Summary
The colon and the rectum make up the ‘large bowel’ which is a 6 to 8 cm wide tube that leads to the anus. It takes mostly already digested food residue after it has passed through the small bowel, and extracts water form it. The rectum stores faeces before it can be emptied. The large bowel wall is made up largely glandular tissue, and it is from these cells that bowel cancer usually arises. The cancer usually develops though a stepwise process developing from normal tissue, into a polyp then on to cancer. The rate at which is occurs is variable.
Causes
Environmental factors and genetic factors have been found to cause colorectal cancer.
Genetic causes
Familial Adenomatous polyposis is an inherited condition where multiple polyps develop in the colon during childhood. They usually cause symptoms by the age of 16 and if left untreated will develop into cancer in most cases across the next 20 years. The condition is caused by a mistake in a gene, called the ‘adenomatous polyposis coli gene’.
Hereditary nonpolyposis colorectal cancer, also called the ‘Lynch Syndrome’, is a genetic condition that causes colorectal cancer at a younger than normal age, and tends to affect the first half of the colon. Multiple polyps are not present. The condition is also associated with an increased risk of cancers of the ureter, pancreas, bile ducts, small bowel, stomach, ovary and womb.
Other risk factors
A diagnosis of Ulcerative Colitis:
Patients with Ulcerative Colitis have an increased risk of colon cancer, particularly if the whole colon is affected. If patients have ‘primary sclerosing cholangitis’ as well, the risk is increased further.
A Diagnosis of Insulin Dependent Diabetes:
It has been found that this diagnosis can multiply the risk of developing colon cancer by a factor of 1.3.
Alcohol consumption
This increases the risk of cancer of the colon and rectum significantly if more than 3 or 4 units of alcohol are taken a day.
Being Overweight
Being very overweight increases the risk of colorectal cancer by 50%.
Smoking
Active smoking (as opposed to passive smoking) seems to increase the risk of rectal cancer.
Diet
Eating plenty of fruit and vegetables may be protective against colorectal cancer and red meat may increase the risk. However, there is some doubt as to whether this is really true. The role of fibre and folic acid as protective factors is also controversial although garlic and eating oily fish have been show to help.
Medicines
Aspirin, Hormone Replacement Therapy, and Statins (used for lowering cholesterol) may reduce the risk of colorectal cancer.
Incidence
Colorectal cancer is the third leading cause of death from cancer in both males and females in Western society at present comprising 11% of all cancers. There is a nearly identical incidence in males and females, but a slight relative higher frequency of rectal cancer in males (in Western society).
The cancers of the colon and rectum will be considered together as many aspects of their occurrence, histopathological origin and behaviour are identical, although important differences in therapy will be highlighted. Colorectal cancer has an annual incidence in Western society of 500 per million of the population and deaths due to this disease are second only to lung cancer in men and breast cancer in women. By contrast the disease is relatively rare in Africa. Colon cancer is now 2.4 times as common as rectal cancer a change from 30 years ago when rectal cancer was relatively more common.
Rectal cancer is defined as a cancer that arises below the peritoneal reflection or more simply more than 12-15 cm from the anus.
Symptoms & diagnosis: Colon and rectal cancer
The cancer can cause symptoms by either bleeding or causing disruption of the normal bowel function or by affecting organs it may have spread to.
Symptoms include:
- Abdominal Pain
- Blood from the back passage, often mixed in with the stools, but not always
- A loss of appetite
- Non deliberate weight loss
- A change in bowel habit
- A permanent feeling of having to empty the bowel (called tenesmus)
- Faecal incontinence
- Passing mucous from the bottom
- Anaemia (a low amount of red blood in the circulation)
Diagnosis
A digital examination of the rectum is part of the routine examination of the rectum by every doctor and should be able to palpate the majority of rectal cancers.
A faecal occult blood test should alert the doctor to a bleeding lesion (not necessarily a tumour) in the bowel.
However, the most important test is the proctoscopy and colonoscopy where the doctor directly visualises the entire rectum and colon and is able to biopsy (take for analysis) any parts of the lining wall (the site of origin of all cancers) that look suspicious for cancer.
An indirect alternative to examine the large bowel is the barium enema or CT colography, where the colon is filled with radio-opaque barium solution such that a negative image is projected on x-ray film and any irregularities of the colonic wall are noted.
The biopsy for microscopic (histological) analysis is taken at the time of the colonoscopy and once the diagnosis is established, then a CT scan of the abdomen, pelvis and chest is performed to determine if the disease has spread.
Stages
Pre-operative staging will include the proctoscopy (the direct visualisation of the rectum through a telescopic apparatus) or colonoscopy (the same fibre optic telescopic system for the colon) with biopsy and then abdominal scanning, particularly looking for local spread outside the bowel and the liver, and the chest by chest x-ray.
