Characteristics of Included RCTs

Nineteen RCTs were included in the analysis. The COLOR trial2 has been published in abstract and was presented at the annual meeting of the European Association of Endoscopic Surgeons in Glasgow Scotland in 2003. Because of the large amount of patients recruited by this trial (>1000), data available from the Glasgow presentation have been included in this analysis. Final data analysis from the COLOR trial is still awaiting publication in printed form. Therefore, slight changes of these data are possible.

The 19 RCTs identified included more than 3500 patients, but 10 trials recruited less than 100 patients. Five RCTs included cancer patients as well as patients with benign indications for surgery. All RCTs included colonic cancer but only seven trials included (mostly upper) rectal cancers. Only six publications gave any information concerning the type of incision used in conventional surgery and these studies all used a midline incision. Details of the postoperative analgesic technique were given in nine publications. In four of these trials, a thoracic epi-dural analgesia was administered for pain relief, whereas three trials used a systemic opioid patient-controlled analgesia (PCA) regimen, and in two trials opioids were given on demand (Table 11.7.1).

Only six RCTs were considered to be of good methodological quality. Problems with the other RCTs included: Eight publications did not define a main study criterion, only 11 manuscripts mentioned an a priori sample size calculation, and most publications did not give details about the randomization process (i.e., technique and concealment of randomization). Only 11 trials used an "intention-to-treat" approach, analyzing the data of patients converted from laparoscopic to conventional surgery within the laparoscopic group (Table 11.7.1).

Table 11.7.1. Characteristics of RCT comparing laparoscopic and conventional colorectal resection

Author No. of and year Method patients

Indications/location

Laparotomy Analgesia Outcomes

Ortiz et al.1 1996

Stage et al.1: 1997

Hewitt et al.13 1998

Milsom et al.1 1998

Leung et al.1! 2000

Curet et al.16 2000

Tang et al.17 2001

No SSC; preop. random; no ITT

No SSC; preop. random; no ITT

SSC; random?; no ITT

SSC; intraop. random; ITT

SSC; preop. random; ITT

No SSC; preop. random; no ITT SSC; preop. random; no ITT

Cancer, benign disease; left/right colon, rectum >2 cm from dl Cancer; colon

Cancer; left/right colon, rectum >10 cm from dl

Cancer; left/right colon, no transverse, rectum >12 cm from dl or requiring APR Cancer; rectosigmoid >5 cm from dl

Cancer; left/right colon

Cancer; left/right colon, no transverse, no TME

Not stated Not stated

Midline or tPDA-LA/O paramedian incision

Not stated PCA-O

Midline

Not stated

Not stated

Not stated

PCA-O

OD-O

Not stated

Not stated

MST: duration of ileus; other data: operative time, morbidity

MST: not stated; other data: operative time, pain, pulmonary function, morbidity, hospital stay MST: immunology; other data: operative time, analgetic dose, morbidity, hospital stay MST: pulmonary function; other data: operative time, analgetic dose, duration of ileus, morbidity, hospital stay MST: cytokine and

C-reactive protein; other data: operative time, pain, analgetic dose, duration of ileus, morbidity, hospital stay MST: not stated; other data: operative time, morbidity, hospital stay MST: immune and stress response; other data: operative time, morbidity

(Continued)

Table 11.7.1. Characteristics of RCT comparing laparoscopic and conventional colorectal resection (Continued)

Author and year

Method

No. of patients Indications/location

Laparotomy Analgesia Outcomes

Lacy et al.3 2002

Braga et al.18 2002

Liang et al.19 2002

Winslow et al.1' 2002

Danelli et al.21 2002

SSC; preop. random; ITT

SSC; preop. random; ITT

No SSC; preop. random; no ITT SSC; preop. random; ITT

No SSC; preop. 39 random; ITT

Schwenk et al.20 SSC; intraop. 103

2002 random; ITT

Cancer; left/right Not stated Not stated colon above 15 cm from dl, no transverse

Cancer, benign disease; Not stated tPDA-LA left/right colon, rectum >4 cm from dl

Cancer, polyps; Not stated Not stated sigmoid colon

Cancer, large polyps; Midline PCA-O

left/right colon, no transverse, rectum >12 cm from dl or requiring APR Cancer; left/right Midline Not stated colon, no transverse

