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Cancer is defined as any malignant tumor that arises from uncontrolled normal cell aggregation therefore leading to de-differentiation, invasion and local destruction of surrounding tissues. Cells are the building blocks that make up the human body. Progression from a single cell, aggregates of which forms a tissue, then an organ and finally the system highlights the importance of governing the function of this unit. Cancer Research UK's Cancerstats revealed that the incidence of new cancer cases exceeds 293,000 cases per annum with breast, lung, bowel and prostate cancer collectively contributing to half the sum; the over 60's age group being the most vulnerable accounting to up to 75% of the sum while the under 25's conversely accounting to less than 1% suggesting age to be a factor.1 Therapeutic advancement with time is promising as figures have shown that mortality rates has decreased over the years and significantly as much as 10% in the past decade.2
Over 200 types of cancer were reported, each of which has differing symptoms, causes and treatment options.2 Colorectal cancer, also known as colonic cancer or large bowel cancer, is a type of cancer involving the colon, rectum and appendix.3 Colorectal cancer appears to develop from either the colon or the rectum, both of which have very similar features, differing slightly only in terms of treatment. The location of which the cancer develops determines the type of symptoms that will be observed. Colorectal cancer is a slow progressing disease, developing slowly over the years from a polyp; abnormal tissue growth projecting from the lining of the membrane protruding into the center of the colon or rectum.4 Over 95% of colon or rectal cancers are adenocarcinomas; cancers that develop in cells that line the inner region of organs.
Colorectal cancer is the third most common cancer after lung and breast cancer and also the second leading cause of death in the UK.5 It is believed to be an age-related disease as 85% of the patients are aged over 60 years. Colonic cancer is more common (two thirds) relative to rectum cancer (one third) and the incidence among both genders being relatively balanced with a 1 in 20 chance of developing this fatal disease.5
The exact cause of bowel cancer is yet to be known but a small proportion of cases are linked with genetic correlations because a person with a familial history of cancer is at a higher risk of developing colorectal cancer. Low fibre and high fat diets such as high intake of red meat coupled with low intake of greens precipitates the risk of developing colorectal cancer suggesting that diet is a key factor in preventing bowel cancer.6 Since bowel cancer is age-related, risks increasing proportionally with age. Other risk factors include a history of chronic inflammatory bowel disease; long-standing ulcerative colitis and Crohn's disease, being obese, a smoker and low levels of participate in physical activities.7
Symptoms of the disease include altered bowel habits; being constipated or having diarrhea for prolonged period (2 weeks or more) or increased frequency in bowel movements.3 Rectal bleeding, blood flecks seen in stools particularly if the blood is dark coloured, appears to be another symptom. Apart from being anemic due to the microscopic bleeding in the gastrointestinal tract, some patients are also reported to be suffering from unexplained weight loss, abdominal pain and intestinal obstruction.4 A point worth noting is that the symptoms of bowel cancer is similar to those of haemorrhoids and irritable bowel syndrome therefore generating a possibility that the disease is misjudged hence delaying treatment if the wrong disease is diagnosed initially. In 2006, the NHS bowel screening programme was introduced to offer routine screening once every 2 years for those aged between 50 to 74 years old in Scotland. Colonoscopy, where a long thin tube with a tiny camera is inserted in to the back passage in search for polyps or abnormal growth, is done to detect bowel cancer but this process may cause discomfort and pain.8 Alternatively, a barium enema is conducted. This involves injecting a dye into the lower bowel area via an enema and an x-ray image will detect the presence of cancerous cells.8 If cancer is diagnosed, the tumour will be staged and it is often useful to order an X-ray computed tomography (CT) or Magnetic resonance imaging (MRI) scan to confirm if the cancer has metastasised to other organs as this will then require additional measures to be taken in terms of treatment and precautions. Tumour staging is vital to determine the best-suited treatment. Figure 1 illustrates an example of the four stages of tumour size in colorectal cancer. Confined within the wall of the colon are stages 1 and 2 and are curable with surgery. However, the consequences of not treating at both these stages is a progression to stage III when a spread to the regional areas and penetration into the cells that line the colon/rectum.3 There is a 73% success rate to achieve a cure at this stage via surgery or chemotherapy. It would be rather unfortunate if the progression reaches stage IV because at this stage, it is impossible to achieve a cure and chemotherapy will just be used to prolong survival.
