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Colorectal carcinoma (CRC) is the third most common malignancy worldwide (Heiken, 2006); 1 million cases of CRC are reported annually, with approximately 528,000 individuals dying from this disease (Tonus, Neupert & Sellinger, 2006). CRC incidence varies considerably worldwide. The highest CRC incidence is observed in North America, Oceania and Europe; by contrast, CRC incidence is much lower in Asia, Africa and South America (Center, Jemal, Smith & Ward, 2009).
However, even countries charachaterized by a low CRC incidence such as many Asian countries, including China, Japan, South Korea and Singapore, have experienced an increase of 2 - 4 times in CRC incidence during the last few decades (Sung, Lau, Goh & Leung, 2005). In 2008, 231 cases of CRC were reported in Malta (Malta National Cancer Registry, 2011).
1.1.2 Risk factors for CRC
Most cases of CRC are sporadic and risk factors include (Chan et al., 2008; Cunningham et al., 2010; Fatemi et al., 2010):
Increasing age - 90% of CRC cases occur after the age of 50.
Gender - the incidence of CRC is slightly higher in males.
Previous colonic adenomas or CRC.
Inflammatory bowel disease (IBD) - long standing Crohn's disease or ulcerative colitis.
Environmental factors - a high fat diet, a low intake of dietary fibre, excessive consumption of red meat, sedentary lifestyle, obesity, smoking, diabetes mellitus and excessive consumption of alcohol.
Hereditary syndromes - Around 6% of CRCs are inherited CRC syndromes which includes Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer), and less commonly, Familial Adenomatous Polyposis (FAP), MYH-associated Polyposis and others. But even for CRC that is not due to any highly-penetrant hereditary syndrome, a history of CRC in a first-degree relative (sibling, parent or offspring), doubles the risk of developing CRC.
1.2 Colorectal Carcinogenesis and its Associated Genetics
It is estimated that around 95% of CRCs are adenocarcinomas (Ahmed, Dawson, Smith & Wood, 2007, p. 505). More than 90% of CRCs arise from adenomatous polyps while only a small fraction of CRCs develop de novo (Neri, Faggioni, Cini & Bartolozzi, 2011). While hyperplastic polyps have little potential for malignant transformation (Bauer & Papaconstantinou, 2008), adenomas, especially those that are large (>20mm), villous and sessile, have the highest risk of neoplastic degeneration (Neri et al., 2011).
The colorectal adenoma-carcinoma sequence describes the sequential development of CRC from adenomas. After an adenoma has developed, it may increase in size further and may develop ultimately into CRC, although the majority of adenomas remains benign and asymptomatic (Tanaka, 2009). It may take up to 10 years for an adenoma to progress to CRC (Neri et al., 2011). Moreover, it may take another 2 - 3 years for an asymptomatic early CRC to become an advanced symptomatic CRC (Davies, Miller & Coleman, 2005).
Although there is no definitive evidence for the concept of the adenoma-carcinoma sequence (Beggs & Hodgson, 2008), strong evidence in favour of it includes (Neri et al., 2011):
Populations with a high incidence of adenomas also have a high incidence of CRC.
The geographical distribution of colorectal adenomas overlaps with the distribution of CRC i.e. adenomas are rare in geographical areas characterized by a low CRC prevalence.
The incidence peak for adenomas precedes that for CRC by a few years.
CRC risk is directly proportional to the number of adenomas and also to the degree of dysplasia in adenomas.
Resection of adenomas is linked to a decrease in CRC incidence.
The transition from benign adenomatous precursors to CRC is associated with an accumulation of genetic defects (Sedivy et al., 2000). Two main types of genetic instabilities have been described in CRC, namely the Chromosomal Instability (CIN) Pathway and the Microsatellite Instability (MSI) Pathway (Migliore, Migheli, Spisni & Coppede, 2011). Furthermore, transcriptional silencing of tumour suppressor genes by hypermethylation of CpG dinucleotide "islands" also seems to be a significant epigenetic mechanism crucial for carcinogenesis (van Rijnsoever, Elsaleh, Joseph, McCaul & Iacopetta, 2003). These different pathways may not be completely independent of each other (Deenadayalu & Rex, 2004).
