1. UPPER GI BLEEDING: COLON CANCER
GROUP A
BGD February 1, 2010

2. Clinical Manifestations
Cecum and ascending colon
May become quite large without resulting in any obstructive symptoms or noticeable alterations in bowel habits
Lesions of the right colon
Commonly ulcerate, leading to chronic, insidious blood loss without a change in the appearance of the stool
Tumors of the ascending colon
Fatigue, palpitations, angina pectoris
Hypochromic, microcytic anemia indicative of iron deficiency

3. Clinical Manifestations
Transverse and descending colon
Tend to impede the passage of stool
Abdominal cramping, occasional obstruction, perforation
Rectosigmoid
Hematochezia, tenesmus, narrowing of the caliber of stool
Anemia is an infrequent finding
Random fecal occult blood test may be negative
Cancer may bleed intermittently
Radiographs of the abdomen often reveal characteristic annular, constricting lesions ("apple-core" or "napkin-ring")

4. Clinical Manifestations
Patient Correlation
Hematochezia
Chief complaint
6 hours PTA passed out half a tsp of blood after defecation
4 hours PTA 1 tbsp of blood
30 minutes PTA 2 cups of fresh blood
Rectal exam showed fresh blood on examining finger

5. Clinical Manifestations
Patient Correlation
Impeded passage of stool
Constipation for several years
Palpitations
Sitting HR 110 beats/min
Supine HR 90 beats/min
Felt dizzy, had cold clammy perspiration

6. Pathophysiology
Most colorectal cancers, regardless of etiology, arise from adenomatous polyps.
Polyp - a grossly visible protrusion from the mucosal surface
Non-neoplastic hamartoma (juvenile polyp)
Hyperplastic mucosal proliferation (hyperplastic polyp)
Adenomatous polyp – premalignant
Only a minority of such lesions becomes cancer

7. Pathophysiology Molecular changes
Mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis
Point mutations in the K-ras protooncogene
Hypomethylation of DNA, leading to gene activation
Loss of DNA (allelic loss) 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 (DCC) gene]
Allelic loss at chromosome 17p, associated with mutations in the p53 tumor-suppressor gene

8. Pathophysiology
Progressive somatic mutational steps in the development of colon carcinoma. The accumulation of alterations in a number of different genes results in the progression from normal epithelium through adenoma to full-blown carcinoma. Genetic instability (microsatellite or chromosomal) accelerates the progression by increasing the likelihood of mutation at each step. Patients with familial polyposis are already one step into this pathway, since they inherit a germline alteration of the APC gene. TGF, transforming growth factor.

9. Pathophysiology
Clinically, the probability of an adenomatous polyp becoming a cancer depends on:
Gross appearance of the lesion
Histologic features
Size
Adenomatous polyps:
Pedunculated (stalked)
Sessile (flat-based)
Cancers develop more frequently in sessile polyps

10. Pathophysiology Histologically, adenomatous polyps may be: Tubular
Villous (i.e. Papillary)
Most are sessile- become malignant more than three times as often as tubular adenomas
Tubulovillous

11. Risk Factors Present in the patient Advanced age (78 years old)
Diet: animal fat
History of cancer
Polyps, particularly adenomatous polyps
Hereditary syndromes
Polyposis coli
Non-polyposis syndrome (Lynch syndrome)
Inflammatory bowel disease
Infection (viral exposure, Streptococcus bovis bacteremia)
Uterosigmoidoscopy
Physical inactivity
Smoking/tobacco use
Alcohol
Exogenous hormones
Environmental factors
Present in the patient
Advanced age (78 years old)
Smoking (19 pack years)

12. Risk Factors Diet Animal fats Insulin resistance Obese persons
Upper socioeconomic populations
Japan: increased incidence of colorectal cancer since they adopted a “western” diet
Animal fats
Red meats and processed meat increased proportion of anaerobes in the gut microflora conversion of normal bile acids into carcinogens
Insulin resistance
“Western” diets, physical inactivity- higher prevalence of obesity
Obese persons
Insulin resistance increased circulating levels of insulin higher circulating concentrations of insulin-like growth factor type I stimulate proliferation of the intestinal mucosa

13. Risk Factors Hereditable (Autosomal Dominant) Gastrointestinal Syndromes
Distribution of Polyps
Histologic Type
Malignant Potential
Associated Lesions
Familial adenomatous polyposis
Large intestine
Adenoma
Common
None
Gardner's syndrome
Large and small intestines
Osteomas, fibromas, lipomas, epidermoid cysts, ampullary cancers, congenital hypertrophy of retinal pigment epithelium
Turcot's syndrome
Brain tumors
Non-polyposis syndrome (Lynch syndrome)
Large intestine (often proximal)
Endometrial and ovarian tumors
Peutz-Jeghers syndrome
Small and large intestines, stomach
Hamartoma
Rare
Mucocutaneous pigmentation; tumors of the ovary, breast, pancreas, endometrium
Juvenile polyposis
Large and small intestines, stomach
Hamartoma, rarely progressing to adenoma
Various congenital abnormalities

14. Diagnostic Procedures
Screening
Goal: earlier detection of localized, superficial cancers in asymptomatic individuals to increase the surgical cure rate
Candidates:
50 years old
Family history of the disease in first-degree relatives

15. Diagnostic Procedures
Digital rectal examination
Part of any routine physical evaluation in adults older than age 40
An inexpensive maneuver for the detection of masses in the rectum

16. Diagnostic Procedures
Hemoccult blood test
Detects occult fecal blood
Colonoscopy
Superior to double-contrast barium enema
has a higher sensitivity for detecting villous or dysplastic adenomas or cancers than the strategy employing occult fecal blood testing and flexible sigmoidoscopy