Figure 1: Examples of the four stages of tumour size in colorectal cancer.9
The site of which the tumour resides, the extend of the disease, the patients past medical history and also the patients choice and their general health condition, will influence the choice of treatment for colorectal cancer. The prognosis of the treatment is poor owing to the fact that the disease is often only detected at the advanced stage; the tumour is already well established or the cancerous cells had already spread beyond the bowel. The first line treatment is surgery via a bowel resection operation in which the area of the bowel containing the cancerous cells is removed. Chemotherapy and radiotherapy, collectively known as neo-adjuvant therapy, may be given prior to the surgery as it may improve survival rate.8 The outcome of the treatment depends on the patient's stage of cancer and outcomes differ between individuals.
Anti-emetics are given to prevent nausea and vomiting induced by cytotoxic drugs. Dexamethasone 8mg and Granisetron 1mg are both given before the patient undergoes chemotherapy. Dexamethasone, a corticosteroid, is used to control delayed-emesis following chemotherapy by enhancing the efficacy of 5-HT3-receptor.10 Granisetron, a selective 5-HT3-receptor antagonist, is a potent anti-emetic mediated through the blockade of the 5-HT3-receptor in the vomiting centre and chemoreceptor trigger zone (CTZ) and blockade of peripheral 5-HT3-receptor on extrinsic intestinal vagal and spinal afferent nerves. Calcium gluconate and magnesium sulphate is prescribed to prevent toxicity caused by oxaliplatin.
The regimen comprised of oxaliplatin, folinic acid and 5-fluorouracil. Oxaliplatin is a third-generation diaminocyclohexane platinum analog. It kills cells by binding DNA through the formation of intrastrand and interstrand cross-links and therefore inhibits DNA synthesis and function.10 The primary binding site is the N-7 position of guanine but covalent interaction with adenine and cytosine also occurs.10 The combination of oxaliplatin and 5-fluorouracil is the first line treatment in advanced colorectal cancer. 5-fluorouracil, a pyrimidine antagonist is a pro-drug that is activated to ribosyl and deoxyribosyl nucleotide metabolites. These metabolites are responsible for the inhibition of synthesis of thymidylate, hence leading to inhibition of DNA synthesis and also interfering with RNA processing and mRNA translation. The main side effects of oxaliplatin are neurotoxicity, which is often the reason why the dose is limited, and myelosuppresion.10 Side effects associated with the use of 5-fluorouracil include neurotoxicity, bone marrow depression, nausea and diarrhea.10 Folinic acid is a synthetic tetrahydrofolate (FH4). FH4 is essential for DNA synthesis due to it being a cofactor in the synthesis of purine and pyrimidine. This is given to counteract the folate antagonising effects of anticancer drugs to help in DNA synthesis and consequently cell proliferation can still proceed.11
Post chemotherapy patients often experience delayed emesis hence anti-emetics are continually used to counteract the effects which is usually a combination of domperidone and dexamethasone. Domperidone is a potent anti-nausea and antiemetic agent that exerts its effects by antagonising the dopamine D2 receptors in the CTZ of the medulla.10 Finally, loperamide, a phenylpiperidine derivative, was given to control diarrhea.10
Evidence for Treatment
Although broadly categorised as colorectal cancer, the management of patients suffering from colorectal cancer differs due to the cause of cancer, the location of the tumour, the stage of disease progression and the readiness of the patient's physical and mental condition for treatment are just a few parameters that ought to be considered prior to deciding on the best approach to be taken. According to the SIGN guidelines for the management of colorectal cancer, surgery appears to offer the only chance of cure in apparently localised colorectal cancer and for all cases of metastatic colorectal cancer, chemotherapy should be considered.8 Several issues such as age, fitness to undergo surgery, the stage of cancer and especially the relative risks of operative morbidity; delaying or precluding systemic chemotherapy are a few of the many issues that ought to be addressed to justify the need for surgery.8,12 The risk for a 71-year-old patient who is suffering from metastatic unknown primary colorectal phenotype cancer (end stage) to undergo surgery does not seem to outweigh the benefits for the approach. This is supported by evidence that for advanced stage colorectal cancers, only a minority will benefit from surgery.12 Hence for the rest of the majority, the therapeutic aim is to achieve optimal palliation to enhance life expectancy and the best possible quality of life for the patient.13 In addition, non-operative measures are preferred in elderly patients.13 Chemotherapy is an important therapeutic modality in colorectal cancer and in such situation, it is the preferred option as it can potentially improve and prolong survival in patients with advance disease.8 However, patients should be well educated and counseled about the process, as it would potentially cause disruptions in the patient's lifestyle and treatment related toxicities might interfere the treatment process.8
