Download Controversies Regarding Cancer Surveillance in IBD

Controversies Regarding
Cancer Surveillance in IBD
Stephen B. Hanauer, MD
Professor of Medicine & Clinical Pharmacology
Chief, Section of Gastroenterology & Nutrition
University Of Chicago
Susceptibility to colorectal
cancer (CRC)
Familial 10-30%
1
Sporadic 65-85%
1
Hereditary nonpolyposis 1
CRC (HNPCC) 5%
Familial adenomatous 1
polyposis (FAP) 5%
1
Rare CRC syndromes 0.1%
UC/CD related CRC 2%
1American
Society of Clinical Oncology 1999; 2Choi 1994; 3Gyde 1982
2, 3
Cumulative risk of developing
CRC in UC
Cumulative probability (%)
25
20
15
Lower CL
Cumulative risk of CRC1
10
Upper CL
Copenhagen 1962–19972
5
0
0
5
10
15
20
25
30
Time from diagnosis (years)
1Eaden
2001; 2Winther 2001
CRC slide kit, Munkholm et al 2002
Sporadic Colon Cancer vs. Colitisassociated Colon Cancer
Sporadic
• Arises from protruding
adenomatous polyp
• Only 3-5% experience
multiple synchronous
colon cancers
• Mean age-60’s
• Left sided
predominance
Colitis
• Arises from flat
dysplasia or a DALM
• Approximately 12%
experience multiple
synchronous colon
cancers
• Mean age-30 to 40’s
• More uniformly
throughout the colon
Colorectal Cancer (CRC) and
Ulcerative Colitis
• Cumulative Risk of CRC
– 2% at 10 years of disease
– 8% at 20 years of disease
– 18% at 30 years of disease
• Overall prevalence of CRC in UC
– All UC patients - 3.7%
– Pancolitis patients – 5.4%
Progression of IBD to cancer
IBD
Inflammation
Flat dysplastic tissue
IndefiniteLGDHGD
Cancer
Normal epithelium
Polyp
Dysplasia
Sporadic CRC
Progression of Dysplasia
•
•
•
•
Mayo Clinic
18 pts with UC and Flat LGD followed 32mos
9/18 Progressed
Cumulative incidence of progression 33% at 5
years
• 14 Colectomies
– 1 Adenoca at 74 months
Ullman et al AJG 97;922:02
Progression of Dysplasia
•
•
•
•
•
Mt. Sinai Hospital
46 Pts with Flat LGD followed
7 Cases CRC (5 >Stage II)
4/17 Colectomies with Advanced CA
Actuarial Progression 53% at 5 years
– 2 Despite Surveillance Compliance
Ullman et al Gastroenterol 125:1311:03
Risk Factors
Risk Factors in the
Development of CRC in UC
Risk Factor
Extent of disease
Duration of disease
Presence of PSC
Young age at onset
Positive family history
Severity of
inflammation*
Importance
++++
++++
+++
++
+
+++
Severity of Inflammation & Risk of
Neoplasia in UC
68 Cases matched with 136 Controls 7/88-1/02
– sex, extent, age at onset, duration of colitis, and year of
index surveillance colonoscopy
– Segmental colonoscopic and histological inflammation
scored (0-4, normal-severe)
– Significant correlation between
•
•
•
•
Colonoscopic inflammation (odds ratio, 2.5; P = 0.001)
Histological inflammation (odds ratio, 5.1; P < 0.001)
Risk of colorectal neoplasia.
Multivariate analysis, only histological inflammation score remained
significant (odds ratio, 4.7; P < 0.001).
Rutter et al Gastroenterol 126;141:04
CRC Prevention
Preventing CRC
• Surveillance
• Surgery
– Polypectomy
– Colectomy
• Chemoprevention
Sporadic Colon
Cancer
Aspirin
NSAIDS
Calcium/Vitamin D
Folic acid
Colitis-associated Colon
Cancer
23d
Folic acid
Ursodeoxycholic acid
5-ASA
Azathioprine
Conventional Surveillance
Recommendations
• Colonoscopy
– Extensive Disease - Start 8 - 10 years after
disease onset
– Left-sided disease - Start 15 - 20 years
after disease onset
– Repeat every 1-3 years
• Biopsies
– Four every 10 cms from cecum to rectum
– Additional samples of the rectosigmoid?
