Articles
Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): survival outcomes of an open-label, non-inferiority, randomised controlled trial Seung-Yong Jeong, Ji Won Park, Byung Ho Nam, Sohee Kim, Sung-Bum Kang, Seok-Byung Lim, Hyo Seong Choi, Duck-Woo Kim, Hee Jin Chang, Dae Yong Kim, Kyung Hae Jung, Tae-You Kim, Gyeong Hoon Kang, Eui Kyu Chie, Sun Young Kim, Dae Kyung Sohn, Dae-Hyun Kim, Jae-Sung Kim, Hye Seung Lee, Jee Hyun Kim, Jae Hwan Oh
Summary Background Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. Methods The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT0040951. Findings We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI –15·8 to 2·4; p25
64 (38%)
63 (37%)
ASA grade I
65 (38%)
69 (41%)
II
98 (58%)
96 (56%)
III
7 (4%)
5 (3%)
Preoperative serum concentration of carcinoembryonic antigen (ng/mL) ≤5
154 (91%)
157 (92%)
>5
16 (9%)
13 (8%)
Clinical classification cN0
52 (31%)
59 (35%)
cN+
118 (69%)
111 (65%)
Tumour distance from anal verge (cm) 0–3
46 (27%)
35 (21%)
3–6
59 (35%)
66 (39%)
6–9
65 (38%)
69 (41%)
156 (92%)
156 (92%)
Preoperative chemotherapy Figure 1: Trial profile
Fluoropyrimidines alone
low-rectal cancer who had received preoperative chemoradiotherapy10 and were being treated at any one of three participating Korean hospitals. Patients’ rectal adenocarcinomas had been clinically diagnosed as cT3N0–2M0 lesions on the basis of abdominal and pelvic CT, MRI, and transanal ultrasound. Exclusion criteria were synchronous distant metastases, another primary malignancy, cardiopulmonary dysfunction, active uncontrolled infection, active uncontrolled psychosis, and intestinal perforation or obstruction. The trial was approved by the institutional review board of each participating centre, and all patients provided written informed consent.
Randomisation and masking Patients were randomly allocated to the open or laparoscopic resection group (1:1) via a computergenerated list with a random permuted block design. The random allocation sequence was generated by the Centre for Clinical Trials at the National Cancer Centre Korea. Randomisation was stratified according to sex and preoperative chemotherapy regimen. Local investigators enrolled the patients. Investigators were masked to the randomisation sequence, and randomisation was done at the coordinating centre by telephone. Patients and clinicians could not be masked to treatment assignments. However, during the followup period, radiologists and pathologists were masked to the procedural allocation. 2
Doublet*
1 (1%)
3 (2%)
Triplet†
13 (8%)
11 (6%)
149 (88%)
149 (88%)
Postoperative chemotherapy Fluoropyrimidines alone Oxaliplatin-based None
13 (8%)
11 (6%)
8 (5%)
10 (6%)
Data are mean (SD) or n (%). ASA=American Society of Anesthesiologists. *Capecitabine and irinotecan. †Capecitabine, irinotecan, and cetuximab.
