Experimental and observational research suggests that combined epidural–general anesthesia may improve long-term survival after cancer surgery by reducing anesthetic and opioid consumption and by blunting surgery-related inflammation. This study therefore tested the primary hypothesis that combined epidural–general anesthesia improves long-term survival in elderly patients.
This article presents a long-term follow-up of patients enrolled in a previous trial conducted at five hospitals. Patients aged 60 to 90 yr and scheduled for major noncardiac thoracic and abdominal surgeries were randomly assigned to either combined epidural–general anesthesia with postoperative epidural analgesia or general anesthesia alone with postoperative intravenous analgesia. The primary outcome was overall postoperative survival. Secondary outcomes included cancer-specific, recurrence-free, and event-free survival.
Among 1,802 patients who were enrolled and randomized in the underlying trial, 1,712 were included in the long-term analysis; 92% had surgery for cancer. The median follow-up duration was 66 months (interquartile range, 61 to 80). Among patients assigned to combined epidural–general anesthesia, 355 of 853 (42%) died compared with 326 of 859 (38%) deaths in patients assigned to general anesthesia alone: adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408. Cancer-specific survival was similar with combined epidural–general anesthesia (327 of 853 [38%]) and general anesthesia alone (292 of 859 [34%]): adjusted hazard ratio, 1.09; 95% CI, 0.93 to 1.28; P = 0.290. Recurrence-free survival was 401 of 853 [47%] for patients who had combined epidural–general anesthesia versus 389 of 859 [45%] with general anesthesia alone: adjusted hazard ratio, 0.97; 95% CI, 0.84 to 1.12; P = 0.692. Event-free survival was 466 of 853 [55%] in patients who had combined epidural–general anesthesia versus 450 of 859 [52%] for general anesthesia alone: adjusted hazard ratio, 0.99; 95% CI, 0.86 to 1.12; P = 0.815.
In elderly patients having major thoracic and abdominal surgery, combined epidural–general anesthesia with epidural analgesia did not improve overall or cancer-specific long-term mortality. Nor did epidural analgesia improve recurrence-free survival. Either approach can therefore reasonably be selected based on patient and clinician preference.
Some experimental and observational research suggests that combined epidural–general anesthesia may improve long-term survival after cancer surgery
In patients aged 60 to 90 yr having major noncardiac thoracic and abdominal surgery, combined epidural–general anesthesia compared to general anesthesia alone did not improve overall or cancer-specific long-term survival
Combined epidural–general anesthesia also did not improve recurrence-free survival
Cancer incidence and mortality continue to increase, and cancer is the second leading overall cause of death.1 According to Global Cancer Statistics, 18.1 million new cancer cases were diagnosed in 2018, and 9.6 million people died of cancer.1 Surgery remains the primary initial treatment for most solid tumors. However, despite advances in oncology and surgery, cancers often recur—and recurrences usually ultimately prove lethal.
Metastases are the main cause of cancer death.2 Whether metastases develop depends largely on the balance between the host defense, especially natural killer cells, and the ability of the residual cancer cells to implant, proliferate, and attract new blood vessels.3 Both anesthesia and surgery may push the balance toward the development of metastases. For example, volatile anesthetics and opioids suppress immune function, although it is unknown if this might affect cancer recurrence.3,4 Additionally, surgical stress impairs cell-mediated immunity and promotes cancer growth both directly and indirectly.5,6
Neuraxial (epidural or spinal) anesthesia and analgesia may influence any cancer-related effects of volatile anesthetics, opioids, and surgery. For example, when combined with general anesthesia, epidural analgesia reduces consumption of anesthetics and opioids and blunts the surgical stress response and inflammation, thus preserving cellular immune function.7–9 Consistent with this theory, neuraxial anesthesia reduces metastasis in tumor-bearing rats.10 We hypothesized that epidural anesthesia and analgesia may improve long-term survival after cancer surgery. However, studies in humans are largely observational, and the results have been inconsistent;11–13 a large trial of neuraxial anesthesia on cancer recurrence has yet to be published.
