Perioperative Medicine  |   April 2012
A Comparison of Epidural Analgesia and Traditional Pain Management Effects on Survival and Cancer Recurrence after Colectomy: A Population-based Study
Author Affiliations & Notes
  • Kenneth C. Cummings, M.D., M.S.
  • Fang Xu, Ph.D., M.S.
  • Linda C. Cummings, M.D., M.S.
  • Gregory S. Cooper, M.D.
  • *Assistant Professor of Anesthesiology, Departments of General Anesthesiology and Outcomes Research, Anesthesiology Institute, Cleveland Clinic, Cleveland, Ohio. Statistical Analyst, Digestive Health Research Center, Case Western Reserve University, Cleveland, Ohio. Assistant Professor of Medicine, §Professor of Medicine, Division of Gastroenterology and Liver Disease, Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio.
Article Information
Perioperative Medicine / Gastrointestinal and Hepatic Systems / Pain Medicine / Practice Management
Perioperative Medicine   |   April 2012
A Comparison of Epidural Analgesia and Traditional Pain Management Effects on Survival and Cancer Recurrence after Colectomy: A Population-based Study
Anesthesiology 4 2012, Vol.116, 797-806. doi:10.1097/ALN.0b013e31824674f6
Anesthesiology 4 2012, Vol.116, 797-806. doi:10.1097/ALN.0b013e31824674f6
What We Already Know about This Topic
  • Regional anesthesia likely improves acute postoperative analgesia and recovery after cancer surgery, but whether it affects later metastases or survival is unclear

What This Article Tells Us That Is New
  • In a case cohort study of more than 42,000 patients undergoing resection for colon cancer, 5-yr survival was greater in those receiving epidurals at the time of surgery (61% compared with 55%)

  • Cancer recurrence, measured as later use of chemotherapy or radiation therapy, did not differ in those receiving epidurals and those who did not

COLORECTAL cancer is the third most common cancer diagnosed in the United States and accounted for approximately 9% of all U.S. cancer deaths in 2010.1 A major determinant of survival in patients undergoing cancer surgery is recurrence, with rates of 8–25% reported for colorectal cancer.2 To a large degree, the opposing forces of immune surveillance and a tumor's ability to spread determine whether local recurrence or metastasis occurs.3 –4 
Multiple surgical factors can negatively affect the balance between metastasis and tumor surveillance in the perioperative period.3,5  15 Allogeneic blood transfusion, not uncommon in large abdominal procedures, is also widely recognized as immunosuppressive, as are general anesthesia16  19 and opioid analgesics.20 –21 By reducing the surgical stress response (if used intraoperatively) and significantly reducing exposure to opioids, regional, or neuraxial anesthetic techniques, even when combined with general anesthesia, may suppress immune function less than opioid analgesia.21 –22 Consistent with this hypothesis, regional anesthetic techniques have been associated with lower recurrence rates of breast and prostate cancers.23 –24 Results for colon cancer, however, are mixed,25 –26 prompting the need for additional (and larger) database analyses as prospective trials are conducted.
In addition to effects on cancer recurrence, the impact of neuraxial analgesia on survival after surgery has been a contentious issue. Although widely believed to improve patient outcomes, survival data are less convincing. Whereas original reports suggested a survival benefit of neuraxial anesthesia/analgesia for different types of surgery,27 results for survival after colorectal cancer surgery have been mixed, with some analyses showing a survival benefit28 –29 and others finding none.26 Although cancer recurrence will determine survival to a large extent, other putative mechanisms include a reduction in perioperative cardiac, respiratory, and thromboembolic events.27 
Although limited by their design, administrative database studies provide insights not easily found outside of large randomized clinical trials.30 In particular, Medicare claims data provide a large pool of patient encounters for research. Therefore, the objectives of this population-based cohort study were to use the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database to compare overall survival and cancer recurrence rates between patients who did or did not receive epidural anesthesia and/or analgesia for open resection of nonmetastatic colorectal cancer. Our hypotheses were that epidural anesthesia and/or analgesia is associated with reduced cancer recurrence after colorectal cancer resection and improved all-cause mortality after surgery.
