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