Cancer, benign disease; Midline tPDA-LA

no location given

MST: cancer-related survival; other data: operative time, duration of ileus, morbidity, hospital stay MST: morbidity; other data: operative time, duration of ileus, morbidity, hospital stay, recovery of physical function MST: not stated; other data: operative time, duration of ileus, hospital stay, pain, morbidity, disability, inflammatory and immunologic parameter MST: pulmonary function; other data: operative time, duration of ileus, morbidity, hospital stay, fatigue, quality of life MST: wound complications; other data: operative time, morbidity MST: perioperative core body temperature; other data: duration of ileus

Weeks et al.22 2002 Hildebrandt et al.23 2003

SSC; preop.

random; ITT No SSC; preop. random; ITT

Hasegawa et al.24 No SSC; preop. 2003 random; ITT

COLOR2 2003

COST5 2004

Leung et al.4 2004

SSC; preop. random; ITT

SSC, preop. random; ITT

449 42

SSC; preop. 1005

random; ITT

Cancer; left/right Not stated colon, no transverse Cancer, Crohn's Midline disease; left/right colon, no transverse

Cancer; left/right colon, Not stated no transverse

Cancer; left/right Not stated colon, no transverse, rectum >15 cm from dl

Cancer; left/right colon, Not stated no transverse

Rectosigmoid cancer Not stated

No standard* Not stated tPDA-LA/O

Not stated

No standard*

OD-O

MST: quality of life; other data: pain, hospital stay MST: not stated; other data: operative time, inflammatory and immunologic parameters MST: not stated; other data: operative time, inflammatory and immunologic response, duration of ileus, morbidity, hospital stay MST: cancer-related survival; other data: operative time, duration of ileus, morbidity, mortality, postoperative hospital stay MST: time to tumor recurrence; other data: overall and cancer-related survival, morbidity, mortality, hospital stay MST: survival; other data: morbidity, mortality, hospital stay

SSC, sample size calculation; random, time of randomization; ITT, "intention-to-treat" analysis; dl, dentate line; tPDA, thoracic epidural analgesia; OD, on demand; O, opioid; LA, local anesthetic; MST, main study criterion. ""Not standardized in a multicenter study.

Review:

Short term benefits of laparoscopic colorectal resection (boehmbuch)

Comparison:

02 Operative data

Outcome:

03 Blood loss

Study

Laparoscopic

Conventional

or sub-category

N

Mean (SD)

N

Mean (SD)

Milsom et al.

55

252.00 (222.00)

54

344.00 (626.00)

Curet et al.

18

284.00 (284.00)

18

407.00 (407.00)

Leung et al.

17

103.00 (103.00)

17

141.00 (141.00)

Braga et al.

40

123.00 (107.00)

39

319.00 (307.00)

Braga et al. (2)

136

170.00 (107.00)

133

286.00 (242.00)

Danelli et al.

23

300.00 (300.00)

21

300.00 (300.00)

Lacy et al.

111

105.00 (99.00)

108

193.00 (212.00)

Hasegawa et al.

24

58.00 (0.00)

26

137.00 (0.00)

COLOR study

500

100.00 (100.00)

505

175.00 (175.00)

Leung et al. (2)

203

169.00 (169.00)

200

238.00 (238.00)

Total (95% Cl)

1127

1121

Test for heterogeneity: Chix = 10.08, df =

8 (P = 0.26), lx = 20.7%

Test for overall effect: Z = 8.20 (P < 0.00001)

-1000 -500 0 500 1000 Favours laparoscopic Favours conventional

Figure 11.7.1. Blood loss (WMD including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Outcomes

Short-term Outcome

Intraoperative blood loss was estimated in 2248 patients from nine trials. The WMD between the laparoscopic and conventional group was -84 (-104 to -64) cc (Figure 11.7.1). Operative time was 50 (37-64) minutes longer in laparoscopic compared with conventional procedures (Figure 11.7.2).

Postoperative pulmonary function was assessed in three RCTs. Because of the different time intervals in which postoperative pulmonary function was measured and different approaches in visualizing

N

Laparoscopic Mean (SD)

N

Conventional Mean (SD)

Milsom et al.

55

200.00 (40.00)

54

125.00 (51.00)

Curet et al.

18

210.00 (30.00)

18

138.00 (20.00)

Leung et al.

17

212.10 (64.90)

17

136.80 (51.90)

Tang et al.

118

88.00 (30.00)

118

70.00 (30.00)

Braga et al.

40

234.00 (74.00)

39

173.00 (56.00)

Braga et al. (2)

136

222.00 (74.00)

133

177.00 (56.00)

Danelli et al.

