1. CURRENT STATUS OF LAPAROSCOPY FOR COLORECTAL DISORDERS Steven D. Wexner, M.D., FACS, FRCS, FRCS(Ed) Cleveland Clinic Florida Chairman, Department of Colorectal Surgery Professor of Surgery, Ohio State University Health Sciences Center at the Cleveland Clinic Foundation Clinical Professor of Surgery, University of South Florida College of Medicine

2. Cleveland Clinic Florida Weston

3. Laparoscopy: Colorectal cancer  Short term benefits –Bowel function recovery –Quality of life (including pain) –Hospital stay  Costs  Long term benefits –Recurrence –Survival

4. Laparoscopy: Colorectal cancer IEvidence obtained from at least one properly randomized controlled trial II-1Evidence obtained from well-designed controlled trials without randomization II-2Evidence obtained from well-designed cohort or case control analytic studies, preferable from more than one center or research group II-3Evidence obtained from comparisons between times or places with or without the intervention; dramatic results in uncontrolled experiments were also included in this category IIIOpinion of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Levels of evidence* *Can Med Assoc, 1979

5. Laparoscopy: Colorectal cancer Levels of evidence* National Health, Medical Research Council. 1999 1 Evidence obtained from a systematic review of all relevant randomized controlled trials 2 Evidence obtained from at least one properly designed randomized controlled trial 3-1 Evidence obtained from well-designated pseudorandomized controlled trials (alternate allocation or some other method) 3-2 Evidence obtained from comparative studies with concurrent controls and allocation not randomized (cohort studies) 3-3 Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group 4 Evidence obtained from case series, either posttest or pretest/posttest

6. Laparoscopy: Colorectal cancer Bowel Function Recovery AuthorYear N of patients Bowel function recovery Bowel function recovery (mean/median n of days) Retrospective Melotti19991632.9 Schiedeck20003993 Zhou2003821-2 Prospective Morino20031002.9 Tsang2003442

7. AuthorYear N of patients Bowel function (mean/median n of days) LapOpenLapOpen Seow-Choen1997161122.5 Ramos199718181.93.0 Goh1997202033 Schwandner199932324.15.1 Hartley2001212234 Champault200274831.43.2 Laparoscopy: Colorectal cancer Bowel Function Recovery p<0.05 Case-control/Cohort

8. AuthorYear N of patients Bowel function (mean/median n of days) LapOpenLapOpen Milsom1998545334 Curet200018182.74.4 Lacy20021111081.52.3 Hasegawa2003293023.3 p<0.05 Laparoscopy: Colorectal cancer Bowel Function Recovery Randomized

9.  The evidence that laparoscopy offers faster bowel function recovery than the traditional open approach may be considered high (Level I)

10. Laparoscopy: Colorectal cancer Quality of Life - Pain AuthorYear N of patients Less pain/analgesic requirement (days)? Less pain/analgesic requirement (days)? LapOpenLap p value Seow-Choen19971611No- Ramos19971818Yes<0.005 Goh19972020No- Psaila19982925Yes0.002 Schwandner19993232No- Case-control/Cohort

11. Laparoscopy: Colorectal cancer Quality of Life - Pain AuthorYear N of patients Less pain/analgesic requirement (days)? Less pain/analgesic requirement (days)? LapOpenLap p value Stage19971514Yes < 0.05 Schwenk19983030Yes < 0.01 Milsom19985453Yes0.02 Weeks2002168221Yes0.03 Hasegawa20032930Yes0.002 Randomized

12.  Randomized trial (COST trial)  449 patients  228 Laparoscopy (Lap), 221Open  Pain, hospital stay  Quality of life (2 days, 2 weeks, 2 months) –Symptom distress scale –Quality of life index –Global rating scale (1-100) Weeks, JAMA 2002 Laparoscopy: Colorectal cancer Quality of life

13. Results Lap n = 228 Open n = 221 Age (years) 68.269.4 Gender M:F 108:120108:113 Tumor stage IIIIIIIV 88 8877575 69 78 6211 ASA classification I or II I or II III III 19832 18932 P=NSWeeks, JAMA 2002

14. Results Lap n = 228 Open n = 221 p value Oral analgesics 1.92.20.03 IV narcotics/analgesics 3.24.0<0.001 Hospital stay 5.66.4<0.001 Weeks, JAMA 2002 > Patients in the Lap group had only greater mean global rate scores at 2 weeks after surgery (76.9 vs. 74.4; p=.0009) > No other differences in quality of life Values are means

15. Laparoscopy: Colorectal cancer  The superiority of laparoscopy in reducing pain during the same length of the postoperative period seems evident (Level I)  Other aspects of quality of life warrant further investigation