1.2.1 Chromosomal Instability Pathway
The CIN phenotype is observed in around 85% of sporadic CRCs (Imai & Yamamoto, 2007). The most frequent changes observed in this pathway are mutations on the K-Ras proto-oncogene and in 3 tumour suppressor genes, namely Adenomatous Polyposis Coli (APC) gene on chromosome 5q, p53 on chromosome 17p, and loss of heterozygosity at chromosome 18q (Beggs & Hodgson, 2008).
Fig. 1 - Chromosomal Instability pathway to CRC - Mutations in APC and K-ras genes occurs early in the adenoma-carcinoma sequence while loss of heterozygosity at chromosome 18q and p53 mutations occur at a later stage (Ogino et al., 2009; Tanaka, T., Tanaka, M., Tanaka, T. & Ishigamori, 2010;) (Retrieved from Tagore et al., 2003).
1.2.2 Microsatellite Instability Pathway and Hypermethylation
MSI is the hallmark of Lynch syndrome but MSI is also observed in around 15% of sporadic CRCs (Imai & Yamamoto, 2007). Microsatellites consist of tandem repeats, usually of 1 - 4 base pairs in length, repeated several times (Beggs & Hodgson, 2008).
Microsatellites are prone to mutations by slippage during DNA replication but most often these mutations are repaired by Mismatch Repair (MMR) enzymes. However, mutations in the genes encoding for MMR enzymes can lead to inactivation of these enzymes, resulting in MSI (Beggs & Hodgson, 2008). In most sporadic CRC, MSI occurs due to the epigenetic silencing of the MLH1 (human mutL homolog 1) gene through hypermethylation of its promoter (Zaanan, Meunier, Sangar, Fléjou & Praz, 2011).
Hypermethylation of cytosine in CpG islands in tumour suppressor genes such as p16, can also lead to tumour suppressor gene silencing; a phenomenon which is observed in colorectal adenoma-carcinoma sequence but also in the serrated adenoma-carcinoma sequence (Boland et al., 2009), which gives rise to around 35% of CRCs, in which the CRC precursor is a sessile serrated adenoma (Snover, 2010).
1.2.3 Classification of CRC
The TNM Classification is used internationally to stage CRC and it has the advantage of integrating tumour size, lymph node and metastatic invasion (Mlecnik, Bindea, Pagès & Galon, 2011). However, in Malta, the simpler Modified Dukes' Classification is the preferred classification used to stage CRC. The Modified Dukes' Classification is based on the tumour penetration depth and the presence/absence of lymph node involvement and distant metastasis. The purpose of staging CRC is to determine the prognosis and to administer the appropriate therapy (Ehrenpreis, 2003, p. 125).
By using Modified Dukes' Classification, colorectal adenocarcinomas can be classified as follows (Ehrenpreis, 2003, p. 125; Hayat, 2009, p. 210):
In Stage A, the carcinoma is restricted to the mucosa only. The 5-year survival rate is 90%.
In Stage B1, the carcinoma has invaded into but has not gone through the muscularis propria and the 5-year survival rate is 80%. In Stage B2, the carcinoma has penetrated through the muscularis propria and serosa and the 5-year survival rate is 60%.
Stage C1 is the same as B1 but there is also regional lymph node metastasis and the 5-year survival rate is 40%. Stage C2 is the same as B2 but there is also regional lymph node metastasis and the 5-year survival rate is also 40%.
In Stage D there is metastasis to distant organs. The 5-year survival rate is only 5%.
Fig 2. - Modified Dukes' Classification of Colorectal Adenocarcinoma (Retrieved from Ehrenpreis, 2003, p. 126).