Table 1: Baseline characteristics
Procedures Radiotherapy was delivered to the whole pelvis at a dose of 45 Gy in 25 fractions, followed by a boost to the primary tumour of 5·4 Gy in three fractions during 5·5 weeks. One of three chemotherapeutic regimens was used for preoperative chemoradiotherapy: (1) fluoropyrimidines alone (5-fluorouracil and leucovorin or capecitabine or tegafur-uracil [UFT-E]) and leucovorin; (2) doublet (capecitabine and irinotecan); (3) triplet (capecitabine, irinotecan, and cetuximab).10 Open or laparoscopic resection was done 6–8 weeks after completion of preoperative chemoradiotherapy. All patients underwent radical proctectomy, including high ligation of the inferior mesenteric vessels and total mesorectal excision. Laparoscopic surgery was done with five trocars. The rectum was mobilised with monopolar cautery or an ultrasonic scalpel, dissecting between the visceral and parietal pelvic fascia without injuring the hypogastric nerves. All surgeons did both open and laparoscopic
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
Articles
procedures. At each hospital, three pathologists (HJC, GHK, and HSL) who were masked to group allocation, examined the surgical specimen according to standardised protocol.10 Postoperative adjuvant chemotherapy was recommended for all patients, irrespective of the surgical pathology results, in accordance with both the National Comprehensive Cancer Network (NCCN) and Korean NCCN guidelines.11 From week 4 after surgery, one of three adjuvant chemotherapeutic regimens was delivered for 4 months: (1) 5-fluorouracil and leucovorin (four cycles of an intravenous bolus injection of 5-fluorouracil [400 mg/m²/day] and leucovorin [20 mg/m² per day] on days 1–5 every 4 weeks); (2) capecitabine (six cycles of capecitabine [1250 mg/m²] twice daily for 14 days, followed by 7 days rest for each cycle); or (3) FOLFOX (eight cycles of oxaliplatin [85 mg/m²/day] on day 1, 5-fluorouracil intravenous bolus [400 mg/m² per day] on day 1, and continuous infusion of 5-fluorouracil [2400 mg/m²] for 46 h every 2 weeks). Patients were followed-up at 3 months for the first 2 years, at 6 months for the next 3 years, and at 6 months or yearly thereafter. For the postoperative follow-up, a physical examination, complete blood-cell count, liver function tests, serum carcinoembryonic antigen tests, and chest radiography were done every 3 months or 6 months; abdominal and pelvic CT were done every 6 months. Colonoscopic examinations were done 1 year postoperatively and once every 2 years thereafter. When a patient missed two consecutive scheduled visits or voluntarily withdrew consent to participate during the follow-up period, we regarded them as lost to follow-up. Any loss to follow-up was censored. The last follow-up was completed in August, 2012—3 years after the last patient was randomised.
Outcomes The primary outcome was disease-free survival 3 years after surgery, defined as the time of randomisation to disease progression, death from any cause, or development of second primary cancer, and assessed by a central independent reviewer. Secondary outcomes were overall survival, local recurrence, and quality of life. Events that negated disease-free survival were recurrence, death from any cause, or a second primary cancer. Recurrence was diagnosed pathologically by surgical resection, or by biopsy or radiological detection of lesions that increased in size over time. Radiologists and pathologists independently assessed the radiological imaging and pathological specimens. Local recurrence was defined as any recurrence within the pelvic cavity or the perineum. Systemic recurrence was defined as any recurrence outside the pelvic cavity. Overall survival was defined as time from surgery to death from any cause. We used the validated Korean version of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)–C30
Open surgery (n=170)
Laparoscopic surgery (n=170)
p value
Procedures Abdominoperineal resection Low anterior resection
24 (14%)
19 (11%)
146 (86%)
151 (89%)
0·42* ··
Tumour differentiation Well or moderately differentiated
163 (96%)
164 (96%)
Poorly differentiated, signet ring cell, or mucinous
6 (4%)
5 (3%)
1·00† ··
Unknown
1 (1%)
1 (1%)
··
1
35 (21%)
25 (15%)
2
89 (52%)
74 (44%)
··
3
24 (14%)
31 (18%)
··
4
22 (13%)
40 (24%)
··
ypT0/ypTis/ypT1/ypT2
71 (42%)
95 (56%)
ypT3/ypT4
99 (58%)
75 (44%)
ypN0
113 (66%)
135 (79%)
ypN1
43 (25%)
18 (11%)
··
ypN2
14 (8%)
17 (10%)
··
Tumour regression grade scale 0·03*
ypT classification 0·01* ··
ypN classification 0·002*
Circumferential resection margin Positive (≤1 mm)
7 (4%)
5 (3%)
Negative (>1 mm)
163 (96%)
165 (97%)
0·77† ··
Macroscopic quality of specimen from total mesorectal excision Complete or nearly complete
150 (88%)
156 (92%)
Incomplete
11 (6%)
8 (5%)
0·55* ··
Unknown
9 (5%)
6 (4%)
··
Data are n (%). *χ² test. †Fisher’s exact test.