Following operation, which, in this disease, may still go ahead even if there is early evidence of metastatic spread (to forestall bowel obstruction) the most important aspects for staging are given by the pathologist’s report. The pathologist (histologist) will comment on whether the tumour is confined to the inner bowel wall (stage A) or into the superficial bowel wall without reaching the outer coat (the serosa in the case of the colon) = stage B1, or whether there is full penetration through the bowel wall with local extension through into the surrounding tissues (stage B2). If the lymph nodes in the operative specimen are involved then the staging is C and if there is evidence of spread to other organs then the patient is referred to as having metastatic colorectal cancer.
These staging categories are important as they influence the treating doctors as to which patients are at higher risk of subsequent relapse and who should receive adjunctive post-operative therapy. The staging A-C being progressively less favourable with five year survivals of 80% for stage A, 60% for stage B and 30% for stage C; less than 5% of patients presenting with overt metastatic disease will be alive at five years.
Although the Duke’ staging system above has stood the test of time in usefulness, it has now been replaced by the TNM system of staging:
T1: The tumour has grown into the submucosa.
T2: The tumour has grown into the muscularis propria (muscle wall of the colon/rectum).
T3:|The tumour has grown through the muscularis into the subserosa (only the colon has a serosa – not the rectum).
T4: The tumour has grow into the surface of the visceral peritoneum (T4a) or into adjacent organs (T4b).
N1: Tumour has spread inot one (N1a) to three (N1b) regional nodes or nodules adjacent to the bowel (N1c).
N2: Tumour has spread into 4-6 nodes (N2a) or more (N2b)
M+: metastases present.
Treatment & outcomes: Colon and rectal cancer
The treatment of colorectal cancer varies according to the stage of the disease and whether the aim of treatment is cure, or aimed at improving and to maintain the quality of life.
When the aim is cure
This is expected if the tumour has not spread to other organs and the patient is fit enough for treatment. If the tumour has spread to a small amount of the liver and nowhere else, cure may still be possible (vide infra).
The main curative treatment is an operation on the primary cancer, with other treatments given before and/or after the operation to improve the chances of cure.
For rectal cancer, the best operation is called a Total Mesorectal Excision (TME), where the rectum is removed with a good safety margin around it, and is removed in toto with a clear microscopic margin around the resected specimen. If the tumour is very close to the anus, it is impossible to safely get below the cancer and leave enough uninvolved rectum to allow a ‘joining up’ operation (‘anterior resection) to be safely performed without leaving margins that are either involved or so close to increase the risk of local relapse at the site of the anastomosis (the site of the sewing of the two ends together). In this situation (lower third rectal cancers), the lower rectum and anus are therefore removed and the patient needs a permanent colostomy i.e. the bowel drains through a stoma that is brought out onto the anterior abdominal skin wall, emptying into a bag. The perineum – where the anus previously was – is sewn over. This operation is called an abdoperineal resection/excision (APR or APE).
The success of an operation for rectal cancer depends on the surgeon being able to remove the whole tumour with a safety margin around it. When the initial scans are done, it may be seen that this is not possible or the cancer is deemed high risk for the surgeon to obtain those essential clear margins. When this is the case the tumour may be shrunk first by a course of radiotherapy and chemotherapy, given at the same time – often tablet capecitabine given each day during the course of pelvic radiotherapy. This usually lasts 5 to 5 1/2 weeks and the chemotherapy is given continuously throughout this time. The operation is the performed usually 6 to 12 weeks after the end of the chemo-radiotherapy. A temporary colostomy may be done before this to make the treatment easier to go through or if there are difficult symptoms that need dealing with quickly. Pre-operative chemo-radiation has no role for colon cancer.
For colon cancer, the operation depends on the site of the tumour but only certain operations are possible due to the blood supply to normal colon. For cancers of the caecum and ascending colon a right hemicolectomy is performed. For those arising in the transverse colon a transverse colectomy is performed and a left hemicolectomy for those arising in the descending and sigmoid colon. In each case the bowel is joined up end-to-end such the patient comes out of the procedure with a normal functioning bowel. Sometimes if the patient has bowel obstruction due to the tumour, the surgeon may leave in a temporary colostomy above the operation site, until the bowel has settled.
After the operation (for either rectal or colon cancer), the resected tumour is analysed in the pathology laboratory and the true stage is decided – reported on the TNM system (Tumour, Nodes, Metastasis). The lab will also perform genomics particularly for KRAS , NRAS and BRAF oncogenes and also for MMR deficiency – mismatch repair deficiency/microsatellite instability – due to usually to MLH1, MSH2, MSH6 or PMS2 repair gene mutations (vide infra). These will all be relevant to the optimal systematic therapy recommended.
