Colorectal Cancer
Updated: Dec 15, 2022
Colorectal cancer is common and one of the leading causes of cancer death.
66-year-old man presents to his general practitioner after noticing blood mixed in the stool and increased frequency of his bowel movement. He also complains of progressive fatigue and unintentional weight loss over the past several months. Initial laboratory findings suggest iron-deficiency anaemia and positive faecal occult blood test.
Key PointsColorectal cancer is common and one of the leading causes of cancer death.
Common symptoms include change in bowel habit and rectal bleeding.
Family history and familial cancer syndromes. Familial adenomatous polyposis and Lynch syndrome are key risk factors.
Screening test is available for those aged above 60 and those at high risk.
Colonoscopy is the standard investigation for those suspected of colorectal cancer.
The main tumour marker is Carcino-embryonic Antigen (CEA).
Surgical resection is the mainstay.
Introduction Colorectal cancer, also frequently abbreviated as CRC, develops in the colon of the rectum. Both colon cancer and rectal cancer are often grouped together as they share multiple common features.
EpidemiologyIn the UK, colorectal cancer is the 4th most common cancer, representing 11% of new cases. There are around 42,900 new cases each year or about 120 each day [1].
In the UK, colorectal cancer is the 2nd most common cause of cancer death, about 10%.
The overall incidence rate has reduced noticeably due to screening practices [1, 2]; however, the incidence rates significantly increase among adults aged < 50 years over the last few decades especially in the developed countries [3].
Incidence rates are higher in the White ethnic group than other groups.
Colorectal cancer is more common in males (1:15) than female (1:18).
Proximal colon tumours (caecum, ascending colon and transverse colon) are more common in females and older people, whilst more distal colon tumours (descending colon, sigmoid colon and rectum) in males and younger people [4].
AetiologyThe majority of colorectal cancer arises from adenomatous polyps regardless of aetiology [2]. Polyps are visible growths or protrusions on the inner lining of the colon or rectum. Not all polyps are classified as adenomatous, but only adenomas are the most common precursor lesions although less than 1% of them become malignant. Adenomatous polyps can be found in about 50% of older people.
The development of colorectal cancer can be contributed by a complex interaction of genetic and environmental factors [5]. In the majority of cases, colorectal cancers are sporadic rather than familial.
Risk Factors
Increasing age
Family history
Familial adenomatous polyposis (FAP)
MYH-associated polyposis (MAP)
Lynch syndrome
Hamartomatous polyposis syndromes
Inflammatory bowel disease (IBD)
Social and Environmental Factors
Diet
Alcohol consumption
Tobacco use
Sedentary lifestyle
Obesity
Increasing age
Increasing age is the biggest risk factors for sporadic colorectal cancer. In the UK, incidence rates are highest in people aged 85 to 89 and about 43% of all new colorectal cancers are diagnosed in people aged 75 and above [1]. Although it is rare in those people under the age of 40, as already mentioned, the incidence rates increase significantly among adults aged < 50 years over the past few decades [3].
Family history
The relative risks for colorectal cancer are 2.24 for those with one affected first degree relative and 3.97 for those with two affected relatives [5]. Family cancer syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome accounts for 2-5% for all colorectal cancers. However, less than 20% of patients provide a family history of colorectal cancer.
Familial adenomatous polyposis (FAP)
An autosomal dominant condition associated with a deletion in the long arm of chromosome 5 including the APC gene [2, 5]. The loss of this genetic material leads to the absence of tumour-suppressor genes which would normally inhibit neoplastic growth.
Familial adenomatous polyposis is classically characterised by the presence of hundreds to thousands of polyps throughout the colon. The adenoma development is generally evident in affected individuals by the age of 25. The adenomas will turn into cancer in almost all cases before the age of 40 if left untreated. Therefore, colectomy should be offered once multiple polyps are detected and screening tests should be provided to the offspring of those patients with this condition.
Gardner's Syndrome : colorectal polyps with multiple soft tissue and bony tumoursTurcot Syndrome : colorectal polyps with malignant tumours of the central nervous system.MYH-Associated Polyposis (MAP)
A rare autosomal recessive syndrome caused by a bi-allelic mutation in the MUT4H gene. The clinical presentation for this condition is highly variable: (1) resembling polyposis or (2) colorectal cancer in young adults without polyposis.
Lynch Syndrome
An autosomal dominant condition, also known as Hereditary Non-polyposis Colon Cancer (HNPCC), associated with gremlin mutations of several genes, particularly hMSH2 on chromosome 2 and hMLH1 on chromosome 3. These lead to errors in DNA replication and defective repair of DNA mismatches. Lynch syndrome also pre-disposes to other cancers including endometrial, ovarian, gastric and pancreatic cancers.
