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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3061-3068 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.7758 Randomized Trial of Laparoscopic-Assisted Resection of Colorectal Carcinoma: 3-Year Results of the UK MRC CLASICC Trial Group
From the Academic Unit of Surgery, St James's University Hospital; Clinical Trials Research Unit, Leeds Institute of Molecular Medicine, University of Leeds; and the Academic Unit of Pathology, University of Leeds, Leeds, United Kingdom Address reprint requests to David G. Jayne, MD, Academic Unit of Surgery, Level 8, Clinical Sciences Bldg, St James's University Hospital, Beckett St, Leeds, LS9 7TF United Kingdom; e-mail: david.jayne{at}leedsth.nhs.uk
Purpose The aim of the current study is to report the long-term outcomes after laparoscopic-assisted surgery compared with conventional open surgery within the context of the UK MRC CLASICC trial. Results from randomized trials have indicated that laparoscopic surgery for colon cancer is as effective as open surgery in the short term. Few data are available on rectal cancer, and long-term data on survival and recurrence are now required. Methods The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial study comparing conventional versus laparoscopic-assisted surgery in patients with cancer of the colon and rectum. The randomization ratio was 2:1 in favor of laparoscopic surgery. Long-term outcomes (3-year overall survival [OS], disease-free survival [DFS], local recurrence, and quality of life [QoL]) have now been determined on an intention-to-treat basis. Results Seven hundred ninety-four patients were recruited (526 laparoscopic and 268 open). Overall, there were no differences in the long-term outcomes. The differences in survival rates were OS of 1.8% (95% CI, –5.2% to 8.8%; P = .55), DFS of –1.4% (95% CI, –9.5% to 6.7%; P = .70), local recurrence of –0.8% (95% CI, –5.7% to 4.2%; P = .76), and QoL (P > .01 for all scales). Higher positivity of the circumferential resection margin was reported after laparoscopic anterior resection (AR), but it did not translate into an increased incidence of local recurrence. Conclusion Successful laparoscopic-assisted surgery for colon cancer is as effective as open surgery in terms of oncological outcomes and preservation of QoL. Long-term outcomes for patients with rectal cancer were similar in those undergoing abdominoperineal resection and AR, and support the continued use of laparoscopic surgery in these patients.
Laparoscopic-assisted resection of cancers of the colon and rectum was a logical application of the principles of laparoscopic surgery to the management of intra-abdominal malignancies. However, the application of laparoscopic colorectal surgery has met with considerable reserve because of concerns relating to the adequacy of resection, atypical patterns of recurrence, and health care cost considerations. Mindful of these concerns, in the mid-1990s a number of groups1-3 initiated randomized clinical trials of laparoscopic-assisted versus conventional open surgery for colon cancer. Most of these groups have now reported their early results4-6 of safety and short-term benefits and have concluded that laparoscopic surgery for resection of the right, left, and sigmoid colon is safe and provides the benefits of a shorter hospital stay, earlier mobilization, and quicker functional recovery.7 Paradoxically, in neither of the two major trials,4,5 in which short-term quality of life (QoL) has been examined, has any advantage for laparoscopic surgery been observed. The United Kingdom Medical Research Council Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (UK MRC CLASICC; clinical trials number ISRCTN 74883561) trial is a randomized clinical study of laparoscopic-assisted versus conventional open surgery in patients with colorectal cancer. A novel aspect of the CLASICC Trial is its inclusion of patients with rectal cancer. An important component of this trial was the detailed pathological examination of every resection specimen, not just for conventional measurements of dimensions and resection margin involvement, but also the adequacy of surgical technique, especially for rectal cancers. One of the findings that emerged from this pathological examination5 was that in patients undergoing laparoscopic anterior resection (AR), but not laparoscopic abdominoperineal resection (APR), circumferential margin positivity rates were slightly higher than in those undergoing conventional open AR. This article presents the long-term survival data in patients with colorectal cancer who were enrolled onto the CLASICC trial, examines the patterns of local and distant recurrence rates in the laparoscopic and open surgery arms, and reports on long-term QoL assessment.