If there are tumour cells in any of the lymph nodes or of the tumour extends into any nearby tissues, then a course of chemotherapy will reduce the chance of the disease returning – adjuvant chemotherapy. The choice of chemotherapy depends on the age and fitness of the patient. Traditionally, such chemotherapy (and a regime of 5-Fluorouracil and oxaliplatin is preferred currently – if the patient is fit enough to receive this) has lasted for 6 months, given as a day case every 2 or 3 weeks, but in 2018 an important study showed non-inferiority for a three month regime of this chemotherapy and this has changed practice in patient with intermediate risk disease. This change in practice is anticipated to reduce the peripheral neuropathy (numbness and often discomfort) of the finger-tips and toes, which is dose related (i.e. cumulative) effect of the oxaliplatin. The role of adjuvant chemotherapy is less well established for right sided (midgut origin) colon cancer and particularly those with MMR deficiency (MSI high) where immunotherapy is taking a more important role.
There is no routine role for post-operative radiotherapy in the therapy of colon cancer cases. With the adoption of pre-operative chemo-radiotherapy for intermediate and high risk rectal cancers, the question of post-operative radiotherapy for rectal cancer patients seldom arises nowadays. However, if the patient has not received pre-operative chemo-rad and the histology of the resected specimen shows locally advanced disease then, indeed, post-operative pelvic radiotherapy is important.
Following the adjuvant therapy, the patient is put on follow-up with six monthly CT scans and cancer markers – CEA and CA 19-9. The post-operative adjuvant chemotherapy recommendations for rectal cancer patients have traditionally been based on initial staging but are currently revised to some extent by the post-operative histology. However, adjuvant chemotherapy reaches cells outside the pelvis and the initial staging relates to the risk of such cells being present.
Treatment for more advanced disease:
If the tumour has spread to other organs then, generally, it is not possible to cure the disease. However, if there is only one site (or perhaps two or at most three sites of spread – and we use the term: oligometastatic disease for this situation) then aggressive systemic therapy (chemotherapy plus ‘smart drugs’) is used to shrink the tumour at all sites and then, if the oligometastatic disease remains in shrunken form, then local therapy to these few sites is brought into play (surgery, radiofrequency ablation, cyberknife in particular) with proven benefit to the survival to the patient.
The choice of treatment approach in such cases is tailored to each patient individually; surgery, radiotherapy and chemotherapy may be useful, but the down sides and side effects must be considered with respect to the potential benefit. Indeed, the same strategy is employed for patients with apparently incurable liver metastatic disease (or indeed lung or other sites of metastases): i.e. if the disease responds well to chemotherapy and only the original sites of bulky metastatic disease remain in reduced form. There has been a much more aggressive approach to these patients nowadays with better outcomes for the patients – using surgery, focal radiation therapy (SABR), radiofrequency ablation (RFA) and other focal methods.
Often chemotherapy is given, with the aim of shrinking and controlling the tumour. The choice of chemotherapy depends on whether and which treatment has been given before, and how long ago it was given. The side effects of chemotherapy drugs vary, and these may influence which is chosen. It is currently standard practice to give Folfox (the 5-fluorouracil plus oxaliplatin chemotherapy) with a smart drug : bevacizumab/avastin (a vascular endothelial factor receptor – VEGF antagonist). However, if the patient relapses having had this regime, e.g. in the adjuvant setting, then irinotecan is substituted. Where the genomics of the tumour shows that KRAS oncogene is not mutated, then another ‘smart drug’: cetuximab (and its sister drug: panutumuab) is used in combination with chemotherapy or panutumumab as a single agent. BRAF also is important although only a minority of cases demonstrate an actionable mutation.
It has been recently been appreciated that the site of the tumour may have an influence on the responsiveness of that particular tumour to both chemotherapy and smart drug therapy: e.g. tumours of the ascending colon and caecum (of midgut embryonal origin) have different responsiveness to EGFR directed therapy – e.g. cetuximab – than left sided colorectal cancer (hind-gut origin).
Where there is MMR deficiency or microsatellite instability, the cancers are hypermutated (and this is more commonly encountered in midgut origin, right sided or Lynch syndrome cases). Here there is new hope for immuno-therapy therapies using PD1 inhibitors as the hypermutation causes the tumours to be more antigenic and hence more vulnerable to immunotherapy attack. Immunotherapy has not been found to be effective so far in patients whose tumours are MMR proficient.
Surgery may be used if the tumour is at risk of causing bowel obstruction, or a stent may be use to hold the bowel open to prevent or relieve obstruction.
