COST Trial

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The Clinical Outcomes of Surgical Therapy Study Group. "A comparison of laparoscopically assisted and open colectomy for colon cancer". The New England Journal of Medicine. 2004. 350(20):2050-2059.
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Clinical Question

In patients undergoing colectomy for colon cancer is there a difference in disease free/overall survival, safety, morbidity, cost, and quality of life between patients who underwent a laparoscopic assisted colectomy compared to the standard open approach?

Bottom Line

The rate of recurrent colon cancer in patients who underwent laparoscopically assisted vs. open colectomy were not significantly different. Therefore, the laparoscopic approach is an acceptable alternative to open surgery for colon cancer.

Major Points

Minimally invasive surgical techniques have contributed to decreased hospitalizations and improved outcomes for patients. Previously procedures such as cholecystectomies required a large incision, with a relatively long hospital stay. Now, with laparoscopic approaches patients typically require 4 small incisions and are able to be safely sent home the same day [1][2]. Minimally invasive surgery has been considered for colorectal cancer since 1990 [3], however there was concern that this approach was not sufficient to achieve a proper oncologic resection or staging, or that it may alter patterns of recurrence (due to frequent reports of tumor recurrence in wounds[4]). These concerns prompted the Clinical Outcomes of Surgical Therapy Study Group (COST Study Group) to develop a trial to asses these questions.

This trial included 872 patients with stage I-III colon cancer, who were randomized to undergo laparoscopic or traditional open colon resection for their disease. The researchers sought to evaluate if laparoscopic techniques could provide adequate oncologic resection and proper lymph node staging. They also compared recurrence rate between techniques. Ultimately the authors discovered that the rate of recurrence was similar between patients with laparoscopic assisted colectomies and standard open colectomies. The overall survival rate was also similar between groups, with no significant difference in time to recurrence or overall survival for any stage of cancer.

The author's analysis demonstrated that laparoscopic colectomies had benefit in decreased narcotic use and length of hospitalization, and was equivalent to the standard open approach in terms of oncologic resection. However, the authors also found a 21% conversion rate from laparoscopic to open, and a significantly longer operative time in laparoscopic cases. Ultimately the authors concluded that laparoscopically assisted colectomies do not pose an additional risk for cancer, and are therefore an acceptable alternative to open colectomies for colon cancer.

Guidelines

  • Laparoscopic surgery is an acceptable option for the treatment of stage I-III colon cancer and should be considered an alternative to conventional open surgery
  • Surgeons performing laparoscopic techniques must have adequate operative experience (recommended minimum of 20 cases)
[5] [6] [7] [8] [9] [10] [11] [12] [13]

Design

  • Multicenter, noninferiority, randomized, control trial
  • N=872
    • Laparoscopically assisted colectomy (n=435)
    • Open colectomy (n=428)
  • Setting: 77 centers in the United States and Canada
  • Enrollment: August 1994-May 2004
  • Mean follow-up: 4.4 years
  • Analysis: Intention-to-treat
  • Primary outcome: Time to tumor recurrence

Population

Inclusion Criteria

  • 18 years and older
  • Clinical diagnosis of primary adenocarcinoma
    • Involving a single colon segment:
      • Right colon from the ileocecal valve up to and including the hepatic flexure
      • Left colon from the splenic flexure to the junction of the sigmoid and descending colong
      • Sigmoid colon between the descending colon and the rectum (at least 15cm from the dentate line)
  • Diagnosis based on physical exam plus either a proctosigmoidoscopy and barium enema or a colonoscopy
  • Negative pregnancy test for female patients
  • Fertile patients must use effective contraception

