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11-16-10-Colon-Cancer-Prevention-Hendershot-Outline

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					11-16-10 Colon Cancer Prevention (Hendershot) – Outline

Epidemiology
     Age >50 90%
     Hx of colorectal polyps (adenomatous) or CRC
     IBD
     Fam hx
            o 20% of people have fam hx
                                             st
            o Risk is doubled in those with 1 deg relative
            o Increased risk if diagnosed before age 45
                    No increase risk based on left or right sided CRC
                    Slight increased risk with rectal cancer




       Inherited syndromes: (5-10% of those diagnosed) familial adenomatous polyposis (1% of all CRC) and
        hereditary non-polyposis(3-5% of all CRC) lifetime risk up to 80% for getting CRC
             o Others include: Turcot and Peutz-Jeghers syndromes
             o Almost all genes known to cause a predisposition to CRC are inherited in autosomal dominant
                  pattern; Fam hx that suggests this pattern
                       vertical transmissions, sequential generations
                       If a parent caries the predisposition every child male or female has 50% chance of
                           inheriting
                       clinically – earlier age, predisposition to other cancers(endometrial), two or more
                           primary cancers in a single individual
             o High risk
                       Strong fan hx of CRC and/or polyps
                       Multiple primary cancers in a patient with CRC
                       Others cancers consistent with known syndromes causing inherited risk of CRC such as
                           endometrial cancer
                       Early age at diagnosis of CRC
       RACIAL AND ETHNIC
             o African Americans - highest incidence and mortality in US
             o Ashkenazi Jews one of highest CRC risks of any ethnic group
       Lifestyle
             o Diets high in meat and low in fruits and vegetables, lack of physical activity, obesity, smoking,
                  heavy alcohol use, diabetes increase risk
       The third most common cancer in U.S.
             o 142,570 new cases expected in 2010
             o The second deadliest cancer
                       51,370 deaths nationwide
             o Cancer rates are declining in both men and women over age 50
                       Overall survival rate (5 year) @ 64%
                       More than 1 million Americans living with colorectal cancer
             o  Colon and rectal cancers for men and women have higher combined mortality rate than prostate
                or breast
       5% of Americans will develop disease in their lifetimes
            o Risk increase after age 40, rises sharply at age 55, then doubles each decade
Clinical
      Pathophysiology
             o Colorectal tumors present as: benign growths to invasive cancers; epithelial derived tumors(
                 adenomas and adenocarcinomas)
             o Pathologists generally classify as: non-neoplastic polyps, neoplastic polyps, and invasive cancers
             o 95% of CRCs are carcinomas and 95% of theses are adenocarcinomas
                        Adenomatous polyps are benign tumors that may undergo malignant transformation:
                           tubular, tubulovillous, villous (increasing malignant potential left to right)
             o Genetics
                        Increased incidence in CRC with family hx
                                 In families with multiple members and CRC, there is an autosomal dominant
                                     pattern of cancer susceptibility
                        75% sporadic
                                 25% fam hx that suggests genetic contribution, common exposure or both
                                 5-6 % are genetic mutation
                        At least 5-7 major deleterious molecular changes may occur when normal epithelium
                           cell progresses in a clonal fashion to carcinoma
                                 2 major pathways
                                          o 85% chromosomal instability (CIN)
                                                    APC – FAP autosomal dominant
                                          o 15% microsatellite instability (MSI or replication error)
                                                    HNPCC autosomal dominant germ line mutations in
                                                        microsatellite instability pathway (MSI)
      SYMPTOMS
             o Change in bowel habits, constipation, diarrhea; Change in shape of stool
                        Blood in stool, melena
             o Persistent abdominal pain
             o Unintentional weight loss, Loss of appetite
             o Unexplained fatigue
             o Nausea or vomiting
             o Anemia
             o Jaundice
      Natural History
             o Colorectal tumors present as: benign growths to invasive cancers; epithelial derived tumors(
                 adenomas and adenocarcinomas)
             o Pathologists generally classify as: non-neoplastic polyps, neoplastic polyps, and invasive cancers
             o 95% of CRCs are carcinomas and 95% of theses are adenocarcinomas
             o Adenomatous polyps are benign tumors that may undergo malignant transformation: tubular,
                 tubulovillous, villous (increasing malignant potential left to right)
      Polyp Types
             o Different types
                        Hyperplastic
                                 minimal cancer potential
                        Adenomatous
                                 approximately 90% of colon and rectal cancers arise from adenomas
Prevention
      Primary prevention – identifying genetic, biological, and environmental factors that are etiologic or
         pathologic in the development of cancer.
o   Screening
         Digital Rectal Exam
                Often part of a routine physical examination.
