Table of Contents  

Capdevila, Macaire, Nouette-Gaulain, Dadure, Godwin, and Nadhari: Regional anaesthesia and analgesia for cancer surgery

Introduction

The cellular and immune system has been developed to protect us not only against infectious diseases but also to a distortion of the metabolism of cells division, especially those evolving towards cancer. Reaction to perioperative stress affects our immune system. For most cancers, treatment often involves surgical resection of the primary tumour. Tumour resection surgeries are usually associated with a systemic release of tumour cells. Consequently, we might argue that these patients undergoing oncological surgeries weaken their defence mechanism against metastasis at a critical moment. During oncology surgery, micro-metastasis and spread of tumoral cells (t cells) occur during the procedure.13 The evolution of t cells into clinical metastasis depends mainly on two factors: on one hand, the natural immune antimetastatic activity and, on the other hand, the ability of the tumour to proliferate and to produce new blood vessels (neoangiogenesis).46 This raises the issue of whether or not certain techniques of anaesthesia/analgesia might improve the body’s ability to eliminate cancer cells and improve survival, as recent data suggest.

The pathogenesis of tumour metastasis

Tumour metastasis is closely related to the balance between the metastatic potential of the primary tumour and the antimetastatic defence system. A brief description would summarize the different steps of the metastatic genesis as follows:7 initially, the genotypic and phenotypic ability of some cells from an organ of a host to replicate would be quickly followed by the proliferation of these cells. Local angiogenesis will result as a response to this increase and the nutritional needs of the latter. This neovascularization is typically stimulated by the secretion of proangiogenic factors. Finally, neoplasic cells will begin to migrate systemically, particularly through the lymphatics. These cells are initially destroyed by the defence mechanism of the host's immune system. Certain cells will eventually develop immune resistance, associated with multiple metabolic changes, including in their own energy metabolism. Thus, they will be able to migrate within solid organs remote from the primary tumour, where they proliferate, developing their own angiogenesis [notably vascular endothelial growth factor (VEGF) and prostaglandins E2].

The immune system response to the presence of t cells inside the circulatory system depends on the natural killer (NK) cells, lymphocytes which spontaneously recognize and lyse the t cells.8 Experimental and clinical studies have shown an inverse relationship between NK cells at the time of surgery and the development of distant metastasis. For instance, it is usual to mention that interleukin (IL)-2 and interferon (IFN)-γ are stimulating factors of NK-cell activity, whereas noradrenaline has a rather inhibitory activity. Moreover, this immune defence mechanism also involves cytotoxic T lymphocytes, mononuclear cells and dendritic cells. The integrity of the immune system is essential for host defence against the spread of cancer cells. The increased incidence of metastasis of some cancers (sarcoma, melanoma, bladder and kidney) among patients who receive immunotherapy after transplant illustrates this.

What perioperative factors are involved in the alteration of immune system?

Perioperative factors tip the balance towards an increase in residual disease.

Surgery and surgical stress

The goal of surgery in cancer pathology is ideally to provide a complete resection of the primary tumour cells, allowing the patient's recovery. In practice, the situation appears much more complex. Indeed, some experimental and preliminary clinical studies suggest that surgery could help to promote the development of pre-existing micrometastases and facilitate the appearance of new metastases. Manipulation and excision will be responsible for numerous vascular breaks, promoting the migration of residual tumour cells into the systemic circulation. The surgery will be accompanied by release of cellular growth factors both locally at the the operating site and systemically, and systemic circulation promoting the development of micrometastases. The control of this immune response during the migration of tumour cells and micrometastasis is mainly dependent on cell-mediated immunity: cytotoxic T lymphocytes, NK cells, dendritic cells and macrophages. A number of inflammatory mediators, such as IFN and IL, and in particular IFN-γ and IL-12, and Th1 cytokines increase the cytotoxic activity of T cells and NK cells. In addition, Th2-type cytokines are involved in increasing humoral immunity. The suppression of Th2-type responses greatly impairs the immune response to the oncologic aggression. The surgery releases tumour cells therefore in circulation and depresses cellular immunity, including the functions of cytotoxic T lymphocytes and NK cells.912 Meanwhile, β-adrenergic stimulation, which increases during stress, suppresses NK activity and promotes metastasis. Human studies show that low levels of perioperative NK activity are associated with increased morbidity in cancer.8 The surgical trauma reduces circulating concentrations of anti-angiogenic factors related to the tumour (angiotensin and endostatin).1316 Angiogenesis is a complex process involving components of the extracellular matrix and regulated by multiple angiogenic factors, including IL-6, -8, and -1β; cyclo-oxygenase 2; nitric oxide; tumour necrosis factor and endothelial growth factor.17,18 Surgery increases the concentrations of pro-angiogenic factors, and releases growth factors that promote local and remote cancer tissue.5 It is conceptually conceivable, but unproven, that minimally invasive approaches may have less effect on the immune system.