Exclusion Criteria

  • Less than 18 years old
  • Transverse colon cancer (i.e., between distal hepatic flexure and proximal splenic flexure)
  • Rectal cancer (i.e., below the peritoneal reflection, lower edge of tumor less than 15 cm from dentate)
  • Advanced local disease that renders laparoscopic resection impossible
  • Acutely obstructed or perforated colon cancer requiring urgent surgery
  • Stage IV disease
  • American Society of Anesthesiologists IV/V disease classification
  • Associated gastrointestinal diseases (i.e., Crohn's, chronic ulcerative colitis, or familial polyposis) that require additional extensive operative evaluation or intervention
  • Concurrent investigational treatments or invasive diagnostic procedures within 30 days after surgery
  • Prior or concurrent malignancy within the past 5 years except superficial squamous cell or basal cell skin cancer or carcinoma in situ of the cervix
  • Pregnancy or breastfeeding
  • Prohibitive scars/adhesions from prior abdominal surgery

Baseline Characteristics

  • Laparoscopically assisted colectomy group
    • Male: 51%
    • Female 49%
    • Age (years): 70
    • ASA class:
      • 1 or 2: 86%
      • 3: 14%
    • Location of tumor:
      • Right side of colon: 54%
      • Left side of colon: 7%
      • Sigmoid colon: 38%
    • TNM sate
      • 0: 5%
      • I: 35%
      • II: 31%
      • III: 26%
      • IV: 2%
      • Unknown: 1%
    • Depth of invasion
      • Submucosal, not muscle wall: 15%
      • Muscle wall, not serosal or perirectal: 24%
      • Serosal: 52%
      • Beyond serosa or perirectal fat, involvement of contiguous structure: 3%
      • Not applicable (benign pathological findings): 5%
      • Unknown 1%
    • Grade of differentiation
      • 1 (Well): 8%
      • 2 (Moderately): 72%
      • 3(Poorly): 12%
      • 4 (Undifferentiated): 1%
      • Not applicable (benign pathological findings): 5%
      • Unknown: 2%
    • Number of previous operations
      • 0: 57%
      • 1: 26%
      • >1: 9%
      • Unknown: 8%

Interventions

  • Randomized to conventional open colectomy or laparoscopic-assisted colectomy
  • Open colectomy
    • Open laparotomy and colectomy
    • Standard abdominal wall incision and abdominal cavity exploration
    • Right or left colectomy or sigmoid resection is performed
    • Quality of life assessed at baseline, on days 2 and 14 after surgery, at 2 months, and 18 months
    • Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually for 3 years.
  • Laparoscopic assisted colectomy
    • Laparoscopic assisted colectomy
    • Small infraumbilical incision made through the abdominal skin
    • Abdomen insufflated with carbon dioxide to allow access and visualization
    • Abdominal cavity explored
    • If advanced local disease is present a celiotomy and colectomy are performed
    • If no advanced local disease a right or left colectomy or sigmoid resection is performed using laparoscopic assisted techniques.
    • Quality of life assessed at baseline, on days 2 and 14 after surgery, at 2 months, and 18 months
    • Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually for 3 years.

Outcomes

Comparisons are laparoscopic assisted vs. open colectomy.

Primary Outcomes

Difference in three year recurrence free rate
2.4% in favor of laparoscopic assisted technique (HR 0.86; 95% CI 0.63-1.17; P=0.32)

Secondary Outcomes

Disease free survival (number of patients)
118 vs. 117 (HR 0/95; 95% CI 0.74-1.23; P=0.70)
Median length of incision (cm)
6 vs. 18 (P<0.001)
Duration of surgery (min)
150 vs. 95 (P<0.001)
Proximal margin (cm)
13 vs. 12 (P=0.38)
Distal margin (cm)
10 vs. 11 (P=0.09)
Other organs resected
8% vs. 14% (P=0.001)
Abdominal wall adhesions
34% vs. 25% (P=0.002)
Bowel adhesions
22% vs. 14% (P=0.001)
Pelvic adhesions
15% vs. 14% (P=0.53)
Other intraabdominal disease
12% vs. 10% (P=0.48)
Median duration of use of oral analgesics (days)
1 vs. 2 (P=0.02)
Median duration of use of parenteral narcotics (days)
3 vs. 4 (P<0.001)
Median duration of hospitalization (days)
5 vs. 6 (P<0.001)
30 day mortality
<1% vs. 1% (P=0.40)
Overall complications
21% vs. 20% (P=0.64)
Intraoperative complications
4% vs. 2% (P=0.10)
Postoperative complications (before discharge)
19% vs. 19% (P=0.98)
Grade 1 postoperative complications
52% vs. 55% (P=0.73)
Grade 2 postoperative complications
42% vs. 41% (P=0.73)
Grade 3 postoperative complications
0% vs. 2% (P=0.73)
Grade 4 postoperative complications
4% vs. 4% (P=0.73)
Tumor recurrence in surgical incision (number of patients)
2 vs. 3 (P=0.50)