Radiotherapy may be used to help shrink tumours that are causing symptoms, particularly in the rectum (if the patient has not previously received pelvic radiotherapy) or to palliate metastases – particularly painful bone metastases.
What to do if/when the cancer has resisted all the best drug therapies??
Nowadays, this situation is best approached from a genomic viewpoint viz. Are ther any discoverable gene mutations that are ‘driving’ the cancer to divide and are they actionable (the Americans say: ‘druggable’)?
The patient should either have a new tissue biopsy upon which next generation sequencing (NGS) can be performed or, nowadays, (if the cancer is releasing enough cfDNA into the blood) a NGS analysis of the cell-free DNA (cfDNA) – from a simple blood draw . Although it may be a minority chance, but there are an increasing number of escape genetic mutation paths, which render the cancer open to genomically targeted therapy. Circulating tumour cell clusters represent another form of “liquid biopsy” (from a blood draw) and may better mirror the genomics of cells that will forward metastases.
The interesting rare mutation of BRAF occurs in 5-10% of colon cancer, usually in older patients with right sided colon cancer, carries a poor prognosis compared to non-mutated cases. BRAF encodes a protein kinase in the Mitogen Activated Protein Kinase (MAPK) pathway and the commonest mutation is at the V600 site (valine usually substituted for Glutamic acid). This is very similar to the situation in malignant melanoma, where this mutation is a driving mutation and can be very successfully blocked by dabrafenib or verumafenib and good and long-lasting remissions of the melanoma can be achieved. Such remissions in BRAF melanoma can be prolonged and further survival benefit achieved by adding a MEK inhibitor: Trametinib to the BRAF blockade (as the MEK driving oncogene pathway is the commonest escape route for the melanoma to go if BRAF is blocked). Following on from these important observations in Melanoma, Oncologists have tried to achieve comparable responses in BRAF mutated colon cancer. Unfortunately, and probably due to feedback signals that re-activate MAPK signalling, these have been less successful but the combination of dabrafenib and trametinib (or encorafenib with binimetinib) dose have a minority chance of response in BRAF V600 mutated metastaic colon cancer. This is a good example of where genomic evaluation by NGS can be helpful. NGS is also picking up PI3K mutations in relapsed metastatic colon cancer and this is important as there are now PI3K inhibitors entering clinical use. NGS analysis of the cancer at the time that it is becoming resistant to standard therapies may help in deciding next therapy and the subject of genomics and cancer therapy is well illustrated by such examples as mutations in KRAS, NRAS and BRAF genes in this disease.
NGS analysis can also be used to tell if the tumour is likely to respond to immunotherapy – for, if there is mismatch repair deficiency (MMR deficiency) or MSI, then there are likely to be enough mutations in the cancer to render it antigenic and hence open to immune attack.
If further chemotherapy is considered, then Ramucurumab based therapy can be useful (perhaps less so than in gastric cancer) and the chemotherapy drug: Lonsurf may bring something to the table and is well tolerated. However, our experience in the ‘heavily pre-treated’ patient is that any response is not very durable.
With regard to further ‘Smart Drug’ therapy, Regorafenib’ and, as just mentioned, Ramucurumab can bring about responses in KRAS mutant cancers and can be useful, although there is moderately marked drug toxicity with Regorafeninb. In KRAS ‘wild-type cancers that have responded to chemotherapy including cetuximab, then maintenance: panutumumab can extend the remissions and with usually low toxicity.
P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics). Tel: +44-207-631-1632
Outcomes
The outcome depends on the stage of the disease and the behaviour of the tumour.
Early cancers, including those which are node positive, are treated with curative intent and the patient should be re-assured of this.
In patients with very early metastatic dsiease (e.g a single liver metastasis on the initial staging scan) we still treat with radical/curative intent but add focal therapies to the metastasis at the end of the surgery and systemic therapy programme (e.g surgery, radiofrequency ablation or Cyberknife), as there are occasional truly single site metastases and this programme will stand a chance albeit a minority one) of obliterating the disease at all sites.
Screening for colon and rectal cancer
Screening is recommended in those patients who have a positive family history of colorectal cancer (see the section on ‘Incidence’).
Regular colonoscopies and rectal examinations should start in early adult or even late teenage life where there is a significant genetic risk.
Similarly, colonoscopoic surveillance is required for those with a history of colonic polyps, or other large bowel related symptoms (e.g. change of bowel habit, blood in stools – a ‘red flag’ symptom).
The routine use of faecal occult blood screening (the examination of three stool specimens by a smear test that picks up traces of blood mixed in with the stool) for everyone between the ages of 60 an 69 is being rolled out in the UK (NHS Bowel Screening Programme) because it has been shown to reduce the risk of dying from bowel cancer by 16%.