Table 2: Operative and pathological data
3-year survival (95% CI) Disease-free survival Open surgery
72·5% (65·0 to 78·6)
Laparoscopic surgery
79·2% (72·3 to 84·6)
Difference
–6·7% (–15·8 to 2·4)
Overall survival Open surgery
90·4% (84·9 to 94·0)
Laparoscopic surgery
91·7% (86·3 to 95·0)
Difference
–1·3% (–7·4 to 4·8)
Local recurrence Open surgery
4·9% (2·5 to 9·6)
Laparoscopic surgery
2·6% (1·0 to 6·7)
Difference
2·3% (–1·8 to 6·4)
Table 3: 3-year survival
questionnaire (version 3.0)12 and the colorectal cancer module QLQ–CR3813 to assess quality of life preoperatively and at months 3, 12, 24, and 36 after proctectomy or ileostomy takedown—ie, closure (reversal) of ileostomy—in patients who underwent diverting ileostomy.
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
3
A
A
100
100 Disease-free survival (%)
Disease-free survival (%)
Articles
80 60 40 20
Open surgery Laparoscopic surgery
0 0 Number at risk Open surgery 170 Laparoscopic surgery 170
12
24
36
48
60
146 150
131 137
113 129
65 76
29 27
60 40 20
Open surgery Laparoscopic surgery
0 Number at risk Open surgery 62 Laparoscopic surgery 87
59 84
57 81
52 79
32 47
14 13
42 44
40 39
35 34
20 16
9 10
24
36
48
60
13 13
6 4
B
B
100 Disease-free survival (%)
100 Local recurrence (%)
80
80 60 40
80 60 40 20
20 0 0
0 Number at risk Open surgery 170 Laparoscopic surgery 170
12
24
36
48
60
163 165
150 154
136 141
75 84
31 33
C 100 Disease-free survival (%)
C 100 Overall survival (%)
Number at risk Open surgery 51 Laparoscopic surgery 48
80 60 40
80 60 40 20 0
20
0
12
Time since surgery (months)
0 0
12
24
36
48
60
Time since surgery (months) Number at risk Open surgery 170 Laparoscopic surgery 170
167 166
161 160
148 149
89 92
42 40
Figure 2: Kaplan-Meier curves showing disease-free survival (A), local recurrence (B), and overall survival (C)
Statistical analysis We estimated 3-year disease-free survival for open and laparoscopic surgery to be 75% and set the noninferiority margin at 15%; the same margin was used in a previous study.1 Thus, to show non-inferiority, the upper limit of the 95% confidence boundary of the difference (open minus laparoscopic surgery) in 3-year disease-free survival between the two groups could not exceed 15%. With 85% power and a one-sided type 1 error of 2·5%, we needed 340 patients (170 in each group) to allow for 10% follow-up loss. We based all analyses on the intention-to-treat population, which included all randomised patients, and did not plan to undertake interim analyses. 4
Number at risk Open surgery 57 Laparoscopic surgery 35
45 22
34 17
26 16
Figure 3: Kaplan-Meier curves showing disease-free survival according to tumour stage: stage 0/1 (A), stage 2 (B), and stage 3 (C)
We analysed operative and pathological variables with the χ² or Fisher’s exact test, dependent on variable distribution. We used the Kaplan-Meier method to estimate disease-free survival, overall survival, and local recurrence; the log-rank test to compare survival distribution; and univariate and multivariable Cox regression models to estimate the hazard ratios (HRs) of the treatment and covariates. We used multivariable Cox regression analysis to adjust for confounding factors that were significant in univariate analysis and for non-balanced between-group variables, and used stratified Cox regression to estimate the HRs, with incorporation of the stratification factors. We examined the proportionality of the Cox regression models by plotting logs of survival times (–log [survival time]) and analysed QLQ–C30 and QLQ–CR38 scales with
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
Articles
ANCOVA with repeated measures. We considered a ten-point difference in quality-of-life mean score as clinically meaningful.14,15 All p values were two-sided. All analyses were done with STATA (version 12). This study was registered with ClinicalTrials.gov, number NCT00470951.
