VOLUME

32

䡠

NUMBER

17

䡠

JUNE

10

2014

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Multicenter Randomized Controlled Trial of Conventional Versus Laparoscopic Surgery for Colorectal Cancer Within an Enhanced Recovery Programme: EnROL Robin H. Kennedy, E. Anne Francis, Rose Wharton, Jane M. Blazeby, Philip Quirke, Nicholas P. West, and Susan J. Dutton Robin H. Kennedy, St Mark’s Hospital, Harrow; E. Anne Francis, Rose Wharton, and Susan J. Dutton, University of Oxford, Oxford; Jane M. Blazeby, University of Bristol and University Hospitals Bristol National Health Service Foundation Trust, Bristol; and Philip Quirke and Nicholas P. West, University of Leeds, Leeds, United Kingdom. Published online ahead of print at www.jco.org on May 5, 2014. Supported by Grant No. CRUK/07/019 from the Bobby Moore Fund, Cancer Research United Kingdom; by the National Institute for Health Research through the National Cancer Research Network; and in part by Ethicon Endo-Surgery Europe (R.H.K.), Medical Research Council ConDuCT Hub (J.M.B.), and Yorkshire Cancer Research. Study was reviewed and endorsed by Cancer Research United Kingdom Clinical Trials Awards and Advisory Committee, and thus, it influenced study design. It had no further role in study or in writing of article. Ethicon Endo-Surgery (Europe) had no involvement in study design, trial management, or article writing. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: ISRCTN48516968. Corresponding author: Robin H. Kennedy, MS, St Mark’s Hospital, Watford Rd, Harrow HA1 3UJ United Kingdom; e-mail: robin.kennedy@ nhs.net. © 2014 by American Society of Clinical Oncology 0732-183X/14/3217w-1804w/$20.00 DOI: 10.1200/JCO.2013.54.3694

1804

A

B

S

T

R

A

C

T

Purpose Laparoscopic resection and a multimodal approach known as an enhanced recovery program (ERP) have been major changes in colorectal perioperative care that have improved clinical outcomes for colorectal cancer resection. EnROL (Enhanced Recovery Open Versus Laparoscopic) is a multicenter randomized controlled trial examining whether the benefits of laparoscopy still exist when open surgery is optimized within an ERP. Patients and Methods Adults with colorectal cancer suitable for elective resection were randomly assigned at a ratio of 1:1 to laparoscopic or open surgery within an ERP, stratified by center, cancer site (colon v rectum), and age group (⬍ 66 v 66-75 v ⬎ 75 years) using minimization. The primary outcome was physical fatigue at 1 month postsurgery. Secondary outcomes included hospital stay, complications, other patient-reported outcomes (PROs), and physical function. Patients and outcome assessors were blinded until 7 days postsurgery or discharge if earlier. Central independent and blinded pathologic assessment of surgical quality was undertaken. Results A total of 204 patients (laparoscopy, n ⫽ 103; open surgery, n ⫽ 101) were recruited from 12 UK centers from July 2008 to April 2012. One-month physical fatigue scores were similar in both groups (mean: laparoscopy, 12.28; 95% CI, 11.37 to 13.19 v open surgery, 12.05; 95% CI, 11.14 to 12.96; adjusted mean difference, ⫺0.23; 95% CI, ⫺1.52 to 1.07). Median total hospital stay was significantly shorter after laparoscopic surgery (median: laparoscopy, 5; interquartile range [IQR], 4 to 9 v open surgery, 7; IQR, 5 to 11 days; P ⫽ .033). There were no differences in other secondary outcomes or in specimen quality after central pathologic review. Conclusion In patients treated by experienced surgeons within an ERP, physical fatigue and other PROs were similar in both groups, but laparoscopic surgery significantly reduced length of hospital stay. J Clin Oncol 32:1804-1811. © 2014 by American Society of Clinical Oncology

INTRODUCTION

Laparoscopic colorectal resection has been shown to reduce postoperative pain and complications when compared with traditional open surgery.1,2 As a result, mobilization and recovery after surgery improve, and length of hospital stay is reduced. In addition, there may be reductions in late complications, such as adhesional obstruction and incisional hernia.2,3 Over the past few decades, there have been major changes in perioperative care pioneered by Kehlet that have resulted in reduced length of hospital stay to, on average, 3 days after colonic resection.3,4 This approach, known as fast-track surgery or enhanced recovery care, is based on a multimodal

program aimed at improving all facets of perioperative care. Subsequent single-center randomized trials have confirmed that the use of an enhanced recovery program (ERP) also reduces postoperative complications.4,5 Debate exists regarding whether the application of an ERP to open surgery will improve outcomes to the extent that they can match those achieved after laparoscopic resection within an ERP. This is important because despite the uptake of minimal access techniques, it has not become universal, and many established specialist surgeons continue to perform open surgery with excellent outcomes. It is possible that the application of an ERP to wellperformed open surgery may optimize outcomes

