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Controversies Regarding Cancer Surveillance in IBD
Stephen B. Hanauer, MD Professor of Medicine & Clinical PharmacologyChief, Section of Gastroenterology & Nutrition
University Of Chicago
Susceptibility to colorectal cancer (CRC)
Familial 10-30%
Sporadic 65-85%
Hereditary nonpolyposisCRC (HNPCC) 5%
Familial adenomatouspolyposis (FAP) 5%
Rare CRC syndromes 0.1%
UC/CD related CRC 2%
1American Society of Clinical Oncology 1999; 2Choi 1994; 3Gyde 1982
1
1
1
1
1
2, 3
Cumulative risk of developing CRC in UC
0
5
10
15
20
25
0 5 10 15 20 25 30
Time from diagnosis (years)
Lower CL
Cumulative risk of CRC1
Upper CL
Copenhagen 1962–19972
1Eaden 2001; 2Winther 2001
Cum
ulat
ive
prob
abili
ty (
%)
CRC slide kit, Munkholm et al 2002
Sporadic Colon Cancer vs. Colitis-associated 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
Normal epithelium
Inflammation
Polyp Dysplasia
Sporadic CRC
IBD
Cancer
Flat dysplastic tissue
IndefiniteLGDHGD
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 in the Development of CRC in UC
Risk Factor Importance
Extent of disease ++++
Duration of disease ++++
Presence of PSC +++
Young age at onset ++
Positive family history +
Severity of inflammation*
+++
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
23d
Preventing CRC
• Surveillance
• Surgery– Polypectomy– Colectomy
• ChemopreventionSporadic Colon
CancerColitis-associated Colon
CancerAspirin
NSAIDS
Calcium/Vitamin D
Folic acid
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.
Who With UC Should Be Screened?
• Extensive colitis– >10 years duration
– Distal colitis?
• Patients with PSC– Pericholangitis?
What if You Identify Dysplasia in Crohn’s?
• Colectomy ?
• Segmental resection ?
• Mucosal mapping ?
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
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
Polyps Under Age 40
Sessile Pedunculated
In Colitis Proximal
Colectomy Survey Around Lesion
Dysplasia No Dysplasia Colectomy Follow (?)
Survey Around Lesion
Dysplasia No Dysplasia
Colectomy Follow (?)
Polyps Over Age 50
Small Sessile Pedunculated
In Colitis Proximal
PolypectomySurvey Around Polyp
Dysplasia No Dysplasia Colectomy
Survey Around Polyp
Dysplasia
Colectomy Polypectomy
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 of CRC – drug therapy
Salicylates – aspirin1,2
NSAIDs - Sulindac etc4
Drug therapy 5-ASA – mesalamine3
CRCAdenomas
CRCAdenomasCell proliferation
Apoptosis
CRCAdenomas
1Thun 1991; 2Kune 1988; 3Allgayer 2002; 4Giardiello 1993; 5Reddy 2000
5
5
5
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
(%)
General population
Adenomas/
dysplasia
Ongoing1 12–562 15–293 - 444 265 876
(Mouse)
Cancer - 607 758 - 29–359 966
(Mouse)
IBD
Adenomas/
dysplasia
- - 55–6810 8511 - - -
Cancer 8112 1613 2810 - - - -
1Salofalk German National Trial; 2Giovannucci 1994; 3Giovannucci 1993;
4Bonithon-Kopp 2000; 5Calle 1995; 6Torrance 2000; 7Thun 1991;
8Giovannucci 1998; 9Grodstein 1998; 10Lashner 1997; 11Tung 2001;12 Eaden 2000
EGF; epidermal growth factor
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
Risk of development of CRC in a meta-analysis of 116 studies of ulcerative colitis patients
Correlation Between Aminosalicylate Use and the Incidence of Colorectal Cancer
Pharmacotherapy Dose Odds ratio
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 < 2 g / d 0.56 0.17-1.84 0.34
Sulfasalazine > 2 g / day 0.41 0.18-0.92 0.03
olsalazine / balsalazide 0.40 0.04-3.58 0.41
Eaden et al.
Preventing CRC – 5ASA
Study Drug % Risk Reduction
Pinczowski sulphasalazine 62
Eaden Various 5-ASAs 53
Eaden Mesalazine
( 1.2 g/day)
81
Rubin Various 5-ASAs 72
Effect of folic acid supplementation on the relative risk (RR) for CRC or
dysplasia in UC1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Low-grade dysplasiaHigh-grade dysplasia
Cancer
Folic acid
1Lashner 1997
Rel
ativ
e ris
k
(CL 0.28-2.02)
(CL 0.16-1.77)(CL 0.05-3.80)
P = NS
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)
Ursodeoxycholic acid therapy and CRC chemoprevention in IBD
Tung 2001