1.2.4. Treatment of CRC
While surgical resection alone may be sufficient in non-metastatic CRC (Khan, Bari & Raza, 2011), adjuvant chemotherapy involving 5-fluorouracil (5-FU) alone or combined with leucovorin and oxaliplatin (André et al., 2004), is usually used in conjunction with surgical resection in case of Stage C colon cancer. Neo-adjuvant radiation in conjunction with chemotherapy is the preferred treatment for Stage B/C rectal carcinoma (Schmiegel et al., 2009). Treatment for Stage D CRC may include any combination of surgery, chemotherapy and radiotherapy (Wilkes & Hartshorn, 2009 as cited in Courneya & Friedenreich, 2011, p. 239).
1.3. CRC Screening
Earlier diagnosis and improved treatment of CRC have lead to a significant increase in survival rates in patient with CRC (Cunningham et al., 2010). Survival rates could be further increased if a higher proportion of adults aged 50 years and older adhere to regular screening (Levin et al., 2008). CRC is highly suited for screening because it is a common disease with a high mortality rate, most CRCs develop slowly from adenomas and have a long preclinical phase, and treatment for the disease is available and is most effective when CRC is detected at an early stage (Neri et al., 2011).
A good screening test should improve lives of invidividuals by improving the quality of life or by prolonging it. The aim of CRC screening is detecting colorectal adenomas while still benign and their subsequent removal (Geiger & Ricciardi, 2009). In order to be effective, a screening test must be performed in a large population, should be highly sensitive and highly specific, should have a high patient-acceptability and must be cost-effective (Saidel-Odes & Shmuel-Odes, 2005). However, CRC screening programs have not been entirely successful, due to low patient compliance (Heiken, 2006).
To be effective, screening should begin at the age of 50 years in average-risk individuals as risk for CRC increases exponentially after this age. Screening in individuals at increased risk (such as family or personal history of CRC, personal history of adenomas, IBD and hereditary syndromes) can start at an earlier age and can be performed at shorter intervals depending on the underlying pathology (Saidel-Odes & Shmuel-Odes, 2005). A number of testing options are available, as shown in Table 1.
Table 1 - CRC screening test options for average-risk individuals aged 50 years and older. (Retrieved from Levin et al., 2008). Locally, Guaiac-based Faecal Occult Blood Test is often used as non-invasive screening test for CRC while colonoscopy remains the gold standard for a definite diagnosis
1.3.1 Guaiac-based Faecel Occult Blood Test (G-FOBT)
CRC screening by G-FOBT has the advantages of being easy to perform, having a relatively high patient compliance, being inexpensive (costing around â‚¬0.72 per test) and non-invasive (Saidel-Odes & Shmuel-Odes, 2005). The basis of the G-FOBT is that CRC and large adenomas bleed (Crespi & Lisi, 2002). The test relies on the detection of faecal haemoglobin pseudo-peroxidase oxidizing activity (Heiken, 2006). When guaiac (present on the test card) is exposed to hydrogen peroxide, pseudo-peroxidase in haemoglobin (if present) will catalyze the oxygenation of guaiac, resulting in a blue colour change (van Dam, Kuipers, van Leerdam, 2010).
Two large prospective-controlled studies have shown that CRC screening by serial G-FOBT reduces mortality rate by 15 - 33% (Mandel et al., 1993; Hardcastle et al., 1996); however, this success in diminishing mortality rate may decrease if the patients refuse to undergo repeated screenings (Fenton et al., 2010). In fact, G-FOBT should be performed annually or biennially in order to be effective (Heiken, 2006).
1.3.2. Dietary and Medication Restrictions for G-FOB testing
Individuals undergoing the G-FOBT are advised to adhere to dietary restrictions 72 hours prior to testing, which may result in decreased patient compliance. Dietary restrictions are performed in order to increase specificity of G-FOBT; however, evidence for this is very limited (Konrad, 2010). Non-human haemoglobin from red meat and peroxidase from peroxidase-rich fruit and vegetables (such as spinach) are generally thought to give false positive results (Crespi & Lisi, 2002).