                No cleansing of the colon is necessary.
                The test is usually quick and painless.
                The test can detect abnormalities only in the lower part of the rectum.
                Additional procedures are necessary if the test indicates an abnormality.
         AAFP screening with FOBT, sigmoidoscopy, or colonoscopy beginning at age 50
                Grade A
                age 76-85 not routine (grade C)
                > 85 recommends against screening(grade D)
                insufficient to assess benefits and harms of CT colonography and fecal DNA
                    testing as screening tests (grade I)
                recommends against routine use of ASA and NSAIDS to prevent CRC in
                    individuals at average risk
         SCREENING INTERVALS
                FOBT annual
                Sigmoidoscopy every 5 years with FOBT every 3 years
                Colonoscopy every 10 years
         Benefits
                Cancer Prevention
                         o Removal of pre-cancerous polyps prevent cancer (unique aspect of
                             colon cancer screening)
                Improved survival
                         o Early detection markedly improves chances of long term survival
         Average risk adults age 50 and older
                Tests that detect adenomatous polyps and cancer
                         o Colonoscopy every 10 years, (preferred)
                                   view the rectum and the entire colon.
                                             can perform a biopsy and remove polyps or other
                                                abnormal tissue during the test, if necessary.
                                   This test may not detect all small polyps, nonpolypoid lesions,
                                       and cancers, but it is one of the most sensitive tests currently
                                       available.
                                             Thorough cleansing of the colon is necessary before
                                                this test.
                                             Some form of sedation is used in most cases.
                                             Although uncommon, complications such as
                                                bleeding and/or tearing/perforation of the lining of
                                                the colon can occur
                         o Flexible sigmoidoscopy (FSIG) every 5 years*
                                   Usually quick, with few complications.
                                             For most patients, discomfort is minimal.
                                             may be able to perform a biopsy (the removal of
                                                tissue for examination under a microscope by a
                                                pathologist) and remove polyps during the test, if
                                                necessary.
                                             Less extensive cleansing of the colon is necessary
                                                with this test than for a colonoscopy.
                                   View only the rectum and the lower part of the colon. Any
                                       polyps in the upper part of the colon will be missed.
                               There is a very small risk of bleeding or tearing/
                                perforation of the lining of the colon.
                   Additional procedures, such as colonoscopy, may be
                       necessary if the test indicates an abnormality
        o Double contrast barium enema (DCBE) every 5 years*
                   view the rectum and the entire colon.
                             Complications are rare.
                             No sedation is necessary.
                   This test may not detect some small polyps and cancers
                             Thorough cleansing of the colon is necessary before
                                the test.
                             False-positive results are possible.
                             cannot perform a biopsy or remove polyps during
                                the test.
        o CT colonography (CTC) every 5 years*
   Tests that primarily detect cancer
        o Annual guaiac-based fecal occult blood test (gFOBT)* with high test
             sensitivity for cancer
                   No cleansing of the colon is necessary.
                             Samples can be collected at home.
                             The cost is low compared with other colorectal
                                cancer screening tests.
                             FOBT does not cause bleeding or tearing/perforation
                                of the lining of the colon.
                   This test fails to detect most polyps and some cancers
                             False-positive results (the test suggests an
                                abnormality when none is present) are possible
                             Dietary restrictions and changes are often
                                recommended for several days before a guaiac
                                FOBT.
                   Additional procedures, such as colonoscopy, may be
                       necessary if the test indicates an abnormality.