Univariate analysis Hazard ratio
Multivariable analysis p value
Hazard ratio
Open versus laparoscopic surgery for mid-rectal or low-rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): survival outcomes of an open-label, non-inferiority, randomised controlled trial Seung-Yong Jeong, Ji Won Park, Byung Ho Nam, Sohee Kim, Sung-Bum Kang, Seok-Byung Lim, Hyo Seong Choi, Duck-Woo Kim, Hee Jin Chang, Dae Yong Kim, Kyung Hae Jung, Tae-You Kim, Gyeong Hoon Kang, Eui Kyu Chie, Sun Young Kim, Dae Kyung Sohn, Dae-Hyun Kim, Jae-Sung Kim, Hye Seung Lee, Jee Hyun Kim, Jae Hwan Oh
Summary Background Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. Methods The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT0040951. Findings We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI –15·8 to 2·4; p25
64 (38%)
63 (37%)
ASA grade I
65 (38%)
69 (41%)
II
98 (58%)
96 (56%)
III
7 (4%)
5 (3%)
Preoperative serum concentration of carcinoembryonic antigen (ng/mL) ≤5
154 (91%)
157 (92%)
>5
16 (9%)
13 (8%)
Clinical classification cN0
52 (31%)
59 (35%)
cN+
118 (69%)
111 (65%)
Tumour distance from anal verge (cm) 0–3
46 (27%)
35 (21%)
3–6
59 (35%)
66 (39%)
6–9
65 (38%)
69 (41%)
156 (92%)
156 (92%)
Preoperative chemotherapy Figure 1: Trial profile
Fluoropyrimidines alone
low-rectal cancer who had received preoperative chemoradiotherapy10 and were being treated at any one of three participating Korean hospitals. Patients’ rectal adenocarcinomas had been clinically diagnosed as cT3N0–2M0 lesions on the basis of abdominal and pelvic CT, MRI, and transanal ultrasound. Exclusion criteria were synchronous distant metastases, another primary malignancy, cardiopulmonary dysfunction, active uncontrolled infection, active uncontrolled psychosis, and intestinal perforation or obstruction. The trial was approved by the institutional review board of each participating centre, and all patients provided written informed consent.
Randomisation and masking Patients were randomly allocated to the open or laparoscopic resection group (1:1) via a computergenerated list with a random permuted block design. The random allocation sequence was generated by the Centre for Clinical Trials at the National Cancer Centre Korea. Randomisation was stratified according to sex and preoperative chemotherapy regimen. Local investigators enrolled the patients. Investigators were masked to the randomisation sequence, and randomisation was done at the coordinating centre by telephone. Patients and clinicians could not be masked to treatment assignments. However, during the followup period, radiologists and pathologists were masked to the procedural allocation. 2
Doublet*
1 (1%)
3 (2%)
Triplet†
13 (8%)
11 (6%)
149 (88%)
149 (88%)
Postoperative chemotherapy Fluoropyrimidines alone Oxaliplatin-based None
13 (8%)
11 (6%)
8 (5%)
10 (6%)
Data are mean (SD) or n (%). ASA=American Society of Anesthesiologists. *Capecitabine and irinotecan. †Capecitabine, irinotecan, and cetuximab.