Design This was a multicenter, randomized, controlled, open, and parallel group trial comparing laparoscopic-assisted surgery with conventional open surgery in patients suitable for right, left, or sigmoid colectomy, AR or APR. Details of eligibility criteria, treatment protocol, quality control procedures, hypotheses, and justification for sample size are provided elsewhere.5 CIs of 10% around differences were regarded as clinically significant. Randomization was by surgeon in the ratio 2:1 laparoscopic to open. QoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)8 and the colorectal cancer module QLQ-CR389 preoperatively, and at 2 weeks and 3, 6, 18 and 36 months postoperatively.
Follow-Up
End Points
Statistical Methods The EORTC questionnaires were scored according to EORTC guidelines,8,9 and postoperative mean QoL scores and 95% CIs and differences between arms were calculated using a multilevel repeated measures model accounting for data at all time points (assuming missing data to be missing at random) and allowing for time, treatment, treatment by time interaction, adjusting for baseline QoL (all fixed effects), patient, and patient by time interaction (random effects). All hypothesis tests were at 5% and 1% significance level (two-sided) for the primary and secondary long-term end points, respectively, and were performed using intention-to-treat analysis. All statistical analyses were performed (H.T. and J.B) using SAS version 8.2 (SAS Institute, Cary, NC). A UK MRC trial development group was involved in the study design only.
Between July 1, 1996, and June 28, 2002, 794 (268 open and 526 laparoscopic) patients from 27 UK centers and 32 surgeons were randomly assigned.5 Both types of surgical procedure were performed, according to the random assignment, by the same surgeon. The two groups were balanced with respect to baseline characteristics5 and pathological staging (Table 1). The rate of intraoperative conversions (laparoscopic converted to open surgery) decreased by year of study from 38% in year 1% to 16% in year 6.5
The provision of chemoradiotherapy was similar in the two groups, with 77 (28.7%) of 268 patients in the open and 148 (28.1%) of 526 patients in the laparoscopic group receiving adjuvant chemotherapy, and 18 (6.7%) and 29 (5.5%) patients in the open and laparoscopic groups receiving adjuvant radiotherapy, respectively.
End Points
OS
Overall, there was no evidence of a difference between the two techniques for any stage of disease, though a nonsignificant trend was observed for improved 3-year OS after laparoscopic surgery in patients with Dukes' A rectal cancers (log-rank = 3.28; P = .07). Among patients undergoing AR, there was no difference in 3-year OS between the two techniques (log-rank = 1.91; P = .17; open OS was 66.7%, and laparoscopic OS was 74.6%, for a difference of 7.9%; 95% CI, –3.6% to 19.4%). For those undergoing APR, no difference in 3-year OS was seen between the groups (log-rank = 0.69; P = .41; open OS was 57.7%, and laparoscopic OS was 65.2%, for a difference of 7.5%; 95% CI, –13.6% to 28.6%).
DFS The 3-year DFS for all patients was 66.8% (95% CI, 63.0% to 70.6%). There was no difference between the two surgical techniques in 3-year DFS (log-rank = 0.15; P = .70; open DFS was 67.7%, and laparoscopic DFS was 66.3%, for a difference of –1.4%; 95% CI, –9.5% to 6.7%). Also, there was no difference when patients with colon and rectal cancer were analyzed separately (P = .75 and P = .87, respectively). There was no statistical difference in 3-year DFS between the two techniques for patients undergoing either AR (log-rank = 0.13; P = .72; open DFS was 70.4%, and laparoscopic DFS was 70.9%, for a difference of 0.5%; 95% CI, –13.0% to 14.0%) or APR (log-rank = 0.22; P = .64; open DFS was 46.9%, and laparoscopic DFS was 49.8%, for a difference of 2.9%; 95% CI, –20.9% to 26.8%). There was no difference between the two techniques for any stage of disease, though the nonsignificant trend observed in OS for laparoscopic surgery to be better for patients with Dukes' A rectal cancers also was observed in 3-year DFS (log-rank = 3.09; P = .08).