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EnROL: RCT of Open and Laparoscopic Surgery for CRC Within an ERP

sufficiently to achieve recovery that is similar to or better than that associated with laparoscopic techniques. Two small single-center randomized studies have examined these issues, comparing outcomes after laparoscopic or open colorectal resection within an ERP.6,7 The UK study6 showed a 2- to 3-day reduction in length of hospital stay for laparoscopic surgery, whereas the Danish study8 reported no difference in length of hospital stay between open and laparoscopic surgeries, with patients and carers blinded to intervention. Recently, a multicenter study (LAFA [Laparoscopy and/or Fast Track] trial) compared the two interventions,9 but patients and carers were not effectively blinded, and there were a number of exclusions, including rectal cancer resection. The EnROL (Enhanced Recovery Open Versus Laparoscopic) trial was designed to examine the postoperative outcomes between laparoscopic surgery and conventional open resection of colorectal cancer within the same ERP. PATIENTS AND METHODS Trial Design and Participants The EnROL trial was a phase III, multicenter, randomized trial of open versus laparoscopic surgery for colorectal cancer within an ERP. Details of the trial design and study procedures have been reported.10 Eligible patients were adults (age ⱖ 18 years) suitable for elective resection of their colorectal cancer (any stage) using either technique. Excluded patients were those with acute intestinal obstruction, those unsuitable for epidural insertion, and those in whom conversion from a laparoscopic to an open procedure was likely. The study was approved by National Research Ethics Service Committee South Central–Oxford B (Reference No. 07/H0605/150), and centers obtained local research and development approval before starting recruitment. An independent data safety monitoring committee reviewed accumulating safety data throughout the trial. Randomization and Blinding Patients recruited from 12 UK hospitals ranging from specialist centers to district general hospitals were randomly assigned at a ratio of 1:1 to open or

laparoscopic surgery with recovery optimized within an ERP, using minimization via a central Web-based electronic system with stratification for hospital, disease site (colon v rectum), and age (⬍ 66 v 66-75 v ⬎ 75 years), seeded by a simple randomization of the first 30 patients. Patients and outcome observers were blinded to type of surgery for 7 days postsurgery or until discharge if earlier. Blinding was facilitated by the provision of large opaque Allevyn adhesive dressings, which were changed by staff not directly involved in patient care, and by blinding envelopes, in which records detailing the surgical procedure were stored during the blinding period. Procedures The accredited trial surgeons performed surgery within 6 weeks of randomization. Surgeons were required to have previously performed ⬎ 100 laparoscopic colorectal resections (median, 248; range, 105 to 800) and ⬎ 50 open total mesorectal excisions (median, 162; range, 47 to 300) to minimize conversion. Conversion was defined as the inability to complete the dissection fully laparoscopically, including the vascular division, and it usually but not always required the use of a larger incision than that needed to remove the specimen. A standardized ERP comprising 30 possible interventions was provided to all sites, as described previously.10 Centers were able to adapt the ERP locally, provided it was identical for patients in each arm of the trial. Following guidelines according to the Northern European Enhanced Recovery After Surgery Group,11,12 compliance with 20 of the components was recorded for all patients. The primary outcome was a patient-reported outcome (PRO) measure of physical fatigue, as measured by the physical fatigue domain of the Multidimensional Fatigue Inventory 20 (MFI-20).13 The secondary outcomes included postoperative hospital stay; complications; second surgery and readmission rates; other measures within the MFI-20, Short Form 36 (SF-36), and Body Image Scale (BIS) tools; standardized performance indicators (SPIs) testing balance, walking, and lower limb strength; and health economic analysis. Central, independent, blinded pathologic assessment of surgical quality was undertaken. Blood and urine samples were collected from consenting patients for a translational substudy. Statistical Methods The study was designed to recruit 266 patients (133 per arm) to detect a difference of 0.45 standard deviation in the physical domain of MFI-20 with 90% power and 5% two-sided significance, allowing for 15% loss to follow-up

Assessed for eligibility (N = 849) Excluded Did not meet inclusion criteria Declined to participate Other reasons

(n = 645) (n = 374) (n = 271) (n = 0)

Randomly allocated (n= 204) Fig 1. CONSORT diagram. ITT, intention to treat. Allocated to open surgery (n = 101) Received allocated intervention (n = 101) Did not receive allocated intervention (n = 0)

Allocated to laparoscopic surgery (n = 103) Received allocated intervention (n = 101) Did not receive allocated intervention (n = 2)

ITT fatigue analysis Excluded from analysis Withdrew after surgery Missing baseline or 1-month form Hospital stay analyzed Excluded from analysis Withdrew after surgery

ITT fatigue analysis Excluded from analysis Missing baseline or 1-month form Hospital stay analyzed Excluded from analysis Withdrew before surgery

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(n = 89) (n = 12) (n = 2) (n = 10) (n = 99) (n = 2) (n = 2)

(n = 88) (n = 13) (n = 13) (n = 101) (n = 2) (n = 2)

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Kennedy et al

and 8% conversion rate from laparoscopic to open surgery. The study was also powered to detect a difference in length of hospital stay with 90% power. After slower than expected recruitment, the power was reduced to 80% (as frequently used in phase III trials), requiring a sample size of 202 patients (101 per arm) for both outcomes. The primary outcome of MFI-20 physical fatigue and secondary outcomes, including the other MFI-20 scales, SF-36 mental and physical scales, SPIs, and BIS, were analyzed using two-way analysis of covariance (ANCOVA) at 1 month (primary time point) and repeated-measures ANCOVA (taking into account all time points) adjusting for baseline values, cancer site, and age if the normality assumptions held and using the Mann-Whitney nonparametric test without adjustment if the data could not be transformed to normality. Length of hospital stay was analyzed using the Breslow weighted log-rank test,14 which is a generalization of the Kruskall-Wallis test. Length of primary hospital stay was analyzed as time from the date of surgery until discharge. This analysis was repeated for total length of hospital stay, which included the primary hospital stay and the additional number of days spent in hospital if readmitted within 30 days postoperatively. Patients who died while in hospital were censored at their date of death. Comparisons of surgical, cardiorespiratory, and infectious complications; readmissions; and second surgeries were made between treatment groups by tabulations and ␹2 tests. The severity of complications was retrospectively subdivided using the Clavien-Dindo classification by two assessors (R.H.K., J.M.B.) blinded to treatment allocation, with discrepancies resolved by consensus.15 Analysis was by intention to treat (ITT) for all outcomes, with a sensitivity analysis undertaken for physical fatigue and length of hospital stay using the predefined per-protocol (PP) population. A prespecified analysis of patients with colon or rectal cancer was also undertaken via the same analyses, using actual disease site where this differed from that identified at random assignment. All analyses were performed using STATA (version 12.0; STATA, College Station, TX).

