• Clinical science

Colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both women and men in the United States. Risk factors include a positive family history, hereditary syndromes, diet, and a number of conditions, such as inflammatory bowel disease. Most colorectal cancers are adenocarcinomas (95%). Clinical signs are often nonspecific and may include a change in bowel habits, rectal bleeding, and weight loss. Iron deficiency anemia in men > 50 years and postmenopausal women should be considered a warning sign for CRC. Since the introduction of screening with colonoscopy or sigmoidoscopy and fecal occult blood testing, early stage carcinomas have become easier to diagnose in asymptomatic patients. Complete colonoscopy with histopathologic analysis confirms the diagnosis. Staging of the cancer is necessary to evaluate the extent of the disease and determine the appropriate treatment. Curative surgical resection of colorectal cancers and metastases is the preferred method of treatment. Colon cancers are resected via hemicolectomy, while rectal cancers are preferably resected via low anterior resection with total mesorectal excision. Resection is complemented by adjuvant chemotherapy for colon cancer, and neoadjuvant and adjuvant chemoradiation for rectal cancer. Regular follow-ups are recommended after surgical resection.

Epidemiology

  • Incidence: ∼ 130,000 new cases per year
    • Third most common cancer in women and men
  • Age: continuous increase in incidence after the age of 50
  • Mortality: third leading cause of cancer-related deaths in the US overall


References:[1][2][3][4][5][6]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Predisposing factors

Protective factors

  • Physical activity
  • Diet rich in fiber and vegetables and lower in meat
  • Long-term use of aspirin and other NSAIDs

References:[1][3][7][8][9]

Clinical features

  • Often asymptomatic, particularly during the early stages of disease
  • Nonspecific symptoms: constitutional symptoms (weight loss, fever, night sweats), fatigue, abdominal discomfort
  • In general, right-sided tumors chronically bleed, and left sided tumors cause obstruction
  • Symptoms according to location
    • Rectosigmoid > ascending colon > descending colon
    • Right-sided carcinomas (10%): cecum and ascending colon
    • Left-sided carcinomas (10%): transverse and descending colon
      • Changes in bowel habits (size, consistency, frequency)
      • Blood-streaked stools
      • Colicky abdominal pain due to obstruction
    • Rectum (50%) and sigmoid (30%)
      • Hematochezia
      • ↓ Stool caliber (pencil-shaped stool)
      • Rectal pain
      • Tenesmus
      • Flatulence with involuntary stool loss
  • Symptoms according to stage of disease

Colorectal cancer must be ruled out in a patient presenting with rectal bleeding, even if the patient has a history of hemorrhoids!

Iron deficiency anemia in men > 50 years and postmenopausal women should be considered a sign of colorectal cancer until proven otherwise!

Cancer Distance to the anocutaneous line Lymphogenic spread Hematogenic spread
Colon cancer ≥ 16 cm Mesenterial lymph nodes Portal veinliver
Rectal cancer Upper third 12–16 cm Para-aortic lymph nodes Portal veinliver
Middle third 6–12 cm Para-aortic lymph nodes + pelvic floor

Portal veinliver

Vena cava → lung

Lower third < 6 cm Para-aortic lymph nodes + pelvic floor + inguinal lymph nodes Vena cava → lung

References:[10][11][12][13][9]

Stages

The stages of colorectal cancer are based on the TNM staging system by the American Joint Committee for Cancer (AJCC).

TNM Staging Corresponding Duke's Classification stage Description
I (up to T2, N0, M0) A Tumor confined to intestinal wall (confined to the muscularis propria)
II (up to T4, N0, M0) B Infiltration into the visceral peritoneum, adjacent organs, or perirectal tissue
III (any T, N1/N2, M0) C Lymph node involvement
IV (any T, any N, M1) D Distant metastases

Detailed classification

UICC stage TNM
0 Tis (carcinoma in situ)
I up to T2, N0, M0
II IIa T3, N0, M0
IIb T4a, N0, M0
IIc T4b, N0, M0
III IIIa up to T2, N1, M0 or T1, N2a, M0
IIIb T3/T4a, N1, M0 or T2/T3, N2a, M0 or T1/T2, N2b, M0
IIIc T4a, N2a, M0 or T3/T4b, N2b, M0 or T4b, N1, M0
IV IVa any T, any N, M1a
IVb any T, any N, M1b

TNM Staging

References:[11][12]

Diagnostics

Work-up of colorectal cancer is indicated in symptomatic patients and asymptomatic patients with abnormalities detected during routine screening.

