Colorectal Cancer

Overview

Colorectal cancer is the fourth most common cancer in the UK^[1]. It is the second leading cause of cancer-related deaths in the UK^[2]. Almost half of all cancer-related deaths are due to lung, bowel, breast, or prostate cancers^[3].

Colorectal cancer can occur anywhere from the caecum to the rectum. The most common sites are the rectosigmoid region (55%), followed by the ascending colon (approximately 20%), the transverse colon (around 10%), and the descending colon (about 5%)^{[4, 5]}.

Causes of colorectal cancer include:

• Sporadic cases (95%)^[6]
• Hereditary non-polyposis colorectal carcinoma (HNPCC) (5%)^[7]
• Familial adenomatous polyposis (FAP) (less than 1%)^[8]

Pathophysiology

Adenoma-carcinoma sequence

The adenoma-carcinoma sequence is a mechanism that describes the progression of normal epithelial cells to dysplastic cells such as adenomas, and eventually to carcinoma through a series of genetic mutations ^{[6, 9]}.

Metastasis

Colorectal cancer can spread to the liver, lungs, or peritoneum^[1]. The mechanisms of spread include:

• Local invasion: the tumour infiltrates nearby structures.
• Lymphatic spread: cancer cells move to regional lymph nodes, causing metastasis to distal lymph nodes^[10].
• Haematogenous spread: cancer cells travel through blood vessels, leading to metastases in the liver and lungs^[10].

Epidemiology

• Colorectal cancer accounts for approximately 41,000 new cases annually in the UK^[1].
• Incidence is highest in people aged >85 years old^[2].
• The incidence of this cancer is significantly higher in developed countries. This is possibly due to factors such as higher consumption of processed meats, lower intake of fruits and vegetables, sedentary lifestyles, and increased obesity^[11].
• There are around 50,000 deaths from colorectal cancer annually.

Hereditary Non-Polyposis Colorectal Cancer

Overview

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant condition and represents the most common form of hereditary colorectal cancer. Individuals with HNPCC have up to an 80% lifetime risk of developing colorectal cancer, which often presents as poorly differentiated and aggressive^[7]. HNPCC is also associated with an increased risk of other cancers, including up to a 60% chance of developing endometrial cancer^[7].

The development of HNPCC is linked to multiple genetic mutations. These mutations affect genes responsible for DNA mismatch repair, leading to microsatellite instability. This instability results in an inability to correct DNA replication errors, which contributes to HNPCC. The MSH2 gene is involved in 20-40% of cases, while the MLH1 gene is implicated in 15-40% of cases^[12].

Amsterdam criteria

The Amsterdam criteria are used to assist in the diagnosis of HNPCC. The criteria include:

• At least three members of a family with colorectal cancer.
• Cases spanning at least two generations.
• At least one case diagnosed before the age of 50 years^[7].

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is a rare autosomal dominant condition. It leads to the development of hundreds of polyps in the colon by the ages of 30 to 40 years. Without intervention, all patients with FAP will eventually develop colorectal cancer^[8].

FAP is caused by a mutation in the adenomatous polyposis coli (APC) gene, which is a tumour suppressor gene located on chromosome 5. Patients with FAP typically undergo a prophylactic total proctocolectomy with ileal pouch-anal anastomosis (IPAA) in their 20s^[8].

Additionally, patients with FAP are at increased risk for duodenal tumours. A variant known as Gardner’s syndrome can also present with osteomas of the skull and mandible, retinal pigmentation, thyroid cancer, and epidermoid cysts on the skin^[8].

