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Outcomes After Radical Prostatectomy for Cancer: A Comparison Between General Anesthesia and Epidural Anesthesia with Fentanyl Analgesia A Matched Cohort Study

Sprung, Juraj MD, PhD*; Scavonetto, Federica MD*; Yeoh, Tze Yeng MB ChB*†; Kramer, Jessica M. DO*‡; Karnes, R. Jeffrey MD§; Eisenach, John H. MD*; Schroeder, Darrell R. MS; Weingarten, Toby N. MD*

doi: 10.1213/ANE.0000000000000320
Patient Safety: Research Report

BACKGROUND: The use of regional anesthesia for cancer surgery has been associated with improved oncologic outcomes. One of the proposed mechanisms is a reduction in the use of systemic opioids that may cause immunosuppression. We used a retrospective matched cohort design to compare long-term oncologic outcomes after prostatectomy for cancer performed under general anesthesia with systemic opioids or with epidural anesthesia with epidural fentanyl analgesia. Since epidural fentanyl is quickly reabsorbed systemically, we hypothesized that there would be no difference in long-term oncological outcomes between the 2 groups.

METHODS: There were 486 men who underwent prostatectomy performed under epidural anesthesia between January 1, 1991, and January 31, 1996. They were 1:1 matched based on age (±5 years), surgical year (±1 year), and baseline prostate cancer pathology to patients who had general anesthesia with systemic opioids. Long-term cancer outcomes and all-cause mortality were examined. Analyses were performed using stratified proportional hazards regression models, with hazard ratios >1 indicating worse outcome for general anesthesia only compared with epidural anesthesia and fentanyl analgesia.

RESULTS: After adjusting for positive surgical margins and adjuvant therapies, patients in the general anesthesia group were found not to be at increased risk of prostate cancer recurrence (hazard ratio [HR] = 0.79, 95% confidence interval [CI], 0.60–1.04], systemic tumor progression (HR = 0.92, 95% CI, 0.46–1.84), cancer-specific mortality (HR = 0.53, 95% CI, 0.18–1.58), or overall mortality (HR = 1.23, 95% CI 0.93–1.63) when compared with patients who received epidural anesthesia.

CONCLUSIONS: Compared with general anesthesia with systemic opioids, epidural anesthesia and analgesia with fentanyl were not associated with improvement in oncologic outcomes in patients undergoing radical prostatectomy for cancer.

Published ahead of print June 23, 2014.

From the *Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota; Department of Anesthesiology, National University Hospital, National University Health System, Republic of Singapore; Midwest Anesthesiologists, P.A., Plymouth, Minnesota; and §Department of Urology and Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.

Accepted for publication April 26, 2014.

Published ahead of print June 23, 2014.

Funding: Research Electronic Data Capture (REDCap®) system is supported by Center for Translational Science Activities grant support (UL1 TR000135). This research was carried out with departmental Small Grant. The funders played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Juraj Sprung, MD, PhD, Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Address e-mail to sprung.juraj@mayo.edu.

Tumor excision is a mainstay of cancer treatment, but surgical manipulation may promote systemic dissemination of malignant cells. Intact immunologic response is considered an important element of protection against tumor recurrence and spread,1–6 and during the perioperative period, immune function can be altered.3 For example, when opioids are given systemically, they induce depression of both humoral and cellular immunity3,7–9; specifically, their systemic presence inhibits antibody production, natural killer (NK) cell activity (cytotoxic lymphocytes critical to the innate immune system), cytokine expression, and phagocytic activity.7,10 In contrast, intrathecally administered hydrophilic opioids (e.g., morphine, hydromorphone) remain in the intrathecal space and thus are opioid sparing; therefore, they do not cause immunosuppression.9 Another factor associated with impairment of immunologic defense is exposure to inhaled anesthetics.3,11–14 Finally, the use of amide-linked local anesthetics per se has been shown to exert an antitumor effect.15 Therefore, potential anesthetic elements that can theoretically improve oncologic outcomes after cancer surgery performed under regional anesthesia are (1) reduction of systemic opioids,16 (2) avoidance of inhaled anesthetics,3,11–14 and (3) the use of local anesthetics.15

We recently reported that general anesthesia supplemented with neuraxial hydrophilic opioids (e.g., morphine) during prostatectomy for cancer was associated with improved oncologic outcomes compared to general anesthesia with systemic opioids.17 However, in examining the role of regional anesthesia on oncological outcomes, one should consider whether regional technique provides an opioid-sparing effect. One of the anesthetic techniques used between 1991 and 1996 at the Mayo Clinic for prostatectomy was epidural anesthesia, followed by analgesia with continuous infusion of epidural fentanyl. Epidural fentanyl provides analgesia primarily through rapid systemic absorption and does not result in opioid sparing.18,19 This practice allowed us to examine, in a retrospective matched cohort design, whether prostatectomy for cancer performed under epidural anesthesia and fentanyl analgesia was associated with oncologic outcomes. Because the anesthetic modalities that we compared in the present study were nonopioid-sparing techniques, we hypothesized that the patients who received epidural fentanyl would not have improved oncologic outcomes.

