COLORECTAL CANCER - PowerPoint by sammyc2007

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									COLORECTAL CANCER
    COLORETAL CANCER




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
                  NARUEMON
          INCIDENCE

 Relatively unchanged during the past 30
  years while mortility rate has
  decreased,particularly in females
 U.S.146,940 new cases occurred in 2004
  ,and 56,730 deaths were due to
  colorectal cancer
 Colorectal cancer generally occureds in
  individuals >= 50 years
  Polyps and molecular
      pathogenesis
 Most colorectal cancers regardless of
  etiology,arise from adenomatous polyps
 A polyp protrusion from the mucosal surface
  classified pathologically as
  -a nonneoplastic hamartoma(juvenile polyp)
  -a hyperplastic mucosal proliferation
  (hyperplastic polyp)
  -an adenomatous polyp
only adenomas are clearly premalignant
 and only a minority of such lesions
 ever develop into cancer
 Populations-screening studies and
  autopsy surveys : adenomatous polyps
  may be found in the colons of >30% of
  middle aged or elderly people <1% of
  polyp ever become malignant
 Occult blood found<5% of patient with
  such lesions
 Point mutations in the K-ras
  protooncogene;hypomethylation of DNA
  leading to gene activation;loss of DNA at
  the site of a tumor-suppressor gene( the
  adenomatous polyposis coli (APC)gene)
  on the long arm of chromosome 5 (5q21)
 Allelic loss at the site of a tumor
  suppressor gene located on chromosome
  18q (the deleted in colorectal
  cancer(DDC)gene)
 And allelic loss at
  chromosome 17p,associated with
  mutations in the p53 tumor-suppressor
  gene
 Thus,the altered prolifferative pattern of
  the colonic mucosa,which results in
  progression to a polyp and then to
  carcinoma(mutation activation of an
  oncogene + loss of genes normally
  suppress tumorigenesis
 Cancers develop more frequently in
  sessile polyps
 Villous adenomas as often as tubular
  adenomas ,but become malignant more
  than three times
Etiology amd risk factors

 DIET
  often in upper socioeconomic population
  mortality direct correlated with
  consumption of calories, meat protein,fat
  and oil
 Coloretal cancer increase in Japan
  ,adpoted more western diet
 ANIMAL FAT
  hypothesis; ingestion of animal fats found
  in red meats and processed meat leads
  to an increased proportion of anaerobes
  in the gut microflora,resulting in
  conversion of normal bile acids into
  carcinogens
Reports of increase fecal anaerobe stool in
 patients with colorectal cancer
 In animals high fat diet ;high cholesteral
  enhance risk for the development of
  colorectal adenoma and carcinoma
 INSULIN RESISTANT
 Excess weight gain develop insulin
  resistant with increased circulating
  insulin,leading to higher circulating
  concentrations of insulin like growth
  factor type 1(IGF-1):stimulate
  proliferation of the intestinal mucosa
 FIBER
 High diet in fruits and vegetables in
  preventing the recurrence of colorectal
  adenoma or development of colorectal
  cancer
HEREDITARY FACTORS
  AND SYNDROMES
   -Polyposis Coli
   -Hereditary Nonpolyposis Colon Cancer
   INFLAMMATORY BOWEL DISEASE
   Other high risk conditions
     -streptococcus bovis bacteremia
     -ureterosigmoidostomy
     -tobacco use
Hereditory GI polyposis
     syndromes
 25% colorectal cancer have family
  history

 1.Polyposis Coli
 rare condition
 thousounds of adenomatous polyps
 throug out the large bowel
 AD trait
         Polyposis Coli

