INTRODUCTION:

CANCER consists of group of diseases involving continuous growth of cells abnormally and possessing the potential to develop and invade other body parts. Cancers can be of different organs amongst these Colorectal Cancer is too the leading cause of cancer deaths and is marching towards a major public health concern. Colorectal Cancer is the cancer of large intestine which makes up the end of alimentary canal along with rectum. Colon cancer and rectal cancer are collectively called as colorectal cancer. These cancers begin as by formation of abnormal projection of tissue or mucous membrane surrounding the inner lining of the colon and rectum called as polyps. These polyps may be malignant or benign and over time can develop into cancers but this may not always take place. The major risks regarding colorectal cancer include increasing age, diet, race, habits, hereditary family history of colorectal cancer and mutations and lifestyle, etc. [1]. The lifetime risk of developing Colorectal Cancer is about 1in 21 (4.7%) for men and 1 in 23 (4.4%) for women [3]. In 2017 colorectal cancer ranked 2^nd in men and 3^rd in women in United States [3]. Early screening and lifestyle changes can help prevent and treat Colorectal Cancers.

The Normal Colon and Rectum:

Large Intestine is around 5feet (152.4 cm) long and 6-7cm in diameter and is a connection between ileum and the rectum. Large intestine consists of the cecum, colon, rectum and anal canal. The tube like part of large intestine is called as colon and is basically of four parts: ascending, transverse, descending and sigmoid [6]. Histologically, the wall of large intestine has four layers- serosa, muscularis, submucosa and mucosa. Colorectal cancer starts at the innermost layer- the mucosa. Large intestine has abundant goblet cells that secrete mucin to form mucus and water [7].

Figure 1: Colorectal cancer: Illustration

Risk Factors for Colorectal Cancer:

Colorectal Cancer studies had shown that the following factors are majorly responsible for development of cancer and may be a leading cause:

1. Age:

The SEER (Surveillance Epidemiology and End Results) Cancer Statistics Review found following results [1]:

Table 1: Risk Factors for Colorectal Cancer: Age

Percentage of New Colorectal Cancer Patients	Age (in years)
<15%	<54
17%	55-64
26.3%	65-74
29.2%	75-84
12.6%	>85

The great majority of people diagnosed with colon cancer are older than 50. It can too occur in younger people, but it occurs much less frequently [2]. Thus, increasing age is the greatest risk for development of Colorectal Cancer.

2. Sex:

Incidence of development of colorectal cancer is more in males than in females.

The SEER studies have shown the incidences of colon and rectal cancer separately as follows [1]:

Table 2: Risk Factors for Colorectal Cancer: Sex

Colon Cancer		Rectal Cancer
Men	Women	Men	Women
43.4/100,000	34.5/100,00	18.5/100,000	11.7/100,000

3. Race:

The incidence of colorectal cancer too varies among various races in the world and the African Americans have the highest incidence rate for development of colorectal cancer. The statistics reported in the year 2000-2004 for new cases per 100,000 population are as follows [1]:

Table 3: Risk Factors for Colorectal Cancer: Race

RACE	MEN	WOMEN
Whites	60.40	44.00
African Americans	72.60	55.00
Asian Americans and Pacific Islanders	49.70	35.30
America Indians and Alaska Natives	42.10	39.60
Hispanics and Latinos	47.50	32.90

4. Smoking:

Along with development of a number of cancers Smoking too is associated with the risk for colorectal cancer. Smokers have a higher risk for development of adenomatous polyps than non-smokers [1].