Materials and Methods
The protocol utilizing the Medicare-SEER database was approved by Case Comprehensive Cancer Center Institutional Review Board (Cleveland, Ohio) and the National Cancer Institute (Bethesda, Maryland).
Data Sources
The SEER tumor registry provides a population-based source of information about patients with colorectal cancer. This tumor registry is a program of the National Cancer Institute at the National Institutes of Health (Bethesda, Maryland) that tracks cancer incidence in a set of cancer registries in the United States. The SEER program began collecting data in 1973, and currently collects patient-specific information about cancer cases from more than a dozen cancer registries encompassing about 26% of the U.S. population. SEER data include primary site, previous cancer diagnoses, histology, stage, site specific surgery, reasons patients did not undergo surgery, surgery of distant sites, and initial course of therapy. These data are contained in the Patient Entitlement and Diagnosis Summary File (PEDSF).
Patients in the SEER database who are also Medicare beneficiaries can be identified by linking the SEER and Medicare databases, resulting in a joint database that consists of patients aged 65 yr or older who were diagnosed with cancer while living in one of the SEER areas. The linked SEER-Medicare database consists of claims from Medicare beneficiaries, which include nearly all individuals 65 yr old or older. Medicare Part A claims for inpatient hospital care and for home health care and hospice services are contained in the Medicare Provider and Analysis Review (MedPAR) file. Medicare Part B claims are for physician services and outpatient services including hospital outpatient, ambulatory surgical centers, and rural health clinics; some home health; and other medical services, and are available in the Outpatient Standard Analytical File and the National Claims History files. Procedures in the linked SEER-Medicare database can be identified from procedure codes (International Classification of Diseases, 9th Edition (Clinical Modification) [ICD-9-CM] and Current Procedural Terminology, 4th Edition [CPT-4]) from Medicare hospital inpatient claims (MedPAR) and physician-supplier claims. A more detailed discussion of the SEER-Medicare database and its use in cancer research can be found in a review by Warren et al.  31 
Study Population
Using PEDSF, we identified a cohort of patients aged 66 yr or older diagnosed with incident nonmetastatic colorectal adenocarcinoma between 1996 and 2005 who underwent colectomy (identified from MedPAR). This provided at least 4 yr of follow-up for cancer recurrence, given that the most recent Medicare data are from 2009. Patients aged 66 yr or older were included to allow for claims to be available to assess comorbidities 1 yr before colorectal cancer diagnosis. Patients who presented with localized or regional stage disease (American Joint Committee on Cancer Stages I, II, and III) according to SEER and underwent colectomy within 6 months of diagnosis as indicated in Medicare claims data were included.
The following exclusion criteria (identified in PEDSF and MedPAR) were applied: carcinoma in situ  , stage IV disease, or unstaged cancers; prior diagnosis of cancer; cancer diagnosed on autopsy or death certificate only; eligibility for Medicare on the basis of end stage renal disease or disability; Medicare Health Maintenance Organization enrollment because of the potential for incomplete claims; diagnosis of familial adenomatous polyposis; and history of inflammatory bowel disease (Crohn's disease or ulcerative colitis). Patients identified as undergoing laparoscopic procedures were excluded because they would be much less likely to have epidural catheters placed. Patients without both Medicare Parts A and B coverage were excluded because both inpatient and outpatient claims are needed for the analysis. Patients with admitting diagnoses suggesting urgent or emergent procedures according to the method of Diggs et al.  32 were excluded. Finally, patients who subsequently developed an unrelated second malignancy (indicated in PEDSF) were excluded.
Using these criteria, two nested cohorts were defined. The cohort for assessment of overall survival was identified as patients who were enrolled in Medicare part A and B within 1 yr before cancer diagnosis until death or 8 months after diagnosis, whichever came first, in order to allow recording of perioperative data and complications. The recurrence cohort for assessment of cancer recurrence was identified as patients who were enrolled in Medicare part A and B within 1 yr before cancer diagnosis until 4 yr after diagnosis or death who survived at least 12 months after surgery.
