Figure 1: www.nlm.nih.gov/medlineplusThroughout the world cancer can be seen as one of the most widely experienced and feared diseases. Even for those who have never experienced the disease first hand, there is a huge public awareness about the disease and its effects, which has meant that it has the power to instill fear in to everyone. Cancer is a group of abnormal cells, known as a tumour, which grows uncontrollably, invading and destroying the surrounding tissue. The colon is the final part of the digestive system, its function is to extract water and salt from solid wastes before they are eliminated from the body.(1) Unlike the small intestine, the colon does not play a major role in absorption of foods and nutrients and in humans. As displayed in the figure 1, it consists of four sections: the ascending colon, the transverse colon, the descending colon, and the sigmoid colon. Cancer usually takes its name according to the type of organ tissue from which it develops, such as lung cancer or colon cancer. Colon cancer can also be known as colorectal cancer, or large bowel cancer. (2)http://ae.medseek.com/bguide/reftext/images/LargeIntestine.jpg
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Mechanisms of Generation
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Colon cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, mostly resulting from mutations which can be acquired or genetic.(4) Wortherly et al. suggest that there are three proposed pathways of generation. The first and most important of these is the Chromosomal Instability Pathway (CIN), also known as the suppressor pathway. This is characterised by stepwise mutation or deletion of K-ras, APC, SMAD2, SMAD4, DCC, and p53. http://www.mindupbioresearch.com/images/angiogenesis.jpg
The K-ras proto-oncogene encodes a GTP-binding protein and when mutated can cause a loss of inherent GTPase activity. Evidence has been found that changes in the RAS oncogene tend to occur early in the pathway to malignant cancer.(5) The Adenomatosis Polyposis Coli (APC) producing gene is the most commonly mutated gene in colorectal cancer. APC binds to Î²-catenin and acts as an important step in dampening down the Wnt-signaling pathway. Wnt-signalling normally helps to regulate growth, apoptosis and differentiation.(6) SMAD2 and SMAD4 are located at 18q21.1. These are involved in the TGF-Î² signalling pathway, which is important in regulating growth as well as apoptosis. DCC (deleted in colon cancer), is also located at 18q21.1. (4) Allelic loss at this site is found in up to 60% of colorectal cancers. Another tumour suppressor gene called 'mutated in colon cancer' (MCC) is located at 5q21, and often causes a loss of function mutations in sporadic colorectal cancer. P53 is mutated usually through loss of 17p, this mutation is often a late event in this pathway and tends to be the cause of transition from pre-invasive to invasive disease.(5) Figure 2 shows a simplistic version of the CIN pathway:
The second pathway is the Microsatellite/Mutator pathway, which results from a germline mutation in a mismatch repair gene.(5) The majority of these cancers occur sporadically following the epigenetic silencing of MLH1. BRAF mutation and associated failure of anoikis may be important in the early stages of this pathway. The final pathway, the Methylator pathway, is usually associated with BRAF mutation with or without silencing of MLH1. DNA methylation is a means of regulating gene transcription. There is an alternate methylator pathway, without BRAF mutation, but instead with the maintenance of K-ras mutation, and methylation of MGMT. (6)
The most common colon cancer cell type is adenocarcinoma, which accounts for 95% of cases.(7) Adenocarcinoma is a malignant epithelial tumour, originating from the glandular epithelium of the colorectal mucosa. The vast majority of cases of colorectal cancer originate as an adenocarcinoma, due to the fact that the colon has numerous glands within the tissue. Colloid or mucinous adenocarcinomas represent about 17% of large bowel tumours.(8) Other rare variants of epithelial tumours include squamous cell carcinomas and adenosquamous carcinomas. Finally, there are also undifferentiated carcinomas, which contain no glandular structures or other features, such as mucous secretions.