23

244.00 (20.00)

21

160.00 (15.00)

Lacy et al.

111

142.00 (52.00)

108

118.00 (45.00)

Liang et al.

18

148.00 (51.50)

21

160.00 (28.60)

Schwenk et al.

53

216.90 (57.50)

49

151.00 (43.10)

Winslow et al.

37

148.00 (47.00)

46

101.00 (57.00)

Hasegawa et al.

24

275.00 (60.00)

26

188.00 (25.00)

COLOR study

500

202.00 (60.00)

505

179.00 (60.00)

COST study

435

150.00 (60.00)

428

95.00 (60.00)

Leung et al. (2)

203

189.90 (55.40)

200

144.20 (57.80)

Total (95% Cl)

1788

1783

Test for heterogeneity: Chi2 = 207.6!

3, df = 14 (P < 0.00001), l2

= 93.3%

Test for overall effect: Z

= 7.37 (P < 0.00001)

-100 -50 0 50 100 Favours laparoscopic Favours conventional

Figure 11.7.2. Operative time (WMD including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 05 lleus

Outcome: 02 Duration until bowel movement

Study

Laparoscopic

Conventional

or sub-category

N

Mean (SD)

N

Mean (SD)

Milsom et al.

55

4.80 (4.80)

54

4.80 (4.80)

Leung et al.

17

3.00 (3.00)

17

3.00 (3.00)

Braga et al.

40

5.00 (5.00)

39

6.00 (6.00)

Braga et al. (2)

136

4.70 (0.80)

133

5.70 (1.10)

Danelli et al.

23

3.00 (3.00)

21

4.00 (4.00)

Schwenk et al.

53

2.89 (1.32)

49

3.78 (0.91)

COLOR study

539

2.85 (2.85)

466

3.73 (3.73)

Leung et al. (2)

203

4.00 (4.00)

200

4.60 (4.60)

Total (95% Cl)

1066

979

Test for heterogeneity: Chi2 = 2.88, df = 7 (P = 0.90), l2 Test for overall effect: Z = 10.30 (P < 0.00001)

Test for heterogeneity: Chi2 = 2.88, df = 7 (P = 0.90), l2 Test for overall effect: Z = 10.30 (P < 0.00001)

Favours laparoscopic Favours conventional

Figure 11.7.3. Time until first bowel movement (WMD including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

postoperative recovery of pulmonary function (mean of each measurement vs. patients recovering 80% of preoperative function), different patients' numbers were measured on postoperative days 1-3. On postoperative days 1-3, pulmonary function was less impaired in laparo-scopic patients. During this time, the WMDs between both groups ranged from 200 to 560 cc. Recovery of 80% of the preoperative pulmonary function was achieved 8 hours earlier in the laparoscopic group.

Duration of postoperative ileus was measured by time interval from surgery to the first bowel movement in seven RCTs. Gastrointestinal function was restored 0.93 days (0.75-1.1) earlier in patients undergoing laparoscopic surgery compared with conventional patients (Figure 11.7.3).

Patients operated on laparoscopically had a shorter hospital stay of 1.5 days (0.9-2.0) than patients who underwent conventional colorectal cancer resection (Figure 11.7.4).

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 06 Hospital stay

Outcome: 01 Postoperative hospital stay

Study

Laparoscopic

Conventional

WMD (random)

or sub-category

N

Mean (SD)

N

Mean (SD)

95% Cl

Milsom et al.

55

6.00 (4.00)

54

7.00 (4.00)

Curet et al.

18

5.20 (1.00)

18

7.30 (2.00)

-

Braga et al.

40

9.10 (2.90)

39

11.70 (5.10)

Braga et al. (2)

136

10.40 (2.90)

133

12.50 (4.10)

-

Lacy et al.

111

5.20 (2.10)

108

7.90 (9.30)

Schwenk et al.

53

9.10 (2.90)

49

10.60 (2.04)

-

Weeks et al.