5. Diet:

Dietary factors are too considered as the risk factor for the colorectal cancer as colon is the part of our alimentary canal. It is reported that high levels of red meat consumption like-beef, venison, lamb, mutton, etc. lead to increased risk of colorectal cancer. Lower fruit and vegetable intake, lack of dietary fibers in the diet too are the other reasons regarding dietary factors for development of colorectal cancer as stated by the European Investigation into Cancer (EPIC) [1]. In epidemiological studies, diets low in folate, particularly in combination with substantial alcohol intake, are associated with increased risks of colon cancer and its precursor, the adenomatous polyp. 5,10-methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism (see fig.). Its product, 5-methylTHF, is the pre dominant form of folate in plasma, whereas the enzyme substrate, 5,10-methyleneTHF, is found mainly intracellularly. 5-methylTHF provides the methyl group for de novo methionine synthesis and DNA methylation. Imbalanced DNA methylation, characterized by global genomic hypomethylation and methylation of usually unmethylated CpG sites, is observed consistently in colonic neoplasia. A decreased 5-methylTHF pool may affect DNA methylation and thereby contribute to carcinogenesis. On the other hand, the substrate for MTHFR, 5,10-methyleneTHF, is required for conversion of deoxy uridylate to thymidylate, and, thus, depletion of this form of folate may interfere with the thymidylate biosynthesis and result in development of deoxynucleotide pool imbalances. This leads to accumulation of deoxy uridylate in DNA and removal of this abnormal base might labialize DNA to strand breaks. Chromosome breaks appear to be important in nearly all human cancers and are especially common in colorectal cancer. Alcohol decreases folate absorption, alters its metabolism, increases its excretion, and therefore may interfere with both DNA methylation and thymidylate synthesis [8].

6. Obesity:

Obesity has been one of the leading health issues among the past few years and it has been reported that obese people are at a greater risk for development of colorectal cancer. People with a BMI>=30.00 kg/m² are at a verge for development of colorectal cancer [1].

7. Physical Activity:

The reports for colon cancer are as follows [1]:

Table 4 Risk Factors for Colorectal Cancer: Physical Activity

	Recreational		Occupational
	Cohort	Case	Cohort	Case
Male	√	√	√	√
Female	√	√	-	√

8. Family History of Colorectal Cancer and Inherited syndrome:

If any member of family (first degree relative) has a history of colon cancer or is a patient of the same, the other members of family too are at a higher risk for development of colon cancer [2]. Inherited syndromes and family history best explain the development of colorectal cancer. The most common inherited syndromes linked with colorectal cancer are:

1. Familial Adenomatous Polyposis (FAP).

2. Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome.

· Familial Adenomatous Polyposis (FAP):

This kind of inherited syndrome is caused due to mutation in the APC gene. It involves single germline mutation in the APC tumour suppressor gene resulting in development of dominantly inherited syndrome called Familial Adenomatous Syndrome [4]. In this syndrome the person develops hundreds to thousands of polyps in the colon and rectum from a very young age which may further become fatal with the increasing age if left untreated. The subtypes associated with FAP are [5]:

Attenuated FAP: In this case the number of polys is low (generally below 100), and colorectal cancer develops at a later stage

Gardner Syndrome: It is a non-cancerous tumor of skin, soft tissue and bones.

· Hereditary Non-Polyposis Colon Cancer (HNPCC) or Lynch Syndrome:

This disorder is caused by the inherited defect in either the MLH1 or MSH2gene which are responsible for repair of damaged DNA. This syndrome differs in that there is development of only few polyps and not hundreds as like in FAP. The development of cancer with this syndrome is seen in relatively young cases.

HNPCC or Lynch Syndrome is a greater risk in women for development of cancer of the endometrium in the uterus. Other cancers associated with Lynch Syndrome are cancers of the ovary, small intestine, stomach, pancreas, kidney, brain, uterus and bile duct [5].

9. Microbial Colonic Environment:

Intestinal microbes have a profound influence on the health and disease status of the human body. Colorectal cancer (CRC) is one of the diseases that have been shown to be modulated by microbes. This modulation raises the possibility that by incorporating the contributions of microbes, more optimized strategies for cancer prevention and treatment may be developed. To realize this potential, a better understanding of the specific details of the microbe-CRC connection is important. Streptococcus gallolyticus subsps. gallolyticus (Sg), previously known as Streptococcus bovis biotype I, is an opportunistic human pathogen that causes bacteremia and endocarditis. Numerous studies over the last several decades have described elevated risks for CRC in patients infected with S. bovis or Sg [9].

10. Group III Phospholipase A₂ resulting in colitis and colorectal cancer:

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A₂ (PLA₂) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA₂group III (sPLA₂-III) is associated with colorectal cancer, although its precise role remains obscure. Continuous production of cytokines, growth factors, matrix proteases, angiogenic factors, and reactive oxygen species promote tumorigenesis by creating a microenvironment favoring colonic epithelial proliferation, survival, and invasiveness [10].