Risk Factors

• Advancing age: The incidence of colorectal cancer is highest in individuals over 85 years old^[2]. Ageing is associated with changes in methylation patterns, which can be used to identify colorectal cancer^[13].
• Family history: Having a first-degree relative with colorectal cancer significantly increases risk, particularly if the relative was diagnosed before 50 years old^[14].
• Hereditary non-polyposis colorectal cancer (HNPCC): Also known as Lynch syndrome, HNPCC is the most common form of inherited colorectal cancer. It significantly raises the risk of developing colorectal cancer before the age of 50^[15].
• Familial adenomatous polyposis (FAP): Individuals with FAP develop hundreds of colonic polyps by 20-30 years old and almost invariably progress to colorectal cancer^[16].
• Inflammatory bowel disease: Conditions such as ulcerative colitis and Crohn’s disease increase the risk of colorectal cancer. The risk is related to the extent and duration of the disease^{[17, 18]}. Chronic inflammation can cause telomere shortening and chromosomal instability^[19].
• Obesity: Obesity is linked to a higher risk of developing colorectal cancer and an increased risk of mortality from the disease^[20]. Obesity may contribute to chronic inflammation, which can elevate cancer risk^[21].
• Processed and Red Meat: Consumption of processed and red meats has been associated with colorectal cancer^[22]. These meats can contain N-nitroso compounds (NOCs), which are carcinogens formed during digestion. Bacteria in the colon metabolise amino acids to produce NOCs. Additionally, lipid peroxidation can lead to the formation of malondialdehyde, a carcinogen^[23].
• Selenium Deficiency: A deficiency in selenium has some evidence linking it to colorectal cancer^[24]. Enzymes involved in selenium metabolism may provide anti-oxidative and anti-inflammatory effects^[25].

Protective Factors

• Hormone replacement therapy (HRT): HRT has some evidence linking it to a reduced risk of colorectal cancer^[26]. Oestrogen may induce apoptosis, inhibit cell proliferation, and downregulate inflammatory signalling in colon cells. This is achieved by upregulating the oestrogen receptor beta^[27].
• Aspirin, NSAIDs, and COX-2 Inhibitors: these classes of drugs appear to lower the risk of colorectal cancer and improve mortality^[28]. They work by inhibiting platelet aggregation, which can reduce immune cell recruitment and inflammation. This, in turn, decreases the release of growth factors and cytokines that promote the growth and proliferation of cells in the colonic mucosa^[29].

Presentation

Features that may suggest colorectal cancer include:

• Changes in bowel habits: this can manifest as constipation, diarrhoea, or alternating between the two. Patients may also experience faecal urgency.
• Rectal bleeding: blood in the stool or rectal bleeding is a common symptom. The blood may appear as bright red or as melaena.
• Abdominal pain and discomfort: this includes pain, cramping, and general discomfort. These symptoms may be due to the tumour causing bowel obstruction or inflammation.
• Unexplained weight loss: significant weight loss without an obvious cause can indicate advanced disease.
• Anaemia: chronic bleeding from the tumour can lead to anaemia, which may present with fatigue, weakness, and dyspnoea.
• Bowel obstruction: in advanced stages, the tumour may cause a complete bowel obstruction, leading to severe abdominal pain, nausea, and vomiting.
• Jaundice and hepatomegaly: these signs suggest advanced disease with liver metastases. Ascites may also develop.

Screening

The NHS provides faecal immunochemical test (FIT) screening for older adults. The national colorectal screening programme offers screening every 2 years to all men and women aged 60-74 years in England and 50-74 years in Scotland. Individuals over 74 years old may request screening.

Key Points:

• Eligible patients receive FIT kits by post.
• FIT is a type of faecal occult blood test that uses antibodies specifically targeting human haemoglobin (Hb).
• Unlike traditional faecal occult blood tests, FIT only detects human haemoglobin and not animal haemoglobin, which may come from dietary sources.
• Only one faecal sample is required for FIT, compared to 2-3 samples needed for conventional tests.
• Although a numerical value is generated from the test, it is not reported to the patient or GP. Instead, patients are notified whether the test results are normal or abnormal.
• Patients with abnormal results are referred for a colonoscopy.

At colonoscopy:

• Approximately 50% of patients will have a normal examination.
• About 40% of patients will have polyps, which may be removed due to their potential for becoming malignant.
• Around 10% of patients will be diagnosed with cancer.

Referral Guidelines

In 2023, NICE updated its referral guidelines to enhance the use of Faecal Immunochemical Test (FIT) screening for colorectal cancer. A FIT should be performed in the following situations:

• Presence of an abdominal mass.
• Notable change in bowel habits.
• Iron deficiency anaemia.
• Individuals under 40 years old with unexplained weight loss and abdominal pain.
• Individuals under 50 years old with rectal bleeding and unexplained abdominal pain or weight loss.
• Individuals aged 50 or older with rectal bleeding, abdominal pain, or weight loss.
• Individuals aged 60 or older with anaemia, regardless of iron deficiency.