 Deletion in the long arm of chromosome
  5 (APC gene )
 Soft tissue and bony tumors,congenital
  hypertrophy of the retinal pigment
  epithelium,mesenteric desmoid
  tumors,and of ampullary cancers in
  addition to the colonic polyps ; subset of
  polyposis coli known as
  Gardner ‘s syndrome
 The appearance of malignant tumors of the
  central nervous system accompanying
  polyposis coli defines
  Turcot’ s syndrome
  Colorectal cancer in almost patients develop
  before 40
  Once the multiple polyps that constitute
  polyposis coli are detected,patients should
  undergo a total colectomy
 Medical therapy with NSAIDs such as
  sulindac and cyclooxygenase-2 inhibitors
  such as celecoxib can decrease the
  number and size of polyps in patients
  with polyposis coli; however this effect on
  polyps is only temporary
 Colectomy remains the primary therapy
 Off spring polyposis coli:prepubertal
  when diag in parent,50% risk develop
  premalignant and should be carefully
  screened by annual flexible
  sigmoidoscopy until 35
 Proctosigmoidoscopy: screening ,tend to
  distribute from cecum to anus
 Colonoscope or BE unnecessary
 Testing occult blood stool ; inadequate
  screening
 Alternative method ; testing DNA from
  peripheral blood mononuclear cells for
  the presence of a mutated APC gene
 The detection germline mutation ;lead
  to definitive diagnosis(before
  development of polyps)
Hereditary nonpolyposis
     colon cancer
 Lynch syndrome
 AD trait
 The presence of three or more relatives
  with histologically documented colorectal
  cancer
 More case diagnosed before 50
 At least two genarations
 HNPCC;high frequency of cancer arising in the
  proximal large bowel
 Median age aenocrcinoma < 50 (10-15 years
  younger than general population)
 The proximal colon tumors in HNPCC have a
  better prognosis than sporadic tumors from
  patients of similar age
 The association of colorectal cancer with either
  ovarian or endometrial CA strong in women
 Recommended that members of such
  families : biennial colonoscopy
  beginning at age 25 years, with
  intermittent pelvic ultrasonograghy and
  endometrial biopsy offered for
  potentially germline mutations of several
  genes,particularly hMLH1 on
  Chromosome3
   Inflammatory bowel
         disease
 Cancer develop more commonly in UC
  than with granulomatous colitis
 Risk colorectal cancer small during initial
  10 years of the disease,but increase
  ~0.5-1% per year , develop 8-30% of
  patients after 25 years risk higher in
  younger patients with pancolitis
 Symptoms ;bloody diarrhea,abdominal
  cramping and obstruction is signal of
  tumor
 In patient with history of IBD lasting >=
  15 years who continue to experience
  exacerbations, the surgical removal of
  the colon can significantly reduce the risk
  for cancer
Other high risk conditions