11. Other Risk Factors:

Other risk factors for development of colorectal cancer are as follows [2,5]:

· Inflammatory Bowel Disease

· Diabetes mostly Type-II

· High Alcohol Intake

· Radiation Therapy for Cancer and previous cancer treatment

· Personal History of Colorectal Cancer

· Night shift work.

Types of cancer in the colon and rectum:

Adenocarcinomas make up more than 95% of colorectal cancers. These cancers start in cells that make mucus to lubricate the inside of the colon and rectum. When doctors talk about colorectal cancer, they are almost always talking about this type. Some subtypes of adenocarcinoma, such as signet ring and mucinous, may have a worse prognosis (outlook).

Other, less common types of tumours can also start in the colon and rectum. These include:

· Carcinoid tumors start from specialized hormone-making cells in the intestine.

· Gastrointestinal stromal tumors (GISTs) start from specialized cells in the wall of the colon called the interstitial cells of Cajal. Some are non-cancerous (benign). These tumors can be found anywhere in the digestive tract, but are not common in the colon.

· Lymphomas are cancers of immune system cells that typically start in lymph nodes, but they can also start in the colon, rectum, or other organs. Information on lymphomas of the digestive system is included in Non-Hodgkin Lymphoma.

· Sarcomas can start in blood vessels, muscle layers, or other connective tissues in the wall of the colon and rectum. Sarcomas of the colon or rectum are rare [3].

Symptoms of colorectal cancer:

The signs and symptoms of colorectal cancer include [2, 14]:

· Changes seen in the bowel habits, including diarrhea or constipation or a change in the consistency of stools, which may last for longer than four weeks.

· Rectal bleeding and blood found in stools

· Persistent abdominal discomfort, such as cramps, gas or pain

· Feeling of incomplete emptying of bowel

· Weakness and fatigue

· Unexplained weight loss

· Anaemia

· Intestinal obstruction

· Narrowing of bowel lumen.

Polyp Development and its Pathophysiology:

All colorectal cancer anatomically develops as form of polyps in the inner lining of colon or rectum of which some over time transform into cancer. But the chance of changing into cancer depends on the type of polyp. The major types of polyps in case of colorectal cancer are as follows:

Colorectal Polyps [5, 7]:

A. NON-NEOPLASTIC POLYPS:

1. Hyperplastic (metaplastic) Polyps

2. Hamartomatous Polyps

a. Peutz-Jeghers polyps and polyposis

b. Juvenile (Retention) polyps and polyposis

3. Inflammatory Polyps (Pseudopolyps)

4. Lymphoid Polyps

B. NEOPLASTIC POLYPS (Adenomas):

1. Tubular Adenoma (Adenomatous polyp)

2. Villous Adenoma (Villous papilloma)

3. Tubulovillous Adenoma (Papillary Adenoma, villoglandular adenoma).

C. Familial Polyposis Syndromes:

1. Familial Polyposis Coli (Adenomatosis)

2. Gardner’s Syndrome

3. Turcot’s Syndrome

4. Juvenile Polyposis Syndrome

5. MUTYH-Associated Polyposis

A. Non-neoplastic polyps:

Non-neoplastic polyps are more common and include the following 4 subtypes [7]:

1. Hyperplastic (Metaplastic) Polyps:

The hyperplastic or metaplastic polyps are the most common amongst all epithelial polyps, particularly in the rectosigmoid. They are called ‘hyperplastic’ because there is epithelial hyperplasia at the base of the crypts, and ‘metaplastic’ as there are areas of cystic metaplasia. They may be seen at any age but are more common in the elderly (6th-7th decades). Grossly, hyperplastic polyps are generally multiple, sessile, smooth-surfaced and small (less than 0.5 cm). Microscopically, they are composed of long and cystically dilated glands and crypts lined by normal epithelial cells. Their lining is partly flat and partly papillary. The luminal border of thelining epithelium is often serrated or saw-toothed. Hyperplastic polyps are usually symptomless and have no malignant potential unless there is a coexistent adenoma [7].