Another type of colon cancer cell is Leiomyosarcomas. This type of colon cancer occurs in the smooth muscle of the colon. These account for less than two percent of colorectal cancers and have a fairly high chance of metastasizing.(9) Melanomas and lymphomas are rare in colon cancer. Usually, they start somewhere else and then spread to the colon or rectum. These melanomas account for less than two percent of colorectal cancers. Non-Hodgkins lymphoma can account for about 0.5 percent of all colorectal cancers and Neuroendocrine tumours of the colon and rectum account for about four percent of all colorectal cancers. (8)
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Once the cancer has under gone enough mutations, the cancer cells multiply and invade deeper into the wall of the colon. Some cells may break off into the lymph channels or bloodstream. The cancer may then metastasise to lymph nodes nearby or to other areas of the body, most commonly the liver and lungs. Generally the cancerous mass will look much different in colour than the surrounding tissue. Bleeding from the tumour is often apparent as the tumour tends to grow blood vessels via the secretion of a number of angiogenesis promoting factors such as VEGF. (10) Most colorectal cancer tumours are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.(11)
Over one million new cases of bowel cancer were diagnosed worldwide in 2002. Bowel cancer incidence rates have remained large but relatively stable for over a decade. The lowest incidence rates of bowel cancer are seen in South Central Asia, and Eastern, Western, Northern and Middle African countries. The highest rates are in Europe, North America and Australasia.(12) Currently colorectal cancer can be seen at a higher incidence within more economically developed countries, especially countries where a large proportion of people work within industrial sector. (12)
There have been substantial improvements in the prognosis of people with colorectal cancer over the past decade. Without treatment, colorectal cancer is likely to develop into a larger growth and spread to other parts of the body. If the cancer is not diagnosed until after it has grown through the wall of the colon or rectum, or spread to other parts of the body, there is less chance of a cure. However, treatment can often slow down the progression of the cancer. It can be seen that people diagnosed at an early stage have more than a 9 in 10 chance of surviving the disease. (13) At present, only about 1 in 7 people with colorectal cancer are diagnosed at this early stage. However, improved screening may greatly increase the number of early diagnosis made. The NHS Bowel Screening Programme began in England in 2006. This programme suggested that there could be up to 20,000 fewer deaths from bowel cancer over the next 20 years if 60% of those eligible took up the invitation for bowel screening.(14)
The occurrence of large bowel cancer is strongly related to age, with 83% of cases arising in people who are 60 years or older. (14) Up until the age of 50, statistics show that the occurrence of bowel (colorectal) cancer is similar for men and women, but in later life higher occurrence can be seen amongst males. Overall the Male-Female ratio is 6:5. The lifetime risk for men of being diagnosed with colorectal cancer in the UK is estimated to be 1 in 16, in comparison to 1 in 20 for women. (15) Generally, colon cancer is more common in females, however rectal cancer is more prevalent in males.(16)
There are various lifestyle factors which can be seen to increase the risk of colon cancer. A high intake of dairy products, fat, red and processed meat, have been shown to increase the chances of developing bowel cancer. Those who are inactive, indulging in little exercise are also at an increased risk of developing the disease.(17) Countries that have had a rapid 'westernisation' of diet, such as Japan, have seen a rapid increase in the incidence of colorectal cancer.(18) Epidemiological studies report a rapid increase in risk for colorectal cancer in migrants moving from low to high risk countries.(12) At least 10% of colon cancers in the UK are related to patients being overweight or obese. Smoking and alcohol has also been associated with an increased risk factor, which research showing that people drinking more than 30g/day of alcohol have an increased risk of colorectal cancer.(17) A recent study suggests that male patients present with an 11% increased incidence rate in the most deprived groups compared to those in the affluent groups. (19)
Genetic factors can also be held responsible for an increased risk. People with a close family member with colorectal cancer are at twice the risk of developing it themselves. It is believed that there are genetic risk factors of around 70-90% mainly associated with the familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.(17) There is also a 5% risk of getting a colorectal carcinoma if you are predisposed to adenomatous polyps. Other high risk categories include people with diabetes, ulcerative colitis or Crohn's disease.(17) Conversely, women who take hormone replacement therapy (HRT), and people whose diet is rich in fibre, with a high volume of fruit and vegetables have been shown to be at a reduced risk of suffering from colon cancer.(15) Also Weiss et al have shown that more than 10 years of regular use of non-steroidal anti-inflammatory drugs can reduce the risk of bowel cancer.(20)