RESULTS

A total of 204 patients were randomly assigned between July 2008 and April 2012, 103 to laparoscopic surgery and 101 to open surgery (Fig 1), with 92% patients recruited by six of 12 UK centers. Patients were observed for up to 12 months postoperatively. Overall blinding was maintained until 7 days postsurgery, or discharge if earlier, for 90% of patients (laparoscopy, 88.1%; open surgery, 91.9%). Treatment allocation was correctly predicted by 52% of patients and 59% of staff. Four patients withdrew consent: two before surgery and two after surgery but before collection of postoperative data. Only patients who completed both baseline and 1-month postoperative questionnaires were included in the ITT analysis. The PP analysis excluded six protocol violators: four benign diagnoses and two patients who did not undergo resection at surgery. In addition, in the PP analysis for the primary outcome only, the six patients (5.9%) converted from laparoscopic to open surgery were analyzed within the open group, and eight patients with an incorrectly classified disease site at random assignment were analyzed within the correct subgroup. The two groups were similar with regard to demographic and clinical data at baseline (Table 1), operative data (Table 2), and compliance within the ERP (Appendix Table A1, online only). Median number of ERP interventions in the laparoscopic and open groups was identical at 10 (interquartile range [IQR], 8 to 13). The ITT analysis of MFI-20 physical fatigue included 177 patients (87.6%; laparoscopy, n ⫽ 88 [87.1%]; open surgery, n ⫽ 89 [88.1%]) who completed baseline and 1-month MFI-20 questionnaires. There was no difference between MFI-20 physical fatigue at 1 month between the treatment arms (adjusted mean difference, ⫺0.23; 95% CI, ⫺1.52 to 1.07; laparoscopy, 12.28; 95% CI, 11.37 to 13.19; open 1806

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Table 1. Baseline Patient Demographic and Clinical Characteristics Laparoscopy (n ⫽ 103) Characteristic Site of cancerⴱ Colon Rectum Age group, yearsⴱ ⬍ 66 66-75 ⬎ 75 Mean SD Sex Male Female BMI Underweight Normal Overweight Obese ASA grade I II III IV Relevant previous abdominal surgery Preoperative radiotherapy Blood transfusion within 7 days presurgery Metastatic disease Liver Omentum Liver and lungs Previous malignancy

Open Surgery (n ⫽ 101)

No.

%

No.

%

75 28

72.8 27.2

75 26

74.3 25.7

30 42 31

29.1 40.8 30.1 69.3 9.4

27 44 30

26.7 43.6 29.7 70.1 8.7

56 47

54.4 45.6

70 31

69.3 30.7

1 27 40 34

1.0 26.5 39.2 33.3

3 24 45 29

3.0 23.8 44.5 28.7

12 60 28 1 30 14 4 8 6 1 1 4

11.9 59.4 27.7 1.0 29.1 13.6 3.9 7.8

12 66 23 0 23 10 0 2 2 0 0 0

11.9 65.3 22.8 0.0 22.8 9.9 0.0 2.0

3.9

0.0

Abbreviations: ASA, American Society of Anesthesiologists; BMI, body-mass index; SD, standard deviation. ⴱ Stratification variables.

surgery, 12.05; 95% CI, 11.14 to 12.96; Table 3). The PP analysis confirmed the ITT results (adjusted mean difference, 0.26; 95% CI, ⫺1.05 to 1.56; P ⫽ .70). There were also no differences in physical fatigue between treatment arms for the prespecified subgroup analysis by disease site (adjusted mean difference: colon, ⫺0.70; 95% CI, ⫺2.28 to 0.88; rectum, 1.00; 95% CI, ⫺1.42 to 3.42). The ITT analysis of length of hospital stay included 200 patients (laparoscopy, n ⫽ 101; open surgery, n ⫽ 99). There was a statistically significant difference in length of primary hospital stay between the two treatment arms (median: laparoscopy, 5; IQR, 4 to 6; open surgery, 6; IQR, 4 to 9 days; P ⫽ .011) as well as in total length of hospital stay (includes readmission up to 30 days postsurgery; median: laparoscopy, 5; IQR, 4 to 9; open surgery, 7; IQR, 5 to 11 days; P ⫽ .033). There was also a statistically significant difference in length of primary hospital stay for the prespecified subgroup rectal cancer (median: laparoscopy, 5; IQR, 4 to 6.5; open surgery, 6; IQR, 5 to 10 days; P ⫽ .024), although not for the colon subgroup (median: laparoscopy, 5; IQR, 3 to 7; open surgery, 6; IQR, 4 to 9 days; P ⫽ .08). There were no significant differences between treatment arms for the remaining MFI-20 scales, SF-36 scale (Table 3), SPIs, or BIS. The JOURNAL OF CLINICAL ONCOLOGY

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EnROL: RCT of Open and Laparoscopic Surgery for CRC Within an ERP

Table 2. Operative Data Patients With Colon Cancerⴱ Laparoscopy (n ⫽ 71) Variable Operative procedure‡ Right colonic resection Left colonic resection Other (colon) Anterior resection (PME/TME) APR Other (rectum) Length of incision, cm Mean SD Duration of surgery, minutes Mean SD Blood loss, mL Mean SD Stoma created at surgery Surgery performed by trainee POSSUM total score Mean SD

Patients With Rectal Cancerⴱ

Open Surgery (n ⫽ 74)

No.

