COLORECTAL CANCER

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COLORECTAL CANCER
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COLORETAL CANCER

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  NARUEMON

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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 gt 50 years

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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

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• only adenomas are clearly premalignant and only
  a minority of such lesions ever develop into
  cancer

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• Populations-screening studies and autopsy surveys
  adenomatous polyps may be found in the colons
  of gt30 of middle aged or elderly people lt1 of
  polyp ever become malignant
• Occult blood foundlt5 of patient with such lesions

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• Point mutations in the K-ras protooncogenehypomet
  hylation of DNA leading to gene activationloss
  of DNA at the site of a tumor-suppressor gene(
  the adenomatous polyposis coli (APC)gene) on the
  long arm of chromosome 5 (5q21)

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• 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

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• 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

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• Cancers develop more frequently in sessile polyps
  
• Villous adenomas as often as tubular adenomas
  ,but become malignant more than three times

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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

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• 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

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• patients with colorectal cancer
• In animals high fat diet high cholesteral
  enhance risk for the development of colorectal
  adenoma and carcinoma

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• 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

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• FIBER
• High diet in fruits and vegetables in preventing
  the recurrence of colorectal adenoma or
  development of colorectal cancer

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HEREDITARY FACTORS AND SYNDROMES

• -Polyposis Coli
• -Hereditary Nonpolyposis Colon Cancer
• INFLAMMATORY BOWEL DISEASE
• Other high risk conditions
• -streptococcus bovis bacteremia
• -ureterosigmoidostomy
• -tobacco use

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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

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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

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• 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

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• 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

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• Off spring polyposis coliprepubertal 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

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• 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)

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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

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• HNPCChigh frequency of cancer arising in the
  proximal large bowel
• Median age aenocrcinoma lt 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

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• 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

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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

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• Symptoms bloody diarrhea,abdominal cramping and
  obstruction is signal of tumor
• In patient with history of IBD lasting gt 15
  years who continue to experience exacerbations,
  the surgical removal of the colon can
  significantly reduce the risk for cancer

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Other high risk conditions

• Streptococcus bovis bacteremia endocarditis or
  septicemia from fecal bacteremia
• high occult colorectal tumors,UGI cancer

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• 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 gt35 years
  of tobacco use

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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 )

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• 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)

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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

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• 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 lt10 test positive, benign polyp 20-30

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• 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

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• 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

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• Analysis of stool for mutation in the APC
  tumor-suppresser gene is being tested

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CLINICAL FEATURES

• Symptoms vary with the anatomic location
• Ileocacal valva to right colon,cancer arise in
  cecum and ascending colonlarge 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

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• 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

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• 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)

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Staging and Prognosis of colorectal cancer
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• 5 years survival
• A gt 90
• B1 85
• B2 70-80
• C 35-65
• D 5

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• 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

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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

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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

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• 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)

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• 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
• (oxaliplatinplatinum analog improove response
  rate when added to 5-FU and LV as initial
  treatment with metas disease

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• FOLFOX
• LV, 5-FU,oxaliplatin q 2 weeks
• Solitary hepatic metastasispartial 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

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• 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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