Landmark trials in colon cancer

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Surgical trials in colon cancer
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

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NOTICE SD

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History
• First reports of LAP for colon CA in 1990 - JACOBS
• Technically difficult and challenging
• Time consuming
• Short-term benefits (pain, ileus, hospitalization) have not been then
pronounced compared to open surgery
• PSR has led to resistance among surgeons to learn the technique

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Port site Recurrence
• Definition: Recurrence of tumor in a trocar wound without advanced
abdominal disease
• First report in 1993
• Initially reported rates: 0 - 21%*
• NOT necessarily with advanced cancer
• Cast a dark shadow over laparoscopic surgery for malignancy
Berends, Lancet 1994

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What is known about LC?
• Current high-quality evidence supports the routine use of the laparoscopic
approach for patients with colon cancer.
• Laparoscopic colectomy is associated with earlier resumption of
gastrointestinal function and shorter hospital stay, with no increased
morbidity or mortality.
• Pathology and long-term oncologic outcomes are similar to those achieved
with open surgery.
• The absolute benefits of laparoscopic resection for rectal cancer are still
under evaluation.

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What’s not clear yet?
Two recent randomized controlled trial (RCTs) have questioned
the routine use of MIS even in expert hands, since its non-
inferiority has not been demonstrated when compared with the
gold standard of open rectal surgery.
The impact of robotic technology is still unclear, since the only
RCT available so far failed to demonstrate any benefits compared
with standard laparoscopic rectal resection.

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Major advancements in colorectal
surgery:
The last three decades have witnessed:
1. the concept of total mesorectal excision
(TME),
2. multidisciplinary management,
3. laparoscopic approach, and lastly,
4. robotic technology.

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Barcelona trial
• The first RCT comparing open (OC) and laparoscopic colectomy (LC) for
non-metastatic colon cancer was published by Lacy from Spain.
• Single-institution equivalence RCT.
• Two surgeons
• November 1993 and July 1998.
• Primary endpoint - cancer-related survival.
• The authors considered a difference in cancer-related survival of less than
15% between OC and LC as indicator of equivalence.

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• N – 219
• LC- 111
• OC-108
• Intention to treat analysis
• Median follow up – 43 months

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• Primary long-term end points were 3-year overall survival (OS), 3-
year disease-free survival (DFS), and 3-year local recurrence.
• Secondary long-term end points were 3-year distant recurrence
rates, 3-year wound/port-site recurrence rates, and QoL.
• 794 (268 open and 526 laparoscopic)
• 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.

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COST trial
• Comparison of Laparoscopic-assisted and Open Colectomy for
Colon Cancer
• First multicenter RCT
• Addresses the risks and benefits of laparoscopic resection for colon
cancer.
• A non-inferiority trial
• August 1994 and 2001
• USA and Canada
• Involving 48 centers and 66 credentialed surgeons.

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Results of COST trial
• 873 patients (428 OC, 435 LC).
• Conversion rate was 21% - no differences between high-volume and
low-volume surgeons.
• Faster recovery was observed in the LC group(Shorter length of stay
(median 5 vs. 6 days; p< 0.001)).
• The use of parenteral (median 3 vs. 4 days; p<0.001) and oral
narcotics was lower after LC (median 1 vs. 2 days; p = 0.02).
• No differences were observed in terms of perioperative
complications, 30-day mortality, complications at discharge and at
60 days after surgery, rate of readmission, and reoperation.

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• Primary endpoint – time to tumor recurrence.
• Secondary endpoint- postoperative quality of
life.

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Recurrence rates

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Overall survival across all stages

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• Pathology showed similar number of lymph
nodes harvested, length of bowel resected,
and margin clearance.

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COLOR trial
• Colon Cancer Laparoscopic or Open Resection(COLOR)
• Large multicenter noninferiority RCT
• Europe, March 1997 and March 2003
• 29 participating European centers
• Primary end point:- 3-year DFS after curative LC or OC.
• 621 patients - OC and
• 627 patients - LC.

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Results
• LC took significantly longer Operating time (median 145 vs. 115
min; p-0.0001)
• Significantly less blood loss (median 100 vs. 175 mL; P-0.0001).
• Conversion rate was 17%, mainly due to bulky tumors and extensive
adhesions.
• Resumption of oral intake (mean 2.9 vs. 3.8 days; p0.0001) and
bowel function (mean 3.6 vs. 4.6 days; p0.0001) occurred almost 1
day earlier after LC.
• The need for analgesics was significantly lower after LC.
• Morbidity and mortality rates were similar.
• Postoperative length of stay was 1.1 days shorter after LC (mean 8.2
vs. 9.3 days; p0.0001).

