Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrence: A Retrospective Analysis
Biki, Barbara M.D.*; Mascha, Edward Ph.D.†; Moriarty, Denis C. M.D.‡; Fitzpatrick, John M. M.D.§; Sessler, Daniel I. M.D.∥; Buggy, Donal J. M.D., M.Sc., F.R.C.P.I., F.C.A.R.C.S.I., F.R.C.A.#
Background: Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia.
Methods: In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia–epidural analgesia or general anesthesia–opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen.
Results: After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17–78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22–0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 [1.08, 1.52], P = 0.004, and 1.17 [1.03, 1.34] for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia.
Conclusions: Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.
PROSTATE cancer is the most common malignancy in men; it is a major cause of morbidity and kills approximately 27,000 people per year in the United States alone.**
Although there are various treatment options for prostate cancer, control of advanced disease often hinges on effective surgical removal of the primary tumor. Unfortunately, recurrence occurs in a significant fraction of patients, perhaps in part because even with the best technique, tumor surgery is usually associated with release of tumor cells into the lymphatic and blood streams. Furthermore, many patients already harbor micrometastases and scattered tumor cells at the time of surgery.1–3
Whether this minimal residual disease results in local or metastatic recurrence is thought to depend largely on the efficacy of host defenses, especially natural killer (NK) cells, which are the primary defense against cancer.4,5
At least three perioperative factors shift the balance toward progression of minimal residual disease:
* The first is surgery per se
, which releases tumor cells into the circulation,1–3
depresses cell-mediated immunity including cytotoxic T-cell and NK cell functions,6–8
reduces circulating concentrations of tumor-related antiangiogenic factors (e.g.
, angiostatin and endostatin),9–12
increases concentrations of proangiogenic factors such as vascular endothelial growth factor,13,14
and releases growth factors that promote local and distant growth of malignant tissue.15
* The second factor is anesthesia per se
, which impairs numerous immune functions including neutrophil, macrophage, dendritic cell, T-cell, and NK cell functions.16–19
* The third is opioids, which are given to control surgical pain. Opioids inhibit both cellular and humoral immune function in humans.16,20,21
Furthermore, morphine is proangiogenic and promotes breast tumor growth in rodents.22
Consequently, nonopioid analgesia helps to preserve NK cell function in animals and humans and reduces metastatic spread of cancer in rodents.23
Regional anesthesia and analgesia attenuates or prevents each of these adverse effects. For example, regional anesthesia moderates the neuroendocrine stress response to surgery by blocking afferent neural transmission from reaching the central nervous system and activating the stress response, and by blocking descending efferent activation of the sympathetic nervous system.24–26
Consequently, NK cell function is better preserved and metastatic load to the lungs is reduced in a rat model of cancer metastasis.6
When regional anesthesia and general anesthesia are combined, the amount of general anesthetic required is much reduced—as is, presumably, immune suppression. Furthermore, regional analgesia provides superb pain relief, essentially obviating the need for postoperative opioids and the consequent adverse effects on immune function and of tumor growth.16,21,26
Regional analgesia also reduces release of endogenous opioids.27
Available animal data thus suggest that regional anesthesia and analgesia help to preserve effective defenses against tumor progression by attenuating the surgical stress response, by reducing general anesthesia requirements, and by sparing postoperative opioids. Limited retrospective data in humans are also consistent with this theory: Paravertebral anesthesia and analgesia for breast cancer surgery was associated with an approximate fourfold reduced risk of recurrence or metastasis during a 2.5- to 4-yr follow-up period (95% confidence interval [CI] of estimated hazard ratio is 0.71–0.06).28
However, other results in humans have yet to be reported. Therefore, we evaluated recurrence of prostate cancer after open radical prostatectomy in patients who received either general anesthesia combined with epidural analgesia or general anesthesia and postoperative opioid analgesia. Specifically, we tested the hypothesis that recurrence of prostate cancer is less common with combined general anesthesia and epidural analgesia than with general anesthesia alone.