16. AuthorYearPatients Hospital Stay Retrospective Melotti199916310.9 Schiedeck200039914 Zhou2003828 Prospective Yamamoto2002708 Anderson20021008.3 Morino200310016.6 Tsang2003448 Laparoscopy: Colorectal cancer Hospital Stay

17. AuthorYear N of patients Hospital Stay (mean n of days) LapOpenLapOpen Lord199632325.88.2 Franklin19962242245.79.7 Seow-Choen199716116.58 Ramos199718187.412.9 Goh1997202055.5 Khalili199880906.28.2 Psaila1998292510.717.8 p<0.05 Cohort/case-control studies Laparoscopy: Colorectal cancer Hospital Stay

18. AuthorYear N of patients Hospital Stay (mean n of days) LapOpenLapOpen Schwandner199932 15.321.9 Fleshman1999152337.48.7 Leung200059341625.5 Hartley2001212213.515 Baker200228611318 Anthuber200210133414.419.9 Champault200274838.212.3 p<0.05 Cohort/case-control studies (cont)

19. Laparoscopy: Colorectal cancer Hospital Stay AuthorYear N of patients Hospital Stay (mean n of days) (mean n of days) LapOpenLapOpen Stage1997151458 Schwenk199830 10.111.6 Milsom1998545367 Curet200018 5.27.3 Lacy20021111085.27.9 Weeks20021682215.66.4 Hasegawa200329307.112.7 Randomized p<0.05

20. Laparoscopy: Colorectal cancer Hospital stay  There is high evidence (Level I) that laparoscopy for malignancy is associated with an earlier discharge compared to laparotomy

21. Laparoscopy: Colorectal cancer Costs  Retrospective study Philipson, Wold J Surg 1997 Lap n = 28 Open n = 33 p Direct costs OR/recovery OR/recovery Ward Ward ICU ICU Total Total263126632025496162326415144778 < 0.001 Indirect costs 35683103<0.001 Overall total costs 90647881<0.001 (Australian $)

22. Laparoscopy: Colorectal cancer Costs  Retrospective study Khalili, DCR 1998 Lap n = 80 Open n = 90 p OR costs ($) 2,1001,2000.01 Total costs ($) 14,80014,2000.48

23. Laparoscopy: Colorectal cancer Costs  Retrospective study Psaila, Br J Surg 1998 Lap n = 29 Open n = 25 p Disposable equipment (lb) 140 (200) 400 (220) 0.05 Total cost (lb) 3300 (1700) 2900 (1500) NS Values are mean (s.d)

24. Laparoscopy: Colorectal cancer Costs  The data available does not provide adequate evidence on whether total costs differ between laparoscopy and laparotomy in the treatment of malignancy

25. Laparoscopy: Colorectal cancer Recurrence Author, year N of patients Mean FU time (months) Recurrence (%) OverallLocalDistant Retrospective Huscher, 96 1461611.74.16.1 Schiedek, 00 399307.21.56.2 Prospective Lumley, 02 1547113.61.910.3 Anderson, 02 1004316.1-- Scheidbach, 02 20625.211.63.48.2

26. Cohort/case-control studies Laparoscopy: Colorectal cancer Recurrence Author,year N of patients Mean FU (months) Recurrence (%) OverallLocalDistant LapOpenLapOpenLapOpenLapOpen Franklin, 96 1652126012.222---- Ramos, 97 16162012.5256.218.76.26.2 Khalili, 98 768221/1813.118.3361011 Schwandner, 99 323233.1/32.115.615.63.1012.515.6 Santoro, 99 404324-6020232.52.31518.6 Lezoche, 00 9910932.2/34.21620.239.21111 Hartley, 01 21223854.554.550 Feliciotti, 02 747548.912.713.31.32.710.810.7 p=NS

27. Laparoscopy: Colorectal cancer Survival Author, year N of patients Mean FU (months) Survival time Overall survival (%) TNM/Dukes stages Retrospective Fleshman, 96 37222.63-year I-93; II-72; III-53 Color trial, 00 513-2-year I-95; II-98; III-93 Poulin, 02 70315-year72.1 Lechaux, 02 166653-year79 Prospective Scheidbach, 02 21425.25-year80.9 Anderson, 02 10040.35-year A-100; B-76; C-51 Morino, 03 7045.75-year I-92; II-79; III-67

28. Laparoscopy: Colorectal cancer Survival Author, year N of patients Mean FU (months)Survival Overall survival (%) TNM Stage LapOpenLapOpen Franklin, 96 16521234/485-year89.792.4 Leung, 97 505032.85-year67.264.1 Khalili, 98 7682215-year87.585 Schwandner, 99 323233.13-year9393 Santoro, 99 404324-605-year73.270.1 Leung, 00 192430/284-year84.277.8 Hartley, 01 2122383-year7177 Lujan, 02 10264164.45-year I-73; II-61;III-55 I-75;II-65; III-46 Champault, 02 6266605-year75.874.2 Pantakar, 03 161174525-year I-76; II-68; III-53 I-80; II-64; III-50 Cohort/case-control studies