Other important points include:

• FIT testing should be offered even if the patient previously had a negative FIT result during national screening.
• Patients presenting with a rectal mass, unexplained anal mass, or unexplained anal ulceration do not require a FIT before considering referral.

FIT Results:

• Positive result: refer the patient via a suspected cancer pathway.
• Negative result: implement safety netting and continue to investigate symptoms to obtain a definitive diagnosis. If clinical suspicion remains high (e.g., presence of an abdominal mass), refer via a suspected cancer pathway^[30].

Investigations

Overview

Investigations to consider include:

• Full blood count (FBC): this test may reveal anaemia, which is a common extra-intestinal symptom of colorectal cancer. Iron deficiency anaemia can occur due to gastrointestinal bleeding caused by the cancer. Inflammation associated with colorectal cancer can increase hepcidin levels, reducing dietary iron absorption and inhibiting the release of iron from cellular storage^{[31, 32]}.
• Faecal immunochemical test (FIT): This test detects blood in the stool and helps guide referrals to secondary care.
• Colonoscopy: this is the preferred investigation if there is no evidence of bowel obstruction. It allows for the collection of tissue samples for biopsy and the removal of any suspicious lesions.
• CT chest, abdomen, and pelvis: this imaging technique assesses the extent of the disease and helps in determining treatment options and prognosis.

Staging

Colorectal cancer staging uses the TNM (Tumour, Node, Metastasis) system. This system helps to evaluate the prognosis and plan treatment. Staging investigations include:

• Carcinoembryonic antigen (CEA): this tumour marker test can aid in monitoring the disease.
• CT chest, abdomen, and pelvis): this scan is used to assess the spread of the cancer.
• Colonoscopy/CT colonography: these methods are used for visualising the colon and assessing tumour presence.
• MRI: This is used for evaluating tumours located below the peritoneal reflection and for assessing the mesorectum.

Management

Surgery

Surgery is the primary treatment for colorectal cancer. Resectional surgery can potentially cure this cancer. For individuals with Hereditary non-polyposis colorectal carcinoma (HNPCC), a panproctocolectomy is often preferred over a segmental resection. This is due to the increased risk of cancer developing in other parts of the colon and rectum.

Following a resection, an anastomosis may be performed. This procedure connects two sections of the bowel to restore its continuity. For successful healing of the anastomosis, several factors must be met:

• Adequate blood supply to the area.
• No tissue tension.
• Mucosal apposition, meaning the mucosal layers must align closely.

In cases where the tumour causes bowel obstruction, treatment options include either stenting or resection of the obstructive tumour.

Resection types

Resection types are determined by the tumour’s location, and are performed based on the tumour’s blood supply and lymphatic drainage. The types of resections and corresponding anastomoses are:

Chemotherapy      

Chemotherapy is used in several contexts for colorectal cancer. It can be used as a neoadjuvant therapy to shrink tumours before surgery, particularly in rectal cancers. It is also used as an adjuvant therapy to eliminate remaining cancer cells after surgery, and for treating metastatic disease. Common chemotherapy regimens include FOLFOX and FOLFIRI.

Targeted therapies

Targeted therapies are used primarily for metastatic disease. These include:

• Bevacizumab (anti-VEGF), which inhibits the formation of new blood vessels that tumours need to grow.
• Cetuximab (anti-EGFR), which targets the epidermal growth factor receptor involved in tumour growth.

Emergency surgery

In emergency settings where the bowel has perforated, the risk of complications with an anastomosis (surgical connection between two bowel segments) is high. This risk is especially elevated with a colon-colon anastomosis.

In these cases, an end colostomy is often a safer option. This procedure involves creating an opening in the abdominal wall to divert the bowel contents into a colostomy bag. The colostomy can be reversed at a later time. When resection of the sigmoid colon is required, and an end colostomy is created, the procedure is known as a Hartmann’s procedure. This approach removes the diseased portion of the bowel.

While left-sided resections carry higher risks, ileo-colic anastomoses are generally safer, even in emergency situations. These anastomoses do not usually require defunctioning.

Prognosis

• Almost 60% of people diagnosed with colorectal cancer can survive for at least 5 years^[1].