Colon Cancer

Epidemiology

General

  • 150,000 new cases a year (70% colon and 30% rectum)
  • Risk factors: age, IBD, low fiber and high fat diets

Familial Adenomatous Polyposis (FAP)

  • Gardner syndrome is a variant of FAP
  • 100% malignant transformation without treatment.
  • Prophylactic colectomy need for patients with > 100 polyps
  • 10 - 24 years old start sigmoidoscopy
  • 25 - 34 colonoscopy every two years
  • 35 - 44 colonoscopy every three years
  • every three to five years thereafter

Ulcerative Colitis (UC)

  • DALM, low-grade or high-grade dysplasia, if confirmed by a second experienced pathologist, is usually an indication for elective colectomy.
  • UC has greater risk of colon cancer compared to Chron's disease.

Hereditary Non-polyposis Colorectal Cancer (HNPCC )

  • Lynch Syndrome I (familial colon cancer)
  • Lynch Syndrome II (HNPCC associated with other cancer of the gastrointestinal system or the reproductive system).
  • "up to 6%" of colorectal cancers are due to hereditary nonpolyposis colorectal cancer (HNPCC). [3]
  • Individuals have 80% lifetime risk for colon cancer.
  • If colon cancer or advanced adenoma is found), total colectomy is recommended rather than segmental coloectomy.
  • For those not willing or able to undergo periodic screening prophylactic total colectomy may an option based on carrier status alone.
  • 20+ years-old: colonoscopy every 1-2 years
  • 40+ year-old undergo colonoscopy every year.

Other Genetic Abnormalities

  • 5q, p53, RAS, 17p13.3,17p12, DCC (deleted in colon cancer)
  • equal incidence between men and women
  • 18q LOH (loss of heterozygosity) is associated with worse OS
  • MSI (Microsatillite instability) by itself is not related to improved OS but with bata-1-RII mutation is improved over w/o the mutation
  • Peutz Jegher (beign hamartomatous polyps)
  • Turcot syndrome: A genetic disease characterized by polyps in the colon (large intestine) in addition to tumors in the brain.

Presentation and Evaluation

Anatomy

  • Colon cancers are above the peritoneal reflection or greater than 12cm above the anal verge.
  • Intraperitoneal: cecum, transverse colon, sigmoid colon, and upper 1/3 of the rectum.
  • Extraperitoneal: ascending colon, descending colon, and rest of rectum.

Pathology

  • Most common is adenocarcinoma with subtype including signet ring or mucinous.
  • Squamous cell carcinoma, adenosqamous, undifferentiated, carcinoid, sarcoma, and lymphomas.

Patient Presentation

  • Intermittent abdominal pain, nausea/vomiting, abdominal mass, change in bowel habits
  • Obstruction related to left colon, anemia with right colon and hematochezia for rectal lesions.

Routes of Spread

  • Local: Through the wall, extracolonic tissues and adjacent organs. Radial spread rather than longitudinal.
  • NodaL:
  • Colon: for the left colon to the inferior mesenteric and for the right colon the superior mesenteric nodes.
  • Rectum: Initially the perirectal nodes and then for the upper 1/3 the superior rectal vessels to the inferior mesenteric arteries, the middle portion the middle rectal vessels and to the internal and common iliacs, and the lower to the inferior rectal but also the superficial inguinal nodes.
  • Nodal incidence:
T-stage risk of regional LN(+)
T1 5%
T2 20%
T3 30%
T4 50%
  • Distant mets: liver, lung, and peritoneum.

Diagnostic Studies

  • H/P (family history of polyps) with digital rectal exam
  • Colonscopy with biopsy and to assess location of lesion from the anal verge if rectal cancer (diameter, mobility, size)
  • Radiological studies: Barium enema, CT scan of the abdomen/pelvis, CXR, endorectal MRI or US for the rectal tumors to determine depth of invasion or nodal disease.
  • Labs: CBC, Chemistries, LFT, Renal functions, CEA

TNM Staging

AJCC 2002

Primary Tumor (T)

colon-stages.jpg
  • T4: invasion into other organs or structures and/or perforates visceral peritoneum
  • Note: tumor that is adherent to other structures is T4, but if no tumor is present in the adhesion, microscopically, it is pT3.