Local Recurrence Rate
Distant Recurrence Rate The overall distant recurrence rate at 3 years was 14.9% (95% CI, 11.8% to 18.0%) and is presented separately for open and laparoscopic groups in Table 3. For patients undergoing AR, there was no evidence of a difference in the distant recurrence rates at 3 years between the two arms (log-rank = .0004; P = .98; the open distant recurrence rate was 13.9%, and the laparoscopic distant recurrence rate was 13.3%, for a difference of 0.6%; 95% CI, –10.2% to 11.5%). Also, no differences between the groups were seen in the 3-year distant recurrence rates for patients undergoing APR (log-rank = 0.22; P = .64; the open distant recurrence rate was 25.4%, and the laparoscopic distant recurrence rate was 32.9%, for a difference of –7.6%; 95% CI, –31.3% to 16.1%).
Wound/Port-Site Recurrence Rate
QoL
QLQ-C30 Six-month to 3-year QoL scores remained the same as at baseline for global QoL, role functioning, cognitive functioning, pain, insomnia, and nausea/vomiting for both surgical techniques, whereas financial difficulties remained at baseline levels for the open arm from 6 months onward and returned to baseline levels at 18 months for the laparoscopic arm. More problems than at baseline were reported for physical functioning by both arms at 6 months postoperatively. This continued in the laparoscopic arm up to 3 years, but returned to baseline levels at 18 months for the open arm. Fewer problems than at baseline were reported by both arms for emotional functioning. Social functioning was worse than at baseline for the laparoscopic arm up to 3 years postoperatively, but remained the same as baseline for the open arm. There was more fatigue for both arms at 6 months but levels returned to baseline for both arms by 18 months. Constipation scores were better for the laparoscopic patients from 6 months postoperatively, but remained the same as at baseline for patients in the open arm.
QLQ-CR38
This trial confirms and extends previous studies reporting that, for any stage, 3-year survival and disease-free intervals are no worse in patients undergoing laparoscopic-assisted resection for colon cancer than those undergoing conventional open surgery. Also, this trial has demonstrated that DFS, OS, and local recurrences in patients undergoing laparoscopic resection of rectal cancer are as good with laparoscopic surgery as with open surgery. Local recurrence after laparoscopic rectal excision also was comparable with that of nonrandomized open series10,11 and other randomized data.12 We have previously reported a slightly higher, but nonstatistically significant, circumferential resection margin positivity in patients undergoing laparoscopic AR (but not APR) compared with those resected conventionally.5 This has not translated into any detectable difference between laparoscopic and open AR in terms of OS, DFS, or local recurrence at 3-year follow-up. This may reflect the small numbers involved with only 16 (12%) of 129 laparoscopic patients and 4 (6%) of 64 open patients having positive circumferential resection margins, and further follow-up is required to ensure that a difference does not emerge in the longer term. Overall, 10 wound or port-site recurrences occurred in the 639 patients randomly assigned who had curative colorectal cancer surgery (1.9%). Of these, only one (0.2%) was reported as a true port-site recurrence, with the remainder being retrieval site recurrences. The majority of retrieval site recurrences occurred in patients with larger tumors or more advanced disease, which emphasizes the need for adequate wound protection during specimen extraction. Port-site recurrences in the Barcelona13 and Clinical Outcomes of Surgery Therapy (COST) trials14 were 0.94% and 0.5%, respectively, but have been reported as high as 