2. Hamartomatous Polyps:

These are tumour-like lesions composed of abnormal mixture of tissues indigenous to the part. They are further of 2 types [7]:

· PEUTZ-JEGHERS polyps and polyposis:

Peutz-Jeghers syndrome is autosomal dominant defect, characterized by hamartomatous intestinal polyposis and melanotic pigmentation of lips, mouth and genitalia. The polyps may be located in the stomach, small intestine or colon but are most common in the jejunum and ileum. The most common age is adolescence and early childhood. Grossly, these polyps are of variable size but are often large, multiple and pedunculated and more commonly situated in the small intestine. Microscopically, the most characteristic feature is the treelike branching of muscularis mucosae. The lining epithelium is by normal-appearing epithelial cells. The glands may show hyperplasia and cystic change. Peutz-Jeghers polyps do not undergo malignant transformation unless a coexistent adenoma is present. However, patients with Peutz-Jeghers syndrome are more prone to certain other cancers such as of pancreas, lung, breast, ovary and uterus [7]. The pathological conditions seen in this inherited syndrome are freckles around the mouth (sometimes around hand and feet) and special type of polyp referred as hamartomas in the digestive tract. The syndrome is caused due to mutation in the STK11 (LKB1) gene [5].

· Juvenile (Retention) Polyps:

Juvenile or retention polyps, another form of hamartomatous polyps, occur more commonly in children below 5 years of age. Solitary juvenile polyps occur more often in the rectum, while juvenile polyposis may be present anywhere in the large bowel. Grossly, juvenile polyps are spherical, smooth-surfaced, about 2 cm in diameter and are often pedunculated. Microscopically, the classical appearance is of cystically dilated glands containing mucus and lined by normal mucus-secreting epithelium. The stroma may show inflammatory cell infiltrate if there is chronic ulceration of the surface. Most cases, on becoming symptomatic in the form of rectal bleeding, are removed. In common with other non-neoplastic polyps, they are also not precancerous [7].

3. Inflammatory Polyps (Pseudopolyps):

Inflammatory polyps or pseudopolyps appear due to re-epithelialisation of the undermined ulcers and over hanging margins in inflammatory bowel disease, most frequently in ulcerative colitis (colitis polyposa) and sometimes in Crohn’s disease. Grossly, they are usually multiple, cylindrical to rounded overgrowths of mucosa and may vary from minute nodules to several centimetres in size. Microscopically, the centre of inflammatory polyp consists of connective tissue core that shows some inflammatory cell infiltrate and is covered superficially by regenerating epithelial cells and some cystically-dilated glands. These lesions have no malignant potential; carcinomas seen in long-standing cases of ulcerative colitis arise in the region of epithelial dysplasia and not from the polyps [7].

4. Lymphoid Polyps

Reactive hyperplasia of lymphoid tissue that is normally also more prominent in the rectum and terminal ileum, gives rise to localize or diff use lymphoid polyps, also called rectal tonsils. Localized form occurs more often in the rectum in elderly, while diff use form is seen at younger age and in children. Grossly, they are solitary or multiple, tiny elevated lesions. Microscopically, they are composed of prominent lymphoid follicles with germinal centres located in the submucosa and mucosa, and are covered by epithelium that may be inflamed. They are benign lesions and have to be distinguished from malignant lymphoma [7].

B. Neoplastic Polyps (Adenomas):

Neoplastic polyps are colorectal adenomas which have potential for malignant change while polypoid carcinoma is the term used for invasive epithelial tumours. Adenomas have 3 main varieties (tubular, villous and tubulo villous), each of which represents a difference in the growth pattern of the same neoplastic process and variable biological behaviour. This kind of adenomatous phase is also called pre-cancerous condition [7]. These are mostly developed from benign polyps and in fact about 85% of all colorectal cancers develop from adenomatous polyps [1].Development of colorectal cancer in this case is a multistep process involving inactivation of a variety of genes that suppress tumours and repair DNA resulting in stimulation of oncogenes which further utilizes the advantage for transformation into adenomatous polyps from normal epithelium of colon [4]. These adenomatous polyps result further in and develop invasive colorectal cancer.