Materials and Methods
After approval by the ethics committee of the Mater Misericordiae University Hospital (Dublin, Ireland), we reviewed the medical records of all patients who underwent radical prostatectomy in Mater Misericordiae University Hospital and the Mater Private Hospital between January 1994 and December 2003. Only the records from patients with invasive prostatic carcinoma where radical prostatectomy was indicated were included. We excluded patients who presented only for transurethral prostatic resection or patients diagnosed with prostate cancer who did not have an open radical prostatectomy.
All patients undergoing radical prostate surgery at the Mater Misericordiae University Hospital are given balanced general anesthesia. Most typically, this includes 1–2 μg/kg fentanyl and 1–2 mg/kg propofol for induction, and neuromuscular antagonism to facilitate tracheal intubation with 0.5 mg/kg atracurium. Anesthesia was maintained with nitrous oxide in oxygen, with a fraction of inspired oxygen of 0.3–0.5 at the anesthesiologist’s discretion. Nonsteroidal antiinflammatory drugs, e.g., 75–100 mg diclofenac, and 0.1–0.15 mg/kg morphine were given for postoperative analgesia.
Epidural anesthesia and analgesia has been an integral part of the Mater Hospital’s acute pain service since 1990. Typically, it is offered in combination with general anesthesia to patients undergoing radical prostatectomy. When an epidural is used, it is usually inserted preoperatively at a low thoracic level (e.g., T11–T12), and a preemptive dose of local anesthetic is given before the surgical incision. Local anesthetic administration is then continued as an infusion for 48–72 h after surgery. However, a sizeable minority of patients for this procedure did not receive epidural anesthesia and analgesia for a variety of reasons, including the presence of absolute or relative contraindications, or by preference of the anesthetist, surgeon, or patient. These patients received postoperative patient-controlled morphine analgesia. Patient-controlled analgesia was administered via a CADD-Legacy ambulatory infusion pump (model number 6300; Deltec Inc., St. Paul, MN) programmed to deliver morphine boluses of 1 mg with a lockout time of 6 min.
Our primary outcome measure was the incidence of “biochemical recurrence,” i.e., increase in prostate-specific antigen (PSA) after radical prostatectomy compared with its immediate postoperative nadir, which prompted the clinician to instigate adjuvant treatment (radiation therapy, endocrine therapy, or chemotherapy). Postprostatectomy increase in PSA is indicative of metastatic spread or local cancer recurrence. The time epoch evaluated ended October 2006 (i.e., follow-up interval of 2.8–12.8 yr). Recurrence-free time was defined as the time between the date of surgery and the date of the last PSA, which was at or below the early postoperative nadir. Biochemical recurrence was in turn defined as an increase in PSA above the early postoperative nadir value, which prompted adjunctive therapy (chemotherapy or endocrine therapy or radiation therapy). Recurrence-free time for those patients without a recorded recurrence was defined as the time between the date of surgery and the date of last follow-up.
The following data were obtained from medical records: demographic characteristics; tumor size, grade, and type; PSA status; extent of inguinal nodal disease; whether postoperative or preoperative adjuvant chemotherapy, endocrine therapy, or radiation therapy was used; and each patient’s current status as determined by documentation of follow-up visits to the hospital’s outpatient clinic or general practitioner. In addition, we recorded the histologic tumor margins and whether the tumor was androgen receptive positive. If the most recent follow-up documentation in the hospital records exceeded 3 months from the date of our assessment, we contacted the patient’s general practitioner by telephone to ensure that no consultation had occurred in the interim. This occurred in nine cases: six patients who received general anesthesia alone and three patients who received combined general–epidural anesthesia. In all cases, this clarified whether the patient had contacted his or her general practitioner regarding prostate cancer recurrence.
A total of six patients who received an epidural had documented administration of intramuscular morphine at some point in the first 36 h postoperatively, indicating either epidural failure or inadequate block needing rescue analgesia. These patients were included in the general anesthesia plus epidural group, according to intention-to-treat analysis. Reasons for censoring data included loss to follow-up or inadequate or lost documentation in the medical records.
The anesthetic groups were compared on potential baseline confounders (table 1
) using chi-square tests for categorical variables and either t
tests or Wilcoxon rank sum test for continuous variables, as appropriate. Univariable association between recurrence-free survival and anesthetic technique was assessed with Kaplan-Meier survival estimates, and the groups were compared with the log-rank test.29
In addition, univariable association between recurrence and all potential baseline confounders was assessed using Cox proportional hazards regression.