Table 1: Baseline characteristics
Procedures Radiotherapy was delivered to the whole pelvis at a dose of 45 Gy in 25 fractions, followed by a boost to the primary tumour of 5·4 Gy in three fractions during 5·5 weeks. One of three chemotherapeutic regimens was used for preoperative chemoradiotherapy: (1) fluoropyrimidines alone (5-fluorouracil and leucovorin or capecitabine or tegafur-uracil [UFT-E]) and leucovorin; (2) doublet (capecitabine and irinotecan); (3) triplet (capecitabine, irinotecan, and cetuximab).10 Open or laparoscopic resection was done 6–8 weeks after completion of preoperative chemoradiotherapy. All patients underwent radical proctectomy, including high ligation of the inferior mesenteric vessels and total mesorectal excision. Laparoscopic surgery was done with five trocars. The rectum was mobilised with monopolar cautery or an ultrasonic scalpel, dissecting between the visceral and parietal pelvic fascia without injuring the hypogastric nerves. All surgeons did both open and laparoscopic
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
Articles
procedures. At each hospital, three pathologists (HJC, GHK, and HSL) who were masked to group allocation, examined the surgical specimen according to standardised protocol.10 Postoperative adjuvant chemotherapy was recommended for all patients, irrespective of the surgical pathology results, in accordance with both the National Comprehensive Cancer Network (NCCN) and Korean NCCN guidelines.11 From week 4 after surgery, one of three adjuvant chemotherapeutic regimens was delivered for 4 months: (1) 5-fluorouracil and leucovorin (four cycles of an intravenous bolus injection of 5-fluorouracil [400 mg/m²/day] and leucovorin [20 mg/m² per day] on days 1–5 every 4 weeks); (2) capecitabine (six cycles of capecitabine [1250 mg/m²] twice daily for 14 days, followed by 7 days rest for each cycle); or (3) FOLFOX (eight cycles of oxaliplatin [85 mg/m²/day] on day 1, 5-fluorouracil intravenous bolus [400 mg/m² per day] on day 1, and continuous infusion of 5-fluorouracil [2400 mg/m²] for 46 h every 2 weeks). Patients were followed-up at 3 months for the first 2 years, at 6 months for the next 3 years, and at 6 months or yearly thereafter. For the postoperative follow-up, a physical examination, complete blood-cell count, liver function tests, serum carcinoembryonic antigen tests, and chest radiography were done every 3 months or 6 months; abdominal and pelvic CT were done every 6 months. Colonoscopic examinations were done 1 year postoperatively and once every 2 years thereafter. When a patient missed two consecutive scheduled visits or voluntarily withdrew consent to participate during the follow-up period, we regarded them as lost to follow-up. Any loss to follow-up was censored. The last follow-up was completed in August, 2012—3 years after the last patient was randomised.
Outcomes The primary outcome was disease-free survival 3 years after surgery, defined as the time of randomisation to disease progression, death from any cause, or development of second primary cancer, and assessed by a central independent reviewer. Secondary outcomes were overall survival, local recurrence, and quality of life. Events that negated disease-free survival were recurrence, death from any cause, or a second primary cancer. Recurrence was diagnosed pathologically by surgical resection, or by biopsy or radiological detection of lesions that increased in size over time. Radiologists and pathologists independently assessed the radiological imaging and pathological specimens. Local recurrence was defined as any recurrence within the pelvic cavity or the perineum. Systemic recurrence was defined as any recurrence outside the pelvic cavity. Overall survival was defined as time from surgery to death from any cause. We used the validated Korean version of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)–C30
Open surgery (n=170)
Laparoscopic surgery (n=170)
p value
Procedures Abdominoperineal resection Low anterior resection
24 (14%)
19 (11%)
146 (86%)
151 (89%)
0·42* ··
Tumour differentiation Well or moderately differentiated
163 (96%)
164 (96%)
Poorly differentiated, signet ring cell, or mucinous
6 (4%)
5 (3%)
1·00† ··
Unknown
1 (1%)
1 (1%)
··
1
35 (21%)
25 (15%)
2
89 (52%)
74 (44%)
··
3
24 (14%)
31 (18%)
··
4
22 (13%)
40 (24%)
··
ypT0/ypTis/ypT1/ypT2
71 (42%)
95 (56%)
ypT3/ypT4
99 (58%)
75 (44%)
ypN0
113 (66%)
135 (79%)
ypN1
43 (25%)
18 (11%)
··
ypN2
14 (8%)
17 (10%)
··
Tumour regression grade scale 0·03*
ypT classification 0·01* ··
ypN classification 0·002*
Circumferential resection margin Positive (≤1 mm)
7 (4%)
5 (3%)
Negative (>1 mm)
163 (96%)
165 (97%)
0·77† ··
Macroscopic quality of specimen from total mesorectal excision Complete or nearly complete
150 (88%)
156 (92%)
Incomplete
11 (6%)
8 (5%)
0·55* ··
Unknown
9 (5%)
6 (4%)
··
Data are n (%). *χ² test. †Fisher’s exact test.