Anaesthesia and postoperative pain

Anaesthesia decreases immune functions, including the functions of neutrophils, macrophages, dendritic cells, T lymphocytes and NK cells.1922 Melamed et al.23 demonstrated, in rats, that ketamine, thiopental and halothane reduce the activity of NK cells and generate an increased retention of lung tumours or lung metastases. The number of circulating NK cells per ml of blood was significantly reduced by ketamine and thiopental. The effect of ketamine, in particular, may result from its adrenergic stimulant properties, which suppress the activity of NK cells and promote metastasis. However, propofol does not appear to affect migration or retention of metastases, which may be related to its (low) β-adrenergic-antagonist activity.24 The treatment of postoperative pain could play an important role in limiting metastatic migration after oncologic surgery. Page et al.11 demonstrated, in rats, that pain relief probably caused a reduction in stress response and thereby reduced the spread of the metastasis induced by the surgery. They showed also that intrathecal bupivacaine combined with preoperative morphine significantly improved host resistance to a surgery-induced increase of lung metastases.

Opioids

Opiates used during and after surgery inhibit cellular and humoral immune functions in humans.19,25,26 Moreover, morphine has pro-angiogenic properties and promotes natural breast tumour growth in rats.27 Opioids also decrease NK cell cytotoxicity (20%), the effect being more prolonged than the dose.25 However, this aggravating effect is not systematically found and depends on the type of study and model.2830 In a mouse model, repeated administration of morphine was associated with a decreased volume of destruction of the original tissue, induced by a decrease in the proliferation of neoplastic cells.30 For sufentanil and fentanyl, a depression of NK-cell activity is generally reported.8 However, tramadol would present a very different profile of opioid, characterized by the preservation of NK cell activity.

What is the role of regional anaesthesia/analgesia?

Regional anaesthesia and analgesia should reduce or limit these side effects. Regional anaesthesia attenuates the neuroendocrine stress response related to surgery by blocking afferent neuronal transmission and preventing it from reaching the central nervous system, where it activates the stress response, and by blocking the activation of the descending efferent sympathetic nervous system.31,32 Perioperative regional analgesia reduces or eliminates the need for agents such as volatile anesthetics or analgesia by opioids.

Data from cell studies

These local anesthetics may act at different levels. Locally, lidocaine inhibits proliferation of human tumour cells of lingual origin by inhibiting the activity of a receptor for epidermal growth factor.33 Ropivacaine-induced inhibition of cell proliferation of human colonic adenocarcinoma proteins associated with a depolarization of the cell membrane.34 Similarly, levobupivacaine, bupivacaine and ropivacaine decreased the cell viability of human cancer cells, and have a different effect depending on the cell lines tested.35 These local effects reported by these earlier studies would suggest the use of a local application of local anesthetics during surgery for cancer. These processes are probably not directly involved in the clinical studies cited earlier in this manuscript, because the doses used are compatible with local doses (0.5–1 mM) and are not systemic. However, this hypothesis of local application remains to be confirmed for different types of cancers and clinical settings.

Data from animal studies

The use of epidural anaesthesia attenuates the response to surgical stress, and prevents the inhibition of the immune system.

As might be expected, it was shown that spinal anaesthesia helps to preserve NK-cell function and reduces the metastatic load to the lungs.7 Similarly, non-opioid analgesia during and after surgery helps maintain the function of NK cells and reduces the metastatic spread of cancer in rodents.911 More paradoxically, when administered intrathecally, opioids do not seem to exert the same immunosuppressive effects as those observed after systemic administration. This finding has important clinical implications, because the perimedullary analgesia by local anesthetics are often supplemented by small doses of opiates.

