Journal Article:

BMJ_Colorectal_Adenocarcinoma

Summary:

Colorectal adenocarcinoma: risks, prevention, and diagnosis

Sri G Thrumurthy, Sasha S D Thrumurthy, Catherine E Gilbert, Paul Ross, Amyn Haji

Epidemiology:

• Fourth MCC cancer related mortality globally = Colorectal Cancer (CRC)
  • 4 million new cases annually
  • 700,000 deaths annually

CRC Defined:

• Tumors of:
  • Rectum
  • Colon (Large Bowel)
  • Appendix
• Tumors are derived from colorectal mucosa
• MC form of CRC = Adenocarcinoma (<95%)
  • Other forms:
    • Carcinoid Tumor
    • Sarcoma
    • Lymphoma

Development of CRC:

• Adenomatous polyps à dysplastic changes à malignant
  • Polyps and tumors may occur sporadically or in several heritable conditions.

Demographics of Those Afflicted by CRC:

• After 50yo, the incidence of CRC increases significantly
• Median age at diagnosis = 70yo

Trends in Various Countries:

• Spain, Eastern European, East Asian countries were once considered to be low risk regions
  • Recently, increase in incidence of CRC
    • Thought to be related to adoption of high fat diet (red meat, processed meat), physical inactivity, excessive EtOH, smoking
  • United States and others have witnessed decrease in incidence of CRC
    • Thought to be the result of increased screening: use of diagnostic endoscopy and polypectomy

Risk Factors:

• Sociodemographic
  • Increasing age (especially >50yo)
  • Male sex
• Lifestyle
  • Red meat, processed meat consumption
  • Obesity
  • EtOH
  • Smoking
• Medical
  • Inherited Syndromes predisposing to CRC
    • Hereditary non-polyposis colorectal cancer (HNPCC) AKA Lynch Syndrome
    • Familial adenomatous polyposis (FAP)
  • Family History
  • Colorectal adenomas or polyps
  • Inflammatory bowel disease (IBD)
  • DM

Clinical Presentation:

• MC = abdominal pain, change in bowel habits, rectal bleeding, microcytic anemia
• Differences between tumor location:
  • Left-Sided:
    • Altered bowel habits = loose stools, inc. frequency, intestinal obstruction, rectal bleeding, tenesmus
  • Right-Sided:
    • May be more insidious = weight loss, abdominal pain/mass, iron deficiency anemia
  • Investigation may be warranted in unexplained iron deficiency anemia = approx. 10% will have CRC
  • Pre-Diagnostic Features of CRC (from a UK population based case-control study of 2093 patients)
    • OR of:
      • Abnormal rectal exam = 4.0
      • Rectal Bleeding = 2.4
      • Anemia = 2.3
      • Weight Loss = 1.2

Which patients require urgent referral for suspected CRC?:

• National Institute for Health and Care Excellence (NICE) Criteria

Symptoms and Signs	Age Threshold (Years)
Unexplained weight loss and abdominal pain	>40
Rectal Bleeding	>50
Iron deficiency anemia, altered bowel habit, positive FOBT	>60
Rectal bleeding plus any of: abdominal pain, altered bowel habit, weight loss, iron deficiency anemia	<50
Palpable rectal or abdominal mass	Any

Investigation for Suspected CRC:

• Colonoscopy = First Line
  • With biopsy of suspicious lesions
• If incomplete colonoscopy (eg intra-procedural discomfort, poor bowel prep)
  • Repeat colonoscopy
  • CT colonography
  • Barium enema
• If major comorbidity (frail, elderly, poor mobility, poor tolerance to bowel prep) consider alternative imaging
  • CT colongraphy
  • Flexible sigmoidoscopy

Diagnostic Imaging:

• Colonoscopy
  • Operator dependent
  • Completion Rate = passage of colonoscope to the cecum
  • Biopsies
  • Marking areas highly suspicious for malignancies with dye contrast
  • Risks:
    • Perforation
  • Causes of False Negative Tumor Detection:
    • Poor bowel prep
    • Incomplete colonoscopy
  • CT colonography
    • Similar sensitivity for cancer detection, though lower specificity for polyp detection
    • In patients referred for more generalized complaints, like weight loss or abdominal pain, CT colongraphy may show extraluminial pathology causing the signs or symptoms
    • Cannot be used in pregnancy or those with iodine allergy
  • Other Tests
    • FOBT and serum tumor markers (CEA) are not useful in investigating for CRC
    • The role of FOBT is for screening; largely asymptomatic individuals
    • The role of serum tumor markers (CEA) is such that they are used in the follow-up of patients undergoing treatment

Prevention:

• Primary Prevention:
  • Diet
    • Extra total dietary fiber ingested daily
      • Meta-analysis (25 prospective studies) = 10% risk reduction in developing CRC if extra 10g total dietary fiber ingested daily (cereal fiber and whole grains)
    • Dairy Products
      • Meta-analysis (19 cohort studies) = consumption of 400g dairy products daily reduced development of CRC significantly (RR = 0.83 95% CI 0.78 to 0.88); daily consumption of 200g milk or 50g cheese decreases development of CRC
    • Daily Calcium Intake
      • Meta-analysis (15 studies, n = 12305 patients) = every 300mg of daily calcium intake (up to 1900mg/day) reduced risk of developing CRC
    • Physical Activity:
      • Increased Physical Activity
        • Meta-analyses (cohort studies) = 17-24% risk reduction in CRC between most and least physically active participants
      • Pharmacological:
        • Aspirin
          • Two large trials in 1980s (looking at vascular event prevention) revealed 37% risk reduction in CRC in patients with daily intake of 300mg ASA x at least 5y
          • Large RCT revealed 600mg ASA qd x 2y led to risk reduction in CRC among patients with HNPCC (hazard ratio = 0.41)
        • NSAIDs
          • Shown to reduce CRC in several cohort and case-control studies
        • COX-2 Inhibitors
          • RCTs showed that they reduce adenoma incidence (RR 0.72 (0.68 to 0.77)); this may contribute to reduced subsequent cancer risk
        • Calcium
          • Large, randomized, double-blind trial revealed 1200mg Ca2+ qd decreased colorectal adenoma recurrence (adjusted RR 0.85 (0.74 to 0.98), P = 0.03).
        • Secondary Prevention (Screening)
          • Fecal Occult Blood Testing:
            • Meta-analysis of RCTs = FOBT reduced CRC mortality by 25% (RR 0.75 (0.66 to 0.84))
              • Same meta-analysis suggested that FOBT prevented approximately 1 in 6 deaths from CRC
            • Flexible Sigmoidoscopy:
              • Large RCT (14 UK centres) = single flex sigmoidoscopy between 55-64yo reduced CRC incidence by 23% (hazard ratio 0.77 (0.70 to 0.84)) and mortality by 31% (hazard ratio 0.69 (0.59 to 0.82)).

Informing Clinical Practice:

• United States Preventive Services Task Force (USPSTF), in 2016, recommended:
  • Adults aged 50-59y with a >10% 10-y CVD risk
    • Initiate low-dose ASA for primary prevention of CVD and CRC in those not at increased risk for bleeding, they have a life expectancy of at least 10y, and are willing to take the low-dose ASA daily x 10y
  • USPSTF, in 2016, recommended:
    • Screening for CRC should start at 50yo and continue until age 75yo
    • Decision to screen for CRC in adults 76yo-85yo should be made on a case-to-case basis