Transcript COLORECTAL CANCER

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
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-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 2030%
 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
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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 5FU 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)