Epidural analgesia inhibits the neuroendocrine response and reduces the production of adrenaline and noradrenaline. In a mouse-model study undergoing laparotomy during anaesthesia with sevoflurane, the number of liver metastases increases significantly compared with sevoflurane anaesthesia combined with spinal anaesthesia. Intrathecal local anesthetics attenuated the suppression of tumouricidal function of liver mononuclear cells, probably by preserving the Th1/Th2 balance and thereby reducing the production of metastases.36

Data from clinical studies

Recent studies seem to emphasize the importance of the association of regional anaesthesia for reducing the incidence of recurrence of secondary solid tumours.37,38 An initial study was performed in 4329 patients undergoing surgical excision of melanoma under local anaesthesia or general anaesthesia.39 In this retrospective study, patients undergoing general anaesthesia had a slightly significant higher risk of death during the observation period. A retrospective study by Exadaktylos et al.40 observed 129 patients with breast cancer undergoing mastectomy with or without axillary dissection under general anaesthesia. Patients were divided into two groups: one group of patients receiving paravertebral block (level T2–T3) with placement of a catheter (initial bolus of 0.2 ml/kg levobupivacaine 0.25% followed by a continuous infusion for 48 hours) and a second group of patients who received analgesia with morphine in patient-controlled analgesia (PCA). During the postoperative period (the first 24 hours), pain scores were significantly lower in the paravertebral group. After 36 months of follow-up, the proportion of patients showing no recurrence of the tumour was 94% in the paravertebral group and 77% in the morphine group (z-test P = 0.007). The secondary location was most often local or at the level of the axilla (one patient in the regional analgesia group vs 11 in the morphine group), but was also observed at the systemic level (two patients in the regional analgesia group vs eight in the morphine group). A third study, published by Biki et al.,41 was performed retrospectively in patients diagnosed with prostate cancer who underwent prostatectomy by laparotomy under general anaesthesia. The 225 patients were divided into two groups: one group of patients received a thoracic epidural (T11–T12 level) with an initial bolus followed by continuous infusion catheter for 48–72 hours, the second group receiving a intravenous morphine PCA. Perioperatively, few differences are described between the two groups, with no information on pain scores. At the end of follow-up (beyond 9 years), PSA (the primary endpoint of the study) was not significantly elevated in 76% and 49% of cases in men with and without regional analgesia, respectively. These results were not found by the team of Tsui et al.42 whose outcome was identical, but the limitations were numerous: the methodology is not prospective or randomized, and the results are not blindly analysed.43 In gastrointestinal surgery, the combination of regional anaesthesia and general anaesthesia remains unclear: it could allow an improvement in survival or decrease recurrence with no metastasis at the time of surgery,4446 results not found by Myles et al.47 The variety of cancer types included in these studies probably makes it difficult to interpret data. Somewhat controversial results have also be found in gynecological (ovarian) cancer surgery4849 and ear, nose and throat (ENT)50 as part of preliminary results.51 Major trials are summarized in Tables 1 and 2.

TABLE 1

Regional anaesthesia and cancer surgeries

Reference Surgery Anaesthesia technique Patients Survival Criteria
Gupta A. et al.46
Retrospective analysis
Inclusion period 2004–2008
Inclusion criteria
Colorectal surgery stage 1–3
Exclusion criteria
Cancer stage 4, coelioscopy, non elective surgery
655/750 patients
562 patients: GA + epidural (LA ± fentanyl)
vs
92 patients: GA + PCA morphine
Duration 2–5 days
Mean age in years [range]
Colon: 73.3 [21–96]
Rectum: 68.6 [25–92]
ASA 3–4:
Colon: 68/360
Rectum: 37/295
% years:
Dead
Colon 72/360
Rectum 77/295
Mortality:
Multifactor analysis
Colon:
Age > 72 years, Cancer stage 3 vs 1
Rectum
Age > 72 years,
PCA vs epidural
Cancer stage 2–3 vs 1
Kaplan–Meier (5 years): Rectum Death
PCA > epidural (P = 0.02)
Myles et al.47
Retrospective analysis based on a prospective randomized trial
Inclusion period 1995–2001
Inclusion criteria
Cancer abdominal surgeries
Exclusion criteria
Non-cancer abdominal surgeries
Incomplete surgeries
446/506 patients/candidates
230 patients: GA + thoracic epidural T4
216 patients: GA + PCA morphine
Duration 72 hours
Age in years
Epidural: 71
PCA: 70
TNM score
T3–T4
Epidural: 73/230
PCA: 60/216
N1–N2
Epidural: 45/230
PCA: 38/216
Recurrence rate or death at 15 years and 5 years
Epidural vs GA, ns P > 0.05
Predictive factors:
Age, female sex, transfusion
Recurrences or death
Epidural 2.6 years (IQR: 0.7–8.7)
PCA Morphine 2.8 years (IQR: 0.7–8.7)
Christopherson et al.44
Retrospective analysis based on a prospective randomized trial
Inclusion period 1992–1994
Inclusion criteria:
Cancer abdominal surgery
Exclusion criteria:
MI < 6 months
Abdominal surgery < 3 months
Previous chemotherapy or immunotherapy
177/247 patient candidates
92 patients: GA + epidural bupivacaine, analgesia T6+
85 patients: GA + PCA morphine
Age in years
Epidural: 68.6 (77)
PCA:69.1 (7.8)
ASA III–IV
Not measured
Stage III–IV
Epidural: 24/92
GA: 41/85
Survival with or without prior metastasis
Kaplan–Meier (120 months), survival
Without prior metastasis
Epidural > GA only between 2.5 and 4 years; survival benefit 1.5–2 years
With prior metastasis
GA > epidural after 1 year