In a previous multicenter trial, we randomized 1,802 elderly patients having major noncardiac surgery to combined epidural–general anesthesia or to general anesthesia alone.14 Short-term results showed that combined epidural–general anesthesia decreased consumption of anesthetics and opioids, improved postoperative analgesia, and reduced postoperative delirium. More than 90% of enrolled patients had surgery for cancer. We here report 5-yr results for overall and cancer recurrence-free survival, both of which were preplanned outcomes. We also report event-free survival and cancer-specific mortality, which were added after data collection but before analysis. Event-free survival was defined as the time from surgery to cancer recurrence/metastasis, new onset cancer, new serious noncancer disease that led to rehospitalization, or death from any cause.
Materials and Methods
The underlying trial was registered at www.chictr.org.cn (ChiCTR-TRC-09000543) and at ClinicalTrials.gov (NCT01661907). It was approved by the institutional review boards at each institution, and written consent was obtained from all participating patients. The rationale and design of the underlying trial were reported previously,14 with short-term results presented in our companion article.15
The protocol for the current analysis was approved by the Clinical Research Ethics Committee of Peking University First Hospital (Beijing, China; 2014; principal investigator: Dong-Xin Wang) on August 8, 2014, and by other centers, and registered with ClinicalTrials.gov (NCT03012945); changes to the study protocol and statistical analysis plan are presented in Supplemental Digital Content 1 (http://links.lww.com/ALN/C626). Because patients consented to the underlying trial and because no new interventions were involved, the ethics committee approved telephone follow-up and access to medical records without additional written consent. Nonetheless, patients and/or their family members were informed of the study purposes, and verbal consent was obtained before any data were requested.
Patients, Randomization, and Intervention
Patients included in the underlying trial were recruited from November 21, 2011, to May 25, 2015. The 1,802 patients were aged 60 to 90 yr and were scheduled for major noncardiac thoracic and abdominal surgery. They were randomly assigned to either to general anesthesia alone with postoperative intravenous analgesia or combined epidural–general anesthesia with postoperative epidural analgesia as previously reported.14,15
Specifically, for patients assigned to general anesthesia alone, anesthesia was induced with midazolam, propofol, sufentanil, and rocuronium and maintained with either intravenous (propofol), inhalational (sevoflurane with or without nitrous oxide), or combined intravenous-inhalational anesthetics. Additional opioids (remifentanil, sufentanil, fentanyl, or morphine) and muscle relaxant (rocuronium, atracurium, or cisatracurium) were given as necessary. Patient-controlled intravenous analgesia was provided after surgery, which was established with 50 mg of morphine in 100 ml of normal saline, programed to deliver 2-ml boluses with a 6- to 10-min lockout interval and a 1 ml/h background infusion.
For patients assigned to combined epidural–general anesthesia, epidural catheterization was performed before induction of general anesthesia. A test dose of 3 to 4 ml of 2% lidocaine was administered to confirm the success of epidural block. General anesthesia was then induced and maintained as in the general anesthesia group, together with 0.375 to 0.5% ropivacaine administered through the epidural catheter. Patient-controlled epidural analgesia was provided after surgery, which was established with 0.12% ropivacaine and 0.5 μg/ml sufentanil in 250 ml of normal saline, programed to deliver 2-ml boluses with a lockout interval of 20 min and a background infusion of 4 ml/h.
Patients with unsuccessful epidural blocks were given general anesthesia and postoperative intravenous analgesia just as in the general anesthesia alone group. However, outcomes from these patients were included in the combined epidural–general anesthesia group in our primary intention-to-treat analysis.
The investigators who performed the long-term follow-ups (C.F., Y.-F.L., T.C., W.-J.Z., J.L., and Y.-T.D.) were not involved in patient management during the original study and had no knowledge of study group assignment. They were trained and authorized by the principal investigator before starting data collection. The pathologic results including the tumor-node-metastasis stage for patients after cancer surgery were classified according to the American Joint Committee on Cancer 8th Edition Cancer Staging System16 and collected from the inpatient medical record system. The results of postdischarge evaluations were collected from outpatient medical records. Inpatient and outpatient electronic medical record systems were reviewed, and the relevant information was collected by investigators before each follow-up contact.
