Colorectal Cancer Screening and Prevention

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Colorectal Cancer Screening and Prevention

• RFUMS
• The Chicago Medical School 2005
• David R. Rudy, MD, MPH
• Professor and Chairman,
• Family and Preventive Medicine
• Preventive Medicine MTD 601

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Prevention

• Primary prevention keeping a disease process
  from happening (smoking cessation prevents (95
  of) lung cancer
• Secondary prevention interruption of a disease
  process in a curable phase (Ca cervix, colon -
  place for screening)
• Tertiary prevention stopping or retarding a
  symptomatic disease (improving risk status after
  MI)

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Terms of Epidemiology

• Incidence - new cases over unit of time/unit of
  population
• Prevalence - number of cases at a point in
  time/unit of population
• Sensitivity (of a test) - proportion of cases
  diagnosed by a test
• Specificity - proportion of population without
  the disease that will test negative

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Criteria for screenability

• 1. Condition has significant effect on life
• 2. Significant treatment available
• 3. Asymptomatic period of diagnoseability
• 4. Treatment in asymptomatic phase yields result
  superior to delaying until symptoms appear
• 5. Tests of reasonable cost- sensitivity and
  specificity appropriate for population risk
• 6. Incidence sufficient to justify cost

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Terms

• Positive predictive value - chance of a positive
  test signifying disease
• Negative predictive value - chance of a negative
  test result signifying absence of disease
• None of the forgoing can be told without
  knowledge of prevalence of the disease

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Colon Cancer Causation

• Combined environmental and genetic
  Environmental causes include diet low in fiber
  and gut bile salts, higher in fat.
  (Harrison's Principles of Medicine 11th Ed).
  Genetics to be addressed in 2.
• 95 arise from adenomas 70-90 from adenomatous
  polyps (10-30 from sessile adenomas).

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TYPE PREVALENCE MALIGNANT

• Tubular adenoma 75 5
• Tubulovillous 15 22
• Villous adenoma 10 40
• Weighted chance (100 ) 10.5
• 15-30 of (US) pop. adeno- polyps/life
• Lifetime colon Ca risk 2.5-2.6 (sporadic).

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Hyperplastic polyps

• Comprise up to 1/3/ of all polyps have no
  malignant potential - recognized only hy
  histopathology

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CRC locations

• About 1/3 of polyps arise proximal to the splenic
  flexure (cephalad).
• (I,e,. 2/3 of polyps can be found by
  sigmoidoscopy
• About 1/2 of colorectal carcinomas arise proximal
  to the splenic flexure.
• (1/2 cancers found by sigmoidoscopy

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Polyps to Carcinoma

• Dwell time average 10 years, therefore five year
  interval between most screen methods is safe.
• Odds of polyp becoming cancer in the individual
  case may be inferred to be about 1 in 10 within a
  lifetime.

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Relative significance of Colorectal Carcinoma

• Tumor Incidence Cause specific Case
  mortality Mort
• Lung 172,570 163,510 95
  MF 5545
• CRC 145,290 56,290 39
• Breast 212,930 40,870 19
• Prostate 232,090 30,350 13
  Jemal A, Tiwari RC, Murry T, Ward E , Samuels A,
  TiwariRC, Ghafoor A, Feuer EJ, Thun M Cancer
  Statistics, 2005. CA Cancer J. for Clin 2005
  55(1) 10-30

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BURDEN OF SUFFERING1

• 145,290 incidence CRC/US est. for 05
• 56,290 deaths US mortality FM
• Second leading cause of cancer death US, without
  sex distinction,
• - albeit well below lung cancer.
• Case Mortality 38.7 (Jemal A, et al Cancer
  Statistics, 2005. CA Cancer J. for Clin 2005
  55(1) 10-30

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Case Mortality CRC

• 56,290 /year US mortality 2005
  145,290 incidence CRC/US
• 38.7 approximate case mortality

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Relative incidences CRC among five ethnic groups
(see Table III 1B)

• Ethnic group RR
• Indigenous 488 1.0
• Asian/PacIsl 699 1.4
• Hispanic/Latino 731 1.5
• Whites 988 2.0
• African 1103 2.26
• Cancer Incidence and Mortality Rates by Race
  and Ethnicity in the US 1996-2000 (Cancer Fact
  and Figures 2004, American Cancer Society)

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Relative mortality CRC among five ethnic groups
(see Table III 1B)

• Ethnic group RR
• Asian/PacIslanders 27 1.0
• Hispanic/Latino 29 1.1
• Indigenous 30 1.1
• African 40 1.5
• Whites 42 1.6
• Cancer Incidence and Mortality Rates by Race
  and Ethnicity in the US 1996-2000 (Cancer Fact
  and Figures 2004, American Cancer Society)

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Burden of Suffering 2 by colon vs rectal (2002)