• Confirmed Dysplasia
– Colectomy recommended
Surveillance May Decrease the Risk or
Mortality of Colon Cancer
Results from a US 18 year surveillance program
• Detection at an early stage:
– Cancer found early in 80% (15/19) receiving
surveillance
– Cancer found early in only 41% (9/22) of those not
receiving surveillance
• 5-year survival rate
– 77% for the surveillance group
– 36% for the non-surveillance group (p<0.03)
Choi PM, et al. Gastroenterol 1993; 105: 418-24.
Limitations of Surveillance
• Dysplasia may be missed when obtaining
biopsies
• Intra- and inter-observer variation in
interpretation of dysplasia
• Patient Compliance
• High Cost to Benefit Ratio
Eaden, JA and Mayberry JF. Am J Gastroenterol 2000; 95(10): 2710-19.
Cancer Screening In IBD
WHO TO SCREEN?
Who With UC Should Be
Screened?
• Extensive colitis
– >10 years duration
– Distal colitis?
• Patients with PSC
– Pericholangitis?
Who With Crohn’s Should Be
Screened?
• Colitis >10 years duration
• PSC
• Strictures?
What if You Identify Dysplasia
in Crohn’s?
• Colectomy ?
• Segmental resection ?
• Mucosal mapping ?
Cancer Screening in IBD
WHEN TO SCREEN?
Cost-effectiveness of Screening
Screening intervals depend upon risk
Controversies Regarding Risk
• Definition of disease onset
– Symptoms vs diagnosis
• Definition of disease extent
– For example, isolated cecal
inflammation
• *Definition of Disease Activity?
• Onset of colitis in PSC
Practical Applications for
Surveillance
Screen more often when risk is higher
• First decade - Ineffective
• Second decade - Every 2-3 years
• Third decade -Yearly
Cancer Screening In IBD
HOW TO SCREEN?
Controversies in Screening
Procedure
•
•
•
•
•
Where to biopsy
How many biopsies
Definition of dysplasia
Confirmation of dysplasia
What to do about polyps
Where to Biopsy
Biopsy Entire Colon
• Sigmoidoscopy is not enough
– Sensitivity of rectosigmoid dysplasia for
proximal lesions, ~42%
– Less for rectal dysplasia
How Many Biopsies?
Seattle Estimates:
• 64 biopsies for 95% probability of
finding highest grade of dysplasia
• 18 biopsies for 95% probability of
finding cancer or dysplasia if truly
present
Rubin et al. Gastro.1992;103:1611.
How Many Biopsies?
• Chicago Data:
– Biopsies at 10 cm intervals throughout
colon
– Additional biopsies of nodular or
polypoid mucosa
– Findings at colonoscopy preceding
colectomy
What To Do About Polyps
•
•
•
•
Age of patient
Location of polyp
Type of polyp
Surrounding mucosa
Polyps Under Age 40
Pedunculated
Sessile
In Colitis
Colectomy
Proximal
Survey Around Lesion
Dysplasia
No Dysplasia
Colectomy
Follow (?)
Survey Around Lesion
Dysplasia
No Dysplasia
Colectomy
Follow (?)
Polyps Over Age 50
Pedunculated
Small Sessile
In Colitis
Survey Around Polyp
Dysplasia
Colectomy
Proximal
Polypectomy
No Dysplasia
Polypectomy
Survey Around Polyp
Dysplasia
Colectomy
No Dysplasia
Polypectomy
Confirmation of Dysplasia
Interobserver Agreement
45-77%
In practice only 43% of doctors request
second pathologic opinions*
*Bernstein et al. Am J Gastro. 1995;90:2106.
