Landmark trials and updates in colorectal cancer presented at TNASICON 20

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Prof. Subbiah Shanmugam M.Ch
Professor and HOD
Dept of Surgical Oncology
Government Royapettah Hospital

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Introduction
• Treatment options for colorectal cancer are
evolutionally changing, even in the last few
years
• Screening
• Surgical advances
• Chemotherapy - targetted therapy
• Chemoprevention?
• Radiation updates

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PILL-CAM

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ENDOTICS( ROBOTIC ENDOSCOPY)

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What is new in 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 precisely controlled by a robotic
arm, which allows for complex movement inside the
body.
– Still complicated and requires high level training.

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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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Sensors and scopies

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History
• First reports of LAP for colon CA in 1990 - JACOBS
• 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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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.
• 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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Robotic vs lap colectomy.?
● Only observational cohort studies.
● In general, the robotic approach
● longer operating times and is more expensive
● 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 - Concept of improved resections?
● Hohenberger- Complete Mesocolic Excision- Germany
● Dissection within embryological planes of dorsal mesentery yields a
scatheless specimen.
● Analogous toTME concept by Heald et al.
● Mesocolon = dorsal mestentery.
● Visceral and parietal peritoneum covers the colon like a sheath
● Submesothelial connective tissue and interlobular septations.

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Surgical Colonic Interfaces
● Extra fascial plane between the mesocolon and
retroperitoneum = “Toldt’s Fascia”.
● (I) “Colo-fascial interface” - confluence of colonic surface and
“Toldt’s Fascia”
● (II) “Meso-fascial interface” confluence of mesocolon and
“Toldt’s Fascia”
● (III) “Retro-fascial interface” confluence of retroperitoneum and
“Toldt’s Fascia”

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CME vs Non CME colectomy?
● Japan (D3 lymphadnectomy) and Germany (CME + CVL).
● 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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To drain or not to drain colorectal anastamosis?

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Stenting in Obstructed colon?
• Left sided colonic carcinoma.
• ESCO trial
• In medically inoperable or metastatic patients.

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RECTAL CANCER- Evolving trends

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Rectal cancer- where do we stand?
• Revolutionary last thirty years.
• Previously, local relapses in the pelvis in 30% LARC.
• 1st step to improve local control = Total mesorectal excision
(Reducing local relapses to less than 5%).
• 2nd step = Preoperative radiation (short course Vs long
course with CCRT).

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Rectal cancer- what is known now?
• Magnetic resonance imaging = useful tool for locoregional staging
and for properly selecting patients for preoperative treatment
(Mercury trial).
• Nowadays, we know that preoperative Total neoadjuvant (TNT)
with chemotherapy also provides better control of systemic
relapses(RAPIDO and Rect 03 trial).
• Moreover, surgery can be avoided in 25% of patients and the
“watch and wait strategy” is considered safe and curative (Habr
Gama).

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EVOLUTION
• The recurrence rate of rectal cancer varied between 4 to 50%
• The main cause remained unproven in patients with curative
resection.

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(1) Recognition of mobility between tissues of different embryological origins
(2) Sharp dissection under direct vision in a good light
(3) Gentle opening of the plane by continuous traction with no actual tearing.
 DEFINE AN OPTIMAL DISSECTION PLANE around the cancer which must clear all
forms of extension and circumscribe predictably uninvolved tissues. ‘
 “the whole rectum and mesorectum are one distinct lymphovascular entity”

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• Circumferential resection margin (CRM) is the closest distance between the
radial resection margin and the tumor tissue by either direct tumor spread,
areas of neural or vascular invasion, or the nearest involved lymph node.

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Total Mesorectal Excision

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Total Mesorectal Excision
• The intramural spread of cancer downward is very rare, but extramural
spread appears both in distal and anterior directions.
• Anatomically three spaces can be distinguished around the rectum.
• The inner space is surrounded by a visceral fascia on the posterior side,
and Denonvillier’s fascia on the front of the rectum.
– Laterally they unite and are related to nerve plexus
• Intermediate space is limited by the parietal pelvis fascia on the posterior
side and the internal iliac arteries and their branches on both lateral sides,
and on the front.

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• The outer space is localized outside the
internal iliac arteries and their branches
• TME = Removal of the internal space with the
visceral fasciation and Denon-Villiers fascia
whilst preserving the pelvis nerve plexus on
both lateral sides.

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Total Mesorectal Excision- Mercury
Criteria

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• TME should be performed to a level of 5 cm below the distal
margin of the primary tumour in the upper rectum or to the
pelvic floor (complete TME) for tumours in the lower or
middle rectum.
• A minimum negative proximal margin of 5 cm is required
• The minimum acceptable negative distal margin is 2 cm for
cancers located above the distal meso-rectal margin. For
cancers located at or below the distal meso-rectal margin, a 1
cm negative distal margin is acceptable.
What remains the gold standard in
surgery?

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High TIE Surgery

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42 and 147 patients were ligated at the origin of the IMA (high tie) and just
below the origin of the LCA combined with LND around the origin of the
IMA (low tie with LND), respectively.
No significant differences were observed in the complication rate and OS
and RFS rates between high tie and low tie groups.