Patients and/or their family members who were familiar with patients’ information were contacted by phone yearly until September 30, 2019. We collected the following information during each call: (1) Results of re-examinations (usually included imagining examinations and serum biomarkers). For patients after cancer surgery, cancer recurrence was defined as reappearance of the same cancer in the original place or in the organs/lymph nodes near the place it first started; cancer metastasis was defined as reappearance of the same cancer in another part of the body, with some distance from where it started. The development of cancer recurrence and/or metastasis was diagnosed by surgeons (and/or radiologists) according to the results of reexamination. (2) Postoperative treatment for the primary surgical diseases. For cancer patients, anticancer therapies included radiotherapy, chemotherapy, reoperation, interventional therapy, and others. (3) Rehospitalization after surgery. Reasons leading to rehospitalization were documented and included recurrence/metastasis of the original cancer, new cancer, new serious noncancer disease, or other conditions. New cancers were defined as those with confirmed diagnoses but different from the primary ones. New serious noncancer diseases were defined by requiring hospital readmission and/or another surgery. (4) For patients who died during follow-up, the causes of death were documented. Cancer-specific death was defined as death fully attributable to the cancer for which the index surgery was performed and usually involving cancer recurrence and/or metastasis after exclusion of other causes such as stroke and myocardial infarction.17 The earliest date for each confirmed occurrence was recorded.
At 3 yr, we assessed cognitive function with the Modified Telephone Interview for Cognitive Status, which is a 12-item questionnaire that verbally assesses global cognitive function via telephone. The score ranges from 0 to 50, with a higher score indicating better function18 ; a minimum difference of 0.4 SD was considered clinically important.19 We also assessed quality of life with the World Health Organization Quality of Life brief version, which is a 24-item questionnaire that assesses the quality of life in physical, psychologic, social relationship, and environmental domains. The score ranges from 0 to 100 for each domain, with a higher score indicating better function20 and a minimal important difference 0.5 SD.21
We attempted to contact patients or their family members on at least 5 different days before considering them lost to follow-up. For those who could not be contacted, we also consulted medical records to obtain what information was available. Patients who were lost to follow-up were censored the time of their last hospital visit. All outcomes were double-entered into the study database (EpiData 3.1, EpiData Association, Denmark).
The primary endpoint was overall survival after surgery. The secondary endpoints were (1) cancer-specific survival, defined as the time from surgery to the date of cancer-specific death with patients who died from other causes being censored at the time of death; (2) recurrence-free survival, defined as the time from surgery to the first date of cancer recurrence/metastasis or death from any cause; and (3) event-free survival, defined as the time from surgery to the first date of cancer recurrence/metastasis, new onset cancer, new serious noncancer disease, or death from any cause.
Other predefined outcomes included the overall, cancer-specific, recurrence-free, and event-free survival in patients who originally had cancer surgery. We also evaluated cognitive function and quality of life in 3-yr survivors, which were original designated as secondary outcomes but were demoted to tertiary outcomes before data analysis because analysis was restricted to 3-yr survivors. Post hoc subgroup analyses were performed as functions of age, sex, body mass index, Charlson comorbidity index, type of surgery, location of surgery, type of cancer, tumor-node-metastasis stage, study center, and postoperative anticancer therapy.
The primary analysis was modified intention to treat, i.e., all patients were analyzed in the groups they were assigned to, excluding those with randomization errors, cancelled surgeries, consent withdrawal before anesthesia, or repeated recruitments. A per-protocol analysis was also performed for the primary endpoint.
The balance of baseline variables between groups was assessed using absolute standardized differences, defined as absolute differences in means, mean ranks, or proportions divided by the pooled SD. Baseline variables with an absolute standardized difference of 0.095 or greater (i.e., ) were considered to be imbalanced.22
Overall survival after surgery was analyzed using a Kaplan–Meier estimator with difference between groups assessed by log-rank test; a Cox proportional hazards model was used to adjust for predetermined factors including age, sex, body mass index, Charlson comorbidity Index, type of surgery, location of surgery, type of cancer, tumor-node-metastasis stage, and study center. Differences in the primary outcome in predefined subgroups were tested using Cox proportional hazard models. Treatment-by-covariate interactions were assessed separately for each predefined factor.