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• Pathological outcomes- no difference between the two groups.
• Long-term oncologic evaluation revealed no significant differences
in DFS, OS, and recurrence.
• Low volume centers and High volume centers
• Similar to Barcelona and COST trials

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ALCCaS Trial
• January 1998 and April 2005
• Intention-to-treat, noninferiority RCT
• 31 Centers in Australia and New Zealand, with a total of 33
surgeons.
• Primary outcomes were 3- and 5-year survival rates.
• total of 592 patients were eligible for analysis:
– 294 LC and
– 298 OC.

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Results
• LC was associated with significantly longer anesthetic (median 170
vs. 115 min; p<0.001) and operative time (median 158 vs. 107 min;
p<0.001).
• No significant differences were observed in blood loss and need for
blood transfusions.
• More intraoperative hemorrhage (3.4% vs. 0.7%; p = 0.020) and
minor colonic serosal tears (2.7% vs. 0.3%; p = 0.019) occurred
during LC, but there were no other significant differences in
complications.
• Conversion to open surgery was 14.6%.
• Postoperative complications were similar (37.8% for LC vs. 45.3%
for OC)

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• Pathology evaluation revealed no significant differences in T stage
between the two arms, while N2 disease and perineural invasion
were more common in the OC group.
• Median distal margin was 2.5 cm shorter in the LC group, with
similar proximal margins.
• With a median follow-up of 5.2 years, 5-year OS, DFS, recurrence
rate, and time to recurrence were similar between groups.

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EnROL trial
The multicenter, randomized, controlled trial
compared conventional and laparoscopic colectomy
with an enhanced recovery program in place.
Outcomes were the same in both arms, with the
exception of median length of hospital stay, which
was significantly shorter in the laparoscopic group (5
days vs. 7 days; P = .033).

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EnROL trial

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Robotic vs lap colectomy.?
● Robotic colectomy has been compared to the laparoscopic approach,
mostly with observational cohort studies.
● In general, the robotic approach appears to result in longer operating
times and is more expensive but may be associated with less blood
loss, shorter time to recovery of bowel function, shorter hospital
stays, and lower rates of complications and infections.

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CME or Non CME colectomy?
● Japan and Germany
● Complete mesocolic excision (CME) with central vascular ligation
resulted in greater mesentery and lymph node yields than the
Japanese D3 high tie surgery.
● Disadvantages - Differences in outcomes were not reported.

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Other supportive evidences for CME
with CVL
● A retrospective, population based study in Denmark also supports
the benefit of a CME approach in patients with stage I–III colon
cancer, with a significant difference in 4-year DFS (P = .001) between
those undergoing CME resection (85.8%; 95% CI, 81.4–90.1) and
those undergoing conventional resection (75.9%, 95% CI, 72.2–79.7).
● A systematic review found that 4 of 9 prospective studies reported
improved lymph node harvest and survival with CME compared with
non-CME colectomy; the other studies reported improved specimen
quality.

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CME- LAP or Open?

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• Left sided colon carcinoma

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New colonoscopy
• The third most common form of cancer worldwide —
relies heavily on colonoscopies.
• Traditional colonoscopies are expensive, painful and
require high levels of skills.
• New approaches
– magnetic probes that are guided by a magnet outside of
the body have been recently developed. - precisely
controlled by a robotic arm, which allows for complex
movement inside the body.
– However, this method is complicated and still requires the
user to be highly trained in order guide the robot arm and
the magnetic probe.

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Semi-automated robotic system
• James Martin, Bruno Scaglioni
• Simple movement commands from the user.
• The probe moves using machine intelligence and image
analysis to automatically guide itself along the colon.

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Take home points
● Routine use of minimally invasive colon resection is generally not
recommended for tumors that are acutely obstructed or perforated
or tumors that are clearly locally invasive into surrounding structures
(ie, T4)
● Laparoscopic vs Open colectomy has advantages of laparoscopic
interventions with preserved oncologic outcomes.
● CME +CVL is better than High tie surgery
● Lap CME is better than Open CME.
● ERAS protocol for colonic resections- intrinsic advantages to return to
near normal life.

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