%

No.

%

40 30 1

56.3 42.3 1.4

38 35 1

51.4 47.3 1.3

Laparoscopy (n ⫽ 29)

All Patients†

Open Surgery (n ⫽ 27)

No.

%

No.

%

22 5 2

76.9 17.2 6.9

20 6 1

74.1 22.2 3.7

Laparoscopy (n ⫽ 100) No.

%

Open Surgery (n ⫽ 101) No.

%

6.6 3.2

17.2 7.3

7.6 5.0

21.7 7.4

6.8 3.7

18.4 7.5

167 64

118 44

220 67

186 48

182 69

135 54

90 148

186 198

181 146

450 397

115 152

257 290

4 22

5.6 31.0

3 28

30.2 6.9

4.1 38.4

22 2

30.2 5.1

75.9 6.9

19 9

33.7 4.4

70.4 33.3

22 24

36.0 6.0

22.0 24.0

26 37

31.2 6.0

25.7 37.0 31.8 6.0

Abbreviations: APR, abdominoperineal resection; PME, partial mesorectal excision; POSSUM, physiologic and operative severity score for the enumeration for mortality and morbidity; SD, standard deviation; TME, total mesorectal excision. ⴱ Subgroup analysis for actual disease site rather than disease site at random assignment. †Intention-to-treat patient groups. ‡Patients undergoing extended right hemicolectomy and transverse colectomy included in right colonic resection group.

number of surgical, cardiorespiratory, and infectious complications was similar for the two groups (Table 4). Within 30 days postsurgery, there were no significant differences between treatment arms, with 33.7% of patients experiencing ⱖ one postoperative complication

(laparoscopy, 32 of 101 [31.7%]; open surgery, 36 of 101 [35.6%]; P ⫽ .55), 11.9% being readmitted (laparoscopy, 14 of 101 [13.9%]; open surgery, 10 of 101 [9.9%]; P ⫽ .38), and 8.4% undergoing second surgery (laparoscopy, 11 of 101 [10.9%]; open surgery, 6 of 101

Table 3. Results for Patient-Reported Outcomes Laparoscopy

Open Surgery

Difference

Scale/Subscale

Adjusted Mean

95% CI

Adjusted Mean

95% CI

Adjusted Mean

95% CI

P

MFI-20 physical fatigueⴱ† General fatigue‡ Activity‡ Motivation‡ Mental fatigue‡ SF-36 physical health‡ Physical functioning‡ Role—physical‡ Bodily pain‡ General health‡ SF-36 mental health‡ Vitality‡ Social functioning‡ Role—emotional‡ Mental health‡

12.2 11.7 12.8 9.5 7.6 57.8 58.6 40.8 66.0 64.3 62.8 47.5 61.3 67.2 74.0

11.3 to 13.1 10.9 to 12.6 11.9 to 13.8 8.7 to 10.4 6.8 to 8.4 54.0 to 61.7 53.7 to 63.5 35.1 to 46.6 61.0 to 70.9 60.7 to 67.9 58.9 to 66.8 43.0 to 52.0 54.9 to 67.6 60.8 to 73.7 70.3 to 77.7

12.1 11.5 12.5 9.3 7.4 55.9 58.2 41.5 62.0 62.5 60.1 44.4 57.9 65.6 72.6

11.2 to 13.1 10.6 to 12.3 11.6 to 13.5 8.5 to 10.1 6.6 to 8.2 52.1 to 59.7 53.4 to 63.0 35.9 to 47.2 57.0 to 66.9 58.9 to 66.0 56.1 to 64.0 39.9 to 49.0 51.6 to 64.2 59.2 to 72.0 68.9 to 76.3

⫺0.06 ⫺0.28 ⫺0.26 ⫺0.24 ⫺0.17 ⫺1.94 ⫺0.41 0.72 ⫺4.01 ⫺1.87 ⫺2.76 ⫺3.07 ⫺3.34 ⫺1.66 ⫺1.40

⫺1.37 to 1.25 ⫺1.52 to 0.95 ⫺1.63 to 1.10 ⫺1.44 to 0.96 ⫺1.29 to 0.95 ⫺7.36 to 3.49 ⫺7.32 to 6.50 ⫺7.40 to 8.84 ⫺11.07 to 3.05 ⫺6.97 to 3.23 ⫺8.41 to 2.88 ⫺9.54 to 3.40 ⫺12.32 to 5.63 ⫺10.81 to 7.49 ⫺6.67 to 3.86

.93 .65 .71 .70 .76 .48 .91 .86 .26 .47 .33 .35 .46 .72 .60

Abbreviations: ANCOVA, two-way analysis of variance; MFI, Multidimensional Fatigue Inventory; SF, Short Form. ⴱ Primary outcome. †ANCOVA adjusted for baseline physical fatigue, cancer site, age, stoma, and metastasis. ‡ANCOVA adjusted for baseline physical fatigue, cancer site, and age.