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METHODS

This study was approved by the Mayo Clinic IRB. Consistent with Minnesota Statute, 144.295, we included only patients who provided written authorization for research use of their medical records. We used our institutional prostatectomy registry and electronic anesthesia database to identify patients who had radical prostatectomy performed under epidural anesthesia only (not supplemented with general anesthesia). These patients were 1:1 matched on age (±5 years), surgical year (±1 year), pathologic stage [exact] (T2, T3/4, TxN+), pathologic Gleason score [exact] (≤6, 7, ≥8), and presence of disease in lymph nodes [exact] (yes, no) with patients given general anesthesia with systemic opioids (but no regional technique).

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Anesthesia and Analgesia Management

During the study period, general anesthesia was usually induced with propofol or sodium thiopental, fentanyl, and midazolam and maintained with isoflurane with or without nitrous oxide. Perioperative analgesia was managed predominantly with IV morphine, fentanyl, hydrocodone, or hydromorphone and occasionally with meperidine or sufentanil. In addition, patients received oral oxycodone, oxymorphone, or propoxyphene postoperatively. Patients who had epidural anesthesia/analgesia (via lumbar epidural catheter in all cases) received an initial loading dose of amide-linked local anesthetic (0.5%–0.75% bupivacaine) with epidural fentanyl (50–100 μg). Additional epidural local anesthetic was intraoperatively administered when needed. During the operation, these patients also received sedation with small doses of fentanyl and/or midazolam, but no patient required conversion from epidural to general anesthesia. After surgery, all patients in the epidural group received epidural analgesia via continuous infusion of fentanyl (10 μg/mL) without local anesthetic at a rate between 7 and 10 mL/h for 1 to 3 days postoperatively.

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Prostatectomy Registry and Follow-Up

All patients in this study were actively followed by Mayo Clinic’s radical prostatectomy registry, with dedicated abstractors maintaining the database by following up annually with patients. The compliance of follow-up is high, with <5% lost to follow-up. The present study includes only patients entered into the prostatectomy registry after January 1991. This date was selected to reduce the potential for including more advanced cancers from the pre–prostate-specific antigen (PSA) era (the PSA test was introduced into wide clinical practice in the late 1980s). Prostate tumor classification and staging were performed according to the American Joint Committee on Cancer 1997 tumor-node-metastasis cancer classification system.20 All patients in the registry who had surgery before 1997 were reclassified according to the 1997 guidelines. Prostate pathology was reviewed by Mayo Clinic staff pathologists and urologists.

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Follow-Up and Outcomes

After prostatectomy, patients at Mayo Clinic are typically asked to have physical examinations and serum PSA measurement quarterly for the initial 2 postoperative years, semiannually for an additional 2 years, and annually thereafter. Our registry proactively collects information regarding biochemical recurrence (defined as postoperative PSA concentrations ≥0.4 ng/mL),21 local recurrence (reports of clinical examination or prostate bed needle biopsy), and systemic progression (presence of metastatic deposits on imaging [bone scan, computerized tomography, radiogram, or magnetic resonance imaging] or on biopsies from locations other than the prostatic bed). A small percentage of patients did not follow the recommended follow-up schedule and presented with local cancer recurrence or even systemic progression without having earlier PSA checkup; therefore, their elevated PSA levels were detected simultaneously with the diagnosis of a more advanced stage of cancer spread. For that reason, we report an oncologic outcome “cancer recurrence,” which included patients who had prostate cancer recurrence diagnosed with biochemical progression, local recurrence, and/or systemic progression. Death was presumed to be from prostate cancer when patients died within 30 postoperative days of surgery (long-term definition by prostate registry) or if medical records or the death certificate listed prostate cancer as a cause. Of note, this death definition is moot since no patients in the current study died within 30 days of surgery. In general, vital status was determined from death certificates and/or yearly correspondence with patients’ personal physicians.