Initial work-up

  • Digital rectal examination: Up to 10% of cancers are palpable!
  • Complete colonoscopy: gold standard
    • Complete surveillance of the colon is mandatory!
    • If colonoscopy is incomplete → perform double-contrast barium enema
      • Apple-core lesion

In up to 5% of cases, multiple adenocarcinomas are present. A complete colonoscopy is necessary to rule out additional tumors!

Staging and further tests

  • Determine the extent of local and distant disease
    • Endorectal ultrasound: determine depth of tumor infiltration (T stage)
    • CT of abdomen, pelvis, and chest
    • CXR
    • Rigid proctosigmoidoscopy: to determine the distance from the anus, which determines the type of resection in rectal cancer
    • Angio-CT or MRI of the liver if liver function testing and/or abdomen CT show abnormalities
    • Gynecologic or urologic consult
  • Tumor marker: carcinoembryonic antigen (CEA) serum levels prior to initiating treatment (positive in ∼ 70% of cancers)

References:[1][1][12][14]

Pathology

95% of all colorectal cancers are adenocarcinomas!

References:[15][16][17]

Differential diagnoses

Small bowel neoplasms

  • Epidemiology
    • Less than 5% of all gastrointestinal cancers
    • Mainly benign lesions (> 95%)
    • Malignant small bowel cancers (1–3%)
  • Complications
  • Diagnostics: ultrasound, hydro-MRI, capsule endoscopy
  • Treatment: resection of the small bowel; R1 resection requires adjuvant chemotherapy
  • Prognosis (if malignant)
    • 5-year survival rate: ∼ 20%

References:[18]

The differential diagnoses listed here are not exhaustive.

Treatment

Treatment primarily depends on the location of the tumor and the TNM stage.

Colon cancer

  • Curative approach: any primary tumor with or without regional spread; resectable metastases in the liver and/or lung
  • Palliative approach: distant metastases beyond the liver and/or lung or if the patient is not a surgical candidate due to poor general health
    • Treatment involves palliative chemotherapy and palliative surgery .

Surgical management

  • Colectomy: The extent of the resection depends on the location of the tumor.
    • Open approach or laparoscopic approach
    • Right hemicolectomy
      • Arterial blood supply: ileocolic, right colic, and right branch of the middle colic artery arising from the superior mesenteric artery
      • Extended right hemicolectomy: if the tumor is in the proximal or middle transverse colon
    • Left hemicolectomy
    • Sigmoid colectomy
    • Total abdominal colectomy: indicated for hereditary and multifocal carcinomas
    • Intraoperative staging: palpate and inspect the liver
  • Regional lymph node dissection (for pathologic staging)
    • Lymph nodes along the path of lymphatic drainage are resected.
    • UICC requires the histological analysis of 12 removed lymph nodes to accurately define the lymph node status (N stage).
  • Resection of resectable metastases in liver and/or lung
  • Palliative surgery
    • Enteral stenting
    • Bypass (e.g., ileocolonic anastomosis)
    • Resection + colostomy

Systemic therapy

Radiation therapy is not a standard modality in the treatment of colon cancers!

Rectal cancer

Surgical management Chemotherapy / Radiation therapy
Stage I
  • Transanal local resection
  • Not required
Stage II–III Lower rectum (< 10 cm from the anal verge)
Middle rectum
Upper rectum (> 10 cm from the anal verge)
Stage IV
  • Palliative transanal local excision to facilitate defecation
  • Palliative