Table 2: Operative and pathological data
3-year survival (95% CI) Disease-free survival Open surgery
72·5% (65·0 to 78·6)
Laparoscopic surgery
79·2% (72·3 to 84·6)
Difference
–6·7% (–15·8 to 2·4)
Overall survival Open surgery
90·4% (84·9 to 94·0)
Laparoscopic surgery
91·7% (86·3 to 95·0)
Difference
–1·3% (–7·4 to 4·8)
Local recurrence Open surgery
4·9% (2·5 to 9·6)
Laparoscopic surgery
2·6% (1·0 to 6·7)
Difference
2·3% (–1·8 to 6·4)
Table 3: 3-year survival
questionnaire (version 3.0)12 and the colorectal cancer module QLQ–CR3813 to assess quality of life preoperatively and at months 3, 12, 24, and 36 after proctectomy or ileostomy takedown—ie, closure (reversal) of ileostomy—in patients who underwent diverting ileostomy.
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
3
A
A
100
100 Disease-free survival (%)
Disease-free survival (%)
Articles
80 60 40 20
Open surgery Laparoscopic surgery
0 0 Number at risk Open surgery 170 Laparoscopic surgery 170
12
24
36
48
60
146 150
131 137
113 129
65 76
29 27
60 40 20
Open surgery Laparoscopic surgery
0 Number at risk Open surgery 62 Laparoscopic surgery 87
59 84
57 81
52 79
32 47
14 13
42 44
40 39
35 34
20 16
9 10
24
36
48
60
13 13
6 4
B
B
100 Disease-free survival (%)
100 Local recurrence (%)
80
80 60 40
80 60 40 20
20 0 0
0 Number at risk Open surgery 170 Laparoscopic surgery 170
12
24
36
48
60
163 165
150 154
136 141
75 84
31 33
C 100 Disease-free survival (%)
C 100 Overall survival (%)
Number at risk Open surgery 51 Laparoscopic surgery 48
80 60 40
80 60 40 20 0
20
0
12
Time since surgery (months)
0 0
12
24
36
48
60
Time since surgery (months) Number at risk Open surgery 170 Laparoscopic surgery 170
167 166
161 160
148 149
89 92
42 40
Figure 2: Kaplan-Meier curves showing disease-free survival (A), local recurrence (B), and overall survival (C)
Statistical analysis We estimated 3-year disease-free survival for open and laparoscopic surgery to be 75% and set the noninferiority margin at 15%; the same margin was used in a previous study.1 Thus, to show non-inferiority, the upper limit of the 95% confidence boundary of the difference (open minus laparoscopic surgery) in 3-year disease-free survival between the two groups could not exceed 15%. With 85% power and a one-sided type 1 error of 2·5%, we needed 340 patients (170 in each group) to allow for 10% follow-up loss. We based all analyses on the intention-to-treat population, which included all randomised patients, and did not plan to undertake interim analyses. 4
Number at risk Open surgery 57 Laparoscopic surgery 35
45 22
34 17
26 16
Figure 3: Kaplan-Meier curves showing disease-free survival according to tumour stage: stage 0/1 (A), stage 2 (B), and stage 3 (C)
We analysed operative and pathological variables with the χ² or Fisher’s exact test, dependent on variable distribution. We used the Kaplan-Meier method to estimate disease-free survival, overall survival, and local recurrence; the log-rank test to compare survival distribution; and univariate and multivariable Cox regression models to estimate the hazard ratios (HRs) of the treatment and covariates. We used multivariable Cox regression analysis to adjust for confounding factors that were significant in univariate analysis and for non-balanced between-group variables, and used stratified Cox regression to estimate the HRs, with incorporation of the stratification factors. We examined the proportionality of the Cox regression models by plotting logs of survival times (–log [survival time]) and analysed QLQ–C30 and QLQ–CR38 scales with
www.thelancet.com/oncology Published online May 16, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70205-0
Articles
ANCOVA with repeated measures. We considered a ten-point difference in quality-of-life mean score as clinically meaningful.14,15 All p values were two-sided. All analyses were done with STATA (version 12). This study was registered with ClinicalTrials.gov, number NCT00470951.
Univariate analysis Hazard ratio
Multivariable analysis p value
Hazard ratio