The exposure variable was epidural anesthesia and/or analgesia. The CPT codes for placement of thoracic and lumbar epidural catheters (62318 and 62319, respectively, with a possible −59 modifier for postoperative pain) as well as the code for daily hospital management of an epidural infusion (01996) were identified from the Standard Analytical File and National Claims History file because MedPAR does not contain information on epidural placement. Epidural codes were searched perioperatively ranging from 1 week before and after surgery. These codes have been used successfully elsewhere in Medicare database research.33  35 Either a code for epidural placement or a code for daily management was taken as evidence of epidural use.
All-cause mortality after cancer resection was determined by the Medicare date of death (recorded in the PEDSF file). Survival time was measured from date of resection to death or 12/31/2009 if censored. The secondary outcome was colorectal cancer recurrence. We defined recurrence within a 4-yr window after surgery. As recommended by a panel of experts with SEER-Medicare data, colorectal cancer recurrence was defined as an ICD-9 metastasis code (197.5) or receipt of chemotherapy 16 months or more after the date of surgery and/or radiation therapy 12 months or more after the date of surgery.36 –37 Radiation therapy was identified using the ICD-9 codes 92.2, V58.0, V66.1, and V67.1 and CPT code 77xxx. MedPAR, National Claims History, and Standard Analytical File were evaluated for chemotherapy administration. The following ICD-9 codes were used to identify use of chemotherapy: chemotherapy administration (99.25), encounter for antineoplastic chemotherapy (V58.1), cancer chemotherapy follow-up (V67.2), convalescence and palliative care following chemotherapy (V66.2), outpatient or physician administration of chemotherapy (Q0083–Q0085), and chemotherapeutic agents (Healthcare Common Procedure Coding System codes J9000–J9999 or G0355–G0363). CPT codes 964xx and 965xx were also included. Revenue center codes for injected chemotherapy (0331), oral chemotherapy (0332), and intravenous chemotherapy (0335) were also used to identify chemotherapy use from physician-supplier claims. This approach has been validated for use of 5-fluorouracil for colon cancer using SEER-Medicare data in a previous study.38 
From the SEER file, we included patient-level demographic and clinical variables including age, gender, race, marital status, SEER site, year of diagnosis, anatomical site, stage of disease at diagnosis, and Medicare date of death. We also noted socioeconomic factors measured at the census tract level (urban/rural residence, median income, and percent of residents with at least a high school diploma). Cases with anatomical site codes for cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction, and rectum were included. Blood transfusions were noted from the MedPAR blood pints furnished variable.
As recommended by the National Cancer Institute,1we identified comorbid conditions using ICD-9-CM codes from MedPAR, Outpatient, and physician-supplier claims to calculate a comorbidity index modified from the Deyo adaptation of the Charlson comorbidity index.39 We adopted Klabunde's 30-day rule out algorithm to incorporate comorbid condition codes from outpatient files.40 
We examined MedPAR for surgical procedure codes. The use of an ICD-9-CM diagnosis code of V64.4 in conjunction with procedure codes for colectomy in the absence of procedure codes for laparoscopy (54.21, 45.81) was considered to be a laparoscopic procedure that was converted to open. These patients were included in the analytic cohort. If a patient had a colectomy and the codes for laparoscopy were not present, then the patient was assumed to have had an open colectomy.