• Colon Ca incidence 105,500/US/yr
• Colon Ca mortality 48,100/US/yr (2002)
  implies 45 colon Ca case mortality
• Rectal Ca incidence 42,000/US/yr
• Rectal Ca mortality 8,500/Us/yr (2002)
  implies 21 rectal Ca case mortality (02)
  Cancer Statistics, 2003. CA - Cancer Journ Clin.
  2003 53(1) 5-26

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Implications for increasing life expectancy

• CRC assumes exponentially increasing incidence
  with age
• The later the age onset of CRC the lesser the
  aggressiveness
• Thus, CRC with age shows an increasing incidence
  and decreasing case mortality
• But - secondary prevention (of progression of
  polyps) may neutralize that tendency

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(COLORECTAL CANCER BURDEN OF SUFFERING)

• Incidence rate /100,000 Pop./year,
• 15/100,000 in 40-50 y.o.,
• gt400/100,000 in gt 80 y.o.Frame, Paul S J Fam
  Pract, 1986 22(6) 511
• Fourth cancer in incidence, behind prostate,
  breast and lung (third in each sex). Third in
  cancer deaths each sex after lung, prostate
  (males) and lung, breast (females)

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Characteristics of Colon Ca

• Left gt Rt lesions in men (earlier diagnosis)
• Right gt Lft in women (worse prognosis).
• Patients gt 70 more likely to present in Stages A
  or B.
• Younger patients have more aggressive disease for
  a given stage

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Characteristics of CRC, ethnicity(1)

• African- and Hispano-Americans less likely to
  present in stages A or B.
• Asians have presentation patterns similar to
  non-Hispanic whites.
• Inflammatory bowel disease is a risk, may be
  considered premalignant.

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Characteristics of CRC, ethnicity(2)

• Askenazi Jews have lifetime risk of CRC equal to
  Caucasians w/ 1st degree relative with
  adenomatous polyp or CRC three times the
  lifetime accumulative risk (2.5 -gt 7.5)

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Characteristics of Colon Ca,( 3)

• Presentation with hematochezia renders a better
  prognosis (only 19 die of disease)
• After presentation with any other symptom 83
  die of disease (e.g. BM change, obstruction).

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GENETICS AND COLON CANCER (1)

• Lifetime risk of CRC 2.5
• Tripled when have first degree relative w/
  adenomatous colon polyp(s) or colon cancer - to
  7.5
• Increasing life expectancy expected to increase
  cumulative incidence
• Several specific genes identified

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Five -10 of colon Ca occurs in definite
hereditary patterns.

• Adenomatous polyposis syndromes (APS) account
  for about 9-10 of CRC
• Hereditary Non-polyposis Colon Cancer (HNPCC,
  Lynch syndrome) - accounts for about 6.
  Characterized by both pedunculated and sessile
  premalignant polyps,

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Adenomatous Polyposis Syndromes

• Familial Adenomatous Polyposis (FAP) 1-2 of
  CRC
• 100s -gt 1000 CR polyps beginning early in life.
  All develop CRC by age 40.
• Gardners syndrome numerous polyps, risk of
  colon cancer, plus osteomas, epidermoid cysts and
  sesmoid tumors.
• Turcots syndrome (assoc.. CNS tumors).

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CLINICAL PRESENTATION, (BRIEFLY)

• Hematochezia (distinct from melena) If first
  symptom, tends to indicate the descending colon -
  with better prognosis.
• Change in bowel habit e.g. alternating
  constipation and diarrhea.
• Obstipation to clinical lower bowel obstruction.

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COLORECTAL CANCER SURVIVAL (Dukes Stages, 5 y)

• Stage A limited to mucosa and submucosa 90
• Stage B extends into muscularis or serosa
  60-75
• Stage C one positive node - 69 six or more
  positive nodes, 27
• Stage D mets. to liver, bone, lung 5

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. COLORECTAL CANCER SURVIVAL(descriptive)

• Overall 5 yr Survival About 55-75
  (reciprocal of 39 case mortality 61)
• With localized disease 80-90
• With regional metastases 36
• With distant metastasis 29
• With disseminated disease 5

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Screening Methods success, simulation model

• Meth FOBT FS FS/OBT DCBE DCBE
  BE/FS Colnoscpy
• q yr 1 5 5
  5 10 5 10
• DcrCases 2378 1975 3087 3394 2812
  3875 3570
• DcrDths 1278 976 1556 1629
  1418 1843 1690
• DcrMort 53.5 40.1 65.1 68.1 59.3
  77.1 70.7
• Decr decrease cases, deaths (net after
  complications) mortality rate as percent
• Based on expectation of 4988 cases CRC/100,000
  pop cumulative from the ages of 50 through 85 yrs
  or death and expectation of 2391 deaths due to
  CRC in this population, cumulatively (Winawer et
  al, Gastroenterology, Sept, 1997).

