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Cancer that effects either the colon or rectum is termed as colorectal cancer (CRC). Worldwide, CRC is the second most common malignancy and is a leading cause of cancer-associated death in many developed countries. The incidence of CRC is high in regions such as North America, Western and Eastern Europe, Japan, Israel, Singapore, Australia and New Zealand. In addition to this CRC is quite prevalent in some areas of Brazil, Argentina, Hong Kong, Southern China and Malaysia (Rozen et al., 2006). In Singapore, CRC is the leading cancer in males and the second most common cancer in females, accounting for 17.9% of all cancers in males and 14.4% in females. When both genders are combined, CRC is the most common cancer in Singapore. The age-standardized rate (ASR) for mortality from CRC in Singapore over the period from 2002 to 2006 was 18.1 per 100,000 per year in males and 12.5 in females (Tey et al., 2008). The ASR for CRC mortality rates in the United States and United Kingdom in 2002 according to the World Health Organization (WHO) were 14.8 and 17.3 per 100,000 per year, respectively (http://www.who.int/healthinfo). Certainly CRC has emerged as a serious threat to public health both locally as well as worldwide.
1.2. Etiology of colorectal cancer
On the basis of etiology CRC can be inherited, inflammatory or sporadic in nature. Lynch syndrome is the most common hereditary syndrome that predisposes patients to CRC, followed by familial adenomatous polyposis coli (FAP). Although the terms Lynch syndrome and hereditary nonpolyposis colorectal cancer (HNPCC) are often used synonymously HNPCC specifically refers to those disorders that have similar phenotypes but lack the specific mutations involved in Lynch syndrome. Lynch syndrome and HNPCC together accounts for 2-5% of all CRC. This form of heritable CRC is characterized by early onset and predominantly right-sided mucinous tumor. Germline mutations in the mismatch repair (MMR) genes namely MLH1 and MSH2 characterized by replication error and hence DNA or microsatellite instability (MSI), comprises the major genetic defect causing HNPCC or Lynch syndrome. Apart from CRC, HNPCC or Lynch syndrome also predisposes patients to other extra-colonic cancers such as small-intestine, renal pelvis and endometrial cancer (Lindor et al., 2005; Lynch et al., 2009). FAP which is responsible for less than 1% of all CRC cases occurs due to a mutation in the adenomatous polyposis coli (APC) gene. Development of hundreds to thousands of adenomatous polyps in the colon and rectum of individuals starting from early adolescence, which inevitably leads to CRC if untreated, is the main characteristic of FAP. FAP also leads to various extra-colonic manifestations like thyroid cancer, duodenal and fundic gland polyposis and desmoids (Jasperson et al., 2010). Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis may also lead to CRC. However patients with IBD represent only 1-2% of CRC cases. The risk of CRC is much higher in individuals having prolonged (more than 30 years) and extensive ulcerative colitis (Lakatos and Lakatos, 2008; Kraus and Arber, 2009). Majority of CRC (upto 80%) is sporadic in nature with no well defined etiology and occurs due to interaction between genetic and environmental factors (Cheah, 1990). Ageing is one of the major risk factors for sporadic CRC as 99% of cases occur in people more than 40 years of age and 85% in those more than 60 years of age. Higher incidence of CRC in affluent societies is related to lifestyle related factors such as high intake of fat and red meat, insufficient intake of fiber rich food and vegetables, obesity and low physical activity. High alcohol consumption, diabetes mellitus and smoking also increase the risk of CRC (Ballinger and Anggiansah, 2007; Cunningham et al., 2010).
1.3. Diagnosis of colorectal cancer
CRC if diagnosed at an early stage improves chances of survival of patient and reduces treatment-related morbidity. An individual may be diagnosed with CRC when he or she presents certain symptoms or as a result of any screening program. Usually early stage of CRC does not produce any detectable symptoms. Moreover most of the symptoms of CRC for instance change in bowel habits, blood in stool, general discomfort in the abdomen, weight loss, tiredness, lack specificity. Therefore it is essential to carry out regular screening programs to detect CRC. Endoscopy using either flexible sigmoidoscopy or colonoscopy with tumour biopsy is the most common diagnostic method for CRC. However these techniques require extensive bowel preparation and lacks patient compliance due to their invasive nature. Double contrast barium enema (DCBE) is used as an adjunct diagnostic technique especially to detect tumours or polyps in tortuous anatomical sites where endoscopic study is difficult to carry out. Although faecal occult blood test (FOBT) for CRC diagnosis is simple and non invasive in nature, it lacks specificity. Faecal DNA based test is more sensitive than FOBT but it is tedious to administer and expensive. Computed tomographic (CT) colonography, also termed as virtual colonoscopy, is a non invasive diagnostic technique that produces two- and three-dimensional images of the colorectal tract. CT colonography is particularly useful in identifying polyps or colonic lesions that are not detected by colonoscopy. CT and magnetic resonance imaging (MRI) are also used to detect extent of disease in patients with suspected liver metastases from CRC. Of the various serum-based markers for CRC that have been investigated, carcino-embryonic antigen (CEA) has been found to be useful for preoperative staging and follow up. However, CEA is not recommended for diagnosis because of its low sensitivity and specificity. Genetic tests are required for screening of heritable forms of CRC like HNPCC and FAP (Cunningham et al., 2010; Labianca et al., 2010).