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When a colorectal cancer first develops it is very small it usually causes no symptoms. As it grows, the symptoms that develop can vary, dependent upon the site of the tumour. The most common detection process is Faecal Occult blood test.(13) Bleeding from the tumour causes blood to be present in faeces. The bleeding is not usually severe and in many cases is not noticed. It may result in a dark colouration of the faeces. Also, passing mucus within the faeces, changes from usual bowel habits, abdominal pains, anaemia, generally feeling unwell, fatigue or a large loss of weight, may also be an indication.(22) If the cancer becomes very large, it can cause an obstruction of the colon. This causes severe abdominal pain and other symptoms such as vomiting. (1)
Following an initial assessment by the doctor there are various tests which might be undertaken. These are: Colonoscopy, Flexible sigmoidoscopy, CT colonography, Barium enema test. A colonoscopy is a test in which a long, flexible telescope enables the detailed analysis of the whole of the colon and rectum. A Flexible sigmoidoscopy is a shorter telescope that is inserted only into the rectum and sigmoid colon. A CT colonography test uses X-rays and a computer to build up a series of images of the colon, identifying any abnormal structures. Finally, the Barium enema test enables any colon and rectum abnormalities to show up on ordinary X-ray pictures. However, in recent times a colonoscopy is the method most commonly used.(21) The cancer tumour marker CEA (carcinoembroyonic antigen) can also be tested for. This marker is elevated in cancer patients and can be used in diagnosis and monitoring.(13)
Once a suspicious structure has been identified a biopsy will then be taken. The sample is then examined under the microscope to look for abnormal cells. A biopsy is carried out by passing a thin instrument down a side channel of the colonoscope or sigmoidoscope. If colorectal cancer is confirmed, further tests may be done to assess if it has spread using, a CT scan, an MRI scan, or an ultrasound scan. Through identification of the stage of the cancer, the doctor is able to use this information to help formulate the best advice and treatment options. It also gives a reasonable indication of outlook (prognosis). (21) A common staging system for colorectal cancer is called the Dukes' classification, as detailed below:
Duke A: the cancer is just in the inner lining of the colon or rectum.
Duke B: the cancer has grown to the muscle layer in the wall of the colon or rectum.
Duke C: the cancer has spread to at least one lymph node near to the colon or rectum.
Duke D: the cancer has spread to other parts of the body ('metastases' or secondary tumours).(23-24)
The commonly five-year survival rates for bowel cancer have doubled over the last 30 years, suggesting that around half of people diagnosed will survive for at least five years after diagnosis. Research suggests over 90% of bowel cancer patients will survive the disease for more than five years if diagnosed at the earliest stage.(25) At Stage 1 patients have around a 95 percent chance of reaching the 5 year survival rate. At Stage 2 the survival rate reduces dramatically to 60 percent after five years. For Stage 3 chances are reduced further to 35-60 percent, whereas patients at Stage 4 only have around a 3 percent chance of reaching the five-year survival time.(24)
It can be seen that younger colorectal cancer patients have a better prognosis than older patients. Large bowel cancer is the second most common cause of cancer death in the UK after lung cancer. Around 16,000 people die from it each year in the UK. The death rate has been falling since the late 1970s and over the last decade death rates have dropped by around 16%. Worldwide, large bowel cancer kills around half a million people each year, with nearly two-thirds of these deaths in the more developed regions.(2,15,25)
Impact on society
Approximately 5 per cent of the NHS budget is spent on cancer treatments and research, equating to around £76 per head each year in England (around £4.5 billion a year in total).(26) The cost of the NHS Bowel Cancer Screening programme is £76.2 million. The NHS Bowel Cancer Screening Programme offers screening every two years to all men and women aged 60 to 69. The cost is about £5900 per life saved. (27)
According to Quinn et al colon and rectal cancers are the third most common cancers in the UK with more than 37,500 people being diagnosed yearly. It is the second most common cancer in women after breast cancer, with around 17,000 new cases diagnosed in 2006. Colon cancer is the third most common cancer in men after prostate and lung cancer with around 20,400 men being diagnosed each year.
