Mr Jim Hill's presentation on the management of obstructing colorectal cancer. Talk given at Dukes' Club weekend 2012

1. Acutely Obstructing Colorectal
cancer – treatment options
Jim Hill
Dukes Club 2012

2. Diagnosis

3. Pre-op. imaging

4. Pseudo-obstruction
 Always need contrast enema/CT scan
 1st line neostigmine
 2nd line colonoscopic decompression
 3rd line surgery

6. Obstructing colorectal cancer
 Large Bowel Cancer Project (Br J
Surg) 1985
 Survival rates unchanged for 30
years
 Primary anastomosis established
right side
 Primary resection 60% left side, 31%
primary anastomosis

7. Treatment options
 Segmental resection +/-
anastomosis
 Subtotal resection +/- anastomosis
 Defunctioning stoma – loop
ileostomy, loop colostomy,
caecostomy
 SEMS

8. Cochrane Database Syst Rev. 2004;(2):CD002101.
Curative surgery for obstruction from primary left
colorectal carcinoma: primary or staged resection?
De Salvo GL, Gava C, Pucciarelli S, Lise M
 REVIEWERS' CONCLUSIONS:
 The limited number of identified trials together
with their methodological weaknesses do not
allow a reliable assessment of the role of either
therapeutic strategy in the treatment of patients
with bowel obstruction from colorectal carcinoma.
It would appear advisable to conduct high quality
large scale RCT to establish which treatment is
more effective. However, it is doubtful whether
they could be carried out in a timely and
satisfactory way in this particular surgical context

9. Left colon-one stage resection
No. One stage Leak
(%) Rate (%)
Stewart 1993 73 86 6
Runkel 1998 35 63 5
Poon 1998 116 81 5
Deen 1998 143 85 1

10. Segmental resection vs Subtotal
colectomy
 Scotia Study Group increased bowel
(Br J Surg) 1995 frequency in subtotal
group
 Torralba et al post operative
(Dis Colon diarrhoea
Rectum) 1994 in 31%

11. Extended right vs Segmental
left
 Nyam et al Dis Colon Rectum 1996
no difference in bowel frequency
no difference in complications

12. Mortality rates
 Scotia Gp (Br J Surg) 1995
12%
 Poon et al (Br J Surg) 1998
7%
 Alvarez et al (Dig Dis) 2005
11%
 Poon et al (Dis Col Rectum) 2005
11%
 McGillicuddy et al (Arch Surg) 2009
15%

16. Rationale – converting emergency
into elective surgery
 Pre-operative correction and stabilisation
of fluid and electrolyte balance
 Reduction of diaphragmatic splinting and
pain with improvement in respiratory
function
 Treatment of medical co-morbid disease
 Accurate pre-operative staging of the
patient
 Referral to a specialist colorectal surgeon
 In a few patients with rapidly progressive
(advanced) disease or unstable comorbid
disease, major surgery may be avoided

17. CReST is funded by CRUK and was developed by the NCRI Colorectal
Cancer CSG
CReST

18. Stenting needs to be properly evaluated in a
randomised controlled trial addressing two key
questions:
* Is there a worthwhile net benefit (in reduced operative
mortality and morbidity, reduced stoma formation and
better quality of life adjusted survival) from endoluminal
stenting for patients presenting with an obstructing
colonic cancer?
* If a benefit exists, is this identifiable in patients
undergoing attempted curative treatment, palliative
treatment, or both?

19. Eligibility criteria
 Left sided colorectal cancer
 Clinical or radiological evidence of
obstruction
 Patient is fit for surgery
 Responsible doctor feels that there
may be some benefit to the patient
from stenting as a bridge to surgery

20. Emergency surgery
Obstructing
Colorectal cancer R
Insertion of Failed stenting
endoluminal stent
Palliative
care
Successful
decompression
Elective
surgery

21. End Points
Primary:
1. 30 day mortality
2. Length of hospital stay
Secondary:
a) Presence and duration of a stoma
b) Stenting completion and complication rate
c) Anastomosis rate
d) Quality of life (EQ 5D and EORTC QLQ-CR 29)
e) Overall survival
f) Disease-free survival at three years (attempted
curative surgery group only)
g) Length of stay on ITU or HDU
h) In-hospital morbidity
i) Cost benefit analysis
j) Rate of adjuvant chemotherapy (stage II and
stage III cancer) and adherence to chosen
chemotherapy protocols

22. Evidence
 >100 case series
 4 systematic reviews
 3 randomised trials

23. Success rates
(non randomised
studies)
 Technical 92-94%,
 Clinical 88-94%
 Bridge-surgery 71-85%
 Perforation 4%
 Migration 10%
 Obstruction 10%

26. NICE draft guidance
 Clinical question: For patients presenting with acute large
bowel obstruction as a first presentation of colorectal
cancer, what are the indications for stenting as a bridge to
elective surgery? What are the indications for stenting
patients and the optimal timing for stenting to occur?
 Clinical evidence
There is very little evidence of any type with which to address this
topic. There are no directly applicable studies and so in assessing
the body of evidence, consideration was given to the possibility
that relevant evidence may not be directly available and so
studies which compared stenting as a bridge to surgery, stenting
for palliative purposes or immediate emergency surgery were also
reviewed to check whether these studies contained information
relevant to the topic. Despite this consideration, very little
evidence of relevance was found from these studies and what was
available was of very poor quality.

