Abstract
Background: Potential benefits of regional analgesia in reduction of cancer recurrence have been reported for breast and prostate cancer. The aim of this study was to evaluate the influence of regional analgesia on recurrence-free survival and overall survival in patients with advanced-stage ovarian cancer (ASOC) following complete cytoreduction. Patients and Methods: This is a retrospective study of 104 patients who had undergone complete cytoreduction for ASOC between 01/2007 and 12/2009: 51 with patient controlled epidural analgesia (PCEA) and 53 without PCEA. Results: No significant difference was found between the two groups in terms of overall survival, while there was a trend in favour of PCEA for disease free survival. Conclusion: In our study, regional analgesia had no clear impact on cancer recurrence. More studies on this subject are warranted in order to determine the possible impact of regional analgesia on ASOC.
When complete cytoreduction is possible, surgery is the only curative treatment for advanced-stage ovarian cancer (ASOC) allowing for improved survival (1). However, recurrences occur frequently. Hypotheses put forward to explain these recurrences are micrometastasis and the circulation of isolated tumour cells due to surgery (2), combined with impaired natural immunity against these cells (3).
Three factors have already been identified as an explanation for disease progression: surgery, general anaesthesia and the use of opioids. Surgery may release tumour cells, depress cell-mediated immunity (4), reduce antiangiogenic factors, increase proangiogenic factors [such as Vascular Endothelial Growth factor (VEGF)] and growth factors responsible for the growth of malignant tissue (5, 6). General anaesthesia, using drugs such as thiopental or volatile agents is known to impair immune response through dendritic cells, Natural Killer (NK) cells, macrophages and neutrophils (7, 8). Finally, the use of opioids during surgery and for postoperative pain treatment, inhibits cellular and humoral immunity (9, 10), and stimulates angiogenesis (11).
As surgery and anaesthesia are mandatory for current therapy, the only way to limit immunodepression is to avoid the use of opioids during and after surgery. This strategy can be achieved, among other solutions, by combining general anaesthesia with regional analgesia such as epidural analgesia.
Epidural analgesia has already been demonstrated to be beneficial for postoperative pain and postoperative ileus (12). Regional analgesia offers a statistically significant improvement in pre-incisional analgesia, supporting its use during as well as after surgery (13). However, its influence on cancer recurrence is more recent and still debated. A few results have been published which suggest a benefit from regional analgesia in regard to recurrence of breast cancer (14) and prostate cancer (15).
However, regional anaesthesia induces a sympathetic blockade which may make it more difficult to stabilise blood pressure in case of surgical events (such as bleeding and emboli). These difficulties explain why most anaesthesiologists do not favour the intraoperative use of epidural analgesia and choose to set it up before surgery but to use it only at the end of surgery for postoperative pain relief, as is the case in our institution.
The aim of this study was to evaluate the influence of regional analgesia on recurrence-free survival and overall survival of patients with ovarian cancer following complete cytoreduction. As complete cytoreduction is the main prognostic factor in ovarian cancer (1, 16) the study population includes only patients with complete cytoreduction for homogeneity purposes.
Patients and Methods
This retrospective analysis included women who had undergone complete cytoreduction for ASOC between January 2007 and December 2009 in a single cancer reference centre. Patients in whom cytoreduction had been incomplete or patients with a non-epithelial ovarian tumour were excluded, as were these who had been treated for recurrent disease.
Disease resectability was initially evaluated by laparoscopy (in most cases) or a short laparotomy. If a complete resection of peritoneal disease was immediately feasible, patients underwent initial cytoreductive surgery. If the disease had spread massively making it impossible to achieve a complete resection, patients first received neoadjuvant chemotherapy combining platinum and paclitaxel and were then proposed interval cytoreductive surgery after 3, 4, or sometimes 6 courses of neoadjuvant chemotherapy. All cytoreductive surgeries were carried out with the intent of maximally removing all visible tumour. Debulking surgery including extensive radical resections was only performed in patients in whom macroscopically complete cytoreduction could be achieved.
Anaesthesia protocol. Surgery was conducted under general anaesthesia combining propofol for induction, desflurane adjusted on the Electro-encephalogram (EEG) bispectral index for maintenance of hypnosis, and remifentanil for intraoperative analgesia, administered as a target controlled infusion and according to blood pressure and heart rate.