Treatment options which may be considered include surgery, chemotherapy and radiotherapy. The treatment advised in each case depends on various factors such as the stage of the cancer and the patient's general health. These stages are detailed below:
Stage 0 treatments: the polyps are removed during a colonoscopy (polypectomy). The chances of them progressing to later stages of cancer is eliminated.
Stage 1 treatment: surgery to remove the section of the colon that is cancerous (resection). The healthy, non-cancerous sections of the colon are reconnected again.
Stage 2 treatment: A resection surgery may also be used to treat this stage of cancer.
Stage 3 treatment: In this stage, the cancer has not spread and treatment is more aggressive. Surgical resection of the colon, chemotherapy, and other medical therapies may be necessary. The current chemotherapy combinations for stage 3 treatment includes Capecitabine as a monotherapy, Oxaliplatin in combination with 5-fluorouracil, and folinic acid (or irinotecan) in combination with 5-fluorouracil and folinic.
Stage 4 treatment: addition to a surgical resection and chemotherapy, radiation treatment and surgery to remove other affected parts of the body may be necessary. The chemotherapy treatment for stage four includes: irinotecan in combination with 5-fluorouracil and folinic acid as first-line therapy, or irinotecan alone in subsequent therapy. Oxaliplatin is also used in combination with 5-fluorouracil and folinic acid.(27)
There are several new groundbreaking drugs which are now being used for colorectal cancer treatment. Bevacizumab is a monoclonal antibody to Vascular Endothelial Growth Factor (VEGF). This is indicated for first line treatment of metastatic colorectal cancer in combination with irinotecan, 5-fluorouracil and folinic acid. Cetuximab is also a monoclonal antibody, but this time to Epithelial Growth Factor Receptor (EGFR). (27)
Future of treatment:
Trials are currently underway to establish the effectiveness of certain treatments. The 'EnROL trial' compares conventional surgery with keyhole surgery in colon cancer. The aim of this trial is to find out whether keyhole surgery will help patients to recover faster. Another trial, the FOxTROT trial, is looking the possible positive impact of giving chemotherapy before and after surgery. Some participants in the trial will also be given the monoclonal antibody panitumumab (another monoclonal antibody). Other research is going into certain tyrosine kinase small molecule inhibitors, for example; imatinib, gefitinib.
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4:Â Marchand, L., Combined influence of genetic and dietary factors on colorectal cancer incidence in Japanese Americans. J Natl Cancer Inst Monogr, 1999. 26: p. 101-105.
5: Colorectal carcinogenesis: Road maps to cancer
Daniel L Worthley Vicki L Whitehall, Kevin J Spring, Barbara A Leggett World J Gastroenterol 2007 July 28; 13(28): 3784-3791
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(9): Kayhan, Burçak and Turan, Nesrin. "A Rare Entity in the Rectum: Malignant Melanoma." The Journal of Gastroenterology 14.4 (2003): 273-275. 5 Jul. 2006.
(11) COX-2 expression and tumor angiogenesis in colorectal cancer
Ai-Wen Wu, Jin Gu, Zhen-Fu Li, Jia-Fu Ji, Guang-Wei Xu: World J Gastroenterol 2004;10(16):2323-2326
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13. Cancer Research UK, CancerStats Incidence - UK.
14. Office for National Statistics, Cancer Statistics registrations: registrations of cancer diagnosed in 2006, England. 2009
15: Statistical Information Team. Cancer Research UK. 2009
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20: Aspirin, Non-steroidal Anti-inflammatory Drugs and Protection from Colorectal Cancer: a Review of the Epidemiological Evidence. H. A. Weisshttp://informahealthcare.com/entityImage/?code=200Bâ€Œ1,2â€ and D. Formanhttp://informahealthcare.com/entityImage/?code=200Bâ€Œ Scandinavian Journal of Gastroenterology 1996, Vol. 31, No. s220, Pages 137-141
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28: GI and Lung cancers - M Small TREATMENT OF GI LUNG CANCERS lecture notes. UEA-2010