1. Tubular Adenoma (Adenomatous Polyp):

Tubular adenomas or adenomatous polyps are the most common neoplastic polyps (75%). They are common beyond 3rd decade of life and have slight male preponderance. They occur most often in the distal colon and rectum. They may be found singly as sporadic cases, or multiple tubular adenomas as part of familial polyposis syndrome with autosomal dominant inheritance pattern. Tubular adenomas may remain asymptomatic or may manifest by rectal bleeding. Grossly, adenomatous polyps may be single or multiple, sessile or pedunculated, vary in size from less than 1 cm to large, spherical masses with an irregular surface. Usually, the larger lesions have recognizable stalks. Microscopically, the usual appearance is of benign tumour overlying muscularis mucosa and is composed of branching tubules which are embedded in the lamina propria. The lining epithelial cells are of large intestinal type with diminished mucus secreting capacity, large nuclei and increased mitotic activity. However, tubular adenomas may show variable degree of cytologic atypia ranging from atypical epithelium restricted within the glandular basement membrane called as ‘carcinoma in situ’ to invasion into the fibrovascular stromal core termed frank adenocarcinoma. Malignant transformation is present in about 5% of tubular adenomas; the incidence being higher in larger adenomas [7].

2. Villous Adenoma (Villous Papilloma):

Villous adenomas or villous papillomas of the colon are much less common than tubular adenomas. The mean age at which they appear is 6th decade of life with approximately equal sex incidence. They are seen most often in the distal colon and rectum, followed in decreasing frequency, by rest of the colon. Grossly, villous adenomas are round to oval exophytic masses, usually sessile, varying in size from 1 to 10 cm or more in diameter. Their surface may be haemorrhagic or ulcerated. Microscopically, the characteristic histologic feature is the presence of many slender, finger-like villi, which appear to arise directly from the area of muscularis mucosae. Each of the papillae has fi bro vascular stromal core that is covered by epithelial cells varying from apparently benign to anaplastic cells. Excess mucus secretion is sometimes seen. Villous adenomas are invariably symptomatic; rectal bleeding, diarrhoea and mucus being the common features. The presence of severe atypia, carcinoma in situ and invasive carcinoma is seen more frequently. Invasive carcinoma has been reported in 30% of villous adenomas [7].

3. Tubulovillous Adenoma (Papillary Adenoma, Villoglandular Adenoma):

Tubulovillous adenoma is an intermediate form of pattern between tubular adenoma and villous adenoma. It is also known by other names like papillary adenoma and villoglandular adenoma. The distribution of these adenomas is the same as for tubular adenomas. Grossly, tubulovillous adenomas may be sessile or pedunculated and range in size from 0.5-5 cm. Microscopically, they show intermediate or mixed pattern, characteristic vertical villi and deeper part showing tubular pattern. The behaviour of tubulovillous adenoma is intermediate between tubular and villous adenomas.

The contrasting features of non-neoplastic and neoplastic colorectal polyps are given in table:

Table 5: Contrasting Features: Non-neoplastic and Neoplastic Polyps [7]

Feature	Non-Neoplastic Polyps	Neoplastic Polyps (Adenomas)
1. Frequency	More common	Less common
2. Number	Often sporadic	Sporadic as well as multiple
3. Familial predisposition	No	Yes, in sporadic cases
4. Types	Hyperplastic (90%) Others: harmartomatous (Peutz-Jeghers, juvenile) inflammatory, lymphoid	Tubular, villous and tubulovillous adenomas
5. Familial syndromes	Juvenile polyposis syndrome	Familial polyposis coli, Gardner’s, Turcot’s
6. Biologic behavior	Always benign	Variable malignant potential: Tubular adenoma 5%, villous 30%, tubulovillous intermediate.

C. Familial Polyposis Syndromes:

Familial polyposis syndromes are a group of disorders with multiple polyposis of the colon with autosomal dominant inheritance pattern. Important conditions included in familial polyposis are:

1. Familial polyposis coli (adenomatosis)

2. Gardner’s syndrome

3. Turcot’s syndrome

4. Juvenile polyposis syndrome

5. MUTYH- Associated Polyposis

Some other conditions in which multiple polyposis of colon occur but do not have familial basis are Peutz-Jeghers syndrome (hamartomatous), Cronkhite-Canada syndrome (inflammatory), and nodular lymphoid hyperplasia. The familial polyposis syndromes are as follows:

1. Familial Polyposis Coli (Adenomatosis):

This hereditary disease is defined as the presence of more than 100 neoplastic polyps (adenomas) on the mucosal surface of the colon; the average number is about 1000. Adenomatosis can be distinguished from multiple adenomas in which the number of adenomas is fewer, not exceeding 100. The condition has autosomal dominant transmission and is due to germline mutations in APC gene which results in occurrence of hundreds of adenomas which progress to invasive cancer. The average age at diagnosis is 2nd and 3rd decades of life with equal incidence in both the sexes. Grossly and microscopically, the commonest pattern is that of adenomatous polyps (tubular adenomas) discussed above. The malignant potential of familial polyposis coli is very high. Colorectal cancer develops virtually in 100% of cases by age of 50 years if not treated with colectomy [7].