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Table 4. Morbidity and Mortality Complication, Readmission, or Second Surgery Complication occurring at surgeryⴱ Pulmonary insufficiency Cardiac insufficiency Intraoperative hemorrhage (⬎ 500 mL) Bladder injury Bowel injury Minor postoperative complicationⴱ Wound infection Urinary tract infection Chest infection Other infection Paralytic ileus (IV fluids ⬎ 7 days) Major postoperative complicationⴱ Respiratory failure requiring ventilation Renal failure requiring dialysis Cardiac failure, myocardial infarction Anastomotic leakage requiring surgery or at autopsy Anastomotic leakage requiring drainage Bowel obstruction requiring second surgery Abdominal wall dehiscence requiring surgery ⱖ One readmission within 30 days† ⱖ One second surgery within 30 days† In-hospital or 30-day mortality†

Laparoscopy (n ⫽ 103)

Open Surgery (n ⫽ 101)

Overall (N ⫽ 204)

5 1 1

7 1 0

12 2 1

2 0 1

2 1 3

4 1 4

25 11 5 2 5

32 8 4 4 9

57 19 9 6 14

2

7

9

17

15

32

3

2

5

2

0

2

2

1

3

2

4

6

3

4

7

3

2

5

2

2

4

14

10

24

11

6

17

1

1

2

Abbreviation: IV, intravenous. ⴱ No. of complications; patients may have experienced ⬎ one. †No. of patients; some readmissions may have been second surgeries.

[5.9%]; P ⫽ .21). There were also no significant differences between patient outcome when complications were categorized into none, minor (Clavien-Dindo classification, I to II), or major (ClavienDindo classification, III to V; laparoscopy, 63.1%; 95% CI, 26.2% to 10.7%; open surgery, 62.4%; 95% CI, 26.7% to 10.9%; P ⫽ .96). The independent pathologic assessment of specimens showed that quality of surgery did not differ significantly between laparoscopic and open resection (Tables 5 and 6). DISCUSSION

The EnROL trial has demonstrated in a multicenter setting that laparoscopic surgery reduces recovery time as measured by length of hospital stay, even when conventional open surgery is optimized within an ERP. Despite the reduction in length of hospital stay associated with laparoscopy, no significant benefit was identified in the primary PRO (physical fatigue at 1 month), other secondary clinical 1808

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outcomes, or other PROs. There was no difference in specimen quality between laparoscopic and open surgery when specimens were analyzed by blinded independent pathologists. Therefore, we conclude that laparoscopic surgery within an ERP is recommended because of the benefits in secondary outcomes associated with shorter hospital stay. The decreased inpatient duration observed in this study was expected to be associated with benefits in secondary outcome measures, because others have reported reduction in pain, ileus, and other complications, leading to earlier mobilization, feeding, and recovery.1 Although no reduction in complications was observed in our analysis, accurate measurement of this can be difficult. A logistic regression analysis of complications in the LAFA trial showed laparoscopic surgery significantly lowered overall and major complications, but the study included twice the number of patients.9 The lack of benefit from laparoscopy as measured by the PROs MFI-20 and SF-36 may reflect their lack of sensitivity when assessing postoperative recovery, or it may be that the two interventions within an ERP led to similar recovery. Only early PRO benefits were identified after laparoscopic colonic cancer resection within the North American COST (Comparison of Laparoscopically Assisted and Open Colectomy for Colon Cancer) trial,17 but benefits were identified at 3 months within the COREAN (Comparison of Open Versus Laparoscopic Surgery for Mid and Low Rectal Cancer After Neoadjuvant Chemoradiotherapy) laparoscopic low rectal resection study.18 Both studies included larger numbers but not enhanced recovery care. Care should be taken when choosing the primary and secondary outcomes in future studies of this type, and consideration should be given to the use of a dual primary end point combining length of hospital stay and early measure of PROs. Our trial ensured that patient care was optimized after both laparoscopic and open resection, because enhanced recovery care was well developed at each center. Twenty of the 30 possible enhanced recovery care interventions were recorded for each patient to allow assessment of quality and comparison between groups and with other studies. There was no difference in the quality of enhanced recovery care between groups, with a median score of 10 ERP interventions in each group. It would have been preferable for epidurals to have been used in all patients undergoing resection, but that was not current practice in all centers. The selective use of epidurals in open surgery would have prevented blinding of the surgical allocation, one of the strengths of this study, and adherence to local practice was agreed to ensure consistency in each arm of the trial. There have been only three other randomized studies in which patients were optimized within an ERP. Two of these were small single-center studies6,8 with conflicting outcomes, and one was a multicenter study with a similar number of patients optimized within an ERP (LAFA trial).9 The latter reported almost identical outcomes, with a 2-day reduction in total length of hospital stay, but the patients were not effectively blinded, and they did not all have malignancies. In addition, the surgeons were not all experienced in laparoscopic colorectal surgery, and there were significant exclusions: metastatic disease, prior midline incision, planned stoma, rectal cancer, and age ⬎ 80 years. The EnROL trial not only involved experienced surgeons but also included a wider range of patients and thus is more representative of the colorectal cancer practice. None of the previous studies examined the quality of oncologic resection. The lack of difference in specimen quality is a reliable marker for cancer outcome,19 but longerterm follow-up data will be pursued. JOURNAL OF CLINICAL ONCOLOGY

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EnROL: RCT of Open and Laparoscopic Surgery for CRC Within an ERP