4%,15 but this appears to be falling.16 There is a suggestion from the current survival analysis that patients undergoing laparoscopic-assisted surgery for Dukes' A rectal cancer may have an improved outcome. Although this result was not statistically significant, it is interesting that this trend was reflected in both the OS and DFS analyses. Only one other trial13 has suggested that outcome is better in patients undergoing laparoscopic colon resection, but contrary to our findings, this was in patients with node-positive disease. The reason for a survival advantage, if one exists, in early rectal cancers is unclear. Previous studies investigating immune dysfunction after laparoscopic surgery have failed to demonstrate any difference in comparison with open surgery.17 Given that early rectal cancers make up only 5% to 10% of all resected colorectal cancers, it is unlikely that the validity of this finding will be adequately tested, though this may change with the implementation of colorectal cancer screening programs. A few previous studies have reported on short-term QoL after laparoscopic and open colorectal cancer resection. Schwnek et al18 in a small study of 60 patients found an advantage after laparoscopic surgery, whereas the larger COST study4 showed only a minimal benefit, and the previously reported short-term QoL analysis of the CLASICC trial did not reveal any significant differences.5 The QoL analysis presented in this article is the only long-term data available from a large multicenter study. One previous single-institution randomized trial using the Short Form 36 questionnaire reported long-term QoL data with a benefit from laparoscopic surgery restricted to the first 12 months postoperative period.19 Although we have shown differences in the pattern of symptom reporting between the two arms, none of these differences were statistically significant, and they confirm that, in the long term, QoL after laparoscopic surgery is no worse than conventional open surgery. In a previous subgroup analysis of rectal cancer surgery, we have reported a nonsignificant trend for worse sexual function in males after laparoscopic resection.20 The long-term QoL analysis presented here further emphasizes the decline in male sexual function after rectal resection, which was present in both treatment arms. With the recent application of telerobotic systems to rectal cancer surgery,21 it will be interesting to see if advances in laparoscopic technology translate into improved autonomic nerve preservation and postoperative bladder and sexual function. The CLASICC trial has added to the body of evidence that vindicates the use of laparoscopic resection for colon cancer without detriment to long-term oncological outcomes. This study has now extended this conclusion to the use of laparoscopic resection of rectal cancer. Importantly, the higher positivity of circumferential resection margin seen after laparoscopic AR has not resulted in an increased incidence of local recurrence, and supports the continued use of the laparoscopic approach in these patients. The purpose of the CLASICC trial and other recently reported trials was primarily to ensure surgical and oncological safety of laparoscopic surgery. Although they have provided evidence for proof of principle in applying laparoscopic techniques to colorectal cancer treatment, they have yet to reveal any advantages in terms of socioeconomic benefits. However, since these trials were designed, there have been significant improvements in surgical technique22 and perioperative patient management,23 which will undoubtedly have an impact on these socioeconomic end points.
The author(s) indicated no potential conflicts of interest.
