Anaesthetic techniques for risk of malignant tumour recurrence

Ozlem S Cakmakkaya; Kerstin Kolodzie; Christian C Apfel; Nathan Leon Pace

doi:10.1002/14651858.CD008877.pub2

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 general anaesthesia + regional anaesthesia (GA + RA) vs general anaesthesia (GA), outcome: 1.1 overall survival.

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Figure 5

Forest plot of comparison: 1 general anaesthesia + regional anaesthesia (GA + RA) vs general anaesthesia (GA), outcome: 1.2 progression‐free survival.

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Figure 6

Forest plot of comparison: 1 general anaesthesia + regional anaesthesia (GA + RA) vs general anaesthesia (GA), outcome: 1.3 time to tumour progression.

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Analysis 1.1

Comparison 1 GA + RA versus GA, Outcome 1 Overall survival.

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Analysis 1.2

Comparison 1 GA + RA versus GA, Outcome 2 Progression‐free survival.

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Analysis 1.3

Comparison 1 GA + RA versus GA, Outcome 3 Time to tumour progression.

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Summary of findings for the main comparison. Epidural anaesthesia in addition to general anaesthesia compared with general anaesthesia alone for patients undergoing primary tumour surgery

Epidural anaesthesia in addition to general anaesthesia compared with general anaesthesia alone for patients undergoing primary tumour surgery
Patient or population: patients undergoing primary tumour surgery Settings: Intervention: epidural anaesthesia and analgesia in addition to general anaesthesia Comparison: general anaesthesia alone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect^† (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	General anaesthesia alone (control)	Epidural anaesthesia in addition to general anaesthesia (intervention)
Death from all causes Range of follow‐up times^a: 7.8‐14.8 years (Myles) 8.3‐10.75 years (Christopherson)	Study population		HR 1.03 (0.86 to 1.24)	647 (3 studies)	⊕⊕⊝⊝ low^b,c
	805 per 1000^a	815 per 1000 (755 to 868)
Tumour progression or death from all causes Range of follow‐up times: 7.8‐14.8 years^d	Study population		HR 0.88 (0.56 to 1.38)	535 (2 studies)	⊕⊝⊝⊝ very low^b,c,e
	944 per 1000^d	921 per 1000 (802 to 981)
Tumour progression Median follow‐up: 4.5 years^f	Study population		HR 1.50 (1 to 2.25)	545 (2 studies)	⊕⊝⊝⊝ very low^b,c,h
	360 per 1000^g	488 per 1000 (360 to 634)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; HR: Hazard ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
HR = hazard ratio, defined as intervention/control. ^†HR < 1 denotes advantage for the intervention group, HR > 1 denotes advantage for the control group. ^aThe assumed risk and the range of follow‐up times are based on data reported by Myles and Christophersen. Data on absolute events per group were not reported by Binczak. ^bSerious indirectness (‐1): Regional anaesthesia techniques are a surrogate for reduced or absent immunosuppression mediated by opioids and volatile anaesthetics, both of which are not controlled for in the included studies. ^cSerious imprecision (‐1): Combined sample sizes are deemed too small to show an effect. ^dThe assumed risk and the range of follow‐up times are based on data from Myles only. Data on absolute risk for tumour progression and death from all causes are not reported by Binczak. ^eSerious inconsistency (‐1): substantial unexplained heterogeneity. ^fThe median follow‐up time is based on data from Tsui. ^gThe assumed risk is based on data from Tsui only. Data on the absolute risk for TTP are not reported by Myles. ^hSerious risk of bias (‐1): 1 study with unclear risk of selective reporting and other bias.

Summary of findings for the main comparison. Epidural anaesthesia in addition to general anaesthesia compared with general anaesthesia alone for patients undergoing primary tumour surgery

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Table 1. Demographic, perioperative and study design characteristics