  Streptococcus bovis bacteremia;
   endocarditis or septicemia from fecal
   bacteremia:
   high occult colorectal tumors,UGI cancer
 Ureterosigmoidostomy: colon cancer
  develops in 5-10% of people 15-30 years
  after ureterosigmoidostomy to correct
  congenital extrophy of bladder
 Tobacco use: colorectal adenoma after
  >35 years of tobacco use
     Primary prevention
 Chemopreventive agents is ASA and other
  NSAIDs; suppress cell proliferation by inhibit
  prostaglandin synthesis
 Regular aspirin use reduces the risk for colonic
  adenoma and carcinomas
 Oral folic acid supplements and oral calcium
  supplements reduced risk of adenomatous
  polyps and colorectal cancer
  ( in case controle studies )
 Antioxidant : adcorbic acid ,tocopheral
  ,beta-carotine ;lower rate of colorectal
  cancer
 Estrogen replacement therapy : reduce
  risk of colorectal cancer in woman (effect
  on bile acid synthesis and composition
  ,decrease synthesis of IGF-1)
            SCREENING
 Important in having family history ,relative risk
  increase 1.75 (before 60)
 Proctosigmoidoscopy ; observation 60% early
  lesions located in rectosigmoid
 Large bowel cancers ;rectum decrease in
  several decades , increase in more proximal
  descending colon
 Rigid proctosigmoidoscopy ;occult neoplasm
  ,cost effective
 Flexible,fiberoptic sigmoidoscopes ; 60 cm
   colon cancer detection
  leaves proximal half of large bowel unscreened
  Digital examination,occult blood testing in older
   than 40 (prostate cancer in men)
  Documented 50% colorectal cancer have
   negative fecal hemoccult test, 2-4% positive
  Cancer <10% test positive, benign polyp 20-
   30%
 Positive test ; sigmoidoscopy,barium
  enema ,and/or colonoscopy
 The American Cancer Society fecal
  Hemoccult screening annually and
  flexible sigmoidoscopy every 5 years
  begin 50 no colorectal cancer risk
  factors
 ‘total colon examination’ every 10 years
 As alternative to Hemoccult testing with
  periodic flexible sigmoidoscopy
 Colonoscopy superior to double-contrast
  barium enema higher sensitivity for
  detecting villous or dysplastic adenomas
  or cancers
 Colonoscopy every 10 years beginning
  after 50 will prove to be cost effective
 Analysis of stool for mutation in the APC
  tumor-suppresser gene is being tested
   CLINICAL FEATURES
 Symptoms vary with the anatomic location
 Ileocacal valva to right colon,cancer arise in
  cecum and ascending colon;large without
  obstruction or bowel habits change,liquid stool
 Lesions of the right colon commonly ulcerate
  chronic insidious blood loss no stool change
 Ascending colon present with symptoms such
  as fatique,palpitations,angina pectoris
  hypochromic microcytic anemia ;iron deficiency
 Cancer may bleed intermittently ;occult
  blood maybe negative
 Unexplained presence of iron-def anemia
  in adult (except premenopause
  ,multiparous women) ;endoscopic and/or
  radiographic visualization of the entire
  large bowel
 Transverse and descending colon tumors
  development of abdominal cramping
  occasional obstruction ,perforation
 Radiograph ;annular ,constricting
  lesions(‘apple core’ or ‘napkin-ring’)
 Cancer in rectosigmoid often associated with
  hematochezia ,tenesmus,and narrowing of
  caliber of stool anemia infrequent finding
 Suspect hemorrhoid (rectosigmoid)
Staging and Prognosis of
   colorectal cancer
   5 years survival
   A    > 90%
   B1      85%
   B2      70-80%
   C       35-65%
   D        5%
 Most recurrent after a surgical resection
  of a large bowel cancer within the first 4
  years
 CEA; tumor recurrence
 Chromosome deletion 18q DEC gene ;
  risk for metastatic spread
 Median survival after detection of distant
  metastasis 6-9 mo to 24-30 mo
        TREATMENT

 Tumor resection
 Evaluate metastasis : PE ,CXR,LFT,CEA
 Large bowel scope ;synchronous
  neoplasm and or polyp
 Radiation therapy ;rectal cancer
  decrease 20-25% regional
  recurrence(B2) serosa: high rate
             Treatment
 Preop radiotherapy indicated for pre or post
  operative pt. with large potentially unresectable
  rectal cancer
 Radiation therapy is not effective in primary
  treatment colon cancer
 Chemotherapy 5-FU the most effective single
  agent
 Advance colorectal cancer : only marginal
  effect
 Concomittant administration of folinic
  acid (leucovorin) improove efficacy of 5-
  FU in patient with advanced colorectal
  cancer ;enhance binding 5-FU to target
  enzyme (3 fold)
 5-FU IV , orally in form capecitabine
 Irinotecan (CPT-11) , a topoisomerase 1
  inhibitor ;prolong survival compared to
  supportive care
 FOLFIRI
  LV,5-FU,oxaliplatin q 2 weeks
  (oxaliplatin;platinum analog improove response
  rate when added to 5-FU and LV as initial
  treatment with metas disease
 FOLFOX
  LV, 5-FU,oxaliplatin      q 2 weeks

Solitary hepatic metastasis;partial liver resection
Stage C ;5-FU,LV for 6 mo after resection of
  tumor decrease 40% recurrent rate,30%
  improove in survival
Stage B2 not benefit for adjuvant therapy
 Rectal cancer post-op 5-FU plus
  radiation reduce risk of recurrence and
  increase chance of cure for stage B2 ,C
 Lack of use of life extending adjuvant
  therapy over 65 yrs.(inappropriate as the
  benefits of adjuvant therapy)

								
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