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Data Collection

Data were abstracted from electronic medical records and entered manually into the web-based Research Electronic Data Capture (REDCap) system (version 3.6.7, Vanderbilt University, Nashville, Tennessee).22 Age, body mass index, ASA physical status, preoperative PSA, pathologic stage, Gleason score, presence of positive surgical margins, and presence of positive lymph nodes were recorded. The use of adjuvant androgen deprivation therapy or radiotherapy was defined as any therapy given within 90 days of surgery at the discretion of the surgeon and patient. Relevant comorbidities were obtained from medical records; we ascertained patient comorbidities, namely coronary artery disease, hypertension (counted only if medically treated), current tobacco use, pulmonary disease (obstructive or restrictive chronic lung disease), diabetes mellitus (counted only if medically treated), cerebrovascular disease (history of stroke, transient ischemic attacks), peripheral vascular disease, severe kidney disease (associated with kidney replacement therapy), and history of other cancers. In addition, anesthesia records were reviewed to obtain specifics regarding anesthetic technique including neuraxial management. All intraoperative and postoperative IV and peroral opioids given within the first 48 hours were converted to IV morphine equivalents (ivMEQ).23 However, in the case of epidural fentanyl, we provided absolute dose in microgram rather than ivMEQ, because there is no validated evidence-based conversion factor for epidural fentanyl to ivMEQ.24 For each patient, opioid requirements in the operating room, recovery room, and for the first 24 and 48 hours postoperatively were recorded.

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Outcomes

The prostatectomy registry was reviewed, and the following outcomes were considered: (1) prostate cancer recurrence, (2) systemic prostate cancer progression, (3) prostate cancer mortality, and (4) all-cause mortality.

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Statistical Analysis

Characteristics of general anesthesia-only and epidural-only patients were summarized using descriptive statistics and compared using 2-sample t, rank sum, or χ2 tests. Prostate cancer recurrence, systemic progression, and mortality were summarized using the Kaplan–Meier method. Stratified proportional hazards regression, considering the matched design, was used to assess differences in outcomes between the general anesthesia-alone and the epidural anesthesia-alone groups. In addition, multivariable analyses were performed using similar proportional hazards models, which included 3 additional binary covariates to adjust for positive surgical margins, adjuvant hormonal therapy, or radiotherapy. For the time-to-event analyses, the assumption of proportional hazards was checked using scaled Schoenfeld residuals.25 Results are presented as point estimates and 95% confidence intervals. All tests were 2-sided, with P ≤ 0.05 considered statistically significant. Statistical analyses were done using SAS statistical software version 9.1.3 (SAS Institute, Cary, NC).

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RESULTS

From January 1, 1991, to January 31, 1996, there were 486 patients who had radical retropubic prostatectomy performed under epidural anesthesia only. In January 1996, the practice of using epidural analgesia with fentanyl was discontinued for prostatectomy at the Mayo Clinic. All 486 patients with an epidural catheter continued to have postoperative epidural analgesia for a minimum of 24 hours, and 463 had it for 2 days or longer. These patients were 1:1 matched with those who were given general anesthesia alone. None of the patients in the current study has been included in our previous report.17

Table 1 shows demographic and clinicopathological characteristics for the 2 groups. By virtue of matching, age, pathological stage, and Gleason scores were identical. Body weight estimated from body mass index was lower in the epidural group (27.9 ± 3.6 vs 28.4 ± 3.8, P = 0.045). ASA physical status and rates of comorbid conditions were not different between the general and the epidural groups. In addition, patients in the 2 groups had a similar rate of positive surgical margins, the same rate of positive lymph nodes, and the same rates of radiation therapies within 90 days, but the general anesthesia group had a lower rate of adjuvant hormonal therapy postoperatively (P = 0.001).

Table 1

Table 1

Table 2 summarizes the perioperative use of systemic opioids expressed in ivMEQ and the absolute doses of fentanyl (mcg) administered through the epidural catheter. Mean (±SD) duration of postoperative epidural fentanyl infusion was 57.3 (±14.3) hours with an average fentanyl dose of 83 (±20) mcg/h. Patients in both groups were also receiving nonsteroidal antiinflammatory drugs and acetaminophen.

Table 2

Table 2

Figure 1 and Table 3 show cumulative percentages of patients experiencing oncologic outcomes and all-cause death in the 2 groups at 5, 10, and 15 years after radical prostatectomy. The median (interquartile range) follow-up after prostatectomy was 16.2 (13.3–18.1) years in the epidural group and 15.1 (12.5–17.0) years in the general anesthesia group.

Figure 1

Figure 1

Table 3

Table 3

Table 4 shows findings from the stratified proportional hazards regression analyses for these outcomes. Within the range of the confidence intervals provided (Table 4), there was no difference between the groups in cancer recurrence, systemic progression, prostate cancer mortality, or overall mortality.

