A COMPARISON of LAPAROSCOPICALLY ASSISTED and OPEN COLECTOMY for COLON CANCER The Clinical Outcomes of Surgical Therapy Study Group (Cost Study) NEJM, May 13, 2004

BACKGROUND METHODS RESULTS CONCLUSIONS EVIDENCE BASED MEDICINE Ranking of the Study

BACKGROUND

Phillips, Ann, Surg, 1992 First to report laparoscopic approach to colectomy for colon cancer in 24 patients Berends, Lancet, 1994 Reported 3 of 14 patients developed trocar wound site recurrences in series of laparoscopically assisted resections for colon cancer.

Reilly, Disease Colon Rectum, 1996 Reported less than 1% wound site recurrences following laparoscopically assisted resections for colon cancer.

Questions Raised 1)Could a proper oncologic resection be performed with the laparoscopic approach? 2)Were there staging inaccuracies with the laparoscopic approach? 3)Were patterns of tumor cell dissemination altered by the laparoscopic approach?

Questions Raised 4)Were wound site recurrence rates truly higher with the laparoscopic approach? 5)Were overall recurrence rates higher with the laparoscopic approach? 6)Were disease free and overall survival rates lower with the laparoscopic approach?

Questions Raised 7)Were post operative complication rates higher with the laparoscopic approach? 8)Was post operative recovery faster with the laparoscopic approach?

COST STUDY Initiated in 1994 to ensure that the laparoscopic approach to colon cancer was properly tested before its use became wide spread. Surgeons generally adopted a virtual moratorium on laparoscopic resection for colon cancer outside of this trial.

METHODS

Design Noninferiority trial Prospective randomized trial Involved 66 credentialed surgeons from 48 institutions in the USA and Canada. Compared laparoscopic vs open approach to colon cancer

Patients Inclusion Criteria 18 years of age or older Diagnosed clinically with colon adenocarcinoma and had histologic confirmation at surgery Right or left colon cancer

Patients Exclusion Criteria Pregnancy Inflammatory bowel disease Familial polyposis Previous malignant tumor Current malignant tumor Severe medical illness Prohibitive abdominal adhesions

Patients Exclusion Criteria Transverse colon cancer Rectal cancer Acute bowel obstruction Perforation from cancer Advanced local disease Metastatic disease

Quality Control 66 credentialed surgeons at 48 institutions Each surgeon was required to have had performed at least 20 laparoscopically assisted colorectal surgeries prior to entry into the trial

Quality Control Prior to entry into trial, each surgeon submitted a videotape of a laparoscopic colectomy that was reviewed for: thoroughness of abdominal exploration identification of critical adjacent structures oncologic techniques degree of avoidance of direct tumor handling level of mesenteric ligation

Quality Control Random audits of videotapes during trial Assessment of bowel resection margins during trial

TECHNIQUE OF LAPAROSCOPIC COLON RESECTION 1)Pneumoperitoneal/ intracorporeal approach to: abdominal exploration mobilization of colon identification of critical structures ligation of vascular pedicles 2)Exteriorization of bowel through small incision for resection/ anastomosis

INDICATIONS FOR COVERSION FROM LAPAROSCOPIC TO OPEN SURGERY Presence of associated conditions Findings of advanced disease Massive adhesions Technical difficulties Inadequate oncologic margins Surgeons descretion for patient safety

Adjuvant chemotherapy was allowed at the physicians or patient’s descretion

RANDOMIZATION Performed centrally at the North Central Cancer Treatment Group statistical office Patients randomly assigned to: a)laparoscopically assisted colectomy b)open laparotomy and colectomy

RANDOMIZATION Through use of minimization algorithm, treatment assignment was balanced with respect to three stratification variables: 1)surgeon 2)primary tumor site – right, left, sigmoid

RANDOMIZATION 3)American Society of Anesthesiologists Class Class I – patient appears healthy Class II – patient has systemic, well controlled disease Class III – patient has multiple symptoms of disease, or well controlled major system disease

FOLLOW – UP: COMPLICATIONS Assessed by single reviewer Reviewer unaware of patient’s treatment assignment Assessed at date of discharge, 2 months, and 18 months

Follow – Up Classification of Complications GradeDefinition 1Non-life threatening and temporary 2Potentially life threatening, but temporary 3Causing permanent disability 4Fatal

FOLLOW – UP: TUMOR RECURRENCE Physical exam including inspection of wound sites CEA every 3 months for first year, then every 6 months for 5 years CxR every 6 months for 2 years, then every year Colonoscopy, or proctosigmoidoscopy and barium enema every 3 years Recurrence had to be confirmed with imaging or endoscopy