Lynch syndrome is associated with more proximal colon tumours. The median age for the appearance of cancer is usually less. than 50 years. It is also characterised by either:
Presence of 3 or more relatives with colorectal cancer, one of whom is the first degree relative of the other two.
1 or more cases diagnosed before age 50 in the family.
Colorectal cancer involving at least 2 generations.
Hamartomatous Polyposis Syndromes (HPS)
Rare genetic syndromes including Peutz-Jeghers syndrome, Juvenile polyposis syndrome and PTEN hamartoma tumour syndrome (e.g. Cowden Syndrome) [5]. They are characterised by the development of hamartomatous polyps or an overgrowth of cells native to the area.
Inflammatory Bowel Disease (IBD)
Increased incidence of colon cancer is reported in patients with inflammatory bowel disease, particularly those with ulcerative colitis [2]. The risk is related to the extent and duration of the disease.
Social and Environmental Factors
Diet – low fibre diet, consumption of red and processed meats
Alcohol consumption
Tobacco use
Sedentary lifestyle
Obesity
Screening and PreventionThe following are UK guidelines; however, in certain cases, American guidelines recommended by the National Comprehensive Cancer Network (NCCN), the American College of Gastroenterology (ACG), the American Gastroenterologist Association (AGA), the American Cancer Society (ACS) and the American College of Physicians (ACP) might be followed.
Average-risk population
Public Health England offers bowel cancer screening every 2 years to males and females aged 60 to 74 by providing the home faecal immunochemical test kit (FIT) [6]. Those older than 74 years can request a screening test if they wish to continue. Previously, some people aged above 55 were invited for a colonoscopy, which is now only offered to those with an abnormal screening test.
Inherited Risk
The British Society of Gastroenterology recommends that screening starts at age 50 years in patients whose first degree relative was diagnosed with colorectal cancer [7].
High risk syndromes
For those living with familial adenomatous polyposis, Lynch syndrome, MYH-associated polyposis or hamartomatous polyposis syndrome, colonoscopy with or without endoscopy are generally offered at different periods of interval. The screening usually starts at puberty. For those patients with the inflammatory bowel disease should get a screening colonoscopy approximately 10 years after the onset of symptoms [7]. Subsequent tests will be offered according to risks.
Referral to 2-week-wait Colorectal Cancer Pathway [8]
You are eligible for the urgent referral if one of the following is present:
Positive faecal immunochemical test (FIT)
Presence of a lump or swelling in rectum or abdomen
Age > 40 with unexplained weight loss and abdominal pain
Age > 50 with unexplained rectal bleeding
Age > 60 with iron deficiency anaemia and change in bowel habit
Age < 50 with rectal bleeding, plus either abdominal pain, iron deficiency or weight loss
Diagnostic Approach : History3 possible ways of presentations [5]:
Out-patient with suspicious symptoms and signs.
Asymptomatic individuals with positive screening test or high risk syndromes.
Emergency admission with bowel obstruction, peritonitis or bleeding.
History
1. Age: usually above 60; however, those with high risk syndromes present much earlier
2. Positive risk factors: positive family history, high risk syndromes, social and environmental factors
3. Common symptoms
Rectal bleeding
Change in bowel habit – increased frequency or looser stools
Anaemia – may present as fatigue, pallor, breathlessness and palpitations
Rectal pain, tenesmus and narrowing of the stool calibre – may represent recto-sigmoid involvement
4. Symptoms of advanced disease
Bowel obstruction – abdominal distension, vomiting and constipation
Weight loss and anorexia
Abdominal pain in isolation, rectal bleeding associated with anal symptoms and change in bowel habit with harder stools have a low predictive value for colorectal cancer [5].