Modified de Gramont with oxaliplatin is the first-line treatment used in advanced metastatic colorectal cancer.14 De Gramont regimen is the administration of chemotherapeutic drug 5-fluorouracil (5-FU) in combination with leucovorin calcium (LV), a folinic acid, with the latter drug potentiating the effect of the former. LV prolongs the effects of 5-FU by stabilizing the tertiary complex of thymidine synthase.15 A fortnightly infusion of this regimen not only is less toxic as compared to 5-FU and LV given as a bolus dose, a higher response rate is also achieved together with prolonged progression-free survival. In a study conducted among 348 patients, 14.4% response rate was recorded in the group receiving de Gramont regimen as opposed to 32.6% in the group receiving the modified regimen. On the same scale, the former showed a 22week media progression-free survival length as opposed to the latter's 27.6 weeks. Finally, the former group also showed a significantly higher toxicology profile of 23.9% as compared to the latter's 11.1%.16 However, this regimen is time consuming, complicated and costly.17 To overcome this problem, modified de Gramont regimen will either replace the 5-FU and LV intravenous (IV) infusion combination with and oral prodrug, capecitabine or simplifying the administration process with the use of a portable pump in which the patient can take home.14 The co-administration of oxaliplatin with the modified de Gramont regimen reported outstanding results, convenient and well tolerated in a study conducted by Braun et al.18 Another study was done by Braun et al subsequently to investigate if the results from the first study were reproducible and to further confirm its safety. The results were statistically consistent; shows good response rate when used in treatment of advanced colorectal cancer and in addition, well tolerated, more convenient and has an extremely low toxicity profile.14,18
Capecitabine, a carbonate derivative of 5'-DFUR, is an oral pro-drug of 5-FU that is activated via a three-step mechanism after absorption through the intestines. It is relatively selective in tumour cells owing to the higher concentration of thymidine phosphorylase found in tumour cells.19 A study conducted in 120 centres across the globe to evaluate if capecitabine was as effective as the standard 5-FU/LV combination for locally advanced and metastatic colorectal cancer showed that the median duration of treatment was similar between the two and capecitabine having a shorter time to response.19 Survival rates however did not appear to show any significant difference.19 When capecitabine is used in combination with LV, it did not show any advantage in terms of response rate and time to progression and conversely producing even more adverse effects.20
Oxaliplatin is a platinum based analogue that is different from its predecessors because it retains the diaminocyclohexane moiety after aquation.21,22 This attribute is what defines the differing spectrum of action of oxaliplatin as compare to cisplatin and carboplatin which show low or no activity when used to treat colorectal cancer.23 A preclinical study had shown that oxaliplatin was active against 6 out of 8 colorectal cancer cell lines in the National Cancer Institute's Human Tumor Cell Line Screen panel.23 When used alone for colorectal cancer, oxaliplatin showed a response rate of 12-24%, a median progression-free survival time of 4 months and a media survival time of 13-15 months.24,25 Also, randomized controlled trials have proved that combining oxaliplatin with infusional 5-FU/LV combination has a higher response rate and longer progression-free survival time as opposed to the regimen comprising infusional 5-FU/LV alone.26.27 Oxaliplatin up regulates thymidine phosphorylase and therefore has synergistic effects if combined with capecitabine.28 This combination yields a better response rate (37%-55%) and median survival (17-20 months) as opposed to combining oxaliplatin with infusional 5-FU/LV yielding a response rate of 34%-49% and median survival of 16-21% months.28,29,30,31
Nausea and vomiting are the most common and unpleasant side effects due to chemotherapy. Acute emesis is mediated via 5-HT3 receptors and administering an antagonist in granisetron shows a complete response rate of 70%-80% and 40%-60% with cisplatin-containing regimens.32 Delayed emesis is associated with cisplatin-based drugs and does not appear to be easily manageable with conventional therapies (corticosteroids) showing only a 50% control rate.32 The combination of granisetron and dexamethasone controls nausea and vomiting very well with a 78% complete response in a study conducted to investigate the efficacy of this combination against the use of dexamethasone alone in controlling delayed nausea and vomiting in patients receiving cisplatin chemotherapy.32 Domperidone is an antiemetic that does not penetrate the blood-brain-barrier and shows no psychotropic or neurological problems unlike metoclopramide which is associated with a whole lot of side effects.33 Domperidone is used post-chemotherapy to control emesis because studies have shown that there is no significant difference between the use of domperidone and granisetron.34 This study conducted by the Italian group of antiemetic research showed that there is only a mere 2% and 10% difference in controlling vomiting and nausea respectively but the difference was statistically insignificant when patients are treated using ondansetron and metoclopramide.34 Hence it can be concluded that the use of granisetron, which is a 5-HT3-receptor antagonist similar to ondansetron, will not be superior to domperidone, a D2-receptor antagonist similar to metoclopramide. Therefore, the use of domperidone instead of granisetron is justified as the cost incurred will be significantly less.35