However, peroxidase derived from fruit or vegetables has minimal effects on G-FOBT results as it is broken down while passing through the gastro-intestinal tract. The effects of meat are less clear. While heme originating from meat generally loses its pseudo-peroxidase activity once it is degraded to peroxidase-free porphyrins in the gastro-intestinal tract, consuming meat in sufficient quantities can still lead to false positive FOBT result (Konrad, 2010).
Locally, patients are advised not to use aspirin or other Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) 7 days before and during the test and Vitamin C supplements 2 days before and during the test. Anti-coagulants and NSAIDS can cause leakage of blood into the intestinal tract, which may lead to false positive G-FOBT results (Saidel-Odes & Shmuel-Odes, 2005). Excess Vitamin C (>250mg/day), can block the hydrogen peroxide reaction due to its anti-oxidant properties, leading to false negatives (van Dam et al., 2010).
However, the concept of medication restriction is not universally accepted. While one study has shown that aspirin and other NSAIDs are not risk factors for G-FOBT false positive results (Kahi & Imperiale, 2004), another study showed that NSAIDS, as well as anti-coagulants, decrease the positive predictive value of G-FOBT for advanced CRC and should therefore be stopped prior to testing with G-FOB (Sawhney, McDougall, Nelson & Bond, 2010). The effect of Vitamin C on false negative results is still inconclusive (Pignone, Campbell, Carr & Phillips, 2001).
1.3.3 Limitations of G-FOBT
G-FOBT has a number of disadvantages. G-FOBT may detect pseudo-peroxidase activity of endogenous haemoglobin that may not be necessarily originating from the colon or rectum but from other anatomic sites such as the upper gastro-intestinal tract, leading to false positives (Tanaka et al., 2010).
While patient compliance to G-FOBT is high when compared to other screening methods, it can nonetheless be problematic. Since the test requires 3 faecal specimens from 3 consecutive bowel movements (Hol et al., 2009) and it should be performed annually or biennially to be effective, patient compliance can be quite limited (Heiken, 2006).
One major limitation of G-FOBT is the poor sensitivity for CRC and advanced adenomas. Even though sensitivity varies depending on which G-FOBT variant is used, all variants are characterized by a low sensitivity for CRC and advanced adenomas (van Dam et al., 2010). In a large study involving 8104 participants, sensitivity of Hemoccult II for CRC was estimated at 37.1% only (Allison, Tekawa, Ransom & Adrain, 1996). Another large study showed that the sensitivity for Hemoccult is around 26% while sensitivity for adenomas (size ranging from <0.5cm - >2.0cm) was 8.6% only (Ahlquist et al., 1993).
While there is no reported sensitivity for HemoCARE (CARE diagnostica, Moellersdorf, Austria), the G-FOBT variant used in the Clinical Chemistry Laboratory at Mater Dei Hospital, it is estimated that it also suffers from low sensitivity for CRC and advanced adenomas. This low sensitivity of G-FOBTs for CRC and advanced adenomas is attributed to the fact that small adenomas do not generally bleed,
while CRC and large adenomas may only bleed intermittently; it is for this reason that G-FOBT requests the collection of 3 faecal specimens from 3 consecutive bowel movements rather than 1 faecal specimen only (Levin et al., 2008). This low sensitivity for detecting advanced adenomas and CRC limits the reduction in mortality rate (Guittet et al., 2009).
The specificity of G-FOBT for CRC varies considerably between the different studies and specificities ranging from 20 - 100% have been reported (Hol et al, 2009; Hundt, Haug & Brenner, 2009; Imperiale, Ransohoff, Itzkowitz, Turnbull & Ross, 2004; Koss, Maxton & Jankowski, 2009; Shastri et al, 2006; Young & St. John 1991 as cited in Ewald et al, 2007). This high variability in specificity of G-FOBT for CRC is because specificity, like sensitivity is dependent on a number of factors such as:
Use of different G-FOBT variants in different studies which may have different specificities (Hundt et al, 2009; Gombrich, 2006)
Number of faecal specimens collected (Lieberman et al, 2001).