27. Dutch stent in 1 – Endoscopy 2008
 21 pts with obstruction
 Palliative cases
 Premature closure of the trial
 11 adverse events in stenting arm
 6 perforations
• 4 early
• 2 late on chemotherapy

28. 2nd Dutch Stenting trial – multicentre
van Hooft Lancet Oncol 2011;12:344–52
 Obstructing left sided
 Primary outcome measure QoL
 98 cases randomised
 Increased 30 day morbidity in stent
gp (absolute risk increase 0.19)
 Trial currently halted by DMEC

29. 2nd Dutch Stenting trial – multicentre
van Hooft Lancet Oncol 2011; 12: 344–52
 No difference
• QoL
• Mortality
• Stoma rates
 Stent group
• Perforation 13%
• Successfully placed in 70% (all relieved
obstruction)
• 31 pts bridge to surgery
 Primary anastomosis in 20 (25% leak rate)
 3 silent perforations found histologically

30. The authors concluded that colonic
stenting has no decisive clinical
advantages compared to emergency
surgery. They suggested that it could be
used as an alternative treatment in as yet
undefined subsets of patients, although
with caution because of concerns about
tumour spread caused by perforations.

31. French stenting trial – multi centre
– Pirlet et al Surg Endosc 2010
 Obstructing left sided carcinoma
 Endoscopic or radiological
 60 patients randomised
 53% technical failure stenting arm
 No reduction in stoma rates
• 43% stenting arm, 56% emergency
surgery
 2/30 perforations in stenting arm
 Trial stopped early

32.  Thus the evidence provided by published randomised trials to
date demonstrates no evidence of benefit from stenting and
importantly describes increased morbidity associated with
stenting.
 The key questions relating to the use of stents in obstructing
colorectal cancer remain unanswered. These questions can only
be answered by a large randomised trial.
 The current status of stenting in obstructing colorectal cancer is
analogous to the status of laparoscopic surgery for colorectal
cancer in 2000.
 People should only have laparoscopic surgery as part of a
clinical trial.
 In view of all the above we feel most strongly that the planned
NICE Colorectal Cancer guidelines should state that; in patients
fit enough to undergo emergency surgery, stenting in
obstructing colorectal cancer should be limited to clinical trials
so that we can be clear about its benefit and risks.

33. Clinical question: For patients presenting with acute large bowel
obstruction as a first presentation of colorectal cancer, what are
the indications for stenting as a bridge to elective surgery?
What are the indications for stenting patients and the optimal
timing for stenting to occur?
The guidance on Improving outcomes in
colorectal cancer‘ (2004) recommended stent
insertion instead of emergency surgery for
patients with acute bowel obstruction.
Consequently the question investigated by this
guideline focused on the indications and optimal
timing for stent insertion to occur. The evidence
you cite relates to the issue of stent insertion vs
emergency surgery and is therefore not relevant
to the topic which was considered by the
guideline.

34. “The failure to consider the directly randomised evidence on the
question addressed is indefensible and does a disservice to
patients and their medical carers. As this randomised evidence
points to the potential for serious harm as a result of insertion of
SEMS in patients with obstructing colorectal cancer, the NICE
Guidance’s recommendation that colorectal surgeons should
consider inserting a colonic stent in patients presenting with acute
large bowel obstruction, without mention that randomised trials
have failed to establish superiority of SEMS over decompression
surgery, is ”perverse”. The appropriate recommendation - and the
conclusion of the authors of all three randomised trials (see
below) - is that stenting as a bridge to surgery remains an
experimental procedure requiring further randomised evidence to
establish its clinical and cost-effectiveness. The newly published
guidance on SEMS should be corrected or withdrawn”.

