reference 17 in article),1 it better controls for other variables that could impact the association. However, the main limitation is the retrospective nature of the study. While the authors pose many explanations for their findings, it is likely that these results were due to residual confounding and a lack of the data granularity required to properly control for all the factors that could impact the relationship

between anesthetic type and bladder cancer recurrence. For instance, the type of anesthesia may have impacted the quality of TURBT, which in turn would affect the risk of recurrence. However, data on the quality of the TURBT does not appear to have been captured for this analysis. Regardless, these findings merit further investigation into the proposed immunological association between spinal anesthesia and cancer recurrence as well as clinical validation in a prospective, randomized trial. Sanoj Punnen and Chad Ritch University of Miami Miller School of Medicine Sylvester Comprehensive Cancer Center Miami, Florida

REFERENCE 1. Tekgul ZT, Divrik RT, Turan M et al: Impact of obturator nerve block on the short-term recurrence of superficial bladder tumors on the lateral wall. Urol J 2014; 11: 1248.

REPLY BY AUTHORS To our knowledge our report describes for the first time an association of lower recurrence after TURBT for NMIBC with the patient under spinal compared with general anesthesia. In the mentioned investigation by Tekgul et al it was surmised that an obturator block in addition to a spinal block improved the surgical conditions for lateral tumors and likely improved the quality of resection (reference 1 in comment). Jang et al described only 24 patients who received general anesthesia, including patients with muscle invasive bladder cancer, suggesting a difference in overall survival with only 1 bladder cancer death but no association with recurrence rates (reference 17 in article). We agree that our surprising effect size could be due to chance or residual confounding despite the multiple studies, including at least 1 meta-analysis (reference

8 in article), outlining a possible immunobiological basis for the observation. While acknowledging that some uncontrolled or unrecognized tumor characteristics could affect the recurrence risk as well as the type of anesthesia chosen, we compared surgical times as a surrogate measure of overall case complexity and found no difference between the groups. However, we would like to point out that if anesthetic type leads to more optimal surgical conditions and, therefore, to a higher quality of resection as suggested in the comment, this would represent direct causality (compared to confounding) of the association. In other words, if this observation is corroborated in further prospective studies, the mechanism (immunological or technical) is intriguing but potentially superfluous to its adoption of best practice for TURBT.