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Colorectal cancer

Definition
  • The majority of colorectal cancers are adenocarcinomas derived from epithelial cells
  • About 71% of new colorectal cancers arise in the colon and 29% in the rectum
  • Less common types of malignant colorectal tumours are carcinoid tumours, GI stromal cell tumours, and lymphomas
  • Increasing age is the greatest risk factor for sporadic colorectal adenocarcinoma with 99% of cancers occurring in people aged 40 years or over
Risk Factors
  • Strong
    • Increasing age
    • APC mutation
    • Lynch syndrome (HNPCC)
    • MYH-associated polyposis
    • Hamartomatous polyposis syndromes
    • Inflammatory bowel disease
    • Obesity
  • Weak
    • Acromegaly
    • Limited physical activity
    • Lack of dietary fibre
Differential diagnosis
  • Irritable bowel syndrome (IBS)
    • A clinical diagnosis is based on the Rome III Criteria:
      • at least 3 months' duration
      • onset at least 6 months previously
      • recurrent abdominal pain or discomfort associated with 2 or more of:
        • improvement in abdominal pain with defecation
        • change in frequency of stool
        • change in form (appearance) of stool
    • There is no specific diagnostic test for IBS
    • Patients who fulfil the clinical criteria for IBS and have no alarm features have a very low probability of organic disease
    • Colonoscopy or colonic imaging is recommended for patients older than 50 years of age due to higher pre-test probability of colorectal cancer
  • Ulcerative colitis
    • Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer
    • Patients with inflammatory bowel disease frequently have watery diarrhoea
    • However, patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment
    • Colonoscopy will show:
      • rectal involvement
      • continuous uniform involvement
      • loss of vascular marking
      • diffuse erythema
      • mucosal granularity
      • normal terminal ileum (or mild 'backwash' ileitis in pancolitis)
  • Crohn's disease
    • Average age of onset of inflammatory bowel disease (20 to 40 years) is younger than with colorectal cancer
    • Patients with inflammatory bowel disease frequently have watery diarrhoea
    • Patients with colitis are at higher risk of colorectal cancer and may need reassessment if symptoms are atypical or do not respond to treatment
    • Colonoscopy with intubation of the ileum is the definitive test to diagnose Crohn's disease
      • Will show mucosal inflammation and discrete deep superficial ulcers located transversely and longitudinally, creating a cobblestone appearance
      • The lesions are discontinuous, with intermittent areas of normal-appearing bowel (skip lesions)
  • Haemorrhoids
    • Causes bright red rectal bleeding that is separate from the stool
    • There is no abdominal discomfort or pain, altered bowel habits, or weight loss
    • Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age
  • Anal fissure
    • Severe pain on defecation
    • Blood is usually on wiping
    • There is no abdominal discomfort or pain, altered bowel habits, or weight loss
    • Colonoscopy or colonic imaging is recommended in patients with abdominal symptoms in addition to rectal bleeding and in those older than 50 years of age
  • Diverticular disease
    • Diverticular stricture or inflammatory mass may be clinically indistinguishable from colorectal cancer
    • Colonoscopy with biopsies and CT imaging will usually differentiate
Epidemiology
  • Colorectal cancer is the third most common cancer in the Western world
  • Worldwide, the highest incidence rates for colorectal cancer are seen in Europe, North America, and Australasia and are lowest in Africa and Asia
  • The lifetime risk of developing colorectal cancer is 5.42% and it is the third leading cause of cancer deaths in the US in men and women
  • In 2002, 34,889 new colorectal cancer cases were diagnosed in the UK where in 2006, 15,957 deaths were due to colorectal cancer
  • Age is a major risk factor for sporadic colorectal cancer and it is rare before 40 years of age
    • Between 2000 and 2004 in the US, the median age at diagnosis for cancer of the colon and rectum was 71 years of age
  • The age-adjusted incidence rate was 51.6 per 100,000 men and women per year
  • Incidence and mortality rates are much lower in Hispanics, Asians, Pacific Islanders, American Indians, and Alaskan natives compared with white people and black people
    • Some of these disparities may be due to differences in genetic susceptibility
  • Over the past decade, colorectal cancer incidence and mortality rates have decreased in all populations except American Indians and Alaskan natives
  • The incidence and mortality rates are similar in men and women until 50 years of age and after this time rates are higher in men
Aetiology
  • Colorectal cancer represents a complex interaction of genetic and environmental factors
  • Genetic factors:
    • The majority of colorectal cancers are sporadic rather than familial, but next to age, family history is the most common risk factor
    • There is a 2- to 3-fold increased risk of colorectal cancer in people with a family history in a single first-degree relative
      • The risk is further increased if cancer developed at a young age (<45 years)
    • There is a 3- to 4-fold increased risk of colorectal cancer with 2 affected first-degree relatives
    • The well-defined family cancer syndromes such as familial adenomatous polyposis (FAP) and Lynch syndrome are the most common of the family cancer syndromes
      • These are associated with single gene defects
      • However, these syndromes account for only about 5% to 6% of colorectal cancer cases
  • Obesity confers a 1.5-fold increased risk of developing colon cancer compared with normal weight individuals
    • Obesity is also associated with a greater risk of dying from the disease
    • Obesity, high energy intake, and physical inactivity are probably synergistic risk factors
  • Most studies (but not all) suggest an inverse relationship between dietary fibre intake and colorectal cancer risk
  • Large prospective studies with long follow-up periods have shown that a high intake of red and processed meat is associated with an increased risk of colorectal cancer risk
Clinical features 
  • Iincreasing age
    • Less than 5% of cases are in patients who are younger than 44 years of age and the mean age at diagnosis is 71 years
  • Rectal bleeding
    • Rectal bleeding is usually due to benign disease, but it is a common symptom in patients with colorectal cancer
    • A new episode of rectal bleeding in patients older than 45 years of age has a positive predictive value for colorectal cancer of 5.7%
  • Change in bowel habit 
    • Increased frequency or looser stools, particularly combined with rectal bleeding, is common in left-sided cancers
    • However, a change in bowel habit to reduced frequency and hard stools has a low predictive value for colorectal cancer
  • Rectal mass 
    • There is a palpable rectal mass in 40% to 80% of patients with rectal cancer
    • Digital rectal examination to assess tumour involvement of the pelvic wall and suitability for surgery is unreliable
      • Better assessed by MRI and transrectal endoscopic ultrasound
  • Positive FHx 
    • For individuals with one affected first-degree relative, the relative risk of developing colorectal cancer is 2.24
    • This increases to 3.97 with 2 affected first-degree relatives
    • However, only about 10% to 20% of patients give a family history of colorectal cancer
  • Abdominal mass
    • Usually the abdominal examination is normal
    • Occasionally a tumour a mass is felt, typically in advanced disease
  • Anaemia 
    • Almost 90% of patients with right-sided colon cancer are anaemic at diagnosis
  • Male gender
    • Until 50 years of age, men and women have similar rates for bowel cancer, but in later life male rates are higher
  • Uncommon features
    • Abdominal pain 
    • Weight loss and anorexia 
    • Abdominal distension 
    • Palpable lymph nodes 
Investigations
  • FBC
    • Anaemia
  • Liver biochemistry
    • Normal, except if liver metastases present
  • Renal function
    • Normal, except if advanced pelvic disease is compressing ureters
  • Colonoscopy
    • Ulcerating exophytic mucosal lesion that may narrow the bowel lumen
  • Double-contrast barium enema
    • Mass lesion in the colon and/or as a characteristic 'apple core' lesion
  • CT colonography
    • Appearances similar to conventional colonoscopy, with an ulcerating exophytic mucosal lesion that may narrow the bowel lumen
  • CT scan of thorax, abdomen, and pelvis
    • Colonic wall thickening, enlarged lymph nodes, liver metastases, ascites, lung secondaries
  • Pelvic MRI
    • Tumour invasion of mesorectal fascia
  • Transrectal endoscopic ultrasound (TRUS)
    • Enlarged perirectal lymph nodes indicate malignant involvement
    • Invasion through the submucosa and into muscularis propria identifies a T2 tumour
    • Extension of tumour into perirectal space identifies a T3 tumour
  • Biopsy
    • Confirms the diagnosis with characteristic pathological appearances
    • The degree of tumour differentiation (i.e., well, moderate, or poorly differentiated) will also be reported
  • Carcinoembryonic antigen (CEA)
    • Elevated; normal range for CEA:
      • Adult non-smoker <2.5 micrograms/L (<2.5 nanograms/mL)
      • Adult smoker <5.0 micrograms/L (<5.0 nanograms/mL)
    • Reference range may vary between laboratories depending on assay
  • PET scan
    • Focal areas of increased uptake of 18-fluoro-2-deoxyglucose (FDG) detects metabolic changes of malignancy
Management

a) conservative
  • n/a
b) medical
  • Pre-operative radiotherapy
    • Short course pre-operative radiotherapy is given in some centres, although the benefits of this approach remain unclear
    • It may reduce local recurrence, but can impair wound healing and increase the rate of faecal incontinence and sexual dysfunction
    • It is used more in Europe than in North America
