Multivariate Cox proportional hazards regression analysis was adjusted for propensity score, covariates and some covariate interactions to assess independent risk factors for long-term survival. After adjusting for propensity score, covariates and some covariate interactions, postoperative EA (HR 1.279, 95% CI, 1.007–1.625, P = 0.043) was found to be associated with decreased long-term survival. Other independent risk factors of decreased long-term survival were preoperative α-fetoprotein(+) (HR 1.838, 95% CI, 1.421–2.379, P < 0.001), ASA physical status (HR 3.185, 95% CI 2.318–4.375, P < 0.001), and tumor diameter (HR 1.434, 95% CI, 1.263–1.629, P < 0.001) (Table 4). In a Cox model accounting for the correlation within matched sets, independent risk factors of long-term survival were postoperative EA (HR 1.628, 95% CI, 0.845–3.725, P = 0.031), ASA physical status (HR 5.828, 95% CI, 1.417–17.848, P < 0.001) and tumor stage (HR 3.174, 95% CI, 1.232–5.137, P = 0.015) (Table 5).
A wealth of basic science data supports the hypothesis that the surgical stress response increases the likelihood of cancer dissemination and metastasis during and after cancer surgery. Anesthetic management of the cancer patient, therefore, could potentially influence long-term outcome.13 The effect of anesthetic management on cancer patients is complex; its mechanisms are not completely understood, and to a certain extent, contradictory.
Exadaktylos et al.3 demonstrated that regional anesthesia in combination with general anesthesia was associated with a longer cancer-free interval and a lower incidence of recurrence in a retrospective analysis of patients undergoing surgical treatment for breast cancer. Similar results were obtained in another retrospective study of patients with prostate cancer.2 However, Gottschalk et al.5 found that the use of EA for perioperative pain control during colorectal cancer surgery was not associated with a decreased cancer recurrence. Two other retrospective studies examining prostate cancer6 and cervical cancer7 also demonstrated no association between epidural anesthesia and long-term outcome of cancer patients.
In contrast to previous retrospective studies, the major findings from our observational cohort study suggest that postoperative EA with morphine has a higher incidence of recurrence (37.7% vs 30.7%, P = 0.036) and mortality (40.6% vs 30.4%, P = 0.003). More importantly, in multivariate Cox proportional hazards regression analysis after adjusting for the propensity score, we found that the postoperative EA with morphine was an independent risk factor for decreased long-term survival in patients after resection of HCC (HR 1.279, 95% CI, 1.007–1.625, P = 0.043). However, the use of postoperative EA with morphine did not show a significant effect on recurrence-free survival in this study (HR 2.224, 95% CI, 0.207–23.893, P = 0.509). These results were confirmed by similar analyses of the matched cases. These results also showed that postoperative EA with morphine had a negative effect on survival and cancer recurrence. Long-term survival is the most important end point and is least subject to investigator bias. It was also the primary end point recommended by the expert panel for any phase 3 study in HCC.14
The fact that our observations stand in partial contrast to previous studies can be attributed to at least 3 different mechanisms. First, is the timing of epidural anesthesia. Regional anesthesia, including spinal and epidural anesthesia, reduces the stress response and postoperative immunosuppression associated with surgery15,16 and decreases anesthetic requirements that could result in less immunosuppression.17 These associations may be theoretically beneficial to patients undergoing cancer surgery. In our series, we did not use the epidural intraoperatively to decrease the risk of awareness during anesthesia. Thus, similar suppression of the surgical stress response18 may not have occurred in patients in this study.
Second, we used different opioids in our study. In the EA group, morphine was the primary analgesic, whereas fentanyl and tramadol were used in the IA group. Although it has been established that opioids, morphine in particular, inhibit cellular and humoral immune function in humans,19–21 the synthetic opiates did not seem to exhibit the same immunosuppressive effects. In 1 study, fentanyl increased natural killer (NK) cell activity in healthy volunteers too.22 Tramadol also stimulates NK cell activity, both in rats and humans.20,23 In a rat model, tramadol was shown to block the enhancement of lung metastasis induced by surgery and to prevent surgery-induced suppression of NK cell activity.23 Although plasma levels of morphine after epidural administration are quite low, the central nervous system (CNS) concentration is 100 to 200 times the corresponding plasma levels.24 Morphine cannot only suppress immunity through effects on the CNS19 but can also cause CNS-mediated release of corticosteroids, which may lead to immune suppression.25 Morphine, in clinically relevant concentrations, also stimulates cancer cell survival, cell cycle progression, and endothelial proliferation and angiogenesis,26–28 which may contribute to cancer recurrence or decreased long-term survival.