2. Gardner’s Syndrome:

Gardner’s syndrome is combination of familial poly posis coli and certain extra-colonic lesions such as multiple osteomas (particularly of the mandible and maxilla), sebaceous cysts and connective tissue tumours. The number of polyps in Gardner’s syndrome is generally fewer than in the familial polyposis coli but their clinical behaviour is identical [7].

3. Turcot’s Syndrome:

Turcot’s syndrome is combination of familial polyposis coli and malignant neoplasms of the central nervous system [7]. It is a rare inherited condition with a risk of development of adenomatous polyps resulting into colorectal cancer and also in development of brain tumour. Turcot’s Syndrome is further divided into two types [5]:

· One which is similar to FAP i.e. caused by gene changes which causes brain tumors and medulloblastomas.

· And the one which is similar to Lynch Syndrome and causes brain tumors and glioblastomas.

4. Juvenile Polyposis Syndrome:

Juvenile polyposis is appearance of multiple juvenile polyps in the colon, stomach and small intestine but their number is not as high as in familial polyposis coli. Family history in some cases may show autosomal dominant inheritance pattern, while it may be negative in others. They resemble the typical juvenile polyps as regards their age (under 5 years), sex distribution and morphology. They lack the malignant potential [7].

5. MUTYH-Associated Polyposis:

The syndrome is caused by the mutation in the MUTYH gene which is involved in the “proofreading” the DNA to fix any mistakes. This syndrome leads to cancer at younger age and is too associated with other various cancers like cancers of small intestine, ovary, skin and bladder [5].

Colon cancer stages [2]:

Once you've been diagnosed with colon cancer, your doctor will order tests to determine the extent (stage) of your cancer. Staging helps determine what treatments are most appropriate for you. Staging tests may include imaging procedures such as abdominal, pelvic and chest CT scans. In many cases, the stage of your cancer may not be determined until after colon cancer surgery. The stages of colon cancer are:

· Stage I: The cancer has grown through the superficial lining (mucosa) of the colon or rectum but hasn't spread beyond the colon wall or rectum.

· Stage II: The cancer has grown into or through the wall of the colon or rectum but hasn't spread to nearby lymph nodes.

· Stage IIIp: The cancer has invaded nearby lymph nodes but isn't affecting other parts of your body yet.

· Stage IV: The cancer has spread to distant sites, such as other organs — for instance, to your liver or lung.

Colon Cancer Screening:

The sequence of progression from adenoma to invasive carcinoma in colorectal cancer, along with the accessibility of the lower gastrointestinal tract to endoscopic imaging has led to the development of screening protocols based around direct imaging of colonic mucosa. Currently, the United States Preventive Services Task Force (USPSTF) recommends colorectal cancer screening that involves a combination of stool-based laboratory studies and direct visualization of colonic mucosa. The gold standard for colorectal cancer screening is currently colonoscopy, beginning at the age of 50 in those without family history of colorectal cancer. In a case-controlled comparison of patients undergoing colonoscopy screening with historical patients who did not undergo screening, the use of colonoscopy reduced mortality risk to a great extent. Given the invasive nature of direct colonic visualization, indirect methods of evaluating the colonic mucosa have been developed, these are as follows [11]:

· Double-contrast barium enema (DCBE): involves radiographic imaging of the colon following the instillation of barium followed by distension of the colon with air. But this type of investigation is associated with unacceptable negative false rates, especially for polyps smaller in size (mostly less than 1cm).

· Computed Tomography Colonoscopy: involves thin-slice reconstruction of the colon for radiographic evaluation of the mucosa. While this evaluation may be more desirable topatients, a large meta-analysis showed that these studies too were less sensitive for small polyps than colonoscopy.