  • Pre-operative chemoradiotherapy
    • For patients with rectal cancer stage II and III in many centres
    • Pre-operative radiotherapy or fluoropyrimidine-based chemoradiotherapy followed by a sphincter-preserving LAR
    • Long-term outcomes in terms of survival are improved with short course radiotherapy (5 x 5 Gy), but at the expense of toxicity and a higher risk of second malignancies
    • See local specialist protocols for chemoradiotherapy dosing guidelines
  • Postoperative chemotherapy
    • No trial has demonstrated conclusively that adjuvant chemotherapy improves outcome in patients who have received pre-operative chemoradiotherapy
    • However, based largely on retrospective data, National Comprehensive Cancer Network guidelines recommend postoperative chemotherapy in all patients who receive pre-operative therapy regardless of the pathological stage in the resected specimen
    • Generally, pre-operative therapy with either short-course radiotherapy or chemoradiotherapy is preferable to postoperative chemoradiotherapy
  • Bevacizumab
    • Monoclonal antibody that has anti-angiogenic properties, alters vasculature to improve delivery of chemotherapeutic agents to cancer cells
    • May directly inhibit VEGF-dependent growth of cancer cells
c) surgical
  • Local excision
    • Stage I tumours are T1, N0, M0
    • As a consequence of the localised nature of T1 tumours without lymph node involvement, patients may be suitable for complete local removal
    • The limiting factor for transanal excision using conventional instruments is access
      • This is restricted to the distal 8 cm of the rectum (transanal resection of tumour, TART)
    • Transanal endoscopic microsurgery (TEM) allows better exposure and access to lesions in the proximal rectum than conventional approaches
      • Uses a device that insufflates the rectum with carbon dioxide, maintains the distension and allows suction and water irrigation
    • The margin of excision around the tumour is marked using cautery, the lesion excised and the wound sutured
    • No further treatment is necessary if:
      • The margins of excision are clear on the resected specimen with pathological grade T1 (pT1)
      • There are no unfavourable features (poorly differentiated, lymphovascular invasion)
    • A meta-analysis of available data suggests TEM has fewer complications, but a higher local recurrence compared with standard surgery
  • Surgical resection
    • Patients with rectal cancer that do not meet the requirements for local excision alone should be treated with a transabdominal resection with sphincter preservation if possible
    • Tumours in the upper third of the rectum are removed by high anterior resection
      • Rectum and mesorectum are removed to 5 cm below the tumour
      • A colorectal anastomosis is fashioned
    • Tumours in the mid and lower third require low anterior resection
      • All of the rectum and mesorectum is removed, using a technique called total mesorectal excision (TME)
        • Refers to the surgical removal of the complete perirectal soft tissue envelope
      • A colo-anal anastomosis is performed, in some cases with a colonic pouch or coloplasty to improve function
      • Such a low anastomosis is usually defunctioned with a temporary ileostomy
        • Reduces the incidence of an anastomotic leak and the need for further, emergency surgery following an elective resection
    • Abdominoperineal resection (APR) with permanent colostomy is required if the tumour invades the pelvic floor, sphincter complex or anal canal
  • Stenting
    • Stenting may be appropriate for some patients with obstructing tumours of the rectum
Prognosis
  • There has been a documented increase in survival in patients with colorectal cancer
    • This improvement is attributed to surgical technique, increased use of neoadjuvant and adjuvant therapy, and screening of asymptomatic individuals
  • The outcome of colorectal cancer depends on the stage at diagnosis
    • About half of patients presenting with symptoms have advanced local (stage III) or metastatic disease (stage IV) at diagnosis
    • In contrast, cancers detected by screening are usually at an earlier stage (mostly stage I to II)
  • Rectal cancer survival rates also vary by country
    • While the overall 5-year survival rate for rectal cancer in the US is 59%, it is 42% in Europe
    • Within Europe, 5-year survival rates for colon cancer are lower in the UK, Denmark, and Eastern European countries compared with the European average of about 50%
    • Analysis of the EUROCARE data suggests that lower survival in the UK is due to later stage at presentation and diagnosis rather than inferior treatment for a similar stage
  • Overall, 5-year survival rates for colorectal cancer are:
    • 93% to 97% for stage I disease
    • 72% to 85% for stage II disease
    • 44% to 83% (depending on nodal involvement) for stage III disease
    • <8% for stage IV disease
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