29. Laparoscopy: Colorectal cancer Randomized Controlled Trial  111 Laparoscopy vs. 106 Laparotomy  Non metastatic colon cancer  Median follow-up time: 43 (27-85) months  Postoperative chemotherapy for all suitable patients with Stage II or III rectal cancer  Intention-to-treat analysis Lacy et al, The lancet 2002

30. Laparoscopy: Colorectal cancer Recurrence Lacy et al, The lancet 2002 Laparoscopy(n=106)Open(n=102) Hazard ratio (95% CI) p Tumor recurrence 18 (17%) 28 (27%) 0.72 (0.49-1.06) 0.07 Type of recurrence Distant metastasis Distant metastasis Locoregional relapse Locoregional relapse Peritoneal seeding Peritoneal seeding Port-site metastasis Port-site metastasis773191450--------0.57 Time to recurrence (months) 15 (14) 17 (12) --0.66 Surgical treatment of recurrence with curative intention 6 (33%) 9 (32%) --1.00

31. Laparoscopy: Colorectal cancer Survival Lacy et al, The lancet 2002 Laparoscopy(n=106)Open(n=102) Hazard ratio (95% CI) p Overall mortality 19 (18%) 27 (26%) 0.77 (0.53-1.12) 1.04 Cancer-related mortality 10 (9%) 21 (21%) 0.68 (0.50-0.90) 0.03 Causes of death Perioperative mortality Perioperative mortality Tumor progression Tumor progression Others Others1993186------0.19

32. Laparoscopy: Colorectal cancer Predictive factors Lacy et al, The lancet 2002 Hazard ratio (95% CI) p Probability of being free of recurrence Lymph node metastasis (presence or absence) Surgical procedure (Open vs. Lap) Preoperative serum CEA (> ng/ml vs. ng/ml vs. < 4 ng/ml) 0.31 (0.16-0.60) 0.39 (0.19-0.82) 0.43 (0.22-0.87) 0.00060.0120.018 Overall survival Surgical procedure (open vs. Lap) Lymph-node metastasis (presence vs. absence) 0.48 (0.23-1.01) 0.49 (0.25-0.98) 0.0520.044 Cancer-related survival Lymph-node metastasis (presence vs. absence) Surgical procedure (open vs. Lap) 0.29 (0.12-0.67) 0.38 (0.16-0.91) 0.0040.029 Cox’s regression model

33. Laparoscopy: Colorectal cancer Overall survival Lacy et al, The lancet 2002

34. Laparoscopy: Colorectal cancer Cancer-related survival Lacy et al, The lancet 2002

35. Laparoscopy: Colorectal cancer Recurrence free – by Stage Lacy et al, The lancet 2002

36. Laparoscopy: Colorectal cancer Overall survival- by Stage Lacy et al, The lancet 2002

37. Laparoscopy: Colorectal cancer Cancer related survival – by Stage Lacy et al, The lancet 2002

38. Laparoscopic Colectomy: Cancer  Laparoscopic resection of colorectal malignancies  a systematic review  English language  Randomized controlled trials  Controlled clinical trials  Case series/reports Chapman et al. Ann Surg 2001

39. Laparoscopic Colectomy : Cancer 52 papers met inclusion criteria52 papers met inclusion criteria –“Little high level evidence was available” –“The evidence base for laparoscopic-assisted reection of colorectal malignancies is inadequate to determine the procedures safety and efficacy” Chapman et al. Ann Surg 2001

40. Laparoscopic Colectomy : Cancer Disadvantages vs. Open Colectomy Significantly longer operative timesSignificantly longer operative times Possibly more expensivePossibly more expensive Possibly worse short term immune effectsPossibly worse short term immune effects Chapman et al. Ann Surg 2001

41. Laparoscopic Colectomy : Cancer “Laparoscopic resection of colorectal malignancy was more expensive and time-consuming”“Laparoscopic resection of colorectal malignancy was more expensive and time-consuming” The new procedure’s advantages revolve around early recovery from surgery and reduced pain”The new procedure’s advantages revolve around early recovery from surgery and reduced pain” Chapman et al. Ann Surg 2001