To account for differences in perioperative complications, we searched Medicare claims data from surgery date till 30 days after surgery. Complications included retrieval of retained foreign body (CPT-4 49085, ICD-9 54.92), management of postoperative shock/hemorrhage (ICD-9 39.98), management of abdominal infection (CPT-4 45020, 45562, 45563, 49020, 49021, 49040, 49041, 49060, 49061, 49080, 49081, 75989, ICD-9 54.0, 54.91, 54.19), repair of an organ injury/laceration (CPT-4 38100, 44602, 44603, 44604, 44605, ICD-9 41.5, 44.61, 46.71, 46.73, 46.75, 48.71, 50.61, 51.91, 69.41), reoperative laparotomy (CPT-4 49002, 49000, 49010, ICD-9 54.12, 54.11, 54.21), management of wound complication (CPT-4 10060, 10061, 10120, 10121, 10140, 10180, 12020, 13160, 97601, 97602, ICD-9 54.61, 86.22), management of fistula (CPT-4 44640, 44650, 44660, 44661, 45800, 45805, 45820, 45825, ICD-9 46.72, 46.74, 46.76), management of bowel obstruction (CPT-4 44050), and management of stoma complication (CPT-4 44340, 44345, 44346, ICD-9 46.40, 46.41, 46.42, 46.43).41 
Statistical Analysis
Patient characteristics were compared according to the presence or absence of epidural anesthesia and/or analgesia. For categorical variables, sample sizes with proportions were presented in each group. Pearson's chi-square test was used to compare the groups. For continuous variables, medians with interquartile ranges were presented. Wilcoxon rank sum test were used to compare the groups.
Survival time was defined from the date of surgery to all-cause mortality or last follow-up through December 31, 2009, indicated as censor. Kaplan–Meier survival curves were generated and the group comparison was based on the log-rank test. Based on the nature of the hospital clustered data, a marginal Cox model was constructed. This method uses the pseudolikelihood that yields a consistent estimate of covariate effects. A robust sandwich estimate was implemented in the model.42 As a confirmatory analysis, using logistic regression, a propensity score was generated to predict the use of epidural anesthesia using the same covariates. The propensity score was then used as a continuous covariate to be included in the survival models.
In the analysis of the recurrence cohort, a conditional logistic regression was constructed to predict the likelihood of cancer recurrence, controlling for hospital effect.
All data were analyzed using SAS software version 9.2 (SAS Institute, Cary, NC) and R 2.9.2 (R Foundation for Statistical Computing, Vienna, Austria). All comparisons used two-sided tests at a significance level of 0.05.
Patient Selection
After applying the inclusion and exclusion criteria described above, we identified a primary cohort of 42,151 patients, of whom 22.9% (n = 9,670) had epidurals. The cohort for analysis of cancer recurrence comprised 40,377 patients, of whom 23.0% (n = 9,278) had epidurals at the time of resection. Figure 1details the identification of the primary cohort. The median length of follow-up data was 5.0 yr (5.3 yr in the epidural group, 4.8 yr in the nonepidural group).
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Patient Characteristics
There were a number of differences between the two groups in the primary analysis (table 1). Patients who received epidurals were slightly younger, had lower comorbidity scores, and were more likely to be males, white, married, and residing in Midwest SEER regions. Epidural use differed by American Joint Committee on Cancer stage as well, with stage I patients more likely to have an epidural. Those who received blood transfusion were less likely to have an epidural but the association was not significant (P  = 0.16). When analyzed by cancer location, epidural use was more common in distal tumors (rectosigmoid junction and rectum), but not other sites.
Table 1. Patient Characteristics by Type of Pain Management
Image not available
Table 1. Patient Characteristics by Type of Pain Management
After controlling for hospitals, there was no significant association between epidural use and perioperative complications (conditional logistic regression odds ratio = 0.97, 95% CI[0.85, 1.1], P  = 0.60).
