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

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

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")

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

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

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

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

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.

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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