· Capsule Endoscopy: has been evaluated as another possible indirect method of visualizing the colonic mucosa, but it also lacks adequate sensitivity to be used as a screening test

The isolation of stool DNA, derived from sloughed mucosal and colorectal cancer cells, and the subsequent identification of colorectal cancer associated genetic mutations in stool samples has been described. DNA amplification techniques have improved the nucleic acid yield in stool samples, opening the possibility of screening for specific genetic mutations associated with colorectal cancer. A commercial test has been developed, which detects k-ras, APC, and p53 gene mutations, along with long DNA and the microsatellite instability marker BAT-26. A blinded comparison of the findings of this DNA based test showed sensitivity for advanced adenomas and invasive carcinoma of only 51%.

Current problems with screening tests for colorectal cancer include the lack adequate sensitivity, low cost-effectiveness, general invasiveness, and poor compliance. The current gold standard of colonoscopy demonstrates significant variability between providers in adenoma detection during colonoscopy [11].

Currently there are a number of different types of screening tests that are offered that test for colon cancer. If benign polyps can be caught early and removed, someone will be much less likely to develop cancerous tumours. The first type of test is the faecal occult blood test (FOBT). The FOBT tests for blood in the stool which may be a sign that there are large polyps in the colon. The test is usually given to a patient to conduct themselves at home. Samples of stool are taken from three separate bowel movements and returned to the lab for examination. If blood is found, a colonoscopy is recommended. It is suggested that this test be conducted annually for those over the age of 50 and earlier for those who have a family history of colon cancer. Regular use of the faecal occult blood test can “reduce the risk of death from colorectal cancer by 15% - 33%”. Early detection of large polyps in the colon through FOBT screening can also decrease the incidence of colorectal cancer by approximately 20%.

The next type of screening test is called a flexible sigmoidoscopy. This is when a doctor or other member of a trained medical staff uses a flexible, lighted tube to examine the lower part of the colon as well as the rectum. The tube, also called a sigmoidoscope, “is about 2 feet long (60 cm) and can visualize clearly about one-third of the colon”. If the doctor finds polyps during this test he/she will remove them and collect other tissue samples as well. The doctor may even recommend follow-up with a colonoscopy. For cancers within that lower portion of the colon, a flexible sigmoidoscopy test can reduce the risk of death from colorectal cancer by approximately 60%. The CDC recommends that the sigmoidoscopy is conducted every 5 years and also recommends use of the sigmoidoscopy in conjunction with an annual FOBT.

A colonoscopy is also an effective screening tool for colon cancer. This test is like the sigmoidoscopy but the instrument that is used is much longer and allows the doctor to examine the inside of the entire colon. For both the sigmoidoscopy and the colonoscopy, the patient usually takes some form of laxatives the day before the test to clean out the colon and rectum for examination. During a colonoscopy, the doctor may remove polyps by using a long wire instrument. According to the National Polyp Study, undergoing colonoscopies on a regular basis can prevent anywhere from 76% to 90% of all colon cancers. It is recommended, for people over 50, that colonoscopies be conducted every 10 years and when needed as a follow-up due to results of one of the other screening tests. There are additional screening tests that may be used (barium enema or digital rectal exam) but despite the fact that all of these effective screening tests exist for colorectal cancer it remains one of the leading causes of cancer deaths in the United States [1].

Tests that find polyps and cancer:

· Colonoscopy every 10 years

· CT colonography (virtual colonoscopy) every 5 years

· Flexible sigmoidoscopy every 5 years

· Double-contrast barium enema every 5 years

Tests that mainly find cancer:

· Fecal immunochemical test (FIT) every year

· Guaiac-based fecal occult blood test (gFOBT) every year

· Stool DNA test every 3 years [14].

Biomarkers:

The National Institute of Health (NIH) defines a biological marker (biomarker) as a biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease. In addition to screening for disease, a biomarker may be used to evaluate how well the body responds to a treatment and can also be called a molecular marker or signature molecule. A biomarker can exist as related to DNA, RNA, micro-RNA, epigenetic changes, protein and even antibody expression. Biomarkers have the potential to change treatment and diagnostic algorithms across a broad spectrum of patients. Putative Colorectal Cancer Stem Cell-Associated Biomarkers are also discussed regarding various hypothesis. Properties that define potential CSC’s are: (1) self-renewal; (2) the capacity for differentiation (allowing for recapitulation of all cell types of the original tumor); (3) tumor initiating capacity; and, (4) asymmetric cell division via non-random chromosomal co-segregation. Investigators have used these properties and various membrane and cytoplasmic markers to isolate putative CRCSC: CD133, CD24, CD29, CD44, CD166 (ALCAM), EpCAM, Lgr5, ALDH1A1 and ALDH1B1. [11] These markers represent all reported CRCSC. Using Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platform various colorectal cancer biomarkers have been identified. [12]

Treatment:

The type of treatment your doctor recommends will depend largely on the stage of your cancer. The three primary treatment options are surgery, chemotherapy and radiation.