Patient-controlled epidural analgesia (PCEA) was often proposed for postoperative analgesia, in the absence of contraindications, especially when cytoreduction was expected to be wide or to include a digestive resection. A 22 G catheter was inserted under local anaesthesia just before induction of anaesthesia in T9-T10, T10-T11 or T11-T12 spaces. The catheter was not used intraoperatively in order to avoid inducing a deep sympathetic blockade in patients at high risk of haemorrhage. An epidural bolus of 0.2% ropivacaine (20-25 ml) was injected 45 to 60 minutes before the end of surgery. During 3 days, PCEA with 0.2% ropivacaine was administered at a constant infusion rate of 3 to 6 ml/h, then a bolus of 3 ml, followed by a lockout period of 20 minutes. Morphine (5 mg) was added to every 200 ml vial of ropivacaine.
Patients' medical records were retrospectively reviewed to extract demographic, perioperative and follow-up data. Age, tumour histology and grade were extracted from patients' charts. The disease stage, based on spread during the initial assessment, had been determined using the 1987 FIGO classification (17).
This study compared overall survival and recurrence-free survival between women who had received regional analgesia and women who had not (because surgery was not expected to be wide before incision, because an epidural puncture was contraindicated, due to patient refusal, or because of failure of epidural catheter insertion).
Both groups were first compared for age, BMI, surgical procedure variables (initial versus interval cytoreductive surgery, operating time, transfusion) and for prognostic variables (stage, grade, histology, emboli, lymph node metastasis) with a chi-square test for qualitative variables and with the Student's t-test for quantitative variables.
After verification of proportionality of the hazard ratio, potential prognostic factors for recurrence-free and overall survival were first assessed by univariate analysis using a Cox regression model. Factors identified as being statistically significant or of borderline significance in the univariate analysis were then included in a multivariate Cox regression for recurrence-free survival and for overall survival. SAS 9.1 software (North Carolina 27513, USA) was used for statistical analysis. P values below 0.05 were considered as to be significant.
Comparison between patients with and those without patient-controlled epidural analgesia (PCEA) (mean±SD or % of patients)
Results
One hundred and four women were included in the study. Fifty-one women had undergone epidural analgesia while 53 had not. Ten women had been lost to follow-up, four in the PCEA group (8%) and six in the no-PCEA group (11%). Thus, the analysis was performed on 47 women in each group.
The groups were not similar in terms of age, with younger patients in the PCEA group (50 versus 56 years old, p=0.02), and tumour grade (a similar number of grade 3 lesions in both groups but more grade 1 lesions in the PCEA group (p=0.02) but there were many missing data for this item. Conversely, the groups were similar in terms of lymph node positivity and distribution between initial and secondary complete surgery (Table I). All women had stage IIIC or IV disease according to the FIGO classification.
Epidural analgesia by PCEA was not statistically associated with longer recurrence-free survival nor with overall survival (Tables II and III).
The Kaplan-Meier method showed a mild, non-significant difference in recurrence-free survival (Figure 1) with 24/47 recurrence-free patients in the PCEA group after 1 year versus 21/47 in the no-PCEA group. We found no impact on overall survival (Figure 2).
Univariate and multivariate analyse: Recurrence free survival (Cox model).
Univariate and multivariate Cox models of overall survival.
Regarding recurrence-free survival, no prognostic factor reached statistical significance in the univariate analysis but operating time, histology and the grade were of borderline significance (0.05<p<0.10). When adjusted in the multivariate analysis, only histology (serous or not) and the operating time remained statistically significant factors.
Regarding overall survival, only histology was a statistically significant factor, in both the univariate and multivariate analyses.
Kaplan-Meier recurrence-free survival curve according to use of patient-controlled epidural analgesia (PCEA). Log Rank test (p=0.42).
Discussion
The risk of tumour metastasis depends on the balance between the metastatic potential of a tumour and the antimetastatic host defences. Surgery, which is still the cornerstone treatment in potentially curable solid tumours, can inhibit key host defences and promote the development of metastases. The anaesthetic technique and choice of drug can interact with the cellular immune system. The role of the anaesthetist during the critical perioperative period is emerging as a factor that could influence long-term outcome after cancer surgery (3). The focus is currently placed on the effect of regional anaesthesia. It began with two major, albeit retrospective, studies. The first compared epidural analgesia to intravenous intra- and postoperative opioid analgesia: cancer recurrence was reduced by 57% (76% recurrence-free survival in the epidural group versus 49% in the control group, p=0.012), with a follow-up duration ranging from 2.8 to 12.8 years. The second study employed 129 patients treated for breast cancer by mastectomy and axillary clearance and also showed a reduction in recurrences or metastasis in patients who had a paravertebral block (6% of recurrences in the paravertebral block group versus 23% in the control group at 36 months).