For the primary analysis, we compared the anesthetic technique groups on recurrence-free survival using multivariable Cox proportional hazards regression while adjusting for any baseline or intraoperative factors independently related with the outcome. Variables considered were American Society of Anesthesiologists physical status, tumor size, length of surgery, Gleason score, margin (yes/no), preoperative PSA, estimated blood loss, transfusion (yes/no), and date of surgery. We used stepwise regression and a liberal significance criterion of P < 0.30 to be confident of having adjusted for any potential confounding of the relation between anesthetic and recurrence among the available baseline factors, as well as to obtain a more precise estimate of hazard ratio for anesthetic treatment.
We assessed the proportion hazards assumption of the Cox regression model graphically by plotting the log [−log (survival)] against log (time). We assessed the predictive ability of the multivariable model with the c
This summary measure gives the proportion of all usable pairs in which predicted and actual survival times are concordant, such that a patient surviving longer than another is also predicted by the model to survive longer. However, the c
index is a less informative measure of predictive ability when a significant proportion of the data are censored. The linearity of the relation between continuous and ordinal variables and recurrence was assessed graphically.
To assess the robustness of our primary analysis results, we also used propensity score matching to assess the association between type of anesthesia and cancer recurrence. A propensity score, defined as the probability of receiving regional anesthesia as predicted from all available baseline and intraoperative variables (same variables as previously listed in primary analysis), was calculated for each patient using logistic regression. No significance criterion was used to remove variables; all were retained. A greedy matching algorithm31
was used to match pairs of regional and general anesthesia patients to within 0.05 on the propensity score scale. Then, to assess association with outcome, the matched groups were compared on cancer recurrence using Cox proportional hazards regression—both univariably, and multivariably using a significance criterion of 0.05 to adjust for any residual confounding.
The significance level for all hypotheses was 0.05. A Bonferroni correction to the significance criterion for multiple comparisons was applied where appropriate. SAS software version 9.1 (SAS Institute, Cary, NC) and R software version 2.4.1 (The R Foundation for Statistical Computing, Vienna, Austria) were used for all analyses.
The groups were not perfectly balanced: The epidural–general patients seemed to have had slightly worse American Society of Anesthesiologists physical status (P
= 0.11), more complications (P
= 0.05), and slightly shorter surgeries (P
= 0.06) than the general–opioid patients (table 1
). Complications were postoperative bleeding, pneumonia or other respiratory tract infection, and urinary tract infection. In addition, the epidural–general patients had a smaller fraction of patients with clear surgical margins (P
= 0.06). These factors were thus prime candidates for inclusion in our multivariable model.
contains univariable Cox regression model results for each baseline and intraoperative factor. Without adjusting for potential confounders (i.e.
, univariably), patients treated with a combination of epidural and general anesthesia had a significantly lower estimated risk of recurrence compared with the general anesthesia and postoperative opioid group, with hazard ratio of 0.34 (95% CI, 0.19–0.61). Margin, Gleason score, preoperative PSA, tumor size, and duration of operation were also significantly associated with recurrence in univariable analysis. Kaplan-Meier recurrence-free survival estimates and 95% CIs at landmark follow-up times for each anesthesia group are in table 3
, with the survival curves plotted in figure 1
After adjusting for tumor size, Gleason score, preoperative PSA, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% CI, 17–78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% CI, 0.22–0.83; P
= 0.012) in our multivariable Cox regression model (table 4
). Gleason score and baseline PSA were strongly associated with recurrence independent of the other model factors. An additional model where all preoperative and intraoperative factors were forced into the regression model gave similar results, with hazard ratio of 0.42 (95% CI, 0.21–0.94; P
There was no evidence of nonproportionality in the hazards for the two groups, and the c
index for the final model was estimated at 0.91, suggesting excellent predictive ability. Although only 64% of the possible pairs were usable because of heavy censoring after 4 yr, the c
index is reliable here because a large fraction of prostate cancer recurrences are expected before 4 yr and little loss to follow-up occurred before then.2
As a sensitivity analysis to explore the potential for bias due to censoring, we assessed the association between anesthetic group and recurrence using only the first 3 yr of data for each patient. Using data through 3 yr, before which only 8% of patients were censored, univariable and multivariable associations were similar to the full data results, with P
= 0.012 and P
= 0.033, respectively.