Table 4

Table 4

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DISCUSSION

Our study is the first to examine prostatectomy oncologic outcomes in patients who underwent surgery with epidural anesthesia followed by epidural fentanyl analgesia compared to general anesthesia with systemic opioids. Our main finding is that our patients who had epidural anesthesia and analgesia did not differ in long-term oncologic outcomes compared with those who had general anesthesia only.

Systemic opioids impair both humoral and cellular immunity.8,12,13 The use of regional anesthesia has been associated with improved oncologic outcomes due to reduction of systemic opioid use.16,26–30 However, in the present study, we did not find better outcomes in the regional anesthesia group. This appears to be in contrast with our recent report17 in which combined general anesthesia with neuraxial analgesia (with hydrophilic opioids) was associated with improved prostate cancer outcomes. However, the important difference between our previous17 and the present study is that neuraxial analgesia with hydrophilic opioids provides an opioid-sparing effect,17 while in contrast, epidural fentanyl analgesia, used in the present study, was not associated with opioid sparing (Table 2). This may explain the lack of “expected” beneficial effect of regional anesthetic technique.

Fentanyl and sufentanil are synthetic lipophilic opioids, and when administered epidurally, they undergo rapid systemic uptake to induce analgesia via supraspinal rather than spinal mechanisms.19,31 When present in the systemic circulation, fentanyl induces a prolonged suppression of NK cell activity, which is an important element of antitumor defenses.32 The popularity of neuraxial analgesia emerged around the notion that opioids at the neuraxial level reduce the need for systemic opioid use by efficiently blocking nociception. However, in the mid-1990s, evidence emerged that the equianalgesic effects of epidural and IV-administered fentanyl occur at similar serum fentanyl concentrations,19 and, to reach these serum levels, epidural infusion needs to be set at a higher rate.18 The same principle applies to epidurally administered sufentanil.31 In contrast, neuraxially administered hydrophilic opioids (morphine and hydromorphone) have low systemic absorption (ratio of relative liposolubility for morphine versus hydromorphone versus fentanyl is 1.0 vs 1.4 vs 580); therefore, they reside within the injected neuraxial compartment and provide long-lasting analgesia. As a result, perioperative systemic opioid sparing is achieved, and the adverse systemic opioid effects on immunosuppression are avoided.9 All these effects can explain the differences in outcomes between the present and our past report.17

In assessing the role of anesthesia on oncologic outcomes, other factors need to be considered, and exposure to inhaled anesthetics has been shown to have a profound and prolonged effect on NK cell activity.14 For example, in one study inhibition of interferon stimulation of NK cell activity after inhaled anesthesia was detected at 11 days after exposure.14 The alteration of NK cell activity and various other components of the innate immune system may result in acceleration of cancer spread.3,13,27,33 In the present study, the epidural group was void of any inhaled anesthetic exposure and despite that was not associated with improved oncologic outcome. Furthermore, despite the fact that the amide-type local anesthetics (e.g., lidocaine, bupivacaine) have antitumor effects in vitro,15 our patients who received bupivacaine anesthesia did not have better oncologic outcomes compared with patients in the general anesthesia group. Therefore, accounting for all the elements of the present study, together with the findings of our recent report,17 it appears that reduction of systemic opioids may be an important element of positive association between regional anesthesia and improved oncologic outcomes. This further indicates that we need to critically reassess the conclusions of some of the previous reports, specifically regarding the imprecise disclosures of the opioid used. Therefore, reporting that the patient had “regional anesthesia” may not be sufficient for interpretation of results without considering all elements of analgesic management. For example, most studies in which combined general and regional anesthesia was compared with general anesthesia only, the type or the exact amount of perioperative opioids used was not reported.16,34–37 Furthermore, studies have been published with equivocal results, in which the so-called regional group included patients who had general anesthesia with intraoperative fentanyl, followed by postoperative epidural fentanyl analgesia,38 which in fact is a comparison between the 2 nonopioid-sparing anesthetic techniques.