	Number of participants	Recruitment site(s)	Age (years)	Male sex	ASA	Type of surgery	Outcome data derived from
Christopherson 2008	112	USA; multi‐centre	Control group: 69.1 ± 7.8 Epidural group: 68.6 ± 7.7	Male only	III^a	Elective surgery for colon cancer	Veterans Affairs Beneficiary Information and Records Locator System (VA BIRLS)
Myles 2011	446	Australia, East Asia, Middle East; multi‐centre (MASTERS trial)	Control group: 70 ± 11 Epidural group: 71 ± 9.5	Control group: 53% Epidural group: 60%	'High risk patients'^b	Major abdominal surgery for cancer	1. Medical hospital record 2. Contact with participant's general practitioner 3. State‐based cancer registry or National Health Index 4. Participant contact 5. Contact with next of kin
Tsui 2010	99	Canada; single‐centre	Control group: 63.9 ± 6.1 Epidural group: 63.0 ± 5.5	Male only	ASA I‐III	Radical prostatectomy and bilateral pelvic lymphadenectomy	Participant's hospital charts and medical records
Binczak 2013	89	France; single‐centre	Not reported for subcohort (mean for full cohort 58 years)	Not reported for subcohort (full cohort includes > 62% male)	Not reported	Major abdominal surgery for cancer	1. Hospital intern cancer registry 2. Participant contact 3. French National Registry
ASA = American Society of Anesthesiologists physical status classification. USA = United States of America. ^aThe study by Christopherson 2008 reports that ASA I‐III patients were included. However, the original trial included only ASA III patients (Park 2001). ^bAccording to the inclusion criteria noted in the original study (Rigg 2002), 'high risk' translates to ASA II‐III.

Table 1. Demographic, perioperative and study design characteristics

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Table 2. Intraoperative and early postoperative analgesia

	GA maintenance	Epidural catheter level	Time placed	Duration	LA used	Epidural medications intraoperatively	Epidural medications postoperatively	Intraoperative IV opioids	Postoperative IV opioids
Christopherson 2008	Isoflurane 0.9% (mean) + N₂O	Thoracic or lumbar epidural catheter	Preoperatively	"as long as needed"	Bupivacaine 0.5%	3‐6 mg morphine; 25‐50 mg boluses bupivacaine/3‐5 hours as needed; epinephrine	25‐50 mg boluses bupivacaine/3‐5 hours as needed; morphine 3‐6 mg/12‐24hours as needed	Fentanyl for both groups	Morphine, meperidine as needed (IV in epidural group, IV or IM in control group)
Myles 2011	Balanced anaesthesia (volatile anaesthetic not specified), N₂O use not specified or recorded, but usual practice was to include it	At discretion of the anaesthesiologist "With the exception of some pelvic operations, all epidural catheters were inserted in the thoracic region"	Preoperatively	3 days after surgery	Bupivacaine or ropivacaine	Bupivacaine or ropivacaine	Continuous infusion of ropivacaine or bupivacaine, supplemented with fentanyl or pethidine	Fentanyl pethidine	Postoperative opioids, mostly PCA in control group (fentanyl, pethidine)
Tsui 2010	Isoflurane 1‐2% + N₂O 60%	Low thoracic or high lumbar epidural catheter	Preoperatively	Not reported	Ropivacaine	Ropivacaine bolus + continuous infusion; fentanyl	Not reported	Morphine for control group	Not reported
Binczak 2013	Isoflurane 1‐2% + N₂O 70%	Thoracic 7‐11	Preoperatively	Until 5th postoperative day	Bupivacaine	50 mg bupivacaine as needed; epinephrine	12.5 mg/h bupivacaine; 0.25 mg/h morphine	Fentanyl for both groups	Epidural group: morphine boluses SC as needed; control group: 2.5 mg/h morphine SC via catheter
GA = general anaesthesia. LA = local anaesthetic. IV = intravenous. IM = intramuscular. SC = subcutaneous.

Table 2. Intraoperative and early postoperative analgesia

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Table 3. Additional results reported from included studies