Whether rehydration (a drop of water is added to the slide window) is performed, which lead to increased sensitivity but decreased specificity (Mandel et al, 1993).
Variability in interpretation of test results by medical laboratory analysts (de Wijkerslooth, Bossuyt & Dekker, 2011).
Study design - whether G-FOBT is performed in asymptomatic average-risk population (Imperiale et al, 2004) or if CRC patients were pre-selected (Koss et al, 2007).
Basis of test
Advanced adenomas and CRC bleed (Levin et al., 2008).
Mode of detection
Based on the detecting the pseudo-peroxidase property of faecal haemoglobin (Heiken, 2006)
Faecal haemoglobin is detected using monoclonal and/or polyclonal antibodies (Levin, Brooks, Smith & Stone, 2003)
Can be qualitative or quantitative (Hundt, Haug & Brenner, 2009). In quantitative assay, cut-off value can be varied to optimize sensitivity and specificity (Guittet et al., 2007) and to accommodate the clinical and/or economic setting (Grazzini et al., 2009).
Cannot be automated.
Quantitative I-FOBT can be automated (Guittet et al., 2009).
Dietary and Medication Restrictions
Necessary (van Dam et al., 2010).
Not necessary, i.e. patient compliance may increase (Hol et al., 2009).
Sensitivity and Specificity for advanced adenomas and CRC
Inferior Specificity and sensitivity for advanced adenomas and CRC (Guitter et al., 2007).
Superior specificity and sensitivity for advanced adenomas and CRC (Guitter et al., 2007).
Cheaper (Levin et al., 2008).
More expensive (Levin et al., 2008).
Besides G-FOBT, Immune Faecal Occult Blood Test (I-FOBT) is also cited as a potential screening test for CRC (Levin et al., 2008). The main differences between G-FOBT and I-FOBT have been summarized in Table 2.
Table 2 - Main differences between G-FOBT and I-FOB
Colonoscopy is considered the gold standard for detecting colorectal adenomas and CRC (Fatemi et al., 2010) and is most often used to give a definite diagnosis when another screening test (such as G-FOBT) result is positive (Levin et al., 2008). It is the only CRC screening test that allows direct mucosal inspection of the entire colon (Heiken, 2010) and biopsy sampling in the same session (Levin et al., 2008).
A systemic review shows that colonoscopy has the highest specificity and sensitivity for CRC of all screening tests available estimated at 95 ±4.25% and 100% respectively (Allameh, Davari & Emami, 2011), although a miss rate of 4% for CRC (Bressler et al., 2004) and 6 - 12% for adenomas â‰¥10mm were reported in other studies (Pickhardt, Nugent, Mysliwiec, Choi, & Schindler, 2004; Rex et al., 1997).
One major advantage of colonoscopy is that it is performed at long intervals of 10 years, possibly due to the superior sensitivity (Allameh et al., 2011) and since adenomas progress to CRC slowly (Neri et al., 2011). Another major advantage of colonoscopy is that it is therapeutic as the removal of polyp (polypectomy) and early CRC can be performed during colonoscopy itself (de Wijkerslooth, Bossuyt & Dekker, 2011). Polypectomy has a central role in reducing CRC development by interrupting the adenoma-carcinoma sequence (Hewett, Kahi & Douglas, 2010).
There are different methods for polypectomy including cold forceps, hot forceps and snare polypectomy; the method chosen is usually dependent on the size of the adenoma(s) (Fyock & Draganov, 2010). However, some adenomatous polyp are difficult to remove especially those that are large (>2cm) and those found in unfavourable locations such as a wall that is difficult to evaluate with the colonoscope (Gallegos-Orozco & Gurudu, 2010).