Secondary outcomes including cancer-specific, recurrence-free, and event-free survival were analyzed using Kaplan–Meier estimators with differences between groups assessed by log-rank tests; the Cox proportional hazard models were used to adjust for the prespecified factors listed in the previous paragraph. For other outcomes, numeric variables were analyzed with independent-sample t or Mann–Whitney U tests. Differences between the anesthetic groups and their 95% CIs were estimated using the least squares method. Categorical variables were analyzed with chi-square or continuity-corrected chi-square tests. Time-to-event variables were evaluated with Kaplan–Meier estimators, with differences between groups being assessed with log-rank tests. Differences and their 95% CIs were estimated with Cox proportional hazards models.
For each hypothesis, a two-tailed P < 0.05 was considered statistically significant. For interactions between the treatment effect and preselected covariates, a P < 0.10 was considered statistically significant. Statistical analyses were performed with the SPSS 25.0 software package (IBM SPSS Inc., USA). The forest plot was created with GraphPad Prism 7.0 (GraphPad Software, USA).
Among 1,802 patients recruited and randomized in the underlying trial, 1,720 completed follow-up and were included in this analysis. Eight patients were included twice for different surgeries, but only the first was considered for this analysis. Consequently, 1,712 patients were included in the long-term follow-up analysis, with 853 randomized to combined epidural–general anesthesia and 859 to general anesthesia alone. Three years after surgery, 25 patients (1%) were lost to follow-up, 38 refused cognition assessment, and 27 refused quality-of-life assessments. Upon completion of the entire follow-up period, a median of 66 months (interquartile range, 61 to 80) after surgery, 47 patients (3%) were lost to follow-up (fig. 1). Follow-up efforts concluded September 30, 2019.
Among 1,712 long-term follow-up patients, 1,574 (92%) had surgery for cancer. Baseline variables, including the fraction with pathologically diagnosed cancer and the distribution of tumor-node-metastasis stages, were comparable between the two groups, except that preoperative hypertension was less common, and lymph node staging was more advanced in patients assigned to combined epidural–general anesthesia (table 1; tables S1 and S2 in Supplemental Digital Content 2, http://links.lww.com/ALN/C627).
During the intraoperative and postoperative periods, patients in the combined epidural–general anesthesia group were given less inhalational anesthetics (nitrous oxide and/or sevoflurane), opioids, and antiemetics but more vasopressors and colloid; they had lower mean arterial pressure but higher heart rate and urine output. Patients in the combined epidural–general anesthesia group were less often admitted intubated to a critical care unit, received more epidural sufentanil but less intravenous morphine, and developed less delirium within 7 days. The duration of postoperative follow-up was similar for each group (table 2; table S3 in Supplemental Digital Content 2, http://links.lww.com/ALN/C627).
Overall survival did not differ between the two groups (fig. 2). Among 853 patients assigned to combined epidural–general anesthesia, 355 (42%) deaths were reported, compared with 326 (38%) among 859 patients assigned to general anesthesia alone (adjusted hazard ratio, 1.07; 95% CI, 0.92 to 1.24; P = 0.408). The proportional hazard assumption was not violated (P = 0.374). Per-protocol analysis also showed no significant difference between the two groups: there were 311 of 772 (40%) deaths with combined epidural–general anesthesia versus 309 of 822 (38%) deaths with general anesthesia alone for an adjusted hazard ratio of 1.03 (95% CI, 0.88 to 1.20; P = 0.749; table 3).
There were no significant interactions for the relationship between anesthetic group and overall mortality on any predefined factors (fig. 3). There were no statistically significant or clinically meaningful differences in cancer-specific, recurrence-free, or event-free survival (table 3; fig. 2; fig. S1 and table S4 in Supplemental Digital Content 2, http://links.lww.com/ALN/C627). In the subgroup of patients whose index surgery was for cancer, there were also no statistically significant or clinically meaningful differences in overall, cancer-specific, recurrence-free, or event-free survival between the two groups (table 3; figs. S2 and S3 in Supplemental Digital Content 2, http://links.lww.com/ALN/C627).