	Tumour stage (TNM)	Clinical vs pathologic staging	Median overall survival (95% CI)	Median progression‐free survival	Median time to tumour progression	5‐Year survival	Follow‐up time	Statistical test used (uni‐ vs. multivariable)
Christopherson 2008	All T, N0, M0	Pathological	6.14 (5.22 to 7.99)	Not reported	Not reported	Not reported	Up to 9 years	Data extracted from Kaplan‐Meier curve; HR and SEHR calculated according to Tierney (Tierney 2007)
Myles 2011	All T, all N, no distant metastasis (M0) 'complete surgical excision'	Not reported	Epidural group: 3.3 (95% CI 2.1 to 4.5) Control group: 3.7 (95% 2.0 to 5.4)	Epidural group: 2.6 (IQR 0.7 to 8.7) Control group: 2.8 (IQR 0.7 to 8.7)	Epidural group: 1.1 (95% CI 0.7 to 1.6) Control group: 1.4 (95% CI 0.6 to 2.3)	Epidural group: 42% Control group: 44%	Up to 12 years	Univariable testing, log‐rank statistics, intention‐to‐treat analysis
Tsui 2010	All T, all N, M not reported	Pathological	Not reported	Not reported	1644 days	Not reported	Up to 3403 days (˜9.3 years)	Unadjusted Cox model, no intention‐to‐treat analysis
Binczak 2013	Primary tumour resection (all stages) with or without residual disease postoperatively	Not reported	Not reported	Not reported	Not reported	Not reported	Up to 17 years	Unadjusted HR (reported by the contact author through personal communication)
IQR = interquartile range. TNM classification of malignant tumours: T = tumour size, N = lymph node involvement, M = distant metastasis. HR = hazard ratio. SEHR = standard error of hazard ratio. CI = confidence interval.

Table 3. Additional results reported from included studies

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Table 4. Characteristics of ongoing studies

Study PI	Start date (clinical trials.gov)	Population	Sample size	Intervention	Control group
Sessler 2007	2007	Female patients 18‐85 years of age, diagnosed with primary breast cancer without known extension beyond the breast and axillary nodes, scheduled for unilateral or bilateral mastectomy with or without implant or isolated "lumpectomy" with axillary node dissection (anticipated removal of at least 5 nodes)	1100	Regional anaesthesia and analgesia (epidural or paravertebral), combined with deep sedation or general anaesthesia (sevoflurane)	General anaesthesia (sevoflurane) followed by opioid administration
Kurz 2008	2008	Patients scheduled for open, laparoscopic or laparoscopic‐assisted surgery for colon cancer without known extension beyond colon	2500	Intraoperative and postoperative regional anaesthesia and analgesia (epidural or paravertebral anaesthesia) plus intraoperative general anaesthesia	General anaesthesia followed by postoperative opioid analgesia
Chang 2009	2009	Female patients 21‐75 years of age, ASA I‐II, diagnosed with biopsy‐proven breast cancer, scheduled for mastectomy and axillary node dissection in a single procedure	40	Local anaesthesia + sedation	General anaesthesia
Kurz 2010	2010	Male and female patients 18‐85 years of age, diagnosed with primary non‐small cell lung cancer and scheduled for potentially curative tumour resection	1532	Intraoperative and postoperative general anaesthesia + epidural anaesthesia and analgesia	General anaesthesia and postoperative intravenous analgesia
Ilfeld 2010	2010	Female patients 18 years of age and older, undergoing unilateral or bilateral mastectomy	60	Postoperative paravertebral catheter analgesia with ropivacaine	Placebo (normal saline)
Gupta 2011a	2011	Male and female patients 40‐80 years of age, ASA I‐III, undergoing elective surgery for colorectal cancer	300	Epidural analgesia with ropivacaine and opioid	PCA with morphine
Lee 2011	2011	Male and female patients 25‐80 years of age, diagnosed with non‐small cell lung cancer with clinical staging of I or II for whom thoracoscopic lobectomy (VATS) is feasible	100	Intraoperative thoracic epidural anaesthesia	Intraoperative general anaesthesia
Van Aken 2012	2012	Patients scheduled for inguinal lymph node dissection because of malignant melanoma of the lower limb	230	Spinal anaesthesia	General anaesthesia
Chan 2013	2013	Male and female patients 20‐85 years of age with pancreatic cancer, expected to receive curative Whipple operation	150	Epidural analgesia with ropivacaine and opioid	PCA with opioid
VATS = video‐assisted thoracic surgery. ASA = American Society of Anesthesiologists physical status classification. PCA = patient‐controlled analgesia.