17. Diagnostic Procedures
Biopsy
During a colonoscopy, several biopsies (each at different locations in the colon and rectum) may be taken
Used to diagnose cancer or estimate how far cancer has spread
Used to obtain bits of tissue to be checked in the laboratory for signs of cancer or other diseases

18. Diagnostic Procedures
Proctosigmoidoscopy
Based on the observation that 60% of early lesions are located in the rectosigmoid
Flexible, fiberoptic sigmoidoscopes
To visualize the colon for up to 60 cm, which enhances the capability for cancer detection

19. Diagnostic Procedures
Virtual colonoscopy
Computed tomography colography 
A method under study to examine the colon by taking a series of x-rays and using a high-powered computer to reconstruct 2-D and 3-D pictures of the interior surfaces of the colon from these x-rays
Pictures can be saved, manipulated to better viewing angles, and reviewed after the procedure, even years later

20. Diagnostic Procedures
Air-contrast barium enema
Highly sensitive for detecting polyps greater than 1 cm in diameter
After the barium passes through the intestine, air will then be pumped into it
Using the barium, the technician is able to get a clear picture of the lining of the intestine from multiple angles

21. Diagnostic Procedures
Endoscopic ultrasound
To evaluate the gastrointestinal tract 
Improves tumor characterization, and enables more precise TNM staging

22. Diagnostic Procedures
Pre-operative elevation of the plasma carcinoembryonic antigen (CEA) level predicts eventual tumor recurrence

23. Management Lower GI bleeding
Stable patients may undergo appropriate diagnostic procedures to determine the source of bleeding
Unstable patients
Appropriate fluid and electrolytes
Once stable, determine the source of bleeding for appropriate management
Colon cancer treatment options depends on:
Stage of the cancer
Whether the cancer has recurred
General health status of the patient

24. Management STAGE DESCRIPTION TREATMENT
Cancer has not grown beyond the inner lining of the colon
Polypectomy or local excision through the colonoscope
Colon resection if the tumor is too big to be removed by local excision 1
Cancer has grown through several layers of the colon, but has not spread outside the colon wall
Surgical resection 2
Cancer has grown through the wall of the colon and may extend into nearby tissue; no spread to the lymph nodes
Surgical resection is usually the only treatment needed
Radiation and chemotherapy for cancers likely to recur

25. 4 and Recurrent colon cancer
Management
STAGE
DESCRIPTION
TREATMENT 3
Cancer has spread to nearby lymph nodes, but has not yet spread to other parts of the body
Surgical resection is the first treatment
Adjuvant chemotherapy with 5-FU and leucovorin
Radiation therapy: if cancer was large enough to grow into adjacent tissues
4 and Recurrent colon cancer
Metastasis: liver, lungs, peritoneum, ovaries
Segmental resection (palliative)
Palliative chemotherapy and radiotherapy

26. Management Surgery Pre-operative Procedures Thorough PE Chest X-ray
Liver Function
Plasma CEA level
Colonoscopy

27. Management Surgery Intraoperative Procedures Laparotomy
Inspection of the liver, pelvis, and hemidiaphragm
Palpation of the full length of the large bowel
TOTAL RESECTION OF THE TUMOR

28. Management Surgery Post-operative Procedures
Recovery
5 years
Semi-annual PE
Colonoscopy
Yearly blood chemistry measurements
Plasma CEA levels at 3-month intervals
If a complete colonoscopy was not performed preoperatively, it should be carried out within the first several postoperative months
Measuring plasma CEA levels at 3-month intervals because of the sensitivity of this test as a marker for otherwise undetectable tumor recurrence
Endoscopic or radiographic surveillance of the large bowel, probably at triennial intervals, is indicated, since patients who have been cured of one colorectal cancer have a 3–5% probability of developing an additional bowel cancer during their lifetime and a >15% risk for the development of adenomatous polyps

29. Endoscopic or radiographic surveillance of the large bowel
Management
Surgery Post-operative Procedures
Recovery
CT scans of the abdomen - annually for the first three postoperative years
Endoscopic or radiographic surveillance of the large bowel
- 3 years interval
Endoscopic or radiographic surveillance of the large bowel, probably at triennial intervals, is indicated, since patients who have been cured of one colorectal cancer have a 3–5% probability of developing an additional bowel cancer during their lifetime and a >15% risk for the development of adenomatous polyps

30. Management Chemotherapy 5-FU 5-FU + folinic acid (leucovirin)
Partial response in 15-20% of patients
Backbone of treatment
IV or oral (capecitabine)- similar efficacy
5-FU + folinic acid (leucovirin)
Improves efficacy; three-fold improvement in partial response
Enhances binding to thymidylate synthase

31. Management Chemotherapy 5-FU + LV + Irinotecan (FOLFIRI regimen)
Topoisomerase 1 inhibitor
Improves response rates and survival of patients with metastatic disease
Adverse effect: diarrhea
5-FU + LV + Oxiplatin (FOLFOX regimen)
Platinum analogue
Improves response rate
Adverse effect: dose-dependent neuropathy, resolves following cessation of therapy
FOLFIRI = FOLFOX

32. Management Chemotherapy Monoclonal antibodies
Effective for advanced colorecatal cancer
Cetuximab and Panitumumab- directed against EGFR
Bevacizumab- directed against VEGF; anti-angiogenesis

33. Management Radiotherapy
Not effective in the primary treatment of colon cancer
May be recommended for prevention of regional recurrences after surgical resections (stage 2 or 3)
Pre-operatively: may be indicated for potentially large, unresectable tumors (to shrink them) and permit subsequent surgical removal