Four studies are available in regard to oncologic outcomes related to the type of anesthesia after prostate cancer surgery, and all compare combined general anesthesia and epidural analgesia to general anesthesia only.16,36,37,39 Tsui et al.36 found no advantage with epidural anesthesia. However, this study was underpowered and had short follow-up for slowly progressing tumor (prostate adenocarcinoma); the “regional group” received epidural fentanyl; and there was no mention of the type of postoperative opioid management. A retrospective study by Biki et al.16 compared general anesthesia with postoperative systemic morphine to combined general and epidural anesthesia with local anesthetics continued into the postoperative period. They reported a lower biochemical recurrence in the regional group, but the authors did not quantify opioids used in the 2 groups (it is not clear whether opioid sparing was accomplished in their regional group). Wuethrich et al.37 reported reduced cancer progression in the epidural group, but no significant effect on biochemical recurrence-free survival, cancer-specific survival, and overall survival; however, the regional technique they used included up to 1500 mcg of fentanyl as part of postoperative neuraxial analgesia. Finally, Forget et al.39 studied the impact of intraoperative analgesia (epidural and IV) on the incidence of biochemical recurrence-free survival in a retrospective study that included 1111 consecutive radical prostatectomies for localized prostate cancer. The main opioid used was lipophilic sufentanil, and they reported that epidural analgesia, with local anesthetic and sufentanil, was not associated with a significant effect on prostate cancer biochemical recurrence-free survival. Taking into consideration the pharmacokinetics of epidural sufentanil and the potential adverse role of systemic opioids on oncologic outcomes, these findings39 are consistent with our current study.

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Strengths and Limitations

The strengths of our study are that we examined a single cancer type, with matched cohorts that are well balanced in baseline pathology. Since the early stage of prostate cancer has a low malignant potential, use of Mayo Clinic’s prostatectomy registry allowed us to have a long period of active follow-up, resulting in a sufficient number of oncologic outcomes to perform meaningful analyses.

There are also limitations of our study related to its retrospective design, primarily due to nonrandomized assignment to anesthetic management. In observational and nonrandomized studies, unknown confounders are a limitation. However, our prostate cancer database allowed us to conduct an exact patient match with respect to the most important characteristics for cancer progression. Regardless of this, it remains possible that groups were not balanced on other confounders. For example, one notable imbalance in our series was a higher rate of postoperative hormonal treatments in the epidural group, but we adjusted for this covariate in the multivariable analysis and found similar results. Since adjuvant hormonal treatment is usually prescribed to patients with cancer extension to the lymph nodes or invasion to seminal vesicles (T3b stage),40 and our groups were identical in regard to this pathology (patients were matched according to T3b stage), the observation of a higher use of hormonal therapy in the epidural group was likely attributed to urologist or patient preferences. In addition, it is possible that groups were imbalanced on unmeasured confounders, a variable for which we cannot account.

Our epidural technique was characterized by the use of large amounts of fentanyl, which is rapidly absorbed systemi cally.18 The opioid-associated immuno suppression effect is believed to be mediated through recirculation of fentanyl from systemic circulation to supraspinal opioid receptors. Unfortunately, we did not have measurements of serum fentanyl concentrations, but we assume, based on a previous report,18 that our epidural patients had high serum opioid levels.

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CONCLUSIONS

We did not find an association between the use of epidural anesthesia and analgesia with fentanyl and oncologic outcomes in patients undergoing prostatectomy when compared with general anesthesia with systemic opioids. The opioid-sparing effect has been considered an important factor associated with improved oncologic outcomes after regional techniques. The epidural technique used in the present study was characterized by the use of large amounts of lyophilic fentanyl; therefore, it did not provide systemic opioid sparing, and we believe that this may explain our negative findings. To elucidate the role of opioids on oncological outcomes, future studies should focus on comparing oncologic surgeries performed with general anesthesia and systemic opioids to regional anesthetic techniques, which substantially minimize the perioperative use of systemic opioids.

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DISCLOSURES

Name: Juraj Sprung, MD, PhD.

Contribution: This author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This author contributed to the study conception and design; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; obtained funding, administrative, technical, or material support; and supervision.

Attestation: Juraj Sprung approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.

Name: Federica Scavonetto, MD.

Contribution: This author contributed to the study conception and design, analysis and interpretation of data, drafting of the manuscript, and acquisition of data.

Name: Tze Yeng Yeoh, MB ChB.

Contribution: This author contributed to the study conception and design, analysis and interpretation of data, drafting of the manuscript, and acquisition of data.

Name: Jessica M. Kramer, DO.

Contribution: This author contributed to the study conception and design, analysis and interpretation of data, drafting of the manuscript, and acquisition of data.

Name: R. Jeffrey Karnes, MD.

Contribution: This author contributed to analysis and interpretation of data and critical revision of the manuscript for important intellectual content.

Attestation: R. Jeffrey Karnes approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: John H. Eisenach, MD.

Contribution: This author contributed to the study conception and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

Name: Darrell R. Schroeder, MS.

Contribution: This author contributed to analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and statistical analysis.

Attestation: Darrell R. Schroeder approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Toby N. Weingarten, MD.

Contribution: This author contributed to the analysis and interpretation of data and critical revision of the manuscript for important intellectual content.

This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).

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