Table 4. Characteristics of ongoing studies

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Table 5. Characteristics of non‐randomized studies

Author year	Type of cancer	Type of surgery	Intervention 1 (n)	Intervention 2 (n)	Control (n)	Endpoint	Statistical method	Result*	Date of surgery	Follow‐up until
Exadaktylos 2006	Breast CA	Mastectomy + LND	GA + paravertebral catheter (50)	‐	GA (79)	Time to tumour recurrence (local or metastasis)	Adjusted Cox regression	HR 0.21 (0.06‐0.71)	2001‐2002	2005
Ismail 2010	Cervical CA	First brachytherapy (of several)	SPA or EC (63)	‐	GA (69)	1. Time to tumour recurrence 2. Overall survival	Adjusted Cox regression	1. HR 0.95 (0.54‐1.67) 2. HR 1.46 (0.81‐2.61)	1996‐2003	nr
Gupta 2011b	Colon CA	Colorectal cancer surgery (open)	GA + EC preop (302)	‐	GA (58)	Overall mortality	Adjusted Cox regression with stratification on propensity score	HR 0.82 (0.30‐2.19)	2004‐2009	2009
Gupta 2011b	Rectal CA	Colorectal cancer surgery (open)	GA + EC preop (260)	‐	GA (35)	Overall mortality	Adjusted Cox regression with stratification on propensity score	HR 0.45 (0.22‐0.90)	2004‐2009	2009
Vogelaar 2012 (abstract)	Colon CA	Surgery for colon CA	EC 'perioperative' (407)	‐	GA (198)	Overall survival	Adjusted Cox regression	HR 0.93 (0.93‐0.98)	1995‐2003	2011
Luo 2010 (abstract)	Colon CA	Primary colon surgery	GA + EC (182)	‐	GA (931)	Tumour recurrence	Univariable	HR 1.33 (0.94‐1.87)	2001‐2006	2009
Gottschalk 2010	Colorectal CA	Colorectal cancer surgery	GA + EC preop (256)	‐	GA (253)	Time to tumour recurrence	Adjusted Cox model with stratification on propensity score quintiles	HR 0.74 (0.45‐1.22)	2000‐2007	2008
Cummings 2012	Colorectal CA w/no metastases	Open colectomy	EC (Medicare code) (9670)	‐	No EC (Medicare code) (32481)	1. Overall survival 2. 4‐Year tumour recurrence	1. Adjusted marginal Cox model with propensity score as co‐variate 2. Adjusted logistic regression	1. HR 0.92 (0.88‐0.96) 2. OR 1.05 (0.95‐1.15)	1996‐2005	2009
Day 2012	Colorectal CA	Laparoscopic resection	EC preop (107)	SPA (144)	GA + PCA (173)	1. Overall survival 2. Disease‐free survival	KM estimate, log‐rank test	1. P value 0.622 2. P value 0.490	2003‐2010
Lai 2012	Hepatocellular CA	Percutaneous radiofrequency ablation	GA + EC preop (62)	‐	GA (117)	1. Recurrence‐free survival 2. Overall survival	Adjusted Cox model with propensity score as co‐variate	1. 3.66 (2.59‐5.15) 2. 0.77 (0.50‐1.18)	1999‐2008	2011
Gottschalk 2012	Malignant melanoma	Lymph node dissection	SPA (52)	‐	GA (221)	Long‐term survival	Mean survival (months) of matched pairs (52 pairs)	95.9 (81.2‐110.5) SPA 70.4 (53.6‐87.1) GA P value 0.087	1998‐2005	2009
Seebacher 1990	Malignant melanoma	Melanoma resection	Local anaesthesia (376)	‐	GA (190)	Survival	KM estimate, log‐rank test	P value 0.51 (stage pT1/2, n = 237) P value 0.006 (stage pT3a, n = 195) in favour of local anaesthesia P value 0.47 (stage pT3b/4, n = 134)	Control: 1972‐1980 Intervention: 1981‐88	1988
Schlagenhauff 2000	Malignant melanoma w/no metastases	Primary melanoma excision	Local anaesthesia (2185)	‐	GA (2136)	Survival	Log‐rank test on matched pairs (1501 pairs)	P value < 0.01 in favour of local anaesthesia	1976‐1986	nr
De Oliveira 2011	Ovarian CA	Surgery for ovarian cancer	GA + EC preop (26)	GA intraop/EC postop (29)	GA (127)	1. Overall survival 2. Time to recurrence	1. Median survival time (months), log‐rank test 2. Adjusted Cox model	1. 71 m (62‐80) for GA 96 m (84‐109) for EC intraop 70 m (58‐83) for EC postop P value 0.01 for GA vs EC intraop (favours EC intraop) 2. HR 0.37 (0.19‐0.73) for intraop EC HR 0.86 (0.52‐1.41) for postop EC	2000‐2006	2009