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CRC Screening Guidelines according to
AGAAverage Risk - Option 1

• Digital rectal examination/fecal occult blood
  (DRE/FOBT) start _at_ 50 years every yr (AGA)
  predicts 50 (or less) reduced mortality

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CRC Screening GuidelinesAverage Risk - option 2

• Flexible sigmoidoscopy every 5 years (60 cm)
  Predicts only 40 reduction of CRC mortality

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CRC Screening GuidelinesAverage Risk option

• 3. FOBT Flexible Sigmoidoscopy q 5 yr predicts
  65 reduction CRC mortality

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CRC Screening GuidelinesAverage Risk - options
(AGA)

• 4. Dual Contrast BE every five yr. Predicts 68
  reduction in mortality from CRC

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CRC Screening GuidelinesAverage Risk - options
(AGA)

• 5. DCBE every 10 yr. Predicts 59 reduction in
  mortality due to CRC

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CRC Screening GuidelinesAverage Risk - options
(AGA)

• 6. FS DCBE every 5 yr predicts 77 reduction in
  mortality due to CRC.

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CRC Screening GuidelinesAverage Risk - options
(AGA)

• 7. Colonoscopy every 10 yr predicts 71 reduction
  in mortality from CRC

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Does CRC meet Criteria for screenability!

• 1. Condition has significant effect on life (Yes)
• 2. Significant Treatment available in curative
  phase (Yes)
• 3. Asymptomatic period of diagnose-ability (Yes)
• 4. Tx in the asymptomatic phase yields result
  superior to delaying until symptoms appear (Yes)
• 5. Tests of reasonable cost- sensitivity and
  specificity appropriate for population risk (Yes,
  with some argument)
• 6. Incidence sufficient to justify cost (Yes)

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CRC Screening GuidelinesNormal Risk (ACS)

• For average risk status start _at_ 50 years of age
• or start _at_ 40 years q 1 yr (AGA) if 1st degree
  relative w/ adenomatous polyp or CRC

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CRC Screening GuidelinesHigher Risk (ACS)

• Presence of Familial Adenomatous Polyposis
• Starting _at_ 10 y.o., DRE colonoscopy if
  polyps present repeat in 1 year, otherwise repeat
  in 3 years (ACS per Jessup et al CA Cancer J
  Clin 1997 4770-92)

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CRC Screening GuidelinesHigher Risk (ACS)

• Presence of HNPCC
• Starting in the teen years, proceed as with FAP
  DRE colonoscopy if polyps, repeat in 1
  year, otherwise repeat in 3 years (ACS per Jessup
  et al CA Cancer J Clin 1997 4770-92)

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CRC Screening GuidelinesHigher Risk (ACS)

• Symptoms present
• Starting at 25 years age, same as for 50 without
  symptoms, average risk (DRE FOBT colonoscopy
  if neg repeat in 3-5 years)

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Clinical terms used in CRC

• Carcinoembryonic antigen (CEA) tumor marker -
  sensitive but not specific. Best used for
  follow-up after definitive surgery
• Synchronous (as in polyps or cancers) existing
  at the same time as index cancer in a single
  patient
• Metachronous cancers or polyps occurring
  subsequent to the index cancer or polyp

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Pre-operative Workup Colonoscopy

• Synchronous cancer in 2-7.2
• Synchronous polyps 12-62
• Most surgeons favor colonoscopy gt DCBE

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Pre-op carcinoembryonic antigen (CEA)

• Described by Gold and Freedman 1965
• Usually returns to normal within one month after
  (successful) excision
• If post-op fall to normal is f/b persistent
  steady rise signals recurrent cancer in 95

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Primary Prevention CRC

• ASPIRIN and other NSAIDs 662,424 adults tracked
  1982 through 1988 for occurrence of CRC and
  whether or using aspirin (observational study)
  RR for CRC in those who used ASA gt 15 times/month
  was 0.60 in men, 0.58 in women (Thun MJ et al N
  Engl J Med 1991 3251593-96)

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Primary Prevention of Adenomas

• 793 subjects surveyed at 6 and 12 mos. into
  observation period, for ASA use Those who
  reported use on both questionnaires manifested
  fewer adenomas (OR 0.52) (Greenberg JNCI
  199385(11) 912-16)

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Colon Ca genetics (1),molecular approach

• Adenomatous polyposis coli gene (APC, actually
  APC suppresser), on chromosome 5q, short arm),
• when defective (loss of heterozygosity LOH),
  allele allows submission to CRC.
• 75 of adenomatous polyps have a mutation in the
  APC gene.

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Colon Ca genetics (3),molecular approach

• Deleted in colorectal cancer (DCC) gene, also a
  suppresser.
• Other suppresser genes include mutated in
  colorectal cancer (MCC), and p53.
• Oncogenes develop by mutation they include ras,
  src and myc.

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Colon Ca genetics (4),molecular approach

• Insulin like Growth Factor 30 of "normal
  mucosa" of CRC patients have lost the imprinting
  of IGF2, an epigenetic alteration, as opposed to
  10 of healthy individuals.

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Pre-op 2Staging

• HP, Chest XR
• Ck for evidence of tumor fixation if present, ck
  for hepatomegaly,
• Rectal, pelvic (as applic) necessary
• Chest XR for synchronous lung met (10 will
  develop)