        o Annual fecal immunochemical test (FIT)* with high test sensitivity for
             cancer, or every 3 years
        o Stool DNA test (sDNA)*, with high sensitivity for cancer, interval
             uncertain every 3 years
                   Fecal occult blood tests detect blood in the stool – which is
                       intermittent and non-specific
                   Colon cells are shed continuously
                   Polyps and cancer cells contain abnormal DNA
                   Stool DNA tests detect abnormal DNA from cells that are
                       passed in the stool*
                   Pros
                             No dietary restrictions needed
                             Specificity for cancer may be significantly higher
                                than other forms of stool testing
                             No stool sampling required (entire bowel movement
                                collected)
                             Company-sponsored studies report high levels of
                                patient acceptance
                   Cons
                             Misses some cancers
                                              Sensitivity for adenomas with current commercial
                                               version of test is low
                                              Technology (and test versions) are in transition
                                              Appropriate re-screening interval is not known
                                              Costs much more than other forms of stool testing
                                               (approximately $300 - $400 per test)
                                              Not covered by most insurers
                                              Not clear how to manage positive stool DNA test if
                                               colonoscopy is negative
                                              FDA approval concerns
o   NCI Recommendations
          Chemoprevention
          Dietary factors
          Other factors
o   Polyp removal
          Removal of adenomatous polyps reduces risk of CRC
          Impact of screening left colon > right
          National Polyp Study showed a reduction of CRC incidence by 76-90%
          Risks perforation and bleeding
o   Obesity
          Physical activity – most studies show increased risk with sedentary lifestyle; RR
              reduction of 40-50%
          Obesity increases risk of CRC in premenopausal women
          Alcohol – increased risk shown in males with consumption of beer; week association
o   Smoking
          Cigarettes – increased risk in incidence of CRC and more risk with recurrent adenoma
              after polypectomy
          Estimated that 12% of CRC’s were from smoking in 1997
          > risk with > time and amounts
o   Antioxidents – no benefit shown
o   Nsaids( sulindac and celebrex) induce regression of adenoma in people with FAP; may work by
    inhibiting COX II and protaglandins which are found in higher amounts in CRCs or independent
    pathways that trigger programmed cell death; Affect stops when meds are stopped; no RCT has
    shown that nsaids prevent deaths from CRC
          ASA has shown in some studies to reduce incidence of CRC, and reduce recurrent
              adenomas
          NCI Recommendations
                    NSAIDS
                            o Inadequate evidence that the use of NSAIDS reduces the risk of
                               colorectal cancer (CRC)
                            o Celecoxib decreases the adenoma burden and may help reduce risk in
                               CRC associated with adenomatous polyposis
                            o Celecoxib does not reduce the risk associated with sporadic CRC
                            o Risks include upper GI bleeds, increased cardiovascular events(MI,CHF,
                               CVA)
o   One study has shown that physical activity, and low vegetable intake has had no effect on CRC
    incidence in those with fam hx
          Low fat, high fiber, fruits and vegetables
                    Inadequate evidence to support decrease in CRC, originally looking for decrease
                       in adenomas
                    No risks associated with diet can be attributed to dietary fat and meat intake
                      Women’s health Initiative looked at postmenopausal women age 50-79 and followed
                       them over 8 years. No change in incidence of CRC when they decreased dietary fat by
                       10%
                            6 ccs and 2 ch looked at diet and risk of colorectal adenomas; 3 studies showed
                                increase risk; possible risk reduction after polypectomy for recurrent polyps
                     Mixed evidence to support role of dietary fiber
                            Possible mechanisms:
                                     o Binding bile acids, increasing water, decreasing transit time
                                     o Fiber may cause bacterial fermentation and increase in short chain
                                         fatty acids such as butyrate – in vitro anti-carcinogenic effects
                            13 studies in 9 countries showed intake of fiber rich foods inversely related to
                                CRC’s left and right sided, in men and women, and in all age groups studied
                            Nurse’s Health study showed no difference in risk of CRC compared to fiber
                                intake
                     Calcium
                            Several trials show inverse relationship with calcium intake and cancer risk
                            May be reduced rates for recurrent adenomas
                            Average dose 1250-2000mg daily
                            No decrease with calcium use of 5 years at a 500mg dose
                     Selenium
                            Increased selenium levels was associated with a reduced prevalence of
                                colorectal adenomas
                            Pre colonoscopy levels of serum selenium were measured, those with high
                                levels were less likely to have adenomas
                            Selenium levels and apoptosis were not strongly associated
                            Currently 3 clinical trials with NCI looking at CRC
                     Other vitamins
                            Iowa study 35,000 women showed inverse relationship between Vitamin E
                                intake in CRC
                                     o Women’s Health study and 14 other RCT’s showed no evidence of
                                         vitamin E or antioxidant vitamins reducing CRC risk
                                     o Vitamin E (alpha-tocopherol) ATBC trial, no reduced risk of CRC
                                         incidence and increased risk of adenomatous polyps (higher incidence
                                         may be due to increased colonoscopy due to GI symptoms)
                            Beta-carotene: no effect on the incidence of CRC: ATBC, PHS and WHI; no
                                effect on recurrent polyposis as
                            Vitamin D – daily intake of 1000 IU and serum level of 33 ng/ml were each
                                associated with 50% lower risk of CRC
                            Folate no proven benefit
                                     o Folate intake may reduce incidence in CRC in women with fam hx
            o   Post-menopausal hormones
                     In the Women’s Health Initiative study there was a 44% reduction in CRC incidence (in
                       group taking estrogen and progesterone)
                            18% reduction in women who have ever used hormone replacement
                            > # of positive lymph nodes and more advanced cancers were found in those
                                that did
                     Risks: increased risk of breast cancer, coronary heart disease, thromboembolic events
Summary
    CRC can be prevented through screening
    Most of population at risk is not screened
    Chemoprevention may be promising

				
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