Surgical management

  • Transanal excision
    • Procedure: minimally invasive excision of small superficial tumors
    • Transanal endoscopic microsurgery: alternative procedure using a proctoscope to reach lesions in the upper rectum
    • Indications: early, localized disease (stage I)
  • Low anterior resection (LAR)
    • Procedure: sphincter-preserving resection of the rectum and sigmoid
      • Total mesorectal excision (TME): en bloc excision of the mesorectum , regional lymph nodes, and vasculature
      • Resection 5 cm beyond the proximal margin of the tumor
      • Resection > 2 cm beyond the distal margin of well-differentiated tumors or > 5 cm beyond the distal margin of poorly differentiated tumors
      • If the required tumor margin cannot be resected, a distal margin of 1 cm is acceptable following neoadjuvant chemoradiation to avoid complete proctectomy with colostomy.
      • Intraoperative frozen section should show histologically negative margins.
      • Pararectal lymph nodes and those along the superior rectal artery (arising from the inferior mesenteric artery) are removed.
      • Reconstruction (e.g., side-to-side anastomosis) and optional diverting ostomy
    • Indications: locally advanced disease (Stage III–IV)
  • The completeness of the TME has a strong impact on the prognosis!
  • Abdominoperineal resection (APR)
    • Procedure: resection of the rectum, sigmoid, and anus with TME and permanent colostomy
    • Indications: last resort if the distal margin to the rectum cancer is < 2–5 cm to the anus
  • Palliative procedures include transanal excision or diverting colostomy to facilitate defecation.

Systemic therapy

Metastatic disease

  • Criteria for resectability of hepatic metastases
    • No nonresectable, extrahepatic manifestation of the cancer
    • < 70% of the liver parenchyma affected
    • < 3 hepatic veins and < 7 segments affected
    • No hepatic insufficiency or cirrhosis (Child B/C)
    • No distinct comorbidity
  • Fong-Score
    • For prognosis in the case of hepatic metastases
    • Risk factors
      • Lymph node-positive primary tumor
      • Disease-free period < 12 months between primary resection and occurrence of hepatic metastasis
      • Size of metastasis > 5 cm
      • Number of metastases > 1
      • Preoperative CEA > 200 ng/mL
    • Interpretation
      • 0 risk factors: low-risk group
      • 1–2 risk factors: intermediate-risk group
      • 3–5 risk factors: high-risk group

Follow-up

  • Monitor patients for 5 years following the completion of treatment
    • Patient history, physical examination, CEA level: every 3–6 months for 3 years, then every 6 months for 2 years
      • Elevated CEA warrants further evaluation to determine site of recurrence or metastasis with CT of the chest and abdomen, PET, and/or colonoscopy.
    • Colonoscopy: after surgical resection, then 1 year after surgery, then every 3–5 years
    • Chest CT: every 6–12 months for 3 years
    • Abdominal CT: every 3–6 months for 3 years

85% of recurrences occur within the first three years following treatment!

References:[1][19][13][20][21][22][23][24][25][26][27][28][9][29][30]

Prognosis

  • Overall 5-year survival rate: 65%
  • Survival rate according to disease stage
    • Stage I: 95%
    • Stage II: ∼80%[31]
    • Stage III: 60%
    • Stage IV: 5–10%

References:[11][13][32]

Prevention

Screening for colorectal cancer

Screening for colorectal cancer and adenomatous polyps is performed in asymptomatic men and women ≥ 50 years of age.

  • Low-risk individuals: several options
    • Complete colonoscopy (gold standard): Repeat every 10 years if no polyps or carcinomas are detected.
    • Annual fecal occult blood test (FOBT): screening for occult bleeding, which may indicate colorectal cancer
      • Procedure
        • Apply 3 consecutive stool samples to filter paper and add a few drops of hydrogen peroxide.
        • If blood is present, the test paper will turn blue.
      • False-positive result
        • Presence of myoglobin due to raw meat
        • Presence of hemoglobin of a different origin, e.g., dental, nasal, or hemorrhoidal bleeding
      • False-negative result
    • Sigmoidoscopy every 5 years and FOBT every 3 years
    • Annual fecal immunochemical testing (FIT)
    • CT colonography every 5 years
  • High-risk individuals
    • Complete colonoscopy 10 years earlier than the index patient's age at diagnosis or no later than 40 years of age
    • In case of genetic predisposition: individual screening (see FAP and HNPCC for details)
Surveillance following polypectomy
Histology of removed polyp Recommended interval until next control colonoscopy
10 years
  • Low risk adenoma: 1–2 tubular polyps < 10 mm in size and without intraepithelial neoplasia (IEN)
5–10 years
  • High risk adenoma
    • 3–10 tubular polyps
    • 1 polyp ≥ 10 mm
    • 1 villous or tubulovillous polyp
    • 1 tubular polyp with high-grade dysplasia
3 years
  • More than 10 adenomas
< 3 years; depends on the case (i.e., family history)



References:[13][33][34][35][36]