STATISTICAL ANALYSIS Designed to compare the following end points in the laparoscopic vs the open colectomy groups: 1)Primary end point Time to tumor recurrence defined as the time from randomization to first confirmed recurrence 2)Secondary end points Variables related to recovery Complications Disease free survival Overall survival

RESULTS

Characteristics of Patients and Tumors 872 patients underwent randomization from August 1994 to August 2001 over 7 years 2 patients subsequently declined surgery 7 patients subsequently were ineligible This left 863 patients for final analysis

Characteristics of Patients and Tumors Age Open ColectomyLaparoscopic Colectomy N = 428N = 435 Median69y70y Range29-94y28-96y

Characteristics of Patients and Tumors Sex Open ColectomyLaparoscopic Colectomy N = 428N = 435 Female220 (51%)212 (49%) Male208 (49%)223 (51%)

Characteristics of Patients and Tumors Open Colectomy Laparoscopic Colectomy N = 428N = 435 American Society of Anesthesiologists Class 1 or 2367 (86%)373 (86%) 361 (14%)62 (14%)

Characteristics of Patients and Tumors Open Colectomy Laparoscopic Colectomy N = 428N = 435 Number of Previous Operations 0233 (54%)246 (57%) 1120 (28%)113 (26%) >137 (9%)41 (9%) Unknown38 (9%)35 (8%)

Characteristics of Patients and Tumors # of patients Total863 Benign disease53 (6%) Malignant disease810 (94%) Stage I, II, III784 (97%) Stage IV26 (3%)

Characteristics of Patients and Tumors Open Colectomy Laparoscopic Colectomy N = 428N = 435 Location of Primary Tumor Right side of Colon232 (54%)237 (54%) Left side of Colon32 (7%) Sigmoid Colon164 (38%)166 (38%)

Characteristics of Patients and Tumors Grade of Differentiation Open Colectomy Laparoscopic Colectomy N = 428N = 435 Grade 1 (well)44 (10%)36 (8%) Grade 2 (moderately)271 (63%)315 (72%) Grade 3 (poorly)72 (17%)51 (12%) Grade 4 (undifferentiated)6 (1%)5 (1%) Not applicable (benign)33 (8%)20 (5%) Unknown2 (<1%)8 (2%)

Characteristics of Patients and Tumors Depth of Invasion Open Colectomy Laparoscopic Colectomy N = 428N = 435 Submucosal59 (14%)67 (15%) Muscularis76 (18%)105 (24%) Serosal237 (55%)226 (52%) Beyond serosa, involvement of contiguous structure 23 (5%)12 (3%) Not applicable (benign)33 (8%)20 (5%) Unknown0 (0%)5 (1%)

Characteristics of Patients and Tumors Open Colectomy Laparoscopic Colectomy N = 428N = 435 TNM Stage 033 (8%)20 (5%) I112 (26%)153 (35%) II146 (34%)136 (31%) III121 (28%)112 (26%) IV16 (4%)10 (2%) Unknown 0 (0%) 4 (1%)

# of patients SURGERY Total Surgery Patients Total patients863 Open colectomy 428 (49.6%) Laparoscopic Colectomy 435 (50.4%) Successful laparoscopic colectomy 345 (79%) Converted to open colectomy 90 (21%)

SURGERY Reasons for conversion# of patients Advanced disease22 (24%) Other21 (23%) Adhesions14 (16%) No visualization 12 (13%) of critical structures Unable to mobilize colon10 (11%) Complicating disease 3 (3%) Inadequate resection margins 4 (4%) Intraoperative complications 4 (4%)

SURGERY Conversion Rates P Value High vs low volume surgeons>0.05 Early vs late trial entry surgeons>0.05

SURGERY Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Length of incision<0.001 Median18 cm6 cm Range3 – 35 cm2 – 35 cm Duration of Surgery<0.001 Median95 min150 min Range27 – 435 min35 – 450 min

SURGERY Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Proximal Margin0.38 Median12 cm13 cm Range3 – 50 cm2 – 78 cm Distal Margin0.09 Median11 cm10 cm Range1 – 42 cm2 – 40 cm

SURGERY Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Margin Less than 5 cm26 (6%) pts22 (5%) pts0.52 Median # of lymph nodes examined 12

SURGERY Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Other organs resected62 (14%) pts33 (8%) pts Gyn organs24 (39%)8 (24%) Gall bladder10 (16%)10 (30%) Other9 (15%)5 (15%) Liver9 (15%)1 (3%) Bladder and abdominal wall 6 (10%)1 (3%) Small bowel4 (6%)6 (18%) Malignant histologic findings resected organs 14 (3%) pts6 (1%) pts

RECOVERY Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Duration of parenteral narcotics <0.001 Median4 days3 days Interquartile range3 – 5 days2 – 4 days Duration of oral analgesics0.02 Median2 days1 day Interquartile range1– 3 days1 – 2 days Duration of hospitalization<0.001 Median6 days5 days Interquartile range5 - 7 days4 – 6 days