Association Between Epidural Use and Overall Survival
5-yr overall survival was 61% in the epidural group and 56% in the traditional pain management group. Median survival in the epidural group was 7.24 yr (95% CI[6.96, 7.51]); in the nonepidural group, median survival was 6.09 yr (95% CI[5.97, 7.51]). Figure 2shows Kaplan–Meier survival curves for the two groups; the curves were significantly different (log-rank test P  < 0.001). Table 2presents both the unadjusted and adjusted marginal Cox models. Model checking was based on cumulative sums of Martingale based residuals and the models had a good fit. Adjusting for multiple patient characteristics, there was a significant association between epidural use and improved overall survival (adjusted hazard ratio = 0.91, 95% CI = [0.87, 0.94], P  < 0.001). In the adjusted model, several covariates were significant predictors of mortality: older age, male gender, African-American race, unmarried state, higher comorbidity score, higher stage, poorly-differentiated tumors, distal location (descending colon through rectum), diagnosis before 2005, and blood transfusion were all associated with a higher hazard ratio for death. The association between blood transfusion and mortality was particularly strong (adjusted hazard ratio = 1.34, 95% CI [1.28, 1.40], P  < 0.001). Residence in a census tract with a higher median income or higher percentage of people with high school diplomas was associated with a lower mortality hazard.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P  < 0.001.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P 
	< 0.001.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P  < 0.001.
Table 2. Association between Epidural Use and All-cause Mortality
Image not available
Table 2. Association between Epidural Use and All-cause Mortality
As a confirmatory analysis, we used the same covariates used in the adjusted Cox model (omitting blood transfusion and postoperative complication because they did not predict the use of epidural) to create a logistic regression model to predict a propensity score (likelihood of receiving an epidural). The c-statistic for the propensity score model was 0.647. We then incorporated this propensity score as a covariate in our adjusted Cox proportional hazards analysis (table 2, models 2A, 2B, and 2C). Adjusting for the propensity score as a continuous variable, the results did not change appreciably (hazard ratio = 0.92, 95% CI [0.88, 0.96], P  < 0.001).
Association between Epidural Use and Colorectal Cancer Recurrence
Overall 4-yr cancer recurrence was 14.3% in the epidural group and 13.8% in the nonepidural group. In the unadjusted logistic regression, there was an association between epidural use and increased cancer recurrence (odds ratio = 1.14, 95% CI [1.05, 1.24], P  = 0.002). Adjusting for demographic and clinical covariates, however, there was no significant difference in the odds of recurrence between the groups (odds ratio = 1.05, 95% CI [0.95, 1.15], P  = 0.28). Of note, blood transfusion was a significant predictor of cancer recurrence in the adjusted model (odds ratio = 1.14, 95% CI = (1.03, 1.25), P  = 0.01).
Our results suggest an early and sustained beneficial effect of epidural use on all-cause mortality after colorectal cancer resection. These findings contrast those of the Multicenter Australian Study of Epidural Anaesthesia and Analgesia in Major Surgery (MASTER) trial,43 a reanalysis of which also found no difference in mortality in the subset of patients undergoing surgery for abdominal malignancies.26 Some literature, however, is consistent with our results. Christopherson et al.  demonstrated improved survival up to 1.46 yr with epidural use in patients without metastases.28 In addition, Gupta et al.  found an association between epidural use and decreased all-cause mortality after resection of rectal (but not colon) cancers.29 It is interesting to note that distal cancers were associated with a higher risk for mortality and recurrence than proximal in our analysis. Taken together with previous work, this suggests that there may be important clinical differences between rectal and more proximal cancers.
The 5-yr survival rates observed in this study (61% and 56% for epidural and nonepidural groups, respectively) are somewhat lower than others reported in the literature. For example, Gupta et al  .29 found 77.3% survival at a median follow-up of 2.7 yr, whereas Jayne et al.  44 reported a lower 67.8% overall survival at 3 yr. Both of these values, however, are higher than those seen in our analysis. This could be explained by differences in surgical technique, patient populations, or length of follow-up (our data provided longer term information).
