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

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

CRC Prevention

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.

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

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

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

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?