GA, general anaesthesia; IQR, interquartile range; MI, myocardial infarction; ns, not significant; PCA, patient-controlled analgesia; TNM, the TNM staging system is based on the extent of the tumour (T), whether cancer cells spread to nearby (regional) lymph nodes (N), and whether distant (to other parts of the body) metastasis (M) has occurred.

TABLE 2

Regional anaesthesia and non-abdominal surgery

Reference Surgery Anaesthesia technique Patients Survival Criteria
Lin A et al.49
Retrospective analysis
Cancer: ovarian adenoK
Inclusion period 1994–2006
Inclusion criteria
Not measured
Exclusion criteria
No follow-up
Loss of files
143/234 patient candidates:
106 patients: epidural (LA)
vs
37 patients: PCA morphine
Duration: 48 hours
Age in years [range]
Epidural: 45.7 [30–65]
PCA: 48.1 [32–68]
ASA 3–4:
Epidural: 2
PCA: 1
FIGO III–IV score
Epidural: 57/106
PCA: 26/37
Life duration in 2008
(survival 2–14.5 years)
Survival after 3 years
Epidural: 78%
[IC95 70–86%]
PCA: 58%
[IC95 42–74%]
Survival after 5 years
Epidural: 61%
[IC95 52–71%]
PCA: 49%
[IC95 32–65%]
Mortality at 3 years and 5 years
Methods used
Multifactor analysis
Propensity score
Kaplan–Meier
de Oliveira et al.48
Retrospective analysis
Cancer: ovarian 50% invasive
Inclusion period 2000–2006
Inclusion criteria
Hysterectomy with neoplasic reduction
Exclusion criteria
Benign tumours or tumours impossible to reduce surgically
182/232 patient candidates:
29 patients: GA + PE
26 patients: GA + PPE
127 patients: GA + PCA morphine
Duration: 48–72 hours
Age in years
PE: 55 (12)
PPE: 55 (12)
PCA: 57 (12)
ASA 3–4
PE: 7/29
PPE: 3/26
PCA: 36/127
FIGO III-IV score
PE: 23/29
PPE: 16/26
PCA: 87/127
Total IV opiates (mg) [95th percentile]
PE: 30 [15–42]
PPE: 45 [28–65]
PCA: 78 [54–120]
Follow-up for 3–9 years
Recurrence diagnosed by CT scan or CA-125 > 21 U/ml
Kaplan–Meier (120 months)
No recurrence:
PPE > PE > PCA (P = 0.001–0.002)
No recurrence FIGO III:
PPE > PCA (P = 0.02)
Ismail et al.50
Retrospective analysis
Cancer: cervical
Inclusion period 1996–2003
Inclusion criteria
Uteral cervical cancer
132 patient candidates:
63 patients: epidural or spinal anaesthesia
69 patients: GA
Age in years [95th percentile]
Peripheral nerve block: 61 [22–93]
GA: 56 [27–85]
ASA 3–4
RA peripheral nerve block: 22/63
GA: 17/69
Perioperative opioids
Peripheral nerve block: 20/63
GA: 69/69
FIGO III-IV score
Peripheral nerve block: 14/63
GA: 22/69
Kaplan–Meier probability of survival without recurrence (120 months)
GA vs truncal RA, P = 0.863 (ns)
Multifactor analysis
Recurrence risk factors:
Type of tumour cells
FIGO score
tumour volume
Exadactylos et al.40
Retrospective analysis
Cancer: breast
Inclusion period: 2001–2002
Inclusion criteria
Mastectomy ± axillary resection
Exclusion criteria
Local tumour
Sentinel node
129/194 patient candidates
50 patients: GA + PV block T2–T3, levobupivacaine
79 patients: GA + PCA morphine
Duration: 48 hours
Age in years [95th percentile]
PV block: 57 [51–64]
PCA: 56 [50–64]
Pain
At 4 hours
PV block: 1 [0–3]
PCA: 3[2–5]
At 24 hours
PV block: 1 [0–2]
PCA: 2[0–4]
Histology Grade III
PV block: 21/50
PCA: 42/79
1 patient died in the PCA group Metastases or recurrences in May 2005
(follow-up 2.5–4 years)
PV block: 3/50 patients
PCA: 19/79 patients
Kaplan–Meier (36 months)
No recurrence
ParaV > PCA (P = 0.013)
Biki et al.41
Retrospective study
Cancer: prostate
Inclusion period: 1994–2003
Inclusion criteria
Prostatectomy
Exclusion criteria
Unknown
123 patients:
GA + epidural T11–12
102 patients: GA + PCA morphine
Duration: 48–72 hours
Age in years
Epidural: 62
PCA: 63
ASA 3–4
Epidural: 3/123
PCA: 8/102
PSA
Epidural: 8 [6–13.6]
GA: 8.7 [6.4–12.2]
Recurrence: PSA + Kaplan–Meier: no recurrence
Epidural > PCA
P < 0.001
Multifactor analysis
Fewer recurrences if epidural vs GA
No relation, but low Gleason score
No invasion
PSA preoperative
Propensity score
Tsui et al.42
Retrospective study based on prospective
Cancer: prostate
Inclusion period: 2000–2001
Inclusion criteria
Prostatectomy for cancer
Exclusion criteria
Unknown
99/102 patient candidates
49 patients: GA + epidural
50 patients GA + PCA morphine
Age in years
Epidural: 63 (5.5)
GA: 63.9 (6.1)
PSA
Epidural: 10.5 (8.2)
GA: 63.9 (6.1)
One death due to cancer
Four deaths not due to cancer in the epidural group
control group: four deaths
PCA > 0.2 ng/ml and clinical recurrences
No difference
Epidural 11/49
GA 17:50
Wuethrich et al.43
Retrospective analysis
Cancer: prostate
Inclusion period: 1994–2000
Inclusion criteria
Unknown
Exclusion criteria
Unknown
261/307 patient candidates
103 patients: GA + thoracic epidural T10–T12
158 patients: GA + PCA morphine
Duration: 48 hours
Age in years
Epidural: 63 [57–67]
GA: 64 [59–68]
ASA III
Epidural: 19/103
GA: 17/158
PSA
Epidural: 12.3 [7.5–21.9]
GA: 11 [7–17.1]
Perioperative fentanyl (mg)
Epidural 0.30 [0.2–0.50]
GA: 0.70 [0.55–0.80]
PSA > 0.2 ng/ml
Propensity score
GA + epidural increases the rate of survival (HR: 0.45; IQR: 0.27–0.75)
No difference in recurrence or mortality due to cancer