Table 5. Pathology Data All Patientsⴱ Laparoscopy (n ⫽ 99) Variable pT stage No tumor‡ 1 2 3 4 pN stage 0 1 2 M stage 0 1 X R stage§ R0 R1 (ⱕ 1 mm) V stage V0 V1 Distance to nearest longitudinal margin, mm Mean SD No. of lymph nodes Mean SD No. of positive lymph nodes Mean SD Dukes’ stage A B C No tumor Differentiation Well or moderate Poor Maximum tumor diameter, mm Mean SD Maximum spread beyond muscularis propria, mm Mean SD Distance from tumor to high tie, mm Mean SD Retroperitoneal resection margin involvement No (colon) Yes Tumor relationship to peritoneal reflection Above At Below Shortest distance between tumor and CRM, mm Median IQR

Patients With Colon Cancer†

Open Surgery (n ⫽ 99)

Laparoscopy (n ⫽ 70)

Open Surgery (n ⫽ 72)

Patients With Rectal Cancer† Laparoscopy (n ⫽ 29)

Open Surgery (n ⫽ 27)

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

2 14 17 54 12

2.0 14.1 17.2 54.5 12.1

4 12 18 47 18

4.0 12.1 18.2 47.5 18.2

1 11 9 39 10

1.4 15.9 13.0 56.5 14.5

3 7 11 35 16

4.3 10.1 15.9 50.7 23.2

1 3 8 15 2

3.6 10.7 29.6 53.6 7.1

1 5 7 12 2

3.8 19.2 26.9 46.2 7.7

69 20 9

70.4 20.4 9.2

57 23 17

58.8 23.7 17.5

47 16 6

68.1 23.2 8.7

39 17 14

55.7 24.3 20.0

22 4 3

75.9 13.8 10.3

18 6 3

66.7 22.2 11.1

8 1 89

8.2 1.0 90.8

4 0 91

4.2 0.0 95.8

7 1 61

10.1 1.5 88.4

2 0 66

2.9 0.0 97.1

1 0 28

3.5 0.0 96.5

2 0 25

7.4 0.0 92.6

94 3

96.9 3.1

91 6

93.8 6.2

67 2

97.1 2.9

68 2

97.1 2.9

27 1

96.4 3.6

23 4

85.2 14.8

63 34

64.9 35.1

61 37

62.2 37.8

43 26

62.3 37.7

40 31

56.3 43.7

20 8

71.4 28.6

21 6

77.8 22.2

62.7 50.5

63.8 61.3

75.5 54.2

76.7 66.1

32.1 17.9

28.3 18.9

21.2 10.3

19.6 8.7

22.2 10.4

20.4 9.2

18.8 9.7

17.3 6.8

1.2 2.8

1.7 3.2

1.4 3.0

1.9 3.2

0.9 2.2

1.4 3.1

26 44 27 2

26.3 44.4 27.3 2.0

26 29 40 4

26.2 29.3 40.4 4.0

16 32 21 1

22.9 45.7 30.0 1.4

15 23 31 3

20.8 31.9 43.0 4.2

10 12 6 0

34.5 41.4 20.7 0.0

11 6 9 2

40.7 22.2 33.3 7.4

85 10

89.5 10.5

89 4

95.7 4.3

60 8

88.2 11.8

65 3

95.6 4.4

25 2

92.6 7.4

24 1

96.0 4.0

39.9 23.3

37.5 20.6

41.6 24.7

39.8 20.6

35.8 19.5

31.3 19.6

5.3 4.4

6.4 13.4

5.9 4.7

7.5 15.4

3.4 2.5

3.3 2.5

105.1 49.4

103.9 58.2

97.4 37.1

95.5 58.3

124.0 68.8

125.0 53.6

42 1

97.7 2.3

38 2

95.0 5.0 6 5 12

25.0 20.8 52.2

10.5 5.5-16.5

6 3 14

26.1 13.0 60.9

6 0.3-10.0

Abbreviations: CRM, circumferential resection margin; IQR, interquartile range; SD, standard deviation. ⴱ Intention-to-treat patient groups. †Subgroup analysis is for actual disease site rather than disease site at random assignment. ‡Four patients were found to have benign disease, and two patients had received prior long-course chemoradiotherapy, and so could not be classified. §Margin involvement (R1) defined as tumor ⱕ 1 mm of resection margin.

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Table 6. Specimen Quality Mesorectum (all colons) Laparoscopy

Levator/Sphincter (APE only)

Open Surgery

Laparoscopy

Mesorectum (all rectums)

Open Surgery

Laparoscopy

Open Surgery

Quality

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

Good Intermediate Poor Unknown

32 27 0 13

44.4 37.5 0.0 18.1

36 23 1 14

48.6 31.1 1.4 18.9

1 2 1

25.0 50.0 25.0

3 2 1

50.0 33.3 16.7

11 9 1 4

44.0 36.0 4.0 16.0

11 5 0 5

52.4 23.8 0.0 23.8

NOTE. Regarding specimen quality, good corresponds to dissection within mesocolic, mesorectal, or levator plane; intermediate to dissection within intramesocolic, intramesorectal, or sphincteric plane; and poor to dissection adjacent to or within muscularis propria or within anal sphincter.16 Abbreviation: APE, abdominoperineal excision.