Finally, the specific tumor type, which may be related to different tumor biology and the risk for and mechanisms of metastasis, may be associated with the effect of different types of analgesia on cancer recurrence or long-term survival. HCC is a hypervascular tumor mainly supplied by hepatic arteries and characterized by neovascularization, which plays an important role in the growth and progression of HCC.29 Morphine induces tumor neovascularization and increases tumor progression,28 which may be a possible reason for the negative effect of postoperative EA on the cancer recurrence rate and long-time survival of patients after hepatic resection.
HCC is often clinically silent for a long period and is often discovered at a very advanced stage. At this stage, the tumor progresses aggressively, and its prognosis may be more dependent on other factors. In our study, we excluded patients if the number of tumors ≥2, if thrombosis in portal vein or hepatic vein was noted, or if tumor metastasis were present. All these factors may affect HCC recurrence or long-time survival. We discovered several other risk factors for increased cancer recurrence and decreased survival including preoperative α-fetoprotein(+), ASA physical status, and tumor diameter. Sala et al.30 developed a staging system according to the results of cohort studies and found treatment indications, including tumor stage, liver functional status, physical status, and cancer-related symptoms. This is inconsistent with our results. In our study, liver function was worse (the ratio of Child-Pugh class B was higher) in patients who received EA. However, the multivariate Cox proportional hazards regression analysis adjusted for propensity score and covariates, Child-Pugh class (HR 1.372, 95% CI, 0.257–5.768, P = 0.832), was not an independent risk factor of long-term survival. This result is supported by Vauthey et al.31’s study, which also suggested the Child-Pugh class did not affect survival.
The present retrospective study has several limitations. It was not randomized, and a selection bias can thus not be definitively excluded, even with the propensity score analysis. Although surgical and anesthetic procedures are standardized in our institution and patients in each group had comparable surgery and anesthesia, we cannot exclude imbalanced baseline characteristics and some covariate interactions. Furthermore, our study does not provide information on the cause of death of patients. Cause of death might have been different in the early postoperative period and in later years. Postoperative EA may be associated with cancer recurrence or survival more significantly in the early period after operation than in the later years. Additional studies are needed to confirm these observations. Data on other types of cancer, other patient populations, adjuvant chemotherapy or radiation, and time and location of recurrence would also be important. Accordingly, we offer our findings as an impetus for future research in this area in random trials.
In this retrospective study, we report the cancer recurrence and long-term survival in patients assigned to receive postoperative EA with morphine or postoperative IA with fentanyl. Cancer recurrence rates and mortality were higher in patients who received EA with morphine than those who received IA with fentanyl. In addition, a negative effect of postoperative EA with morphine on long-term survival was observed, but no significant difference was found in recurrence-free survival. Prospective, randomized, and controlled clinical trials are warranted to reliably assess this important clinical question.
Name: Longhui Cao, PhD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Longhui Cao has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Yi Chang, MD.
Contribution: This author helped design the study and analyze the data.
Attestation: Yi Chang has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Wenqian Lin, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Wenqian Lin has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jianhua Zhou, MD, PhD.
Contribution: This author helped analyze the data.
Attestation: Jianhua Zhou has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Hongying Tan, MD, PhD.
Contribution: This author helped conduct the study.
Attestation: Hongying Tan has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Yunfei Yuan, MD, PhD.
Contribution: This author helped write the manuscript.
Attestation: Yunfei Yuan has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Weian Zeng, MD, PhD.
Contribution: This author helped design the study.
Attestation: Weian Zeng has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Edward C. Nemergut, MD.
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© 2014 International Anesthesia Research Society
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