A COMPARISON of LAPAROSCOPICALLY ASSISTED and OPEN COLECTOMY for COLON CANCER

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 – UpClassification of Complications

Grade Definition

1 Non-life threatening and temporary

2 Potentially life threatening, but temporary

3 Causing permanent disability

4 Fatal

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 ANALYSISDesigned 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


Age

Open Colectomy Laparoscopic ColectomyN = 428 N = 435

Median 69y 70y

Range 29-94y 28-96y


Sex

Open Colectomy Laparoscopic ColectomyN = 428 N = 435

Female 220 (51%) 212 (49%)

Male 208 (49%) 223 (51%)


Open Colectomy

Laparoscopic Colectomy

N = 428 N = 435American Society of Anesthesiologists Class

1 or 2 367 (86%) 373 (86%)

3 61 (14%) 62 (14%)


Open Colectomy


N = 428 N = 435Number of Previous

Operations

0 233 (54%) 246 (57%)1 120 (28%) 113 (26%)

>1 37 (9%) 41 (9%)Unknown 38 (9%) 35 (8%)


# of patients

Total 863

Benign disease 53 (6%)

Malignant disease 810 (94%)•Stage I, II, III 784 (97%)

•Stage IV 26 (3%)


Open Colectomy


N = 428 N = 435Location of Primary Tumor

Right side of Colon 232 (54%) 237 (54%)

Left side of Colon 32 (7%) 32 (7%)Sigmoid Colon 164 (38%) 166 (38%)


Grade of Differentiation

Open Colectomy


N = 428 N = 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%)•Unknown 2 (<1%) 8 (2%)


Depth of InvasionOpen

ColectomyLaparoscopic Colectomy

N = 428 N = 435

•Submucosal 59 (14%) 67 (15%)•Muscularis 76 (18%) 105 (24%)•Serosal 237 (55%) 226 (52%)•Beyond serosa, involvement of contiguous structure

23 (5%) 12 (3%)

•Not applicable (benign) 33 (8%) 20 (5%)•Unknown 0 (0%) 5 (1%)


Open

ColectomyLaparoscopic

ColectomyN = 428 N = 435

TNM Stage0 33 (8%) 20 (5%)I 112 (26%) 153 (35%)II 146 (34%) 136 (31%)III 121 (28%) 112 (26%)IV 16 (4%) 10 (2%)

Unknown 0 (0%) 4 (1%)

# of patients

SURGERYTotal Surgery Patients

Total patients 863

Open colectomy 428 (49.6%)

Laparoscopic Colectomy 435 (50.4%)

• Successful laparoscopic colectomy 345 (79%)

• Converted to open colectomy 90 (21%)

SURGERYReasons for conversion # of patients

•Advanced disease 22 (24%)

•Other 21 (23%)

•Adhesions 14 (16%)

•No visualization 12 (13%)

of critical structures

•Unable to mobilize colon 10 (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


N = 428 N = 435 P Value•Length of incision <0.001

Median 18 cm 6 cm

Range 3 – 35 cm 2 – 35 cm•Duration of Surgery <0.001

Median 95 min 150 minRange 27 – 435 min 35 – 450 min

SURGERY

Open Colectomy


N = 428 N = 435 P Value•Proximal Margin 0.38

Median 12 cm 13 cm

Range 3 – 50 cm 2 – 78 cm•Distal Margin 0.09

Median 11 cm 10 cmRange 1 – 42 cm 2 – 40 cm

SURGERY

Open Colectomy


N = 428 N = 435 P Value

•Margin Less than 5 cm 26 (6%) pts 22 (5%) pts 0.52

•Median # of lymph nodes examined

12 12

SURGERYOpen

ColectomyLaparoscopic Colectomy

N = 428 N = 435 P Value

•Other organs resected 62 (14%) pts 33 (8%) pts 0.001

Gyn organs 24 (39%) 8 (24%)

Gall bladder 10 (16%) 10 (30%)

Other 9 (15%) 5 (15%)

Liver 9 (15%) 1 (3%)Bladder and abdominal wall

6 (10%) 1 (3%)

Small bowel 4 (6%) 6 (18%)

•Malignant histologic findings resected organs

14 (3%) pts 6 (1%) pts

RECOVERYOpen

ColectomyLaparoscopic

ColectomyN = 428 N = 435 P Value

•Duration of parenteral narcotics <0.001Median 4 days 3 days

Interquartile range 3 – 5 days 2 – 4 days

•Duration of oral analgesics 0.02

Median 2 days 1 dayInterquartile range 1– 3 days 1 – 2 days

•Duration of hospitalization <0.001

Median 6 days 5 days

Interquartile range 5 - 7 days 4 – 6 days

Complications

Open Colectomy


N = 428 N = 435 P Value

•Intraoperative Complications 8 (2%) pts 16 (4%) pts 0.10Spleen injury 2 pts 0 pt

Bleeding 1 pt 8 pts

Bowel injury 2 pts 6 pts

Miscellaneous 3 pts 2 pts

•Postoperative Complications before discharge

80 (19%) pts

81 (19%) pts 0.98

Complications

Open Colectomy


N = 428 N = 435 P Value

Grade of post operativecomplications before

dischargeTotal 80 (19%) pts 81 (19%) pts 0.73

Grade 1 44 (55%) pts 42 (52%) pts

Grade 2 33 (41%) pts 34 (42%) pts

Grade 3 0 (0%) pts 2 (2%) pts

Grade 4 3 (4%) pts 3 (4%) pts

Complications

Open Colectomy


(N = 428) (N = 435) P Value

•Overall complications 85 (20%) pts 92 (21%) pts 0.66

•Rate of readmission 43 (10%) pts 52 (12%) pts 0.27

•Rate of reoperation 8 (<2%) pts 8 (<2%) pts 1.0

•30 day postoperative mortality

4 (1%) pts 2 (<1%) pts 0.4

RECURRENCE

(after median follow-up of 4.4 years)

Open Colectomy


(N = 428) (N = 435) P ValueRecurrence in surgical wounds 1 (0.2%) pts 2(0.5%) pts 0.5

RECURRENCE


Open Colectomy


(N = 428) (N = 435) P Value

Overall recurrence 84 (20%) pts 76 (17%) pts 0.32

•Stage I 0.65

•Stage II 0.50

•Stage III 0.49

The Clinical Outcomes of Surgical Therapy Study Group, N Engl J Med 2004;350:2050-2059

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


Open Colectomy


(N = 428) (N = 435) P Value

Deaths

•Total 95 (22%) pts 91 (21%) pts 0.51•Before tumor recurrence 34 (36%) pts 43 (47%) pts 0.25

•After tumor recurrence 61 (64%) pts 48 (53%) pts

Survival


Open Colectomy vs Laparoscopic ColectomyP Values

All Stages 0.51

Stage I 0.31

Stage II 0.58

Stage III 0.25

The Clinical Outcomes of Surgical Therapy Study Group, N Engl J Med 2004;350:2050-2059

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

A COMPARISON of LAPAROSCOPICALLY ASSISTED and OPEN COLECTOMY for COLON CANCER

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