More recently, another retrospective study after radical prostatectomy found a significant benefit of epidural analgesia for clinical progression-free survival but not for cancer-specific or overall survival (18). Two retrospective studies also demonstrated a very transient benefit in colorectal cancer (19, 20). In cervical cancer, only one study compared neuraxial versus general anaesthesia for brachytherapy and found no difference (21).
Kaplan-Meier overall survival curve according to use of patient-controlled epidural analgesia (PCEA). Log Rank test (p=0.95).
All these studies share the same limitation with our results: they are retrospective descriptive studies in which allocation to epidural or opioid analgesia was not controlled at all and therefore may be biased. We were unable to identify this bias in our population. Nonetheless, randomised controlled studies will be necessary to conclude whether epidural analgesia exerts a beneficial effect on cancer recurrence.
Such a multicentre randomised trial was initiated in 2007 by The Outcome Research Consortium (Cleveland Clinic, USA), comparing cancer recurrence in patients with paravertebral anaesthesia and analgesia after breast cancer surgery (n=1100), and in patients with epidural anaesthesia and analgesia for laparoscopic colorectal cancer surgery (22). Those studies are ongoing and their results will be very instructive.
To date, no study has been performed on patients with ovarian cancer. Epidural analgesia is increasingly used in this surgery type in order to reduce postoperative pain, to accelerate intestinal recovery and the resumption of previous activity (12, 23). Epidural anaesthesia is safe in this indication and has been validated (24). Our study is the first to compare recurrence in patients with and without epidural analgesia in ovarian cancer. We exclusively included women having undergone complete cytoreduction. It was important to achieve homogeneity regarding the main prognostic factor in ovarian cancer, namely the absence of macroscopically residual disease at the end of surgery (1, 16). No statistical benefit was found for overall survival nor for recurrence-free survival following epidural analgesia during cytoreductive surgery for ovarian carcinoma. A lack of power due to the limited number of patients or a bias due to uncontrolled allocation to treatment groups could partially account for this result. Moreover, PCEA was used only after the end of surgery to facilitate the control of arterial pressure, which could limit the positive oncological impact of PCEA.
Other criteria, such as pain, transfusion, hypothermia and stress in the management of anaesthesia, which it were not possible to analyse in this retrospective study, may have biased the results. Indeed, acute pain suppresses NK cell activity as demonstrated in a rat model (25), and this potentially deleterious effect cannot be separated from the effects of opioids. Most patients undergoing extensive radical surgery for ovarian cancer need transfusions (44% in our study) and perioperative allogeneic blood transfusion may also be associated with an increased risk of tumour recurrence (26). Mild hypothermia, below 35.5°C, exacerbates the immunosuppressive effects of abdominal surgery in humans (27), resulting in more wound infection and potentially influencing the risk of metastasis. With a median operating time of 425 minutes and blood loss requiring transfusion in almost half of the patients, as in our study, it might be difficult to maintain patients' temperature. Psychological stress related to surgery has been shown to contribute to perioperative immunosuppression (28) and such stress can exert a tremendous impact on cancer patients. A patient's nutritional status is also emerging as a crucial determining factor in surgical morbidity (29) and possibly in oncological outcomes in ovarian cancer. This aspect should also be taken into account in a future prospective study. Finally, in our daily practice, in order to avoid inducing a deep sympathetic blockade in these patients at high risk of haemorrhage, the catheter was not used intraoperatively. However, recently, Pereira et al. observed that intraoperative neuraxial anesthesia but not postoperative neuraxial analgesia was associated with increased relapse-free survival in ovarian cancer patients after primary cytoreductive surgery (30).
In conclusion, the benefit of regional analgesia for recurrence-free survival suggested in breast carcinoma and in prostatic carcinoma was not demonstrated in ovarian carcinoma in this retrospective study. However, the lack of statistical power of this study might explain the absence of a benefit, while other important criteria in the management of anaesthesia were not explored. A more powerful randomised study is required in order a conclusion for to be reached regarding the role of epidural anaesthesia in the long-term outcome of patients with ovarian cancer who alas, still frequently develop recurrences even after complete surgical resection. Better knowledge of pre- and perioperative management and its impact on the mechanisms of metastatic dissemination could contribute to improving the prognosis of this disease.
Acknowledgements
We thank Lorna Saint Ange for editing.
Footnotes
-
Disclosure of interests
The Authors have no disclosure or conflict of interest to declare.
- Received January 31, 2012.
- Revision received February 24, 2012.
- Accepted February 27, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
References
In this issue