Cognitive function was similar in each group at 3 yr. The quality-of-life scores in the physical (mean difference, 1.9; 95% CI, 0.4 to 3.4; P = 0.015) and psychologic (mean difference, 1.6; 95% CI, 0.1 to 3.1; P = 0.033) domains were higher in patients with combined epidural–general anesthesia than in those with general anesthesia alone (table S5 in Supplemental Digital Content 2, http://links.lww.com/ALN/C627), but the difference was not clinically meaningful. There were no significant differences in the social relationship and environmental domains.
As expected, patients assigned to combined epidural–general anesthesia required less inhaled anesthesia and less long-acting opioid.9,23 Previous work suggests that these patients would also have less stress response and inflammation than those given general anesthesia alone.7,8,24 Each of these factors is thought to reduce the risk of cancer recurrence after potentially curative tumor resections3,25 —most of which is ultimately lethal. Nonetheless, overall survival was similar in patients randomized to combined epidural–general anesthesia with epidural analgesia and in those assigned to general anesthesia with intravenous analgesia. Patients given combined epidural–general anesthesia also had similar cancer-specific, recurrence-free, and event-free survival after major thoracic and abdominal surgery.
Available evidence about regional analgesia and postoperative cancer recurrence is largely from experimental models,10,24 observational analyses,24–26 and post hoc analyses of randomized trials.11 Animal studies are consistent in showing that regional anesthesia decreases the stress response to surgery,27 and that volatile anesthetics28 and opioids28,29 promote cancer recurrence. Retrospective observational analyses have been inconsistent, with many showing benefit13 and many others finding no difference.12
There are four post hoc analyses of cancer recurrence in patients who, for other reasons, were randomized to epidural with or without general anesthesia or general anesthesia alone.11 In a trial of 177 patients who had colon cancer surgery, survival was enhanced by epidural analgesia only in patients without metastasis before 1.5 yr—a somewhat implausible post hoc subgroup analysis.30 In 99 patients who had radical prostatectomies, combined general/epidural anesthesia did not significantly improve cancer-free survival (hazard ratio, 1.33; 95% CI, 0.64 to 2.77; P = 0.44).31 In 132 patients who had major abdominal surgery for cancer, recurrence-free survival was improved by epidural analgesia (43% vs. 24%) but not significantly so.32 The largest trial included 503 patients who were randomized to epidural anesthesia or general anesthesia for major abdominal cancer surgery. Epidural anesthesia did not improve cancer-free survival (adjusted hazard ratio, 0.95; 95% CI, 0.78 to 1.15; P = 0.61).33
There are also two randomized trials in which cancer recurrence was the primary outcome. Both tested paravertebral analgesia for breast surgery. One randomized 180 patients who had radical mastectomies and observed no benefit from regional analgesia, although the trial was seriously underpowered.34 The second randomized 2,132 women having breast cancer surgery. Although volatile anesthesia and opioid use was reduced, there was again no benefit from paravertebral analgesia.35 Both randomized trials specific to regional analgesia and cancer recurrence therefore showed no benefit. However, both were restricted to breast surgery, which provokes considerably less surgical stress response and postoperative pain than major abdominal or thoracic surgery. It thus remained possible that the putative benefits of regional analgesia on cancer recurrence would be apparent for larger operations.36 However, our results in 1,712 patients who had major abdominal or thoracic surgery provides robust evidence that overall and cancer-specific mortality and recurrence-free survival are not improved by regional analgesia. Taken together, available data from post hoc and specific randomized trials indicate that regional analgesia has no meaningful effect on recurrence or survival.
In the current study, patients with combined epidural–general anesthesia had slightly higher physical and psychologic domain scores 3 yr after surgery. However, the differences were not clinically meaningful, and the remaining two domains did not differ significantly. There was also no difference in cognitive function with the two anesthetic approaches. Thus, although combined epidural–general anesthesia significantly reduced delirium during the initial 7 postoperative days, it did not meaningfully improve any of our long-term outcomes.