Diagnostic Approach : Physical ExaminationAbdominal examination is usually normal – abdominal distension and abdominal mass are typically felt in a more advanced disease
Digital rectal examination – rectal mass palpable in 40-80% of patients with rectal cancer
Palpable lymph nodes
Diagnostic Approach : Investigations1. Routine blood tests
Full blood count (FBC) – anaemia, ↓ MCV, MCH and/or ↑ RDW
Iron studies – ↓ Ferritin, iron level and Transferrin saturation with normal / ↑ total iron binding capacity (TIBC), suggesting iron deficiency
Liver function tests – normal even with liver metastasis
Renal function tests – normal, except when the tumour compresses urinary tract
2. Tumour markers
Carcino-embryonic Antigen (CEA) – not sensitive or specific enough for diagnosis or screening, but may be useful in follow-up post-treatment
3. Imaging
For tumour visualisation
Colonoscopy – for direct visualisation and biopsy of suspicious lesions
CT colonography – can be offered to those patient who are not suitable for colonoscopy or not willing to undergo colonoscopy
Double-contrast barium enema – 'apple core' lesion might be visible
For staging
Common sites of metastasis: liver and lungs
CT Chest-Abdomen-Pelvis – to assess the extent of the disease
MRI Pelvis – for local staging for rectal cancer e.g. mesolectal fascia invasion, peri-nodal involvement
Trans-rectal endoscopic ultrasound – performed if MRI is contraindicated
PET scan – consider when metastasis is suspected but negative on CT/MRI
4. Histological examination – the majority of colorectal cancers are adenocarcinomas
5. Genetic testing – NICE recommends that all people with colorectal cancer are tested for Lynch syndrome: micro-satellite instability/mismatch repair gene mutation [9].
Differential DiagnosisColorectal cancer may present similarly to other conditions, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), haemorrhoids, anal fissure and diverticular disease. Investigations such as colonoscopy can help distinguish between these conditions.
ManagementManagement approach depends on the stage and the location of the disease. The delivery of combined modality therapy reduces the recurrence risk and increases the chance of cure [2].
Surgical Intervention
Surgical resection remains the mainstay of curative treatment. In an early stage cancer, a minimally invasive approach may be recommended using colonoscopy or laparoscopic surgery. In more advanced disease, a partial colectomy may be performed together with lymph node removal. A stoma may required following the colectomy.
Chemotherapy
Chemotherapy can be offered as a neo-adjuvant therapy or an adjuvant therapy in both colon and rectal cancers. The primary options for chemotherapy are:
FOLFOX : Folinic acid, Fluorouracil and OxaliplatinFOLFIRI : Folinic acid, Fluorouracil and IrinotecanCapeOX : Capecitabine and OxaliplatinThese combinations of chemotherapy may be altered or re-grouped in different stages of cancer. In certain cases, targeted therapies are prescribed in combination with chemotherapy. Targeted therapies used are either vascular endothelial growth factor (VEGR) inhibitor or epidermal growth factor receptor (EGFR) inhibitor. The primary option is Bevacizumab.
Radiatherapy
Radiotherapy can only be used in rectal cancer, not in colon cancer.
Immunotherapy
Examples of immunotherapy used in colorectal cancers:
Pembrolizumab
Nivolumab
IpilimumabPembrolizumab is the primary option for these patients with unresectable or metastatic colorectal cancer.
Prognosis1-year survival for those diagnosed with colorectal cancer in England is 78.3% [1].
5-year survival for those diagnosed with colorectal cancer in England is 58.4%.
10-year survival for those diagnosed with colorectal cancer in England is 52.9%.
Resources[1] Bowel cancer statistics, Cancer Research UK, https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer#heading-Three. Last accessed 8 Dec 2022.
[2] Mayer RJ, Lower Gastrointestinal Cancers, Harrison’s Principles of Internal Medicine 19th Edition, 2015, p. 537-544.
[3] GBD 2019 Colorectal Cancer Collaborators, Global, regional and national burden of colorectal cancer and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease study 2019, Lancet Gastroenterol Hepatol, 2022, 7(7):627-647.
[4] American Cancer Society, Colorectal cancer facts and figures 2020-2022. 2020
[5] Stein DE, Lisle DM, Kumar PP, Nowak-Choi KA, BMJ Best Practice, 25 Nov 2022,
https://bestpractice.bmj.com/topics/en-gb/258?q=Colorectal%20cancer&c=suggested. Last accessed 8 Dec 2022.
[6] Public Health England, Bowel cancer screening: programme overview, 17 Mar 2021, https://www.gov.uk/guidance/bowel-cancer-screening-programme-overview. Last accessed 8 Dec 2022.
[7] Cairns SR, Scholefield JH, Steele RJ, et al, British Society of Gastroenterology and Association of Coloproctology for Great Britain and Ireland, Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002), Gut, 2010, 59(5): 666-689
[8] Referral to a specialist, Cancer Research UK, 6 Dec 2021, https://www.cancerresearchuk.org/about-cancer/bowel-cancer/getting-diagnosed/referral-specialist. Last accessed 8 Dec 2022.
[9] National Institute for Health and Care Excellence, Molecular testing strategies for Lynch syndrome in people with colorectal cancer, 22 Feb 2017.
Authors: Ross Tulloch, Thitikorn Nuamek