Subgroup Analysis

  • There was no statistically significant difference in disease free survival, overall survival, and time to recurrence between groups regardless of stage of cancer
  • Conversion from laparoscopic to open colectomy occurred in 90 patients
    • The rate of conversion did not differ based on surgeon case volume, or when the surgeon joined the trial

Criticisms

  • The authors cautioned that this study was performed in a very controlled setting, with surgeons who had demonstrated high quality laparoscopic and oncological skills, in patients with no locally advance disease. This may cause the results to be skewed to be more favorable.
  • Dr. Tinmouth and Dr. Tomlinson suggest that the authors of this article did not define a non inferiority boundary, and the statistical methods used were that of a failed superiority trial. as such they are unable to claim non inferiority. Furthermore, based on their calculations the hazard ratio for risk of death is 1.16 and 1.11 for recurrence of cancer, based on a 95% CI [14].
  • It has been suggested that lack of details regarding perioperative management may have affected the quality of this trial. Techniques such as epidural analgesia, early ambulation and oral nutrition may contribute more to patient outcomes and length of hospitalizations than laparoscopic technique. Analgesia and post operative management techniques are also more cost effective than laparoscopic techniques, and should be analyzed further [15].

Funding

  • The COST trial was supported by funding from the NHI-NCI

Further Reading

  1. A prospective analysis of 1518 laparoscopic cholecystectomies. The Southern Surgeons Club. N. Engl. J. Med. 1991. 324:1073-8.
  2. Soper NJ et al. Laparoscopic general surgery. N. Engl. J. Med. 1994. 330:409-19.
  3. Phillips EH et al. Laparoscopic colectomy. Ann. Surg. 1992. 216:703-7.
  4. Berends FJ et al. Subcutaneous metastases after laparoscopic colectomy. Lancet 1994. 344:58.
  5. Xynos E et al. Clinical practice guidelines for the surgical management of colon cancer: a consensus statement of the Hellenic and Cypriot Colorectal Cancer Study Group by the HeSMO. Ann Gastroenterol 2016. 29:3-17.
  6. Smith, A, et al. “Evidence Based Series: Laparoscopic Surgery for Cancer of the Colon.” Program in Evidence-Based Care, Cancer Care Ontario, Sept. 2005, www.ontla.on.ca/library/repository/mon/15000/266801.pdf.f
  7. Vogel JD et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Treatment of Colon Cancer. Dis. Colon Rectum 2017. 60:999-1017.
  8. Carmichael JC et al. Clinical practice guideline for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons (ASCRS) and Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Surg Endosc 2017. 31:3412-3436.
  9. Labianca R et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2013. 24 Suppl 6:vi64-72.
  10. Gustafsson UO et al. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS(®)) Society recommendations. World J Surg 2013. 37:259-84.
  11. Zerey M et al. SAGES evidence-based guidelines for the laparoscopic resection of curable colon and rectal cancer. Surg Endosc 2013. 27:1-10.
  12. Ku G et al. Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012. Lancet Oncol. 2012. 13:e470-81.
  13. Siegel R et al. Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES). Surg Endosc 2011. 25:2423-40.
  14. Tinmouth and Tomlinson. Laparoscopically Assisted versus Open Colectomy for Colon Cancer: Correspondence. (2004). New England Journal of Medicine, 351(9), 933–934. https://doi.org/10.1056/nejm200408263510919
  15. Dalibon et. al. Laparoscopically Assisted versus Open Colectomy for Colon Cancer: Correspondence. (2004). New England Journal of Medicine, 351(9), 933–934. https://doi.org/10.1056/nejm200408263510919