Complications Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Intraoperative Complications8 (2%) pts16 (4%) pts 0.10 Spleen injury2 pts 0 pt Bleeding 1 pt8 pts Bowel injury2 pts6 pts Miscellaneous3 pts2 pts Postoperative Complications before discharge 80 (19%) pts81 (19%) pts0.98

Complications Open Colectomy Laparoscopic Colectomy N = 428N = 435P Value Grade of post operative complications before discharge Total80 (19%) pts81 (19%) pts 0.73 Grade 144 (55%) pts42 (52%) pts Grade 233 (41%) pts34 (42%) pts Grade 30 (0%) pts2 (2%) pts Grade 43 (4%) pts

Complications Open Colectomy Laparoscopic Colectomy (N = 428)(N = 435)P Value Overall complications85 (20%) pts92 (21%) pts 0.66 Rate of readmission43 (10%) pts52 (12%) pts0.27 Rate of reoperation8 (<2%) pts day postoperative mortality 4 (1%) pts2 (<1%) pts0.4

RECURRENCE ( after median follow-up of 4.4 years) Open Colectomy Laparoscopic Colectomy (N = 428)(N = 435)P Value Recurrence in surgical wounds 1 (0.2%) pts2(0.5%) pts 0.5

RECURRENCE ( after median follow-up of 4.4 years) Open Colectomy Laparoscopic Colectomy (N = 428)(N = 435)P Value Overall recurrence84 (20%) pts76 (17%) pts 0.32 Stage I0.65 Stage II0.50 Stage III0.49

The Clinical Outcomes of Surgical Therapy Study Group, N Engl J Med 2004;350: Cumulative Incidence of Recurrence among Patients with Colon Cancer of Any Stage (Panel A), Stage I (Panel B), Stage II (Panel C), or Stage III (Panel D)

SURVIVAL ( after median follow-up of 4.4 years) Open Colectomy Laparoscopic Colectomy (N = 428)(N = 435)P Value Deaths Total95 (22%) pts91 (21%) pts0.51 Before tumor recurrence 34 (36%) pts43 (47%) pts0.25 After tumor recurrence 61 (64%) pts48 (53%) pts

Survival ( after median follow-up of 4.4 years) Open Colectomy vs Laparoscopic Colectomy P Values All Stages0.51 Stage I0.31 Stage II0.58 Stage III0.25

The Clinical Outcomes of Surgical Therapy Study Group, N Engl J Med 2004;350: Overall Survival among Patients with Colon Cancer of Any Stage (Panel A), Stage I (Panel B), Stage II (Panel C), or Stage III (Panel D)

CONCLUSIONS The conversion rate from laparoscopic to open colectomy was 21% The duration of surgery was significantly longer for laparoscopic colectomy There was no significant difference in margins or in the number of lymph nodes removed

CONCLUSIONS Postoperative recovery is significantly faster with laparoscopic colon resection in terms of duration of parenteral narcotic use and duration of hospitalization No significant difference in the incidence or severity of intraoperative and postoperative complications.

CONCLUSIONS No significant difference in wound site tumor recurrence rates No significant difference in time to recurrence No significant difference in recurrence rates per tumor TNM stage No significant difference in overall recurrence rates

CONCLUSIONS No significant difference in disease free survival rates for each TNM stage No significant difference in overall disease free survival rates No significant difference in overall survival rates for each TNM stage No significant difference in overall survival rates

CONCLUSIONS The study was not designed to test whether laparoscopic assisted colectomy is superior to open colectomy for cancer The study did demonstrate that laparoscopic assisted colectomy is not inferior to open colectomy for cancer The study demonstrates that it is safe to proceed with laparoscopic assisted colectomy for colon cancer

EVIDENCE BASED MEDICINE The evidence based effort to improve patient care began in the late 1980’s at McMaster University Founded on the idea that more emphasis could be placed on the benefits and risks therapy Founded on the idea that it was best to treat patients with therapies from the top of pyramids of research information with methodologically weak studies at the base and strong studies at the top of the pyramid JAMA, 1992 Endo Clin, 2002

MODIFIED McMASTER CLASSIFICATION Grade 1 -benefits clearly outweigh harms and cost Grade 2 -weaker recommendation JAMA, 1992

MODIFIED McMASTER CLASSIFICATION Grade A -randomized controlled trial with consistent results Grade B -randomized trials with less consistent results Grade C -observational studies, or the generalization of randomized trial results from one group of patients to a different group Grade C+ -observational studies with compelling results JAMA, 1992

A COMPARISON of LAPAROSCOPICALLY ASSISTED and OPEN COLECTOMY for COLON CANCER McMaster Classification GRADE IA Strong recommendation