228

5.60 (0.30)

221

6.40 (0.20)

Leung et al. (2)

203

8.20 (3.20)

200

8.70 (3.70)

Total (95% Cl)

844

822

Test for heterogeneity: Chi2 = 25.73, df = 7 (P = 0.0006), l2 = 72.8% Test for overall effect: Z = 5.11 (P < 0.00001)

Test for heterogeneity: Chi2 = 25.73, df = 7 (P = 0.0006), l2 = 72.8% Test for overall effect: Z = 5.11 (P < 0.00001)

Favours laparoscopic Favours conventional

Figure 11.7.4. Hospital stay (WMD including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

The relative risk of postoperative morbidity was 0.72 (0.56-0.92) in the laparoscopic group compared with the conventional approach (Figure 11.7.5). The absolute risk reduction (ARR) was 4.4% and therefore the number to avoid one complication (NNT) was 23. There was an ARR of 1.1% for pulmonary morbidity (P = .07) when patients were treated laparoscopically, meaning that 91 patients would have to undergo laparoscopic surgery to prevent one pulmonary complication. No differences were detected for cardiac morbidity. The relative risk of wound infections was 0.65 (0.47-0.90) in the laparoscopic group (Figure 11.7.6) compared with conventional surgery. The ARR was 2.7% and the NNT was 37 patients. There was no difference in the risk of anas-tomotic leakage, intraabdominal abscess, or reoperation within 30 days after surgery. The relative risk of postoperative ileus was 0.45 (0.260.77) compared with open surgery (Figure 11.7.7). The ARR was 3.3% and the NNT was 31. Mortality was overall low, the relative risk in the laparoscopic group was 0.55 (0.26-1.18) and not significantly different between groups (Figure 11.7.8).

Long-term Outcome

Only few of the RCTs gave additional information on the long-term outcome of laparoscopic or conventional colorectal cancer resection.

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 08 Morbidity Outcome: 01 Total

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 08 Morbidity Outcome: 01 Total

Study

Laparoscopic

Conventional

or sub-category

n/N

n/N

Ortiz et al.

4/15

2/15

Stage et al.

2/15

0/14

Hewitt et al.

0/8

0/8

Milsom et al.

8/55

8/54

Curet et al.

1 /1 8

5/18

Leung et al.

5/17

6/17

Tang et al.

12/118

11/118

Braga et al.

8/40

13/39

Braga et al. (2)

28/136

51/133

Lacy et al.

14/111

37/108

Liang et al.

1 /1 8

7/21

Schwenk et al.

5/53

10/49

Solomon et al.

3/20

9/19

Hasegawa et al.

1/24

5/26

COLOR study

101/500

106/505

COST study

92/435

85/428

Leung et al. (2)

40/203

45/200

Total (95% Cl)

1786

1772

Total events: 325 (Laparoscopic), 400 (Conventional) Test for heterogeneity: Chi2 = 31.79, df = 15 (P = 0.007), l2 = Test for overall effect: Z = 2.63 (P = 0.008)

Total events: 325 (Laparoscopic), 400 (Conventional) Test for heterogeneity: Chi2 = 31.79, df = 15 (P = 0.007), l2 = Test for overall effect: Z = 2.63 (P = 0.008)

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.5. Morbidity [(risk ratio (RR) including the 95% CI] after laparoscopic and conventional surgery for colorectal cancer.

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 08 Morbidity Outcome: 08 Wound infection

Study or sub-category

Laparoscopic n/N

Conventional n/N

Ortiz et al.

2/15

1/15

Curet et al.

1/18

1/18

Leung et al.

0/17

1/17

■4

Tang et al.

3/118

3/118

Braga et al. (2)

8/136

20/133

Lacy et al.

8/111

18/108

Liang et al.

0/18

2/21

4

Schwenk et al.

1/53

5/49

Winslow et al.

5/37

5/46

Hasegawa et al.

1/24

3/26

*

COLOR study

18/500

16/505

Leung et al. (2)

9/203

15/200

Total (95% Cl)

1250

1256

Total events: 56 (Laparoscopic), 90 (Conventional)

Test for heterogeneity: Chi2 = 10.23, df = 11 (P = 0.51), 12 = 0%

Total events: 56 (Laparoscopic), 90 (Conventional)

Test for heterogeneity: Chi2 = 10.23, df = 11 (P = 0.51), 12 = 0%

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.6. Wound infections (RR including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Length of follow-up was very short in 4 of 5 RCTs that provided long-term data. Only three trials with an adequate length of follow-up have been published by Lacy et al.,3 Leung et al.,4 and the COST Study Group.5 All other RCTs giving follow-up data lacked a sufficient number of patients as well as an adequate length of follow-up. Therefore, these

Review: Comparison: Outcome:

Study or sub-category

Short term benefits of laparoscopic colorectal resection

08 Morbidity

09 Postoperative ileus

Laparoscopic

Conventional

n/N

n/N

1/15

0/15

0/18

1/18

3/136

6/133

3/111

8/108

■i

2/37

14/46

0/24

2/26

9/500

15/505

841

851

Ortiz et al. Curet et al. Braga et al. (2) Lacy et al. Winslow et al. Hasegawa et al. COLOR study

Total (95% Cl) Total events: 18 (Laparoscopic), 46 (Conventional) Test for heterogeneity: Chi2 = 3.99, df = 6 (P = 0.68) Test for overall effect: Z = 2.92 (P = 0.004)

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.7. Postoperative ileus (RR including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 08 Morbidity Outcome: 17 Mortality

Study

Laparoscopic

Conventional

or sub-category

n/N

n/N

Ortiz et al.