Because immune surveillance is a primary determinant of cancer progression, it is logical to hypothesize that interventions aimed at reducing exposure to immunosuppressive factors would improve patient outcomes after potentially curative cancer resection. In colorectal cancer, however, this has been difficult to demonstrate. Our analysis found no association between epidural use and colorectal cancer recurrence. In that regard, our results fit well with the existing literature in colorectal cancer. Gottschalk et al.  analyzed 669 patients undergoing colorectal cancer resection and found no overall association between epidural analgesia and recurrence risk, although their study was limited by a relatively short follow-up period. In a subgroup analysis, however, they did demonstrate a lower risk of recurrence in older patients who received epidural analgesia.25 Our logistic regression analysis indicates that increasing age is actually independently associated with a lower risk of cancer recurrence. Whether this is a true association or an effect of age on mortality hazard (and thus providing less time to observe for recurrence) remains to be seen. As mentioned previously, Myles et al.  26 evaluated the recurrence of many types of completely resected abdominal malignancies, of which 106 cases were colorectal, in groups randomized to either epidural or systemic analgesia. They found no significant difference in cancer recurrence between the groups (as a composite of the different malignancies), but the study had limited power to detect an effect on any particular malignancy. Taken together with these studies, our results suggest that the impact of epidural analgesia on colon cancer recurrence is minor at best.
The differences seen in analyses of colorectal cancer versus  other malignancies highlight the difficulties facing investigators in this field. Differences in tumor biology (between and within cancer types), different surgical techniques, varying patient populations, challenges in defining recurrence, and difficulty with long-term follow-up all hamper firm conclusions. These are a few of the challenges that must be addressed in clinical trials. Given the long spans of time and large patient populations required, clinicians will have to wait quite a while for definitive results.
Of note, we found a significant association between perioperative blood transfusion and increased odds of cancer recurrence as well as an increased hazard for mortality. This is consistent with the increasingly recognized negative effects of allogeneic blood transfusion. In colon cancer patients, transfusion has previously been associated with increased odds of recurrence after surgery.45 In a wider surgical population, Glance et al.  found an association between blood transfusion and an increase in multiple perioperative complications, including an increased risk of death.46 In our analysis, however, it is uncertain whether blood transfusion leads to worse outcomes or is simply a marker of a worse perioperative course or more aggressive tumor.
This study has several strengths worth mentioning. The SEER-Medicare database is very large, provides detailed tumor information, and is centrally maintained by the National Cancer Institute. The data quality is very good and provides information from across the United States, not just a single center or region. To our knowledge, this is the first study in the anesthesiology literature to utilize this large database. The closest analysis to this field used the database to evaluate repeated exposure to anesthesia as one of many risk factors for non-Hodgkin's lymphoma.47 
There are, however, important limitations to this analysis. It suffers from the same weaknesses inherent to all observational studies, namely susceptibility to bias, confounding, and effect-cause associations. It is possible that some of our results may be explained by unmeasured confounders or selection bias. We used propensity scores in an attempt to adjust for potential selection bias in treatment assignment, but we were limited to the covariates available in the database. It is important to remember that propensity scores only balance groups on known covariates, so unmeasured confounders may still remain. This limitation, combined with the modest discriminatory ability (c-statistic) of our propensity score model, suggests that successful balancing of covariates, although not assured, is likely.
Because much of the information on procedures comes from administrative claims, there are limited clinical data (surgical and anesthetic techniques, drugs administered, among others) on the care patients received. For example, we inferred a laparoscopic case converted to open if both codes for open procedures and laparoscopy were present. This could introduce bias, as these patients would be less likely to have epidurals and might have worse outcomes. The small proportion of these cases, however (less than 1%), would make any effects on the analysis quite small. In addition, because intraoperative use of an epidural is not billed separately (as opposed to placement solely for postoperative pain), the timing of epidural use (preoperative, intraoperative, or only postoperative) is unclear from this database. However, the combination of either a code for placement or the code for daily management is unlikely to miss a significant number of epidurals. Without any other means of identifying epidural use in this database, some level of misclassification will be inevitable. We contend, however, that misclassifying epidurals as controls would only dilute an association, not falsely indicate the presence of one.
