6 Colorectal Cancer
Ten percent of new cancers in the United States and 10% of cancer mortality.
Lifetime risk in the United States is 6%.
Fewer than 5% inherited.
Most sporadic and incidence dramatically increases with age.
Occur in benign polyps that show overgrowth by epithelium and abnormal differentiation.
Pedunculated polyps larger than 1 cm have 15% risk of progressing to cancer.
Removal of these polyps is recommended. 1
Increased incidence with high caloric diet, red meat consumption, high saturated fats, alcohol and cigarette use, sedentary lifestyle, obesity, diabetes.
Genetics of Colorectal Cancer
All colon cancers begin with adenomatous precursors that, when subjected to genetic mutations, progress to malignancy. Genetic mutations that activate the WNT signaling pathway necessary for initiation of chromosomal instability and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation with the loss of p53 and other tumor suppressors.
About 20% of these cancers have microsatellite instability (MSI) due to defective deoxyribonucleic acid (DNA) mismatch repair gene, which is associated with CpG island methylation or a result of familial predisposition. Mutations occur in KRAS, BRAF oncogenes, p53 tumor suppressor gene, or microsatellite containing genes that are sensitive to defective DNA mismatch repair. BRAF mutation is present in 10 to 20% of colorectal cancer (CRC) linked to microsatellite instability (MSI) with poorer prognosis. 4 – 6
Colorectal Cancer Tumor Syndromes
Familial adenomatous polyposis (FAP): Multiple adenomas throughout gastrointestinal (GI) tract, multiple CRC, hypertrophy of retinal epithelium.
Gardner’s syndrome: Same as FAP with desmoid tumors and mandibular osteomas.
Turcot’s syndrome: Polyposis and CRC with brain tumors, especially medulloblastoma and glioblastoma. 7
Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch’s syndrome): 70% lifetime risk of CRC with mild polyposis and presents at a younger age (<50 years old), high risk of endometrial cancer, mild risk of other GYN (gynecologic) tumors, hepatobiliary tumors, and brain tumors. 8 – 10
Peutz–Jeghers syndrome: Hamartomatous polyps throughout GI tract, mucocutaneous pigmentation, increased risk of cancer by at least ninefold.
Cowden’s disease: Multiple hamartomas in GI tract, soft tissues, thyroid, brain with increased risk of breast, uterus, thyroid, and GI cancer. 11
Fecal occult blood test yearly.
Sigmoidoscopy every 5 years.
Colonoscopy every 10 years.
There is some controversy over colonoscopy versus computed tomography (CT) colonography, but Food and Drug Administration (FDA) panel has recommended that they are equivalent for polyps 8 mm and larger with colonoscopy following immediately after CT colonography if suspicious polyps identified. Consider performing both CT and colonoscopy on the same day with the same preparation; however, this requires extensive collaboration and cooperation with the endoscopy service.
Familial history of CRC or hereditary syndrome.
For FAP, start screening colonoscopy at age 10 years and repeat every 1 to 3 years.
For HNPCC, start screening at age 20 to 15 years.
Tumor, Node, Metastasis Staging Used
Tis = In situ adenocarcinoma confined to the glandular basement membrane or lamina propria.
T1 = Invade into but not through the submucosa.
T2 = Invade into but not through the muscularis propria.
T3 = Invade through the muscularis propria into the subserosa.
T4a = Perforate into visceral peritoneum.
T4b = Invade adjacent organs or structures.
N0 = All nodes examined are negative.
N1a = Tumor metastases in one regional lymph node (LN).
N1b = Tumor found in two or three regional LN.
N1c = Tumor found in fat around but not in lymph nodes.
N2a = Tumor in four to six regional LN.
N2b = Tumor in more than seven LN.
M0 = No evidence of distant metastases.
M1a = Tumor in one set of distant LN or one organ.
M1b = Tumor in more than one set or distant LN or organ or peritoneum.
Residual Tumor after Resection
R0 = Histologically negative surgical margins and all LN negative.
R1 = Microscopic disease present at surgical margin.
R2 = Grossly positive margins.
Stages Due to TNM Classification
Stage 0 = Tis, N0, M0.
Stage I = T1, N0, M0 or T2, N0, M0.
Stage IIA = T3, N0, M0.
Stage IIB = T4a, N0, M0.
Stage IIC = T4b, N0, M0.
Stage IIIA = T1/T2, N1/N2a, M0.
Stage IIIB = T3/T4a, N1, M0 or T2/T3, N2a, M0 or T1/T2, N2b, M0.
Stage IIIC = T4a, N2a, M0 or T3/T4a, N2b, M0 or T4b, N1/N2, M0.
Stage IVA = T any, N any, M1a.
Stage IVB = T any, N any, M1b.
Stages 0, I = Tumor is completely resected and diagnosis of CRC made at pathological examination = greater than 95% 5-year survival without chemotherapy or radiation. 16
Stages II, III = Current adjuvant chemotherapy of FOLFOX (fluorouracil/leucovorin plus oxaliplatin) = 5-year disease-free survival (DFS) of 73 to 85%, which is a statistically significant improvement over 5FULV2 (fluorouracil/leucovorin) of 67 to 68%. 17
Stage IV = Chemotherapy using FOLFIRI (fluorouracil/leucovorin plus irinotecan) or FOLFOX = objective response rate of 55%, time to progression (TTP) = 8.4 months, overall survival (OS) from date of start of therapy = 20 to 22 months, 2-year survival of 41 to 45%. These data represent the use of chemotherapy alone without locoregional therapy. 18