The recently published results of the COLOR II (Colorectal Cancer Laparoscopic or Open Resection) study20 described outcomes after random assignment between laparoscopic and open resection of rectal cancer, within 30 largely European centers. Postoperative stay was significantly reduced from 9 days after open surgery to 8 after laparoscopic surgery—identical figures to the COREAN study.18 These hospital stays were 3 days longer than in the EnROL trial and may reflect the lack of a standardized ERP. Median lengths of postoperative hospital stay after elective colon and rectal cancer resection in England during 2011 were 7 and 9 days, respectively,12 1 to 3 days longer than that with open surgery in the EnROL trial. This may reflect the quality of the surgery or perioperative care in this study. Recruitment to randomized trials of minimal access and open surgery is becoming difficult, because of surgeon and patient preferences. In this study, an extension was required, and approximately 32% of patients approached declined to enter, the majority preferring to opt for laparoscopic surgery. Although this is understandable, without well-designed and well-conducted randomized controlled trials, it is difficult to influence health policy or end outdated practice. To minimize the chance of conversion, patients were excluded if on preoperative imaging the excision margin was threatened, making conversion likely—mainly affecting patients with rectal cancer. This is estimated to occur in ⬍ 10% of potential patients in elective UK practice, depending on the laparoscopic expertise of the surgeon.21 Participating surgeons were all experienced in both open and laparoscopic colorectal resections, resulting in low conversion rates and providing the opportunity to assess the maximal benefit from the intervention. In previous multicenter randomized trials, conversion rates have been between 11% and 29%.5,9,17,20,22-25 The exception was the 1% conversion rate in the COREAN study18 of low rectal cancer resection, which involved expert surgeons in only three centers. The challenge that exists will be to reproduce the results of the EnROL trial in widespread surgical practice. This would be facilitated by the introduction of national programs to train established specialists in laparoscopic colorectal resection and enhanced recovery care, as happened in England from 2008 and 2009, respectively.16,20 REFERENCES 1. Abraham NS, Young JM, Solomon MJ: Metaanalysis of short-term outcomes after laparoscopic resection for colorectal cancer. Br J Surg 91:1111-1124, 2004 1810

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In conclusion, this trial has demonstrated that within an ERP, there are no observed differences in prespecified PROs aimed to assess recovery between open and laparoscopic surgeries, but there was an observed benefit in reduced length of hospital stay, a secondary outcome, in the laparoscopic group. This emphasizes the general benefits of enhanced recovery care combined with expert surgery, whether it is laparoscopic or open in approach. Further study is needed to clarify whether the inability to demonstrate a difference in other outcomes was because of a lack of power or because the two interventions within an ERP led to similar short-term recovery. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Robin H. Kennedy, Ethicon Endo-Surgery, Olympus UK; Philip Quirke, Medical Research Council UK Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Robin H. Kennedy, Jane M. Blazeby, Philip Quirke, Susan J. Dutton Collection and assembly of data: Robin H. Kennedy, E. Anne Francis, Rose Wharton, Nicholas P. West, Susan J. Dutton Data analysis and interpretation: Robin H. Kennedy, Rose Wharton, Jane M. Blazeby, Philip Quirke, Susan J. Dutton Manuscript writing: All authors Final approval of manuscript: All authors

2. Bartels S, Vlug M, Hollmann M, et al: Incisional hernia and adhesion-related complications: Long term follow-up of a randomized trial comparing laparoscopic with open colonic resection within a fast track program [the LAparoscopy and/or FAst track multimodal management versus standard care

study (LAFA)]. Presented at the Seventh Scientific and Annual Meeting of the European Society of Coloproctology, Vienna, Austria, September 26-28, 2012 3. Ng SS, Leung KL, Lee JF, et al: Long-term morbidity and oncologic outcomes of laparoscopicassisted anterior resection for upper rectal cancer: JOURNAL OF CLINICAL ONCOLOGY

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EnROL: RCT of Open and Laparoscopic Surgery for CRC Within an ERP

Ten-year results of a prospective, randomized trial. Dis Colon Rectum 52:558-566, 2009 4. Varadhan KK, Lobo DN, Ljungqvist O: Enhanced recovery after surgery: The future of improving surgical care. Crit Care Clin 26:527-547, x, 2010 5. Lacy AM, Garcı´a-Valdecasas JC, Delgado S, et al: Laparoscopy-assisted colectomy versus open colectomy for treatment of non-metastatic colon cancer: A randomised trial. Lancet 359:2224-2229, 2002 6. King PM, Blazeby JM, Ewings P, et al: Randomized clinical trial comparing laparoscopic and open surgery for colorectal cancer within an enhanced recovery programme. Br J Surg 93:300-308, 2006 7. Basse L, Jakobsen DH, Bardram L, et al: Functional recovery after open versus laparoscopic colonic resection: A randomized, blinded study. Ann Surg 241:416-423, 2005 8. Basse L, Hjort Jakobsen D, Billesbølle P, et al: A clinical pathway to accelerate recovery after colonic resection. Ann Surg 232:51-57, 2000 9. Vlug MS, Wind J, Hollmann MW, et al: Laparoscopy in combination with fast track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: A randomized clinical trial (LAFA-study). Ann Surg 254:868-875, 2011 10. Kennedy RH, Francis A, Dutton S, et al: EnROL: A multicentre randomised trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme. BMC Cancer 12:181, 2012