42. Laparoscopic Colectomy : Cancer Advantages vs. Open Colectomy Improved cosmesis (no data but appears uncontentious)Improved cosmesis (no data but appears uncontentious) Quicker hospital dischargeQuicker hospital discharge Less narcotic use, though possibly larger benefits for certain types of colectomy (low colonic)Less narcotic use, though possibly larger benefits for certain types of colectomy (low colonic) Possibly less pain at rest, at least for patients who have uncovered proceduresPossibly less pain at rest, at least for patients who have uncovered procedures Possibly earlier return of bowel function and resumption of normal dietPossibly earlier return of bowel function and resumption of normal diet Chapman et al. Ann Surg 2001

43. Laparoscopic Colectomy : Cancer  Short term Quality-of-Life outcomes Following Laparoscopic-Assisted Colectomy vs Open Colectomy for Colon Cancer (COST Study)  AIMS –Are disease free and overall survival equivalent ? –Is laparoscopic approach associated with better QOL ? Weeks et al. JAMA 2002

44. Laparoscopic Colectomy : Cancer  Randomized control trial  449 patients –Adenocarcinoma of single segment of colon –Excluded: Acute presentation, rectal and transverse colon cancers, advanced local disease, those lesions with evidence of metastatic disease, ASA IV or V  Quality of surgery: –All surgeons with > 20 cases; Random audit of cases Weeks et al. JAMA 2002

45. Laparoscopic Colectomy : Cancer  Outcomes: –Survival: still pending –QOL at 2days, 2 weeks and 2 months using: »Symptom Distress Scale, Global QOL Scale, QOL index  Results: Intention to Treat Analysis –Shorter use of narcotics –Shorter length of stay by 0.8 days (p<0.01) –Quality of life: no difference Weeks et al. JAMA 2002

46. Laparoscopic Colectomy : Cancer  Conclusions –“The modest benefits in short term QOL measures we observed are not sufficient to justify the use of this procedure in the routine care setting”  Unresolved Issues: –Blunting of QOL differences via analgesic use –QOL differences between POD 2 and POD 14 –Recurrence and survival outcomes –Incidence of small bowel obstruction Weeks et al. JAMA 2002

47. Laparoscopic Colectomy : Prospective, Randomized, Controlled 48 institutions, 872 patients Prospective, randomized Follow-up 4.4 years Conversion 21% Endpoint was time to tumor recurrence Nelson, NEJM 2004

48. Prospective, Randomized, Controlled Laparoscopic (n=435) Open(n=425) Age7069 Female212220 Location Right Right Left Left Sigmoid Sigmoid2373216623232164 TNM Stage 0 1 2 3 4 Unknown Unknown2015313611210433112146121160 Nelson, NEJM 2004

49. Prospective, Randomized, Controlled: Outcome at Surgery Laparoscopic (N=435) Open(N=425) P value Bowel margins (cm) 10-1311-120.4-0.9 Lymph nodes 12121.0 Surgery time (min) 15090<0.001 Conversion90-- Intraoperative complications 815NS Length of incision (cm) 186<0.001 Nelson, NEJM 2004

50. Prospective, Randomized, Controlled: Post-operative Laparoscopic(n=435)Open(n=425) IV narcotics (days) 34<0.001 PO narcotics (days) 120.02 Length of Stay 56<0.001 30-day mortality 24NS Complications9285NS Rates of readmission 1012NS Rates of reoperation <2%<2%NS Nelson, NEJM 2004

51. Prospective, Randomized, Controlled: Outcome Laparoscopic(n=435)Open(n=425) P value Recurrence*(4.4yrs)76840.83 Wound recurrence 1%1% P=0.50 NS 3yr survival 86%85% P=0.51 NS Nelson, NEJM 2004 * Laparoscopic procedure not significantly inferior to Open Procedure.

52. Cumulative Incidence of Recurrence at Any Satge

53. Overall Survival at Any Stage

54. Prospective, Randomized, Controlled: Conclusions  No difference between: –Time to recurrence –Disease-free survival –Overall survival  Oncologic outcome of laparoscopic resection is similar to that of open resection  Laparoscopic Approach is associated with less pain and a shorter hospital stay than conventional surgery Nelson, NEJM 2004

55. Laparoscopy: Colorectal cancer Conclusion  Laparoscopy for colorectal cancer has shown to be potentially superior to laparotomy in regard to short-term benefits and equivalent with regard to long term benefits  Available data appear to support that laparoscopic colectomy and conventional open colectomy have either similar or superior long-term outcomes (Level 1 evidence)

56. Laparoscopy: Colorectal cancer Conclusion  Surgeons with sufficient expertise and ongoing peer-reviewed data collection may offer this therapy to appropriately selected patients

57. International Colorectal Disease Symposium 16 th Annual An International Exchange of Medical and Surgical Concepts Marriott’s Harbor Beach Resort & Spa Fort Lauderdale, Florida February 17 – 19, 2005