We also assessed the association between anesthesia technique and cancer recurrence using propensity score matching. Propensity scores were created (see Materials and Methods) for all 200 patients who had nonmissing data for all baseline and intraoperative potential confounding variables (table 5
). Before matching, epidural and general anesthesia patients differed significantly on the propensity score and length of surgery, with smaller differences on other variables. Seventy-one matched pairs were obtained (n = 142 patients); matching was successful in improving the balance between groups (table 5
). Length of hospital stay is shown in table 5
for informational purposes but was not included in the formation of the propensity scores or in the assessment of association with recurrence.
Association between epidural and general anesthesia on cancer recurrence was then assessed on the propensity-matched pairs using Cox regression. Epidural patients were an estimated 52% less likely (0–77%) to recur at any given time compared with general anesthesia patients, with a univariable hazard ratio of 0.48 (95% CI, 0.23–1.00; P
= 0.049). Although unnecessary because of excellent matching, a multivariable Cox regression analysis on the propensity-matched patients (table 6
) resulted in a hazard ratio of 0.51 (95% CI, 0.25–1.06; P
= 0.07). Our propensity-matched analysis results are thus quite similar to our unmatched multivariable model (table 4
We evaluated cancer recurrence in men undergoing radical prostatectomy. After adjustment for confounding factors, patients who received general anesthesia combined with epidural analgesia had a 57% (95% CI, 17–78%) lower risk of cancer recurrence than patients who had general anesthesia and postoperative opioids. A propensity-matched analysis on a subset of the data gave a similar result: Epidural analgesia had a 52% (95% CI, 0–77%) lower risk of cancer recurrence. These results are strikingly similar to our previous report in women undergoing breast cancer surgery in which disease-free survival was 94% (95% CI, 87–100%) and 82% (74–91%) at 24 months, and 94% (87–100%) and 77% (68–87%) at 36 months in the paravertebral and general anesthesia patients, respectively (P = 0.012).
Both results are consistent with a “decisive period” during and after cancer surgery during which minimal residual disease is either controlled by host defense (presumably largely by NK cells) or is retained in the body—eventually becoming clinically apparent as local recurrence or metastasis. Considerable in vitro and animal data support this theory and suggest that, unlikely as it might thus initially seem, use of regional analgesia may reduce the risk of recurrence after major cancer surgery.
Natural killer cells, the primary host defense against cancer, are a subpopulation of lymphoid cells that spontaneously recognize and kill a variety of tumor cells in vitro
and in vivo 4
and are known to play a determinant role in controlling tumor development—and especially the metastatic process.5
We did not evaluate NK cell function in our patients, but much previous work indicates that suppression of NK cell activity occurs within hours of surgery, lasts a few days, and is proportional to the invasiveness of the surgery.17,32
Tissue damage, inflammation, pain, anesthetic and analgesic compounds, and psychological stress all contribute to NK cell suppression and the tumor-promoting effects of surgery33–36
—and all are moderated by regional analgesia.
Ketamine, thiopental, and halothane have each been shown to suppress NK cell activity and promote metastasis in an animal model.37
Other volatile anesthetics also impair NK cell function17
by as much as 90%.18
Halothane and isoflurane comparably reduce neutrophil motility,38
and sevoflurane impairs T lymphocytes.39
Although the immune effects of other volatile anesthetics differ somwhat,40,41
most—including isoflurane and sevoflurane, which were used in our patients—seem to substantially inhibit various immune functions. We were unable to determine the amount of volatile anesthetic given to our patients. However, it is highly plausible that patients in the epidural group—who were routinely given a preemptive dose of local anesthetic—required considerably less volatile anesthetic than those given general anesthesia alone.