0/15

0/15

Stage et al.

0/15

0/14

Hewitt et al.

0/8

0/8

Milsom et al.

1/55

1/54

Curet et al.

0/18

0/18

Leung et al.

0/17

0/17

Braga et al.

0/40

0/39

Braga et al. (2)

1/136

0/133

Lacy et al.

1/111

3/108

Liang et al.

0/18

0/21

Schwenk et al.

0/53

1/49

Hasegawa et al.

0/24

0/26

COLOR study

6/500

10/505

Leung et al. (2)

1/203

4/200

Total (95% Cl)

1213

1207

Total events: 10 (Laparoscopic), 19 (Conventional) Test for heterogeneity: Chi2 = 2.12, df = 5 (P = 0.83), l2 Test for overall effect: Z = 1.53 (P = 0.13)

Total events: 10 (Laparoscopic), 19 (Conventional) Test for heterogeneity: Chi2 = 2.12, df = 5 (P = 0.83), l2 Test for overall effect: Z = 1.53 (P = 0.13)

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.8. Mortality (RR including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

three larger RCTs provided between 64% (locoregional recurrence) and 100% (port site recurrences) of the pooled data.

Recurrences (Figure 11.7.9) and survival (Figure 11.7.10) were not different between both groups. See Table 11.7.2 for a summary of the outcome statistics.

Review: Short term benefits of laparoscopic colorectal resection

Comparison: 10 Follow-up data Outcome: 02 Recurrences

Study or sub-category

Laparoscopic n/N

Conventional n/N

Curet et al. Leung et al. Lacy et al. COST study Leung et al. (2)

0/18 3/17 18/106 76/435 37/167

Total events: 134 (Laparoscopic), 144 (Conventional) Test for heterogeneity: Chi2 = 5.79, df = 4 (P = 0.22), l2 = Test for overall effect: Z = 0.53 (P = 0.60)

1/18 1/17 28/102 84/428 30/170

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.9. Tumor recurrence (RR including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Laparoscopic Conventional RR (random)

Laparoscopic Conventional RR (random)

Curet et al. Leung et al. Lacy et al. COST study Leung et al. (2)

4/18 1/17 10/106 118/435 26/167

6/18 1/17 21/102 117/428 20/170

H

h

Total events: 159 (Laparoscopic), 165 (Conventional)

Test for heterogeneity: Chi2 = 6.14, df = 4 (P = 0.19), l2 = 34.8%

Test for overall effect: Z = 0.60 (P = 0.55)

735

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

0.1 0.2 0.5 1 2 5 10 Favours laparoscopic Favours conventional

Figure 11.7.10. Long-term survival (RR including the 95% CI) after laparoscopic and conventional surgery for colorectal cancer.

Table 11.7.2. Comparison of outcomes of RCTs for colorectal cancer

Statistical

Outcome

Studies

Participants

method

Effect size

Operative time

15

3571

WMD (random), 95% CI

50.34 [36.95, 63.74]

Blood loss

9

2248

WMD (random), 95% CI

-84.14 [-104.24, -64.04]

Bowel

8

2045

WMD

-0.93 [-1.10,

movement

(random), 95% CI

-0.75]

Hospital stay

8

1666

WMD (random), 95% CI

-1.45 [-2.01, -0.90]

Morbidity

16

3558

(random), 95% CI

0.72 [0.56, 0.92]

Wound infection

12

2506

RR (random), 95% CI

0.65 [0.47, 0.90]

Postoperative

7

1692

RR

0.45 [0.26,

ileus

(random), 95% CI

0.77]

Mortality

6

2420

RR (random), 95% CI

0.55 [0.26, 1.18]

Recurrences

5

1478

RR (random), 95% CI

0.92 [0.67, 1.25]

Survival

5

1478

RR (random), 95% CI

0.90 [0.64, 1.27]

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