11. Enhanced Recovery After Surgery Society. www.erassociety.org 12. UK Department of Health: Enhanced Recovery Partnership Programme: Report—March 2011. https:// www.gov.uk/government/publications/enhancedrecovery-partnership-programme 13. Smets EM, Garssen B, Cull A, et al: Application of the multidimensional fatigue inventory (MFI20) in cancer patients receiving radiotherapy. Br J Cancer 73:241-245, 1996 14. Machin D, Cheung YB, Parmar MKB: Survival Analysis: A Practical Approach. Hoboken, NJ, John Wiley and Sons, 2006 15. Dindo D, Demartines N, Clavien PA: Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205-213, 2004 16. Coleman MG, Hanna GB, Kennedy R, et al: The National Training Programme for Laparoscopic Colorectal Surgery in England: A new training paradigm. Colorectal Dis 13:614-616, 2011 17. Laparoscopically assisted colectomy is as safe and effective as open colectomy in people with colon cancer: Abstracted from: Nelson H, Sargent D, Wieand HS, et al for the Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 2004;350: 2050-2059. Cancer Treat Rev 30:707-709, 2004 18. Kang SB, Park JW, Jeong SY, et al: Open versus laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy (COREAN trial): Short-

term outcomes of an open-label randomised controlled trial. Lancet Oncol 11:637-645, 2010 19. West NP, Morris EJ, Rotimi O, et al: Pathology grading of colon cancer surgical resection and its association with survival: A retrospective observational study. Lancet Oncol 9:857-865, 2008 20. van der Pas MH, Haglind E, Cuesta MA, et al: Laparoscopic versus open surgery for rectal cancer (COLOR II): Short-term outcomes of a randomised, phase 3 trial. Lancet Oncol 14:210-218, 2013 21. Buchanan GN, Malik A, Parvaiz A, et al: Laparoscopic resection for colorectal cancer. Br J Surg 95:893-902, 2008 22. Leung KL, Kwok SP, Lam SC, et al: Laparoscopic resection of rectosigmoid carcinoma: Prospective randomised trial. Lancet 363:1187-1192, 2004 23. Guillou PJ, Quirke P, Thorpe H, et al: Shortterm endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): Multicentre, randomised controlled trial. Lancet 365:17181726, 2005 24. Veldkamp R, Gholghesaei M, Bonjer HJ, et al: Laparoscopic resection of colon Cancer: Consensus of the European Association of Endoscopic Surgery (EAES). Surg Endosc 18:1163-1185, 2004 25. Hewett PJ, Allardyce RA, Bagshaw PF, et al: Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional open surgical treatments for colon cancer: The ALCCaS trial. Ann Surg 248:728-738, 2008

■ ■ ■

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Kennedy et al

Acknowledgment We thank present and former staff at Oncology Clinical Trials Office and Centre for Statistics in Medicine (Oxford University, Oxford, United Kingdom) who have been involved with the EnROL trial, particularly Patrick Julier, who created and managed the trial databases, Andrea Ferch for administrative support, and senior staff for trial management advice and guidance; members of the Trial Management Group, Data and Safety Monitoring Committee, and Trial Steering Committee for their support and advice; the patients who agreed to participate; the research and pathology staff who supported the trial; and the following recruiting investigators: Ian Jenkins, Robin Kennedy, Talvinder Gill, Dharmendra Garg, Jonathan Ockrim, Nader Francis, Andrew Allison, Henk Wegstapel, Kevin Sargen, Tim Rockall, Iain Jourdan, Justin Davies, Richard Molloy, Chelliah Selvasekar, Amjad Parvaiz, Raj Kapadia, and Ken Campbell. Presented at the National Cancer Registry Ireland Colorectal Cancer Clinical Studies Group Annual Trials Meeting, London, United Kingdom, March 11, 2013; Association of Surgeons of Great Britain and Ireland Annual Meeting, Glasgow, United Kingdom, May 1-3, 2013; and Association of Coloproctology of Great Britain and Ireland Annual Meeting, Liverpool, United Kingdom, July 1-3, 2013. Appendix

Table A1. ERP Compliance Laparoscopy (n ⫽ 101)ⴱ Intervention Preoperative intervention Preoperative patient education Avoidance of mechanical bowel preparation (colon patients only) Preoperative oral carbohydrate Avoidance of long-acting sedatives Intraoperative intervention Avoidance of drainage (colon patients only) Thoracic epidural analgesia activated before skin incision Intraoperative heating Avoidance of nasogastric drainage at termination of operation ⬍ 3 L infused intraoperatively Postoperative intervention, day 0 Oral fluid intake ⬎ 800 mL Intake of nutritional supplement ⱖ 200 mL Mobilized Postoperative intervention, day 1 IV fluids terminated Epidural used Solid food eaten Postoperative aperient administered (colon patients only) Intake of nutritional supplement ⱖ 200 mL Mobilized Postoperative intervention, day 2 Urinary drainage stopped (colon patients only) Termination of epidural

Open Surgery (n ⫽ 101)†

All Patients (n ⫽ 202)‡

No.

%

No.

%

No.

%

78 42 62 82

77.2 58.3 61.4 81.2

82 48 65 78

81.2 64.9 64.4 77.2

160 90 127 160

79.2 61.6 62.9 79.2

68 26 73 95 81

94.5 25.7 72.3 94.1 80.2

70 34 76 95 75

94.6 33.6 75.2 94.1 74.3

138 60 149 190 156

94.5 29.7 73.8 94.1 77.2

18 26 18

17.8 25.7 17.8

21 31 18

20.8 30.7 17.8

39 57 36

19.3 28.2 17.8

56 50 54 37 2 26

55.5 49.5 53.5 51.4 2.0 25.7

43 65 41 42 1 23

42.6 64.4 40.6 56.8 1.0 22.8

99 115 95 79 3 49

49.0 56.9 47.0 54.1 1.5 24.3

51 35

70.8 35.0

32 27

43.2 27.0

83 62

56.8 31.0

Abbreviation: ERP, enhanced recovery program. ⴱ Colon, n ⫽ 72. †Colon, n ⫽ 74. ‡Colon, n ⫽ 146.

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