ASA, Physical Status Classification System; CA-125, cancer antigen 125; CT, computed tomography; FIGO, International Federation of Gynecology and Obstetrics; GA: general anaesthesia; HR, hazard ratio; IQR, interquartile range; LA, local anaesthesia; ns, not significant; PCA, patient-controlled analgesia; PE, postoperative epidural; PPE, peri- and postoperative epidural; PSA, prostate-specific antigen; PV, paravertebral; RA, regional analgesia.

These tables summarize the data and highlights the different courses depending on the study: sometimes very old periods of inclusion, a total disharmony and judging criteria very different from biological parameters for survival.

Prospective randomized trials are needed to confirm these initial results. Among the tests recorded at www.clinicaltrial.gov, two multicentre, prospective randomized trials have emerged: one in breast cancer surgery (for paravertebral block versus thoracic epidural analgesia with morphine; NCT00418457) and the second in colorectal cancer surgery (epidural analgesia or paravertebral block with bupivacaine versus postoperative morphine; NCT 00684229). These studies and their prospects will probably help put regional anaesthesia and analgesia at the focal point of interest in the coming years.52

Conclusion

It is too early to recommend specific types of drugs suitable for anaesthesia for cancer surgery or to recommend a technique of regional anaesthesia. If the reduction of halogenated anesthetics or opiates is a major factor, then it might be possible to obtain similar benefits by using drugs such as dexmedetomidine or intravenous lidocaine.53 Prospective, randomized, large-sized studies, focused on cancers at high risk of recurrence, are needed to determine if regional anaesthesia and analgesia could have potential for a clinically important reduction in cancer recurrence after surgery for cancer. The most demonstrative studies will be undoubtedly those focused on cancers with a high risk of recurrence.

As anaesthestic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastasis, there is an urgent need to determine the most appropriate anaesthestic strategy for surgical oncology so that optimal techniques are used to maximise long term survival.

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