Acute and chronic administration of opioids inhibits components of the cellular and humoral immune function, including antibody production, NK cell activity, cytokine secretion, lymphocyte proliferative responses to mitogens, and phagocytic activity.42,43
The immunosuppressive effects of morphine are best studied21,44
; however, other opioids, including fentanyl20,45
and subtype-specific opioid receptor agonists,46
produce comparable immune suppression in most studies.47
Inhibition seems to be dose dependent.20
Endogenous and exogenous opioids bind three major types of receptors: the μ-, δ-, and κ-opioid receptors that have been identified not only in peripheral sensory neurons and the central nervous system, but also in cells of the immune system such as polymorphonuclear leukocytes, macrophages, T lymphocytes, splenocytes, and macrophage-like and T cell–like cell lines.43
Although we were unable to quantify opioid use in our two patient groups, those given epidural analgesia presumably required little opioid, whereas those given general anesthesia alone surely required considerable amounts of opioid for analgesia after open radical prostatectomy, which is a large and painful procedure.
Several important limitations are inherent in this study’s retrospective, observational design. Patients were not randomized and clinical care was not standardized, so that selection bias and the effects of unmeasured confounding variables cannot be excluded. Although our sample size was large enough to detect a strong association, our estimation was rather imprecise, evidenced by wide CIs. And as with most observational studies, even a propensity analysis was not able to completely balance the anesthetic groups on all potential confounders.
There was no significant alteration in clinical practice in the center in question in the relevant time epoch of the study. Laparoscopic or robotic prostate surgery was not introduced, nor were there substantial changes in the frequency of use of epidural analgesia for this type of surgery.
This study, like most retrospective analyses, should be viewed as generating a hypothesis and an estimated effect size for future large randomized controlled trials. (Two are already in progress [ClinicalTrials.gov identifiers NCT00418457 and NCT00531349], and others, including one to evaluate the effect of anesthesia on outcome after radical prostatectomy, will start soon.) Although these studies will require many years of enrollment and follow-up, even a smaller effect size would be clinically important, making the relation between anesthetic technique and cancer recurrence an important hypothesis to pursue, especially given its biologic plausibility.
After primary treatment for clinically localized prostate cancer, including radical prostatectomy, biochemical recurrence (defined as an increase in PSA above its posttreatment nadir) is usually the first evidence of either local recurrence or metastatic progression.48
Radical prostatectomy has been shown to provide high 10-yr PSA recurrence-free survival regardless of whether the prostate tumor involves one or both lobes of the gland, once the tumor is histologically confined within the gland.49
Others have used either PSA doubling time or any increase in PSA above the posttreatment nadir value as indicative of recurrence.50
In summary, cancer surgery releases tumor cells into surrounding healthy tissue and into the systemic circulation. We speculate that whether this minimal residual disease becomes established as recurrent cancer or metastases depends on immune competence in the immediate perioperative period. Regional anesthesia and analgesia may help to preserve immune function by attenuating the surgical stress response, decreasing anesthetic requirement, and diminishing the need for opioids. Consistent with this theory, radical prostatectomy with epidural analgesia was associated with a substantial and statistically significant reduction in biochemical evidence of cancer recurrence. Although limited by its retrospective design, our study suggests that prospective trials evaluating the effects of regional analgesia and opioid sparing on cancer recurrence are warranted.