Chemoprevention
Chemoprevention of CRC –
drug therapy
Salicylates – aspirin1,2
Drug therapy
5-ASA – mesalamine3
5
CRC
Adenomas
5
CRC
Adenomas
Cell proliferation
Apoptosis
NSAIDs - Sulindac etc4
1Thun
1991; 2Kune 1988; 3Allgayer 2002; 4Giardiello 1993; 5Reddy 2000
5
CRC
Adenomas
Evidence for 5-ASA
chemoprevention
• Case-control studies1-3
• In-vitro studies
• Animal studies
• Epidemiological studies
• Expert opinions
1Eaden
2000; 2Pinczowski 1994; 3Moody 1996
5-ASA Mechanism of Action in
CRC Prevention
• Precise mechanism unknown
• Proposed mechanisms
– Increased apoptosis
– Decreased cell proliferation
– Inhibition of production of oxidative
radicals, prostaglandins, and leukotrienes
– Improvement in DNA repair
Bus PJ, et al. Aliment Pharmacol Ther 1999;13:1397-1402.
Risk reduction in the prevention of
adenomas, dysplasia and cancer in
general and in IBD
Prevention/
reduction of
5-ASA
NSAID
ASA
(%)
Folic
acid
(%)
Ursodiol
Calcium
Oestrogen
(%)
(%)
(%)
EGF +
NSAID
(%)
12–562
15–293
-
444
265
876
General
population
Adenomas/
dysplasia
Cancer
Ongoing1
(Mouse)
-
607
758
29–359
-
966
(Mouse)
IBD
Adenomas/
dysplasia
Cancer
-
-
55–6810
8511
-
-
-
8112
1613
2810
-
-
-
-
EGF; epidermal growth factor
1Salofalk
German National Trial; 2Giovannucci 1994; 3Giovannucci 1993;
4Bonithon-Kopp
8Giovannucci
2000; 5Calle 1995; 6Torrance 2000; 7Thun 1991;
1998; 9Grodstein 1998; 10Lashner 1997; 11Tung 2001;12 Eaden 2000
Risk of development of CRC in a meta-analysis
of 116 studies of ulcerative colitis patients
Treatment
10 yrs post dx
20 yrs post dx
30 yrs post d
Cumulative incidence rates of CRC in UC:
With 5-ASA (70%) 0.4%
1.5%
3.4%
Without 5-ASA
2%
8%
18%
Relative risk
reduction
80%
81%
81%
Absolute risk
1.6%
6.5%
14.6%
NNT to avoid one
case of CRC
100 / 1.6 = 62.5
100 / 6.5 = 15.3
100 / 14.6 = 7
Number needed to treat modified after Eaden et al.
Estimated rate of CRC in the Danish cohort
Correlation Between Aminosalicylate Use and the
Incidence of Colorectal Cancer
Pharmacotherapy
Dose
95% CI
P-value
5-ASA
All doses
0.25
0.13-0.48
< 0.00001
Mesalazine
< 1.2 g / d
0.08
0.08-0.85
0.04
Mesalazine
> 1.2 g / d
0.09
0.03-0.28
< 0.00001
Sulfasalazine
<2g/d
0.56
0.17-1.84
0.34
Sulfasalazine
> 2 g / day 0.41
0.18-0.92
0.03
0.40
0.04-3.58
0.41
olsalazine / balsalazide
Odds
ratio
Eaden et al.
Preventing CRC – 5ASA
Study
Pinczowski
sulphasalazine
% Risk
Reduction
62
Eaden
Various 5-ASAs
53
Eaden
Mesalazine
( 1.2 g/day)
Various 5-ASAs
81
Rubin
Drug
72
Effect of folic acid supplementation
on the relative risk (RR) for CRC or
dysplasia in UC1
(CL 0.28-2.02)
Relative risk
w
Lo
1Lashner
1997
Folic acid
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
d
ra
g
-
(CL 0.16-1.77)
(CL 0.05-3.80)
P = NS
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Ursodeoxycholic acid therapy and
CRC chemoprevention in IBD
Study design
• 59 IBD patients with primary sclerosing cholangitis
• Patients undergoing colonoscopic surveillance for
dysplasia
Outcome
• Ursodiol protects against CRC in UC
(OR 0.18; 95% CL 0.05–0.61, P = 0.005)
Tung 2001
Conclusions
• Surveillance is best tool to date
• Apply risk to individual patient
– Severity, Extent, Duration, Age at Onset, Family
History, PSC
• Biopsy According to Mucosa at Risk
– Chromoendoscopy
– Additional Fecal/Biomarkers
• Evidence Favors 5-ASA Maintenance
• Urso in PSC
• Folic Acid?