Among the originally randomized patients, 95.0% (1,712 of 1,802) were included in our long-term follow-up analysis. Patients were mainly excluded for technical reasons and therefore unlikely to result from attrition bias. Similarly, 2.7% of our patients were lost to follow-up, but missingness appears to be completely random and therefore unlikely to bias our conclusions. About 8% of our patients had noncancer surgery, but the fraction was comparable in each group. As might thus be expected, baseline characteristics were well balanced between the two groups.
A limitation is that sample size for the underlying trial was based on postoperative delirium rather than long-term survival. Nonetheless, with 681 deaths over a median of 5.5-yr follow-up, our study was well powered to detect even 10% benefits from epidural analgesia and had 99% power for detecting 20% differences.
We here present follow-up results of patients enrolled in an underlying trial with a predefined primary endpoint of long-term overall survival after surgery. As is common in large trials, we separately compared short-term outcomes presented in a companion article and long-term outcomes presented here. The outcomes for each part of the analysis were physiologically distinct and separated by year. We therefore did not correct for multiple outcomes. However, compensation for multiplicity would not change our interpretations.
Patients randomized to epidural analgesia were given epidural sufentanil, a short-acting opioid, whereas those assigned to intravenous analgesia were given intravenous morphine, which is a long-acting opioid. The two opioids may exert different effects on cancer growth, angiogenesis, and immunosuppression and therefore complicate the explanation of our results.37 Finally, there are surely unknown factors that potentially affected patient survival, especially tumor characteristics; but again, it seems unlikely that there were systematic differences linked to anesthetic management in this large randomized trial.
In summary, in elderly patients having major noncardiac thoracic and abdominal surgery, combined epidural–general anesthesia with epidural analgesia did not improve overall or cancer-specific survival. Combined epidural–general anesthesia or general anesthesia with intravenous opioid analgesia can therefore reasonably be selected based on short-term outcomes, along with patient and clinician preference.
The authors gratefully acknowledge Kun Yu, B.S.Med. (Peking University First Hospital, Beijing, China), Guan-Nan Kang, M.D. (Peking University People’s Hospital, Beijing, China), Xin-Guang Wang, M.D., and Yan-Li Li, M.D. (Peking University Third Hospital, Beijing, China), and Jun-Jie Zheng, M.D. (Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China) for their help in acquisition of data and/or classification of the tumor-node-Metastasis stage. The authors also thank all the participating patients and their family members.
Supported by National Key R&D Program of China (Ministry of Science and Technology of the People’s Republic of China, Beijing, China) grant No. 2018YFC2001800 and Peking University (Beijing, China) Clinical Research Program grant No. PUCRP201101.
The authors declare no competing interests.
Appendix. Additional Members of the Peking University Clinical Research Program Study Group
Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, China: Jun Li, B.S.Med.Tech., Guo-Jin Shan, associate B.S.Med.Tech., Qiong Ma, associate B.S.Med.Tech., Hao Kong, M.D., Da Huang, M.D., Chun-Mei Deng, M.D., Yi Zhao, M.D., Xue-Yi Zheng, M.D., Yue Zhang, M.D., Ph.D., Dan-Feng Zhang, M.D., Mu-Han Li, M.D., Ph.D., Xin-Quan Liang, M.D., Chao Liu, M.D., Shu-Ting He, M.D., Si-Ming Huang, M.D., Si-Chao Xu, M.D.
Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China: Xiao-Yun Hu, M.D., Run Wang, M.D., Li Xiao, M.D., Jing Zhang, M.D., Wen-Zheng Yang, M.D.
Department of Anesthesiology, Peking University Third Hospital, Beijing, China: Wei-Ping Liu, M.D., Wen-Yong Han, M.D.
Department of Anesthesiology, Peking University People’s Hospital, Beijing, China: Yao Yu, M.D.
Department of Anesthesiology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China: Hong-Ye Zhang, M.D., Zhen Hua, M.D., Jing-Jing Zhang, M.D.
Peking University Clinical Research Institute, Peking University Health Science Center, Beijing, China: Ping Ji, Ph.D., Qin Liu, M.P.H., Shu-Qian Fu, M.P.H., Xian Su, M.P.H., Xiao-Yan Yan, Ph.D., Yong-Pei Yu, Ph.D., and Mei-Rong Wang, M.D.