Lin 2011	Ovarian CA	Surgery for ovarian cancer	EC only preop (106)	‐	GA (37)	Survival time	Adjusted Cox regression on propensity matched pairs (29 pairs)	HR 0.83 (0.67‐0.99)	1994‐2006	2008
Koensgen 2013 (abstract)	Ovarian CA	Primary radical tumour debulking	EC preop + GA (72)		GA (33)	1. Recurrence‐free survival 2. Overall survival	KM estimate, log‐rank test	1. HR 1.52 (1.4‐1.56), P value 0.008 2. nr	2003‐2010	nr
Lacassie 2013	Ovarian cancer (Figo IIIc‐IV)	Exploratory laparotomy	EC preop or postop + GA (37)		GA (43)	1. Time to recurrence 2. Cancer‐specific survival	Adjusted Cox regression with propensity score weighting	1. HR 0.65 (0.40‐1.08) 2. HR 0.59 (0.32‐1.08)	2000‐2011	nr
Kienbaum 2010/Alexander 2009 (abstracts)	Pancreatic CA	Radical pancreatic tumour resection	GA + EC (71)	‐	GA (29)	Overall survival	Log‐rank	P value 0.05 (P value 0.025 in favour of control for participants receiving high‐dose epidural opioids)	2005‐2008	nr
Biki 2008	Prostate CA	Open radical prostatectomy	GA + EC preop (102)	‐	GA (123)	BCR‐free survival	Univariable Cox regression on propensity matched pairs (71 pairs)	HR 0.48 (0.23‐1.00)	1994‐2003	2006
Forget 2011	Prostate CA w/no metastasis	Radical prostatectomy	GA + EC preop (578)	‐	GA (533)	BCR‐free survival	Adjusted Cox model	HR 0.84 (0.52‐1.17)	1993‐2006	2006
Wuethrich 2010	Prostate CA (all stages)	Open radical retropubic prostatectomy w/LND	GA + EC preop (103)	‐	GA (158)	1. BCR‐free survival 2. Clinical progression‐free survival 3. Cancer‐specific survival 4. Overall survival	Adjusted Cox model with propensity score as co‐variate	1. HR 0.82 (0.50‐1.34) 2. HR 0.40 (0.20‐0.79) 3. HR 0.95 (0.36‐2.47) 4. HR 1.01 (0.44‐2.32)	Intervention: 1994‐1997 Control: 1997‐2000	nr
Wuethrich 2013	Prostate CA (pT3/4)	Retropubic radical prostatectomy w/LND	GA + EC preop (67)	‐	GA (81)	1. BCR‐free survival 2. Local recurrence‐free survival 3. Distant recurrence‐free survival 4. Cancer‐specific survival 5. Overall survival	Univariable Cox regression on matched pairs (67 pairs)	1. HR 1.00 (0.69‐1.47) 2. HR 1.16 (0.41‐3.29) 3. HR 0.56 (0.26‐1.25) 4. HR 0.96 (0.45‐2.05) 5. HR 1.17 (0.63‐2.17)	1994‐2000	nr
Several statistical methods were used in most studies. We weighted reported results in the following descending order: adjusted regression with propensity score or matched pairs, adjusted regression, univariable analysis. Only the highest weighted analysis is reported in the table. HR = hazard ratio, defined as intervention/control. HR < 1 denotes advantage for the intervention group, HR > 1 denotes advantage for the control group. We adjusted the HR derived from individual trials accordingly, as needed. bold font* denotes significant results in favour of the intervention group (EC). italic font denotes significant results in favour of the control group (GA). CA = cancer. pT = pathological tumour staging. EC = epidural catheter. SPA = spinal anaesthesia. GA = general anaesthesia. LND = lymph node dissection. preop = preoperatively. postop = postoperatively. n = number of participants. OR = odds ratio. n.s. = non‐significant. BCR = biochemical recurrence. nr = not reported. m = months.

Table 5. Characteristics of non‐randomized studies

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Comparison 1. GA + RA versus GA

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall survival Show forest plot	3	647	Hazard Ratio (Random, 95% CI)	1.02 [0.78, 1.34]

2 Progression‐free survival Show forest plot	2	535	Hazard Ratio (Random, 95% CI)	0.88 [0.56, 1.38]

3 Time to tumour progression Show forest plot	2	545	Hazard Ratio (Fixed, 95% CI)	1.50 [1.00, 2.25]

Comparison 1. GA + RA versus GA

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