1. Eschwege P, Dumas F, Blanchet P, Le Maire V, Benoit G, Jardin A, Lacour B, Loric S: Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet 1995; 346:1528–30
2. Foss OP, Brennhovd IO, Messelt OT, Efskind J, Liverud K: Invasion of tumor cells into the bloodstream caused by palpation or biopsy of the tumor. Surgery 1966; 59:691–5
3. Denis MG, Lipart C, Leborgne J, LeHur PA, Galmiche JP, Denis M, Ruud E, Truchaud A, Lustenberger P: Detection of disseminated tumor cells in peripheral blood of colorectal cancer patients. Int J Cancer 1997; 74:540–4
4. Herberman RB, Ortaldo JR: Natural killer cells: Their roles in defenses against disease. Science 1981; 214:24–30
5. Talmadge JE, Meyers KM, Prieur DJ, Starkey JR: Role of NK cells in tumour growth and metastasis in beige mice. Nature 1980; 284:622–4
6. Bar-Yosef S, Melamed R, Page GG, Shakhar G, Shakhar K, Ben-Eliyahu S: Attenuation of the tumor-promoting effect of surgery by spinal blockade in rats. Anesthesiology 2001; 94:1066–73
7. Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G: Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 1999; 80:880–8
8. Wong IH, Lau WY, Leung T, Yeo W, Johnson PJ: Hematogenous dissemination of hepatocytes and tumor cells after surgical resection of hepatocellular carcinoma: A quantitative analysis. Clin Cancer Res 1999; 5:4021–7
9. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J: Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88:277–85
10. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79:315–28
11. Folkman J: Angiogenesis inhibitors generated by tumors. Mol Med 1995; 1:120–2
12. Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med 1998; 49:407–24
13. Lutgendorf SK, Cole S, Costanzo E, Bradley S, Coffin J, Jabbari S, Rainwater K, Ritchie JM, Yang M, Sood AK: Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 2003; 9:4514–21
14. Antoni MH, Lutgendorf SK, Cole SW, Dhabhar FS, Sephton SE, McDonald PG, Stefanek M, Sood AK: The influence of bio-behavioural factors on tumour biology: Pathways and mechanisms. Nat Rev Cancer 2006; 6:240–8
15. Shakhar G, Ben-Eliyahu S: Potential prophylactic measures against postoperative immunosuppression: Could they reduce recurrence rates in oncological patients? Ann Surg Oncol 2003; 10:972–92
16. Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE: The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 2000; 90:1411–4
17. Brand JM, Kirchner H, Poppe C, Schmucker P: The effects of general anesthesia on human peripheral immune cell distribution and cytokine production. Clin Immunol Immunopathol 1997; 83:190–4
18. Markovic SN, Knight PR, Murasko DM: Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. Anesthesiology 1993; 78:700–6
19. Shapiro J, Jersky J, Katzav S, Feldman M, Segal S: Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors. J Clin Invest 1981; 68:678–85
20. Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, Bessler H: Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 1996; 82:492–7
21. Yeager MP, Colacchio TA, Yu CT, Hildebrandt L, Howell AL, Weiss J, Guyre PM: Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers. Anesthesiology 1995; 83:500–8
22. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP: Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002; 62:4491–8
23. Ben-Eliyahu S, Shakhar G, Rosenne E, Levinson Y, Beilin B: Hypothermia in barbiturate-anesthetized rats suppresses natural killer cell activity and compromises resistance to tumor metastasis: A role for adrenergic mechanisms. Anesthesiology 1999; 91:732–40
24. Kehlet H: Modification of responses to surgery by neural blockade: Clinical implications, Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd edition. Edited by Cousins MJ, Bridenbaugh PO. Philadelphia, Lippincott–Raven, 1998, pp 129–78
25. Buggy DJ, Smith G: Epidural anaesthesia and analgesia: Better outcome after major surgery? Growing evidence suggests so. BMJ 1999; 319:530–1
26. O’Riain SC, Buggy DJ, Kerin MJ, Watson RW, Moriarty DC: Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth Analg 2005; 100:244–9
27. Chae BK, Lee HW, Sun K, Choi YH, Kim HM: The effect of combined epidural and light general anesthesia on stress hormones in open heart surgery patients. Surg Today 1998; 28:727–31
28. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI: Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006; 4:660–4
29. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 1972; 135:185–207
30. Harrell FE Jr, Califf RM, Pryor DB, Lee KL, Rosati RA: Evaluating the yield of medical tests. JAMA 1982; 247:2543–6
31. Rubin DB: The use of matched sampling and regression adjustment to remove bias in observational studies. Biometrics 1973; 29:185–203
32. Page GG: Surgery-induced immunosuppression and postoperative pain management. AACN Clin Issues 2005; 16:302–9
33. Munford RS, Pugin J: Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001; 163:316–21
34. Page GG, Ben-Eliyahu S: Indomethacin attenuates the immunosuppressive and tumor-promoting effects of surgery. J Pain 2002; 3:301–8
35. Ben-Eliyahu S: The promotion of tumor metastasis by surgery and stress: Immunological basis and implications for psychoneuroimmunology. Brain Behav Immun 2003; 17 (suppl 1):S27–36
36. Melamed R, Rosenne E, Shakhar K, Schwartz Y, Abudarham N, Ben-Eliyahu S: Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: Suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav Immun 2005; 19:114–26
37. Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S: Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: Mediating mechanisms and prophylactic measures. Anesth Analg 2003; 97:1331–9
38. Erskine R, Janicki PK, Ellis P, James MF: Neutrophils from patients undergoing hip surgery exhibit enhanced movement under spinal anaesthesia compared with general anaesthesia. Can J Anaesth 1992; 39:905–10
39. Loop T, Scheiermann P, Doviakue D, Musshoff F, Humar M, Roesslein M, Hoetzel A, Schmidt R, Madea B, Geiger KK, Pahl HL, Pannen BH: Sevoflurane inhibits phorbol-myristate-acetate-induced activator protein-1 activation in human T lymphocytes in vitro: Potential role of the p38-stress kinase pathway. Anesthesiology 2004; 101:710–21
40. Lieners C, Redl H, Schlag G, Hammerschmidt DE: Inhibition by halothane, but not by isoflurane, of oxidative response to opsonized zymosan in whole blood. Inflammation 1989; 13:621–30
41. Loop T, Dovi-Akue D, Frick M, Roesslein M, Egger L, Humar M, Hoetzel A, Schmidt R, Borner C, Pahl HL, Geiger KK, Pannen BH: Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology 2005; 102:1147–57
42. McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ: Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 2001; 62:111–23
43. Vallejo R, de Leon-Casasola O, Benyamin R: Opioid therapy and immunosuppression: A review. Am J Ther 2004; 11:354–65
44. Eisenstein TK, Rogers TJ, Meissler JJ Jr, Adler MW, Hilburger ME: Morphine depresses macrophage numbers and function in mouse spleens. Adv Exp Med Biol 1998; 437:33–41
45. Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B: Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats: Dose and timing study. Neuroimmunomodulation 2004; 11:255–60
46. Rahim RT, Meissler JJ Jr, Cowan A, Rogers TJ, Geller EB, Gaughan J, Adler MW, Eisenstein TK: Administration of mu-, kappa- or delta2-receptor agonists via osmotic minipumps suppresses murine splenic antibody responses. Int Immunopharmacol 2001; 1:2001–9
47. Welters ID, Menzebach A, Goumon Y, Langefeld TW, Teschemacher H, Hempelmann G, Stefano GB: Morphine suppresses complement receptor expression, phagocytosis, and respiratory burst in neutrophils by a nitric oxide and mu(3) opiate receptor-dependent mechanism. J Neuroimmunol 2000; 111: 139–45
48. Cannon GM Jr, Walsh PC, Partin AW, Pound CR: Prostate-specific antigen doubling time in the identification of patients at risk for progression after treatment and biochemical recurrence for prostate cancer. Urology 2003; 62:2–8
49. Freedland SJ, Partin AW, Epstein JI, Walsh PC: Biochemical failure after radical prostatectomy in men with pathologic organ-confined disease: pT2a versus pT2b. Cancer 2004; 100:1646–9
50. Stephenson AJ, Shariat SF, Zelefsky MJ, Kattan MW, Butler EB, Teh BS, Klein EA, Kupelian PA, Roehrborn CG, Pistenmaa DA, Pacholke HD, Liauw SL, Katz MS, Leibel SA, Scardino PT, Slawin KM: Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. JAMA 2004; 291:1325–32
** American Cancer Society: Cancer Facts & Figures 2007. Available at: http://www.cancer.org/downloads/STT/CAFF2007PWSecured.pdf
. Accessed May 2, 2007. Cited Here...
This article has been cited 35 time(s).
