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
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)
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)
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
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 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