Although colonoscopy has been mentioned as the preferred method for CRC screening in both average and high-risk populations (Davila et al., 2006), it is not known yet if colonoscopy can be used for mass screening of patients (Allameh et al., 2011). Research evaluating the impact of colonoscopy as a CRC screening test is not very numerous; in fact, there is is a lack of randomized, controlled studies and longitudinal follow-up studies. However, one large cohort study showed that patients had a reduction in CRC incidence of 76 - 90% after polypectomy when compared to 3 large control-groups (Winawer et al., 1993).
Disadvantages of colonoscopy includes full bowel cleansing which requires 1 or more days of dietary preparation, the test is invasive and conscious sedation is usually required, bleeding and perforation can occur despite being extremely rare (Levin, 2008), it requires qualified endoscopists (Guittet el a., 2007) and there is the issue of manpower difficulties (Cunningham et al., 2010). Colonoscopic procedure is very expensive costing around $700 (Subramanian, Bobashev & Morris, 2010), although in the long run it may be considered cost-effective when compared to other screening tests (Davila et al., 2006).
1.3.3 Misuse of tumour markers in CRC screening
Since some patients may have compliance issues related to stool testing methods such as G-FOBT, evaluation of serum markers for CRC screening has been studied thoroughly (Geiger and Riccardi, 2009). Clinicians have for long misused tumour markers such as CEA and CA19-9 for CRC screening in asymptomatic individuals but their use should be discouraged as they have low sensitivity and specificity for CRC, especially when the disease is in the early stages (Fletcher, 1986; Kim, H. J., Yu, Kim, H., Byun & Lee, 2008).
The low specificity of CEA for CRC is attributed to the fact that it is also elevated malignant diseases such as gastric, pancreatic, lung, breast and medullary thyroid carcinomas (Lim, Kam & Eu, 2009) and in numerous non-neoplastic conditions such as hepatitis, IBD, pancreatitis, obstructive pulmonary disease (Kim et al., 2008) and even in smokers (Tanaka et al., 2010).
Similarly, CA19-9 has poor specificity for CRC as it is also raised in benign hepato-biliary and pancreatic diseases, pneumonia, pleural effusion, renal failure and systemic lupus erythematosus (Sawabu , Watanabe , Yamaguchi , Ohtsubo & Motoo, 2004) and also in other malignant diseases particularly in pancreatic carcinoma but also in gastric and hepato-biliary carcinomas (Pavai & Yap, 2003). If CEA and CA19-9 were to be used as screening tests for CRC, a high rate of false-positivity is obtained leading to unnecessary colonoscopies.
The low sensitivity of CEA for CRC is due to the fact that it is most often not elevated in early stage CRC (Dukes' A and B) and since the basis of CRC screening is the detection of colorectal adenomas when still benign and early CRC, CEA has no role in CRC screening (Kumar, Tapuria, Kirmani & Davidson, 2007). Furthermore, CEA may not be raised even when CRC is advanced (Tanaka et al., 2010).
A study has found that sensitivity for CRC Dukes' A and B was only 30 - 40% when a cut-off value of 2.5 ng/ml is used (Duffy et al., 2003). In another study, which used a cut-off value of 5 ng/ml, CEA was elevated only in 25% and 39% of CRC Dukes' A and B respectively (Wang et al., 2000). However, in these two studies, patients were pre-selected; therefore sensitivity of CEA for CRC in asymptomatic individuals is likely to be even lower (Fletcher, 1986). CA19-9 is even less sensitive than CEA for CRC (Tanaka et al., 2010).
The low specificity and sensitivity of these 2 tumour markers for CRC limit their role in CRC screening. CEA in particular is more useful as a prognostic marker for CRC progression following resection and in monitoring of metastatic CRC rather than a marker for CRC screening (Kumar et al., 2007; Tanaka et al., 2010).