British Journal of AnaesthesiaCan anaesthetic and analgesic techniques affect cancer recurrence or metastasis?British Journal of Anaesthesia
International Journal of Clinical OncologyPolymorphism of A118G in mu-opioid receptor gene is associated with risk of esophageal squamous cell carcinoma in a Chinese populationInternational Journal of Clinical Oncology
Plos OneEpidural Analgesia during Open Radical Prostatectomy Does Not Improve Long-Term Cancer-Related Outcome: A Retrospective Study in Patients with Advanced Prostate CancerPlos One
Brain Behavior and ImmunitySurgery and stress promote cancer metastasis: New outlooks on peridperative mediating mechanisms and immune involvementBrain Behavior and Immunity
Irish Journal of Medical Science
Effect of anaesthetic technique on ER positive breast cancer cell apoptosis in the presence of CD56+NK cells
Irish Journal of Medical Science, 182():
Medical HypothesesRegulatory T cells: A possible promising approach to cancer recurrence induced by morphineMedical Hypotheses
British Journal of SurgeryPatient optimization for gastrointestinal cancer surgeryBritish Journal of Surgery
Plos OneThe Effect of Anesthetic Technique on Survival in Human Cancers: A Meta-Analysis of Retrospective and Prospective StudiesPlos One
Bmc Veterinary ResearchPerioperative evaluation of tumescent anaesthesia technique in bitches submitted to unilateral mastectomyBmc Veterinary Research
Journal of Clinical AnesthesiaThe effects of anesthetic and analgesic techniques on immune functionJournal of Clinical Anesthesia
Journal of the American College of SurgeonsFirst Report of Hepatectomy without Endotracheal General AnesthesiaJournal of the American College of Surgeons
Journal of Clinical OncologyEffects of Anesthetics on Cancer RecurrenceJournal of Clinical Oncology
Anesthesia and AnalgesiaThe Role of the Perioperative Period in Recurrence After Cancer SurgeryAnesthesia and Analgesia
Immune response in patients with cancer pain
Periodicum Biologorum, 111(2):
British Journal of AnaesthesiaGeneral anaesthesia vs local anaesthesia: an ongoing storyBritish Journal of Anaesthesia
AnaesthesiaRegional anaesthesia and pain managementAnaesthesia
Annales Francaises D Anesthesie Et De ReanimationCould anaesthesia, analgesia and sympathetic modulation affect neoplasic recurrence after surgery? A systematic review centred over the modulation of natural killer cells activityAnnales Francaises D Anesthesie Et De Reanimation
Drug Development ResearchDevelopment and Use of Methylnaltrexone, a Peripherally Acting Opioid Antagonist, to Treat Side Effects Related to Opioid UseDrug Development Research
Canadian Journal of Anaesthesia-Journal Canadien D AnesthesieEpidural anesthesia and cancer recurrence rates after radical prostatectomyCanadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Anesthesia and AnalgesiaDo Intraoperative Analgesics Influence Breast Cancer Recurrence After Mastectomy? A Retrospective AnalysisAnesthesia and Analgesia
Current Drug Targets
New Drugs for Epidural Analgesia
Current Drug Targets, 10(8):
British Journal of AnaesthesiaEffect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitroBritish Journal of Anaesthesia
Journal of ImmunologyImproving Survival Rates in Two Models of Spontaneous Postoperative Metastasis in Mice by Combined Administration of a beta-Adrenergic Antagonist and a Cyclooxygenase-2 InhibitorJournal of Immunology
Canadian Journal of Anaesthesia-Journal Canadien D AnesthesieRegional anesthesia and prostate cancer recurrenceCanadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Mayo Clinic Proceedings
Development of peripheral opioid antagonists: New insights into opioid effects
Mayo Clinic Proceedings, 83():
Neuroimmunomodulation by regional and general anaesthesia
Periodicum Biologorum, 111(2):
Regional anaesthesia - the bride at last?
UrologePain management in urologyUrologe
AnesthesiologyLong-term Consequences of Anesthetic ManagementAnesthesiology
AnesthesiologyRetrospective but Not RigorousAnesthesiology
AnesthesiologyRetrospective but Not RigorousAnesthesiology
Current Opinion in AnesthesiologyAnaesthetic issues in women undergoing gynaecological cytoreductive surgeryCurrent Opinion in Anesthesiology
Current Opinion in AnesthesiologyRegional techniques and outcome: what is the evidence?Current Opinion in Anesthesiology
European Journal of Anaesthesiology (EJA)Adding regional analgesia to general anaesthesia: increase of risk or improved outcome?European Journal of Anaesthesiology (EJA)
© 2008 American Society of Anesthesiologists, Inc.
Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.