35. 2. Recruitment (up to 14th November 2011)
Date recruitment started: 23-Apr-2009
Proposed date for recruitment to end: Extended to August 2013
Total number to be recruited: 400
Number recruited to date: 123

37. First 100 patients
 50 randomised to stenting
 48 stent attempted
 Success rate 85% (7 failures)
 No perforations
 38 surgery
 10 no surgery
• 7 palliative cases
• 1 MI before surgery
• 1 benign disease
• 1 unknown

38. mean 23.2 (22.8)
(s.d.)
Time from stent median (IQR) 19.5 (4 , 35)
to surgery min 0
max 103

39. SAEs in stented patients having
surgery (38 patients)
 Intra-abdominal abscess 2
 Wound infection 2
 PE 2
 Myocardial 1
 Urinary 2
 Chest infection 3
 Constipation 1
 No anastomotic leaks but no. primary
anastomosis unknown

40. Summary
 Colorectal community in UK has
accepted the need for a trial and is
supporting it
 Recruitment is progressing at a
satisfactory rate
 Safety data is reassuring
 Given concerns raised by stenting
trials, CReST trial is important
 Current NICE guidance is disservice
to patients

41. TREC Trial –
Transanal Endoscopic Microsurgery
(TEM) and Radiotherapy in Early
Rectal Cancer
Jim Hill
Manchester Royal Infirmary

43. Phase II feasibility study comparing
radical TME surgery versus SCPRT
plus delayed local excision for
treatment of early rectal cancer (T1-
T2)

44. Early Rectal Cancer
 10,000 new cases rectal cancer per year in England &
Wales
 49 – 62% screen-detected rectal cancers are “early”
(pT1-2N0M0)
 Standard of care: Total Mesorectal Excision (TME)
 High rates of cure (3-6% relapse)
 Significant high mortality (3-4%) & post-operative morbidity

45. Radical Resection vs Local
Excision
Balance of reduction in
morbidity and mortality
vs risk of oncological
disaster

46. Results of Local Excision Alone
T-Stage Local recurrence
%(range)
T1 9.7 (0-24)
T2 25 (0-50)
T3 38 (0-100)

47. Kikuchi levels (sm1-sm3)
2% 8% 23%
Risk of nodal metastasis
Nascimbeni R, Burgart LJ, Nivatvongs S, Larson DR.
Dis Colon & Rectum 2002

48. Radical Resection - morbidity & mortality
 Significant morbidity (up to 60%) and
mortality (0-12%)
 Wound infections, wound and
parastomal herniae, urinary /sexual
dysfunction, anastomatic leakage,
stoma issues, anterior resection
syndrome, incontinence
 APR: Perineal wound and stoma-
related physical, psychological and
financial cost

49. Short Course Pre-operative
Radiotherapy
 Preoperative radiotherapy
more effective than post-op RT
 Pre-op can reduce local
recurrence following TME
 Can induce tumour shrinkage
or even complete pathological
response
 Interval between SCPRT and
surgery key to downstaging
 Surgery follows 1 week after
traditional schedules of
SCPRT

51. TEMS/ TEO SITES

52. Endoscopic view

55.  50 patients randomised to stenting.
 47 have a stent insertion date recorded.
 3 don’t (1071, 1086, 1088)
 Reasons for not having a stent insertion date are
as follows:
 1 not eligible - small bowel tumour on review
(1071)
 1 small bowel obstruction/fistula – going
straight to surgery (1086)
 1 stent attempted but failed – missing date.
Assumed to be = date of surgery = 1 day after
rand. (1088)

56.  Of the 48 with a stent date recorded:
 38 have a surgery date
 10 don’t.
 Good reasons for not having a surgery date are
as follows:
 7 palliative (1016, 1034, 1051, 1059, 1062,
1068, 1069)
 1 died before surgery (1022)
 Bad reasons for not having a surgery date are as
follows: (forms being chased)
 1 possible non-cancer (1092)
 1 unknown (1043)

57. CReST Recruitment
Proposed date for recruitment to end: Oct-2012
Total number to be recruited: 400
Number recruited to date, 19-Nov-10: 65

58. Benign disease
 Small et al, Surg Endosc 2008
 23 cases
 Clinical success 22/23
 Major complications 38%
 87% occurred after 7 days

59. Planned analyses
 Interval analysis after recruitment of 150
patients of post-operative complications,
in hospital stay, stoma formation, 30 day
mortality.
 A primary analysis of outcome will be
made once all patients have 2 years of
follow up.
 Statistical analyses will use standard
methods, e.g. comparisons of proportions
by Mantel-Haenszel or Fisher’s exact test,
logrank analyses of time to event data and
multi-level model with repeated measures
analysis for quality of life scores.