Conception and design: Pierre J. Guillou, Philip Quirke, Julia M. Brown Collection and assembly of data: David G. Jayne, Helen Thorpe, Joanne Copeland, Adrian M.H. Smith, Richard M. Heath Data analysis and interpretation: David G. Jayne, Pierre J. Guillou, Helen Thorpe, Philip Quirke, Joanne Copeland, Adrian M.H. Smith, Richard M. Heath, Julia M. Brown Manuscript writing: David G. Jayne, Pierre J. Guillou, Helen Thorpe, Philip Quirke, Joanne Copeland, Julia M. Brown Final approval of manuscript: David G. Jayne, Pierre J. Guillou, Helen Thorpe, Philip Quirke, Joanne Copeland, Adrian M.H. Smith, Richard M. Heath, Julia M. Brown
The following institutions and surgeons participated in the trial: Airedale General Hospital, Keighley: R. Kapadia, R. Khan; Bedford General Hospital, Bedford: R. Foley; Bristol Royal Infirmary, Bristol: M. Thomas; Castle Hill Hospital, Hull: J. Monson, G. Duthie; Colchester General Hospital, Colchester: R. Motson; Darent Valley Hospital, Dartford: M. Parker; Edinburgh Royal Infirmary, Edinburgh; D. Bartolo; Freeman Hospital, Newcastle-on-Tyne: A. Horgan; Leeds General Infirmary, Leeds: P. Sagar; Leicester General Hospital, Leicester: W. Barrie; Mayday University Hospital, Thornton Heath: R. Swift; Medway Maritime Hospital, Gillingham: H. Wegstapel; Ninewells Hospital, Dundee: K. Campbell; Prince Charles Hospital, Merthyr Tydfil: P. Haray; Princess Elizabeth Hospital, Guernsey: M. Van den Bossche; Queens Medical Centre, Nottingham: J. Scholefield; Royal Gwent Hospital, Newport: K. Vellacott; Royal Liverpool Hospital, Liverpool: M. Hershman; Royal United Hospital, Bath: J. Tate; Royal Victoria Infirmary, Newcastle-on-Tyne: J. Varma, H. Gallagher; St James's University Hospital, Leeds: P. Guillou, A. Windsor; St Peter's Hospital, Chertsey: H. Scott; Stepping Hill Hospital, Stockport: G. Deans; University Hospital of Wales, Cardiff: B. Rees, D. Carey; Whipps Cross Hospital, Leytonstone: J. Wellwood; William Harvey Hospital, Ashford: N. Taffinder; Yeovil District General Hospital, Yeovil: R. Kennedy. The following people were nominated as local pathologists for the trial: Airedale General Hospital, Keighley: P. Da Costa, J. O'Dowd; Bedford General Hospital, Bedford: D Rimmer; Colchester General Hospital, Colchester: P. Conn; Darent Valley Hospital, Dartford: P. Thebe; Edinburgh Royal Infirmary, Edinburgh: H. Gilmour; Hull Royal Infirmary, Hull: A. MacDonald; John Radcliffe Infirmary, Oxford: B. Warren; Leeds General Infirmary, Leeds: P. Quirke; Leicester General Hospital, Leicester: E. Mackay; Mayday University Hospital, Thornton Heath: A. Arnaout; Medway Maritime Hospital, Gillingham: R. Lindley; Ninewells Hospital, Dundee: F. Carey; Prince Charles Hospital, Merthyr Tydfil: S. Kiberu; Princess Elizabeth Hospital, Guernsey: C. Chinyama; Queens Medical Centre, Nottingham: D. Jenkins; Royal Liverpool Hospital, Liverpool: J. Nash; Royal United Hospital, Bath: N. Rooney; Royal Victoria Infirmary, Newcastle-on-Tyne: J. Shrimankar; St James's University Hospital, Leeds: N. Scott, J. Wyatt; St Peter's Hospital, Chertsey: N. Ratcliffe; Stepping Hill Hospital, Stockport: R. Hale; University Hospital of Wales, Cardiff: G. Williams; William Harvey Hospital, Ashford: A. Abdulkadir; Yeovil District General Hospital, Yeovil: J. Sheffield.
We thank M. Stead, Phd, E. Graham, BA, S. Bell, DPhil, V. Hiley, BSc, Z. Bennett, BA, the Trial Steering Committee (A.G. Johnson, MS, FRCS, N. Bosanquet, PhD, P.J. Franks, PhD, J.R.T. Monson MD, FRCP) and the Data Monitoring and Ethics Committee (Z.H. Krukowski, MB, Bch, PhD, FRCS, FRCP, G.D. Oates, FRCS, R. Stephens, FRCS, M. Sculpher, PhD) for their important contributions. We also thank all participating centers, surgeons, pathologists, and researchers without whom this multicenter clinical trial would not have been possible. A full list of participants is available in the online-only Appendix.
