Colorectal Cancer

Epidemiology

• Second leading cause of cancer death in US - approx 148,000 cases/yr and 58,000 deaths

• Equal lifetime risk between men and women

• 93% of cases dx over age 50. Five-year survival of 60%

• Treatment costs over $6.5 billion per year – Among malignancies, second only to breast cancer at

$6.6 billion per year

Epidemiology

• Industrialized nations have the greatest risk

Geographic distribution of sporadic colon cancer

Pathogenesis

• Adenoma to Carcinoma sequence:

Pathogenesis

• Adenomatous polyps and adenocarcinoma are epithelial tumors of the large intestine

• Risk factors for polyps/adenomas to develop into cancer:

• Patient age (greatly increased after 50 yo, with prevalence doubling until age 80)

• Adenomas greater than 1 cm• Extensive villous patterns

Pathogenesis

Polyp/Cancer locations

CRC Risk Factors

• Age: CRC incidence increases rapidly after 50 years of age

• Adenomatous Polyps:• 30% at 50 years, 40-50% at 60 years, and up to

65% at 70 years• Most importantly, the risk of HGD in a polyp is 80%

higher in an older person than younger person

CRC Risk Factors

• Diet: Greatest association is between high fat diet/red meat and CRC

• High cholesterol, obesity linked to CRC

• A prospective study of more than 760,000 people showed diets rich in vegetables and high fiber grains demonstrated significant protection against fatal CRC

Diet and Colon Cancer

• Protective factors:– Fiber:

• decreases fecal transit time by increasing stool bulk

• Dilutes the concentration of other colonic constituents which minimizes interactions btwn carcinogens and colon epithelium

• Reduces colonic pH and generates short chain fatty acids

CRC Risk Factors

• Other risk factors:• Hx of Ulcerative Colitis• Strep Bovis infection• Ureterosigmoidostomy• Dermatomyositis• Pelvic Irradiation• Smoking/ETOH consumption• Obesity

CRC Protective Factors

• Other protective factors:– Exercise– NSAIDs/ASA– Folate– High calcium intake– Hormonal therapy– Selenium

CRC Risk Factors

• Genetics:

CRC Risk Factors

• Familial clustering present in 15% of all cases of CRC

• Increased risk 1.5-2.0 fold

• Individuals with hx of adenomas are at three to sixfold increased risk of metachronous neoplasms

Genetic Sydromes

• Familial adenomatous polyposis (FAP): an inherited condition caused by a germline mutation on chromosome 5 (APC gene)

• Leads to hundreds to thousands of polyps throughout the GI tract

• Other findings include:- duodenal adenomas

- fundic gland hyperplasia- mandibular osteomas- supernumerary teeth

FAP

Genetic Sydromes

• Attenuated FAP: (<100 adenomas) and later onset of CRC

• Turcot’s Syndrome: familial predisposition for colonic polyposis and CNS tumors

• Gardner’s Syndrome: variant of FAP• Osteomas of the skull and long bones• (CHRPE) Congenital Hypertrophy of the Retinal

Pigmented Epithelium

Genetic Sydromes

• Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome: also called Lynch syndrome: characterized by proximal cancer in 3rd and 4th decade of life

• Also associated with extracolonic cancers- (uterus, ovaries, stomach, small bowel and bile duct)

• Mutations in DNA mismatch repair genes (MLH1, MSH2)

HNPCC

• Amsterdam Criteria for Dx of HNPCC

1. > 3 relatives with HNPCC related cancers

2. > 1 case is a first-degree relative of 2 other

cases

3. > 2 successive generations affected

4. > 1 case diagnosed before age 50 years

Genetic Sydromes

• Other Genetic Diseases linked to CRC:• Muir-Torre Syndrome• Peutz-Jeghers Syndrome• Tuberous Sclerosis• Juvenile Polyposis Sydrome• Cowden disease• Cronkhite-Canada Syndrome

Screening

• Annual Fecal Occult Blood Test (FOBT)

• Flexible Sigmoidoscopy every 5 years

• Annual FOBT + Flexible Sigmoidoscopy every 5 years

• Colonoscopy every 10 years

• Double Contrast Barium Enema (DCBE) every 5 years

FOBT

• Uses the peroxidase activity of hemoglobin to cause a change in a reagent

• Consume diets high in fiber, restrict red meat consumption, vitamin C, and NSAID drugs for several days prior to testing

• The sensitivity of fecal occult blood testing ranges from 30–92% with a specificity of 98%

Barium Enema

-- The complication rate with the procedure is very low; the rate of perforation is 1 in 25,000 examinations

-- The sensitivity of double contrast barium enema ranges from 39–90%

Flexible Sigmoidoscopy

• Colonoscope inserted to the descending colon

• 60% of all neoplasms are within this distribution- therefore, flex sigmoidoscopy along with FOBT provides an effective screening tool

• Minimal prep and no sedation required; office procedure performed by internists, fam med docs, NPs

• Perforation risk: 1-2/10,000

Colonoscopy

• Gold standard for CRC screening

• Risk of complications: 0.1–0.3% risk of hemorrhage and perforation

• Allows for mucosal biopsy, polypectomy, tattooing, accurate localization and flushing/suctioning

• Sensitivity of colonoscopy for the detection of polyps greater than or equal to 1 cm and tumors is greater than 95%

Colonoscopy

Chemoprevention

• COX-II inhibitors

• Estrogens

• Ursodeoxycholic Acid

Adenocarcinoma

TNM and Dukes Staging for CRC

Treatment

• Primary treatment for early colon cancer is surgery. For rectal cancer, total mesorectal excision

• In tumors that are > T3 or > N1, preoperative chemo is recommended

• Radiation is useful in rectal cancer, not colon cancer

CRC Treatment

• Common chemotherapeutic regimen includes 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)

• Other agents include bevacizumab, cetuximab,irinotecan, capecitabine

Question 1

• A 32 yo male presents for annual health maintenance visit. His mother was dx with colon cancer at age 55. Patient should undergo screening at what age?

A. Now

B. 40 yo

C. 45 yo

D. 50 yo

Question 1

• Pt has a twofold increase in CRC compared to age matched controls due to first degree relative with cancer

• Guideline- screen ten years before first-degree relative or at age 40 depending on which comes first

Question 2

• Three months ago, a 62 yo BM underwent a flex sig and was found to have an obstructing mass. He underwent a sigmoid resection which was considered curative. Did not receive post-op chemo/radiation. Which is the most appropriate CRC surveillance procedure for this pt?

A. Colonoscopy Now

B. Colonoscopy In 1 year

C. Colonoscopy In 3 years

D. CT Abdomen now

E. CT Abdomen in 3 years

Question 2

• Synchronous cancers occur in 3-5% of pts found to have CRC

• Pt never had colonoscopy previously

• Once resection performed- repeat colon in 1 year then 3 year intervals

• Abdominal CT yearly for 3 years

Question 3

• The test of choice for screening 1rst degree relatives of pts with FAP is:

A. Colonoscopy starting at age 12 every 5 years

B. Genetic testing at age 10 to 12 yo

C. Sigmoidoscopy starting at age 12 every year

D. Sigmoidoscopy starting at age 20 every year

E. No screening

Question 3

• Genetic testing for a mutation in the APC gene if the first screening test.

• If genetic testing is not available, then sigmoidoscopy starting at age 12