60. Conclusions of randomised trials
reported to date
 No proven benefit for all comers
compared to emergency surgery
 May be useful in selected patients (?
Which ones)
 Further studies needed to look at
oncological outcomes

61. Exclusion criteria
 Patients with signs of peritonitis and/or
perforation
 Patients with obstruction in the rectum,
that may require neoadjuvant therapy (i.e.
tumours in the mid or lower rectum)
 Patients who are unfit for surgical
treatments or refuse surgical treatment.
 Patients who are unwilling to consent to
participate
 Pregnant patients

62. Martinez-Santoz et al, Dis Colon
Rectum 2002
 Emergency surgery (n=29)
 Pre-operative stent and elective surgery
(n=26)
 Stenting and elective surgery was
associated
• an increase in the primary anastomosis rate
(84.6% vs 41.4%, p=0.0025)
• a lower need for a colostomy (15.4% vs
58.6%)
• a significantly reduced hospital stay (14.23 vs
18.52 days and intensive care unit stay (0.3 vs
2.9 days)

63. Statistical Power
 400 patients will be randomized over three years
from 40 centres in the UK and selected centres
overseas
 The feasible study size would be adequate to
detect a 50% reduction in 30-day mortality with
stenting and elective surgery compared to
emergency surgery (e.g. 13% vs 27% as
reported in audit data)
 90% power to detect a reduction in operative
complications from 40% to 25% - Martinez-
Santoz et al reported a reduction from 41% to
12% in their non-randomised study).

64. Statistical Power
 90% power to detect a 0.35sd reduction in
days in hospital equivalent to 1-2 days. It
is not anticipated that there will be any
significant loss to follow-up.
 90% power to detect differences in
survival of similar magnitude to those
seen in Birmingham audit data (where
survival at 6 months in the emergency
patients was 73% vs 87% in the elective
group) or those reported in a recent
national audit (mortality of 15.7%
following surgery for obstructing colorectal

65. Statistical Power
 Adequate to detect a 50% reduction in 30-day
mortality with stenting and elective surgery
compared to primary anastomosis
 90% power to detect a reduction in operative
complications from 40% to 25% - Martinez-
Santoz et al reported a reduction from 41% to
12% in their non-randomised study).

66. Sebastian et al, Am J Gastroenterol
2004
 Pooled analysis of 1,198 patients in
54 studies.
 Median technical and clinical success
rates of 94% (i.q.r 90-100) and 91%
(i.q.r 84-94).
 Clinical success when used as a
bridge to surgery was 71.7%.
 Major complications perforation
(3.7%), stent migration (11.8%).
 Stent related mortality 0.58%.

67. Statistical Power
 400 patients
 90% power to detect differences in mortality if
similar to those reported in a recent national
audit (mortality of 15.7% following surgery for
obstructing colorectal cancer and 4% following
elective surgery).
 90% power to detect a 0.35sd reduction in days
in hospital equivalent to 1-2 days.
 90% power to detect a reduction in operative
complications from 40% to 25% - Martinez-
Santoz et al reported a reduction from 41% to
12% in their non-randomised study).

68. CReST to date
 125 pts recruited
 33 recruiting centres
 50 sites open

69. Presentation and Outcome
COLORECTAL CANCER
Mode of % of all In-hospital
5 yr
presentation patients mortality
survival
Elective surgery 60 5
50
Emergency 25 20
25
Non-operative 15 40

70. COMPARING OPERATIVE SURVIVAL IN EMERGENCY & ELECTIVE
CASES
1
N = 502
0.95
Elective
Emergency
0.9
Cumulative Survival
0.85
0.8
0.75
0.7
0 100 200 300 400 500 600
Time (days)

71. Stenting workshops
 Combined endoscopic/fluoroscopic
technique recommended
 Double channel gastroscope
 No pre or post stent insertion
dilatation allowed
 Stent of radiologists/endoscopists
choice
 Confidence levels of radiologists high
 No specific colonic stent numbers

72. Systematic reviews
 Little high level evidence
 No data QoL and economic analysis
 Little long term/survival data

73.  2007 UK National Bowel Cancer Audit
Project reported an 11 per cent
mortality after colonic stenting for
obstructing cancers
 The authors commented that this
was higher than in
previously published
reports and needed
further study

74. NICE stakeholder comments

75. Stenting vs open surgery
Tilney et at Surg Endosc 2007
 451 pts
 Lower mortality p<0.03
 LOS shorter by 7.7 days
 Stenting did not
affect survival

76. Watt et al Ann Surg 2007
 88 articles,
 Mortality comparable
 Shorter LOS
 Lower colostomy rates
 Lower complications

77. Serious Adverse Events
 SAEs – fatal, life-threatening, require or prolong hospitalisation or are
significantly or permanently disabling
 For purposes of trial, adverse events include, but aren’t limited to:
- Failure to deploy the stent
- Bowel perforation
- Stent displacement
 All SAEs reported to BCTU within 24 hrs

80. Question
In the absence of any randomised
clinical trial showing a benefit of
stenting in patients with obstructing
left sided colorectal cancer and
concerns about stenting (sufficient to
stop the trials) in the only three
randomised trials so far conducted,
should stenting be offered outside a
randomised trial?

81. Left colon-Staged resection
 Cahill et al (Annals RCSE) 1991
44% prefer Hartmann
 Wigmore et al (Br J Surg) 1995
32-60% never reanastomosed