1.4. Staging of colorectal cancer
The Duke's classification (Duke, 1932; Weiss, 2000) and the TNM (tumor, node, metastases) system (Fleming et al., 1997) are the two most common staging systems for CRC. The other less commonly used staging system is the modified Astler Coller (MAC) system (Astler and Coller, 1954; Gunderson and Sosin, 1974). The TNM system is mainly based on the size and degree of invasion of the primary tumour (T), extent of lymph node involvement (N) and degree of metastasis (M). It was introduced by the American Joint Committee on Cancer (AJCC) and the most preferred system of staging of CRC. The TNM system and AJCC stage groupings with equivalent Duke's and MAC stages of CRC have been summarized in Table 1.1. The TNM system encompasses both clinical (pretreatment) and a pathological (postsurgical histopathological) staging. The clinical classi¬cation is designated as cTNM and the histopathological classification is designated as pTNM. Usually the cTNM is used to select treatment regimen whereas the pTNM is used for prognosis of CRC. Preoperative staging involves assessment of patient's medical history, physical examination for hepatomegaly, ascites, lymphadenopathy, evaluation of blood count, CEA and liver chemistries, examination of large intestine using endoscopic techniques or CT or MRI. Surgical staging of CRC involves an evaluation of extra-colonic metastases, nodal spread and degree of tumour invasion through the colonic wall and onto surrounding structures (Labianca et al., 2010).
1.5. Prognosis of colorectal cancer
Extent of penetration of tumor through the colonic wall and the involvement of lymph nodes, are important prognostic factors of CRC. Other pertinent prognostic parameters include tumor grade, thymidine labelling index, vascular and perineural invasion and lymphoid inflammatory response. Grading of CRC tumors is carried out on the basis of histopathological parameters such as histologic type, quality of differentiation, polarity of nucleus, con¬guration of tubules, growth pattern, lymphocytic in¬ltration and extent of ¬brosis. At present a three grade system is most widely used. Well differentiated tumors with well formed tubules and showing least nuclear polymorphism and mitoses are termed as grade 1. Poorly differentiated tumors with rare glandular forms, multistructural cells and a high extent of mitoses are termed as Grade 3. Tumors intermediate between grades 1 and 3 are considered as grade 2. Grade 1 tumors are the least aggressive and the 5-year survival rate (YSR) is 59-93%. In case of grade 2 and 3 tumors the 5-YSR falls to 33-75% and 11-56% respectively (Jass et al., 1986; Qizilbash, 1982). The clinical utility of various other prognostic indicators like expression of protein 53 (p53), B-cell lymphoma 2 (bcl-2), tumor growth factor alpha (TGF-α), epidermal growth factor (EGF), transforming growth factor-beta receptor II gene (TGFBR2), deleted in colorectal cancer (DCC) gene, thymidylate synthase (TS), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, MSI status, allelic loss of chromosome 18q tissue have been investigated. Although 18q deletion and MSI status have shown promise their practical utility still remains to be confirmed by large scale studies (Deans et al., 1992; Steinberg et al., 1987; Sternberg et al., 1999). Location of CRC tumor is also a good indicator of prognosis for instance left sided lesions favours patient survival whereas right sided tumors especially those causing bowel obstruction reduces chances of survival (Wolmark et al., 1983). Presence of perforation in the colonic tract indicates negative prognosis (Steinberg et al., 1987). Increased pre-treatment levels of serological markers like carbohydrate antigen 19-9 (CA 19-9) and CEA are associated with poor prognosis (Filella et al., 1992). CRC patients who respond to chemotherapy with drugs like 5-¬‚uorouracil (5-FU), irinotecan and oxaliplatin have longer median survival time than non-responders. Response to chemotherapy and chances of survival in cases of metastatic CRC are dependent on the extent of metastasis which can be evaluated by determining the number of sites to which metastasis has occurred, number of lesions in such sites and the extent to which the liver is affected. Generally female patients have better survival time than male patients. Patients showing no symptoms of CRC exhibit better response to chemotherapy and survive longer than those showing symptoms. Prior chemotherapy results in resistance to second-line treatment (Buyse et al., 2000a, 2000b; Kohne et al., 2002).