One might argue that the study population should be patients who received preoperative epidural dosing to block the surgical stress response and/or in whom general anesthesia was avoided. In many of the previous studies discussed, general anesthesia was combined with regional analgesia. The main benefit proposed by those authors is reduction of anesthetic and opioid requirements. Certainly, many perioperative factors are immunosuppressive, but complete avoidance of general anesthesia and/or ablation of the surgical stress response, while desirable, are not always feasible and probably not necessary for a benefit under the hypotheses of this study. Even if patients did not receive epidural medications until the end of surgery, they would have required far less opioid analgesia (a potent immune suppressant) than nonepidural patients. Again, this would tend to bias toward a null result in our analysis.
Importantly, the database lacks a variable indicating cancer recurrence. Therefore, we were not able to assess disease-free survival and using chemotherapy, radiation therapy, and metastasis codes as proxies for recurrence may lead to cases of untreated recurrence going undetected, which could bias the result of the recurrence analysis. Also, because of the limitations of the database, we may have omitted clinically significant covariates from our statistical models and were unable to directly examine nonsurgical complications (such as cardiac events). This may explain the early survival advantage in the epidural group, although we could not identify any differences in other perioperative complications. Finally, our dataset was limited to individuals ages 66 yr or older. However, patients in this age group have the highest incidence of colorectal cancer.1 
In conclusion, this large population-based cohort study suggests that epidural anesthesia and/or analgesia is associated with improved survival in patients with nonmetastatic colorectal cancer undergoing resection. Our results do not support an association between epidural anesthesia and/or analgesia and recurrent disease. Prospective studies are needed to determine whether the association between epidural use and survival is causative.
This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors.
The authors thank Julie Worthington, Ph.D., M.P.H., Medical Student, College of Medicine, University of Tennessee Health Sciences Center (Memphis, Tennessee), for assistance with initial study design. They also appreciate the efforts of the Applied Research Program, National Cancer Institute (Bethesda, Maryland); the Office of Research, Development and Information, Center for Medicare & Medicaid Services (Baltimore, Maryland); Information Management Services (IMS), Inc. (Silver Spring, Maryland); and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010; 60:277–300
Harris GJ, Church JM, Senagore AJ, Lavery IC, Hull TL, Strong SA, Fazio VW: Factors affecting local recurrence of colonic adenocarcinoma. Dis Colon Rectum 2002; 45:1029–34
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
Smyth MJ, Godfrey DI, Trapani JA: A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2001; 2:293–9
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
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
Eschwège 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
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
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
Page GG, Blakely WP, Ben-Eliyahu S: Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001; 90:191–9
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
Zetter BR: Angiogenesis and tumor metastasis. Annu Rev Med 1998; 49:407–24
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
Folkman J: Tumor Angiogenesis, The Molecular Basis of Cancer. Edited by Medelsohn J, H PM, Israel M A, Liotta L A, Saunders W B, Philadelphia, 1995
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
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
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
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
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
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
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
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
Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI: Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? ANESTHESIOLOGY 2006; 105:660–4
Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. ANESTHESIOLOGY 2008; 109:180–7
Gottschalk A, Ford JG, Regelin CC, You J, Mascha EJ, Sessler DI, Durieux ME, Nemergut EC: Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. ANESTHESIOLOGY 2010; 113:27–34
Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI; ANZCA Trials Group Investigators: Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011; 342:d1491
Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S: Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: Results from overview of randomised trials. BMJ 2000; 321:1493–7
Christopherson R, James KE, Tableman M, Marshall P, Johnson FE: Long-term survival after colon cancer surgery: A variation associated with choice of anesthesia. Anesth Analg 2008; 107:325–32
Gupta A, Björnsson A, Fredriksson M, Hallböök O, Eintrei C: Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: A retrospective analysis of data from 655 patients in central Sweden. Br J Anaesth 2011; 107:164–70
Silber JH: Medicare claims and anesthesia clinical research: A perfect match. Reg Anesth Pain Med 2003; 28:259–61
Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF: Overview of the SEER-Medicare data: Content, research applications, and generalizability to the United States elderly population. Med Care 2002; 40:IV–3–18
Diggs JC, Xu F, Diaz M, Cooper GS, Koroukian SM: Failure to screen: Predictors and burden of emergency colorectal cancer resection. Am J Manag Care 2007; 13:157–64
Wu CL, Anderson GF, Herbert R, Lietman SA, Fleisher LA: Effect of postoperative epidural analgesia on morbidity and mortality after total hip replacement surgery in medicare patients. Reg Anesth Pain Med 2003; 28:271–8
Silber JH, Kennedy SK, Even-Shoshan O, Chen W, Koziol LF, Showan AM, Longnecker DE: Anesthesiologist direction and patient outcomes. ANESTHESIOLOGY 2000; 93:152–63
Silber JH, Kennedy SK, Even-Shoshan O, Chen W, Mosher RE, Showan AM, Longnecker DE: Anesthesiologist board certification and patient outcomes. ANESTHESIOLOGY 2002; 96:1044–52
Earle CC, Nattinger AB, Potosky AL, Lang K, Mallick R, Berger M, Warren JL: Identifying cancer relapse using SEER-Medicare data. Med Care 2002; 40:IV–75–81
Knopf KB, Warren JL, Feuer EJ, Brown ML: Bowel surveillance patterns after a diagnosis of colorectal cancer in Medicare beneficiaries. Gastrointest Endosc 2001; 54:563–71
Warren JL, Harlan LC, Fahey A, Virnig BA, Freeman JL, Klabunde CN, Cooper GS, Knopf KB: Utility of the SEER-Medicare data to identify chemotherapy use. Med Care 2002; 40:IV–55–61
Deyo RA, Cherkin DC, Ciol MA: Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45:613–9
Klabunde CN, Potosky AL, Legler JM, Warren JL: Development of a comorbidity index using physician claims data. J Clin Epidemiol 2000; 53:1258–67
Cooper GS, Xu F, Barnholtz Sloan JS, Koroukian SM, Schluchter MD: Management of malignant colonic polyps: A population-based analysis of colonoscopic polypectomy versus  surgery. Cancer 2011 [Epub ahead of print]
Wei LJ, Lin DY, Weissfeld L: Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. JASA 1989; 84:1063–73
Rigg JR, Jamrozik K, Myles PS, Silbert BS, Peyton PJ, Parsons RW, Collins KS; MASTER Anaethesia Trial Study Group: Epidural anaesthesia and analgesia and outcome of major surgery: A randomised trial. Lancet 2002;359: 1276–82
Jayne DG, Guillou PJ, Thorpe H, Quirke P, Copeland J, Smith AM, Heath RM, Brown JM, UK MRC CLASICC Trial Group: Randomized trial of laparoscopic-assisted resection of colorectal carcinoma: 3-year results of the UK MRC CLASICC Trial Group. J Clin Oncol 2007; 25:3061–8
Amato A, Pescatori M: Perioperative blood transfusions for the recurrence of colorectal cancer. Cochrane Database Syst Rev 2006: CD005033
Glance LG, Dick AW, Mukamel DB, Fleming FJ, Zollo RA, Wissler R, Salloum R, Meredith UW, Osler TM: Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. ANESTHESIOLOGY 2011; 114:283–92
Cerhan JR, Engels EA, Cozen W, Davis S, Severson RK, Morton LM, Gridley G, Hartge P, Linet M: Blood transfusion, anesthesia, surgery and risk of non-Hodgkin lymphoma in a population-based case-control study. Int J Cancer 2008; 123:888–94
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Fig. 1. Identification of analysis cohort. AJCC = American Joint Committee on Cancer; ESRD = end stage renal disease; FAP = familial adenomatous polyposis; HMO = health maintenance organization; IBD = inflammatory bowel disease.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P  < 0.001.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P 
	< 0.001.
Fig. 2. Kaplan–Meier curves for overall survival. Log-rank test P  < 0.001.
Table 1. Patient Characteristics by Type of Pain Management
Image not available
Table 1. Patient Characteristics by Type of Pain Management
Table 2. Association between Epidural Use and All-cause Mortality
Image not available
Table 2. Association between Epidural Use and All-cause Mortality