Regional Lymph Nodes (N)

  • N1 1 to 3 regional lymph nodes
  • N2 4 or more regional lymph nodes

Regional lymph nodes vary depending on the primary location but in general located

  1. along the course of the major vessels supplying the colon and rectum
  2. along teh vascular arcades of the marginal artery
  3. adjacent to the colon

Treatment

Surgery

  • Partial colectomy is the treatment of choice.

Chemotherapy:

  • Adjuvant to surgery:
  • MOSAIC trial: FOLFOX4 (infusional 5-FU/leucovorin, oxaliplatin) vs. 5FU/LV showed DFS advantage 69.7% vs 61.0% for stage III patients (NS for stage II), confirmed by meta-analysis (~ 6 months of chemotherapy)
  • Irinotecan: 3 randomized trials shows NS
  • Capecitabine (Xeloda), an oral 5FU prodrug = 5FU/leucovorin for stage III
  • Bevacizumab (Avastin) and cetuxibmab is being investigated.
  • Post-operative chemotherapy: for node positive and advanced T3/T4N0 is 5FU and levamisole or leucovorin for 1 year supported by Moetel and Intergroup trial.

Post-operative Radiation Therapy:

  • When colon cancer adhere to or invade adjacent structures (T4), local failure rates exceed 30% W/O invasion local failure is uncommon.
  • It is more difficult to achieve good radial margins for retroperitoneal colon such as ascending and descending colon.
  • Can be used to treat patients with B3 to C3 disease as per MGH and Duttenhaver. The dose used is 45Gy and then boosts to 5040cgy. The critical structures are kidney (20Gy), small bowl (45Gy), spinal cord (50Gy), liver (30Gy if treating at least 2/3) and stomach.

Outcome

Prognostic Factors

  • Important Prognostic Factors: nodal status, invasion through wall, perineural invasion, tumor differentiation, vascular space invasion, lymphatic space invasion, CEA levels, tumor characteristics such as size, mobility, ulcerative, and histology
  • Washington University preoperative RT found these adverse clinical factors achieved significance on multivariate analysis along with background of the surgeon and pathological stage at surgery
  1. Distal (< 5 cm) from anal verge
  2. Tumor tethered or fixed to palpation
  3. Circumferential lesion
  4. Near-obstruction lesion (lumen < 1 cm)

Studies

Mass General Hospital2 (Single Institution)

Surgery Alone Surgery + Post-op RT
T Stage Local Control 5 year RFS Local Control 5 year RFS
T3 N0 90% 78% 91% 72%
T4 N0 69% 63% 93% 79% (p < .05)
T3 N+ 64% 48% 55% 70%
T4 N+ 47% 38% 72% 53% (p < .05)
  • Benefit the B3 or C3 patients, B3 patients with perforation or fistula, and those with subtotal resection.
  • RT did not add to T3N0 or T3N+.
  • Long-term bowl toxicity was 4%.

Intergroup study 0130 1

  • patients with T4N0-2 and T3N1-2 disease had surgery, 5Fu/levamisole and randomized to RT or no RT
  • No difference in overall survival (62% vs 58% RT)
  • No difference in local control rates
  • Higher grade III/IV toxicity in RT group
  • Poor study due to lock of accrual and lack of surgical clips

Summary

  • T4 and T3/N+ patients have local recurrence rates of > 30%, similar to rectal cancer if surgery alone is undertaken.
  • Single Instituitional trial from MGH, Mayo and UF have been encouraging with improved local control as well as RFS
  • Intergroup 0130 randomized study showed no benefit to radiation.
  • Radiation can be considered on a case by case bases for patients with T4/N0, N+, T3/N+, fixed tumors, and subtotal resection.
  • Dose should be 45 Gy to tumor bed and regional lymphatics with as boost to 50.4 Gy.
  • Radiation may be given concurrent to 5-FU based chemotherapy
Bibliography
1. Martenson JA Jr, Willett CG, Sargent DJ, Mailliard JA, Donohue JH, Gunderson LL, Thomas CR Jr, Fisher B, Benson AB 3rd, Myerson R, Goldberg RM. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol. 2004 Aug 15;22(16):3277-83. Epub 2004 Jul 12.
2. Willett CG, Fung CY, Kaufman DS, Efird J, Shellito PC. Postoperative radiation therapy for high-risk colon carcinoma. J Clin Oncol. 1993 Jun;11(6):1112-7.
3. Gastroenterology. 1993 (May);104(5):1535-49.
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