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Transanal excision/ Transanal endoscopic surgery
(TES)
• Radical surgery for stage I and II rectal cancer can expect excellent long-
term results which approach 5-year local recurrence rates of 4.5 % and
90% 5-year disease free survival (DFS) rates
• Morbidity is high (30-68%) with a mortality that approaches 7% in
certain pooled studies
Journal of Gastro intestinal Oncology 2015

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Criteria for Local rectal excision ?
Physical examination:
 tumor <3cm
 tumor <30% of bowel circumference
 tumor within 15cm of dentate line
 tumor freely mobile
Imaging (ERUS/MRI)
 Tumor limited to submucosa(T1)
 Lymphnode involvement(N0)
Histology:
 Well to moderately differentiated
 Absence of LVI or PNI
 No mucinous or signet ring cell
component
Journal of Gastro intestinal Oncology 2015

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• Local recurrence rates tend to be higher for both T1 (8.2-23%) and
T2 adenocarcinomas (13-30%) undergoing LE when compared to
radical surgery for T1-T2 disease (3-7.2%).
• No significant difference in DFS when compared to radical surgery.

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Postoperative complications of TAE are
• Rectal bleeding which is the most common (6%),
• Rectal stenosis (5.5%),
• urinary retention (1.5%),
• fecal incontinence (0.5%), and
• rectovaginal fistula (<1%)
The most common complications TEM reported are
• hemorrhage (27%),
• urinary tract infection (21%), and
• suture line dehiscence (14%) and
• 4.3% conversion to radical procedures
Complications following the TAMIS procedure are infrequent with
an overall rate of 7.4% with conversion rate of 4%

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NON OPERATIVE MANAGEMENT IN DISTAL RECTAL
CANCER
• Brazil
• Five-year overall and disease-free survival rates were 88% and 83%,
respectively, in Resection Group and 100% and 92% in Observation
Group
• NCCN 2021:
• “ In select patients achieving complete clinical response as
demonstrated by clinical examination, imaging and endoscopy
following neoadjuvant chemo radiotherapy may be advised
observation with strict serial monitoring after multidisciplinary team
discussion in select high volume centres”

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Laparoscopic Vs Open rectal surgeries
• Two previous large RCT and several meta-
analyses showed similar pathological and
oncological outcomes between laparoscopic
and open approaches for rectal cancer
• The laparoscopic approach was regarded as a
standardized alternative to the open approach

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• Robotic assistance has the potential to overcome limitations of
laparoscopic surgery
• Meta analysis - failed to show superiority of robotic assisted over
conventional laparoscopic surgery
• Safety, efficacy , short and long term outcomes were analysed ( 2017)

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• The primary outcome - conversion to open laparotomy.
• Rate of urinary retention was significantly lower in the
robotic group than in the laparoscopic group (2.5% vs 7.5%, P
= .018).
• 28 of 230 patients (12.2%) in the conventional laparoscopic
and 19 of 236 patients (8.1%) in the robotic assisted
laparoscopic group

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• 701 patients were randomized to the ME with LLND (n = 351) and ME
alone (n = 350) groups. ( 2017 Fujita et al )
• The 5-year relapse-free survival in the ME with LLND and ME alone
groups were 73.4% and 73.3%, respectively
• The 5-year overall survival, and 5-year local-recurrence-free survival
in the ME with LLND and ME alone groups were 92.6% and 90.2%,
and 87.7% and 82.4%, respectively.
• The numbers of patients with local recurrence were 26 (7.4%) and 44
(12.6%) in the ME with LLND and ME alone groups, respectively

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• Ishihara et al reported that the incidence of LLN metastasis was estimated
to be 8.1% (18/222) even after preoperative CRT.
• Kusters et al reported that the lateral local recurrence rate was
significantly higher in patients with LLN larger than 10 mm in pre
treatment imaging.
• The safety and feasibility of laparoscopic versus open LLND showed similar
oncological outcomes between the groups.
• Establishment of criteria to accurately predict LLN status as well as
standardization of the technique of LLND is necessary in the future

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228 patients with low rectal cancer <5cm from anal verge between 1996 to 2004
were enrolled
86% successful
24% morbidity and 0.4% mortality
Five year overall survival 91.9% and 83.4% DFS
Curability with intersphincteric resection was verified histologically, and
acceptable oncologic and functional outcomes were obtained by using these
procedures in patients with very low rectal cancer.

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Liquid biopsy - biopsing your DNA
content.
• Liquid biopsies are a promising new approach
• To detect, analyze, and track DNA, cells, and other substances shed
from tumors into bodily fluids, such as blood and urine.
• COBRA trial which studies how well circulating tumor DNA (ctDNA)
testing in the blood works
• To identify patients with stage IIA colon cancer who might benefit
from additional treatment with chemotherapy after surgery.

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Aspirin
• Recent studies have shown that daily low-dose aspirin may
prevent colorectal cancer.
• However, there are potential harms, particularly the risk of
gastrointestinal bleeding.
• Aspirin is currently recommended by the US Preventive
Services Task Force (USPSTF)Exit Disclaimer to prevent
colorectal cancer and cardiovascular disease in some
individuals age 50 to 69.

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Immunotherapy for patients with
Lynch syndrome
• >5% of CRC
• Immune checkpoint inhibitors nivolumab (Opdivo), ipilimumab
(Yervoy), and pembrolizumab (Keytruda) have been approved for the
treatment of metastatic CRC in patients with Lynch syndrome.
• They also have been approved for metastatic CRC in patients with
microsatellite instability-high cancer (MSI-H).

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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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• T1N0 – select patients with low risk features – Local Excision
• Other T1,T2 – Radical Abdominal surgery with TME
• T3, T4 N+ - Neoadjuvant chemo RT  Surgery
• Operable Early rectal cancer – NACRT- not useful due to
significant toxicity
• LAP > OPEN Radical Rectal Surgery
• Evolving – Robotic Surgery , Lateral Node dissections

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• Thank you