Supported by Grant No. G932812 from the UK Medical Research Council. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Nelson H, Weeks JC, Wieand HS: Proposed phase III trial comparing laparoscopic-assisted colectomy versus open colectomy for colon cancer. J Natl Cancer Inst Monogr 19:51-56, 1995 2. Stead ML, Brown JL, Bosanquet N, et al: Assessing the relative costs of standard open surgery and laparoscopic surgery in colorectal cancer in a randomized controlled trial in the United Kingdom. Crit Rev Oncol Haematol 33:99-103, 2000[CrossRef][Medline] 3. Hazebroek EJ: COLOR: A randomized clinical trial comparing laparoscopic and open resection for colon cancer. Surg Endosc 16:949-953, 2002[CrossRef][Medline] 4. Weeks JC, Nelson H, Gelber S, et al: Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: A randomized trial. JAMA 287:321-328, 2002 5. Guillou PJ, Quirke P, Thorpe H, et al: Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): Multicentre, randomised controlled trial. Lancet 365:1718-1726, 2005[CrossRef][Medline] 6. Veldkamp R, Kuhry E, Hop WC, et al: Laparoscopic surgery versus open surgery for colon cancer: Short-term outcomes of a randomised trial. Lancet Oncol 6:477-484, 2005[CrossRef][Medline] 7. Abraham NS, Young JM, Solomon MJ: Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer. Br J Surg 91:1111-1124, 2004[CrossRef][Medline] 8. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 9. Sprangers MAG, te Velde A, Aaronson NK: The construction and testing of the EORTC colorectal cancer-specific quality of life questionnaire module (QLQ-CR38). Eur J Cancer 35:238-247, 1999[CrossRef][Medline] 10. Dahlberg M, Glimelius B, Pahlman L: Changing strategy for rectal cancer is associated with improved outcome. Br J Surg 86:379-384, 1999[CrossRef][Medline] 11. McCall JL, Cox MR, Wattchow DA: Analysis of local recurrence rates after surgery for rectal cancer. Int J Colorectal Dis 10:126-132, 1995[CrossRef][Medline] 12. Leung KL, Kwok SP, Lam SCW, et al: Laparoscopic resection of rectosigmoid carcinoma: Prospective randomized trial. Lancet 363:1187-1192, 2004[CrossRef][Medline] 13. Lacy AM, García-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[CrossRef][Medline] 14. The COST Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050-2059, 2004 15. Wexner SD, Cohen SM: Port metastases after laparoscopic colorectal surgery for cure of malignancy. Br J Surg 82:295-298, 1995[Medline] 16. Curet MJ: Port site metastases. Am J Surg 187:705-712, 2004[CrossRef][Medline] 17. Tang CL, Eu KW, Tai BC, et al: Randomized clinical trial of the effect of open versus laparoscopically assisted colectomy on systemic immunity in patients with colorectal cancer. Br J Surg 88:801-807, 2001[CrossRef][Medline] 18. Schwnek W, Neudecker J, Bohm B, et al: Postoperative short-term course following laparoscopic or conventional resection of colorectal tumours. Minimal Invasive Chirurgie 11:112-118, 2002 19. Braga M, Frasson M, Vignali A, et al: Laparoscopic vs open colectomy in cancer patients: Long-term complications, quality of life, and survival. Dis Colon Rectum 48:2217-2223, 2005[CrossRef][Medline] 20. Jayne DG, Brown JM, Thorpe H, et al: Bladder and sexual function following resection for rectal cancer in a randomized clinical trial of laparoscopic versus open technique. Br J Surg 92:1124-1132, 2005[CrossRef][Medline] 21. Pigazzi A, Ellenholm JD, Ballantyne GH, et al: Robotic-assisted laparoscopic low anterior resection with total mesorectal excision for rectal cancer. Surg Endosc 10:1521-1525, 2006 22. Senagore AJ, Duepree MD, Delaney CP, et al: Results of a standardized technique and postoperative care plan for laparoscopic sigmoid colectomy. A 30-month experience. Dis Colon Rectum 46:503-509, 2003[CrossRef][Medline] 23. Kehlet H, Dahl JB: Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 362:1921-1928, 2003[CrossRef][Medline] Submitted November 1, 2006; accepted February 20, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