Surgery for Colorectal Cancer [13]:

Surgery is often the main treatment for earlier-stage colon cancers. The type of surgery used depends on the stage (extent) of the cancer, where it is, and the goal of the surgery.

Polypectomy and Local Excision:

Some early colon cancers (stage 0 and some early stage I tumours) or polyps can be removed during a colonoscopy, where a long flexible tube with a small video camera on the end is inserted through the person’s rectum and into the colon. When done this way, the doctor does not have to cut into the abdomen.

· For a Polypectomy, the cancer is removed as part of the polyp, which is cut at its stalk (the area that resembles the stem of a mushroom). This is usually done by passing a wire loop through the colonoscope to cut the polyp from the wall of the colon or with an electric current.

· A localexcision is a slightly more extensive procedure that can be used to remove superficial cancers and a small amount of nearby tissue from the wall of colon.

Colectomy:

A colectomy is surgery to remove all or part of the colon. Nearby lymph nodes are removed as well. If only part of the colon is removed, it is called a hemicolectomy, partial colectomy, or segmental resection. The surgeon removes the part of the colon with the cancer and a small segment of normal colon on either side of the cancer. Usually, about one-fourth to one-third of your colon is removed, but this depends on the size and location of the cancer. The remaining sections of your colon are then reattached. Nearby lymph nodes are removed at this time as well. Typically, at least 12 are removed. If the entire colon is removed, it is called a total colectomy. Total colectomy is not often needed to treat colon cancer. It is generally used only if there is disease in the part of the colon without the cancer, such as hundreds of polyps (in someone with familial adenomatous polyposis) or, sometimes, inflammatory bowel disease. A colectomy can be done in 2 ways: Open Colectomy and Laparoscopic-Assisted Colectomy

Diverting colostomy:

Some patients have colon cancers that have spread but also have tumours blocking the colon. For patients with this problem, sometimes surgery is done to relieve the blockage without removing the part of the colon containing the cancer. Instead, the colon is cut above the tumour and attached to a stoma (an opening in the skin of the abdomen) to allow stool out. This is known as a diverting colostomy. It can often help the patient recover enough to start other treatments (such as chemotherapy).

Surgery for colon cancer spread:

If the cancer has spread to only one or a few spots in the lungs or liver (and nowhere else), surgery may be used to remove it. This is generally done only if the cancer in the colon or rectum is being removed as well (or was already removed). Depending on the extent of the disease, this might help you live longer, or it could even cure you. Deciding if surgery is an effective option to remove areas of cancer spread depends on their size, number, and location.

Surgery for Rectal Cancer:

Surgery is usually the main treatment for rectal cancer, although radiation and chemotherapy will often be given before or after surgery. The type of surgery used depends on the stage (extent) of the cancer, where it is, and the goal of the surgery.

· Polypectomy and Local Excision

· Local transanal resection (full thickness resection)

· Transanal endoscopic microsurgery (TEM)

· Low anterior resection (LAR)

· Proctectomy with colo-anal anastomosis

· Abdominoperineal resection (APR)

· Pelvic exenteration

· Diverting colostomy

· Surgery for rectal cancer spread.

Ablation and Embolization for Colorectal Cancer:

When colorectal cancer has spread to other organs such as the liver, the metastases can sometimes be removed by surgery or destroyed by other techniques, such as ablation or embolization. This might help a person live longer. Ablation and embolization can often be good options for people whose cancer can’t be cured with surgery or who can’t have surgery for other reasons. Typically, you will not need to stay in the hospital for these treatments.

Ablation:

Ablation refers to treatments that destroy tumours without removing them. These are most often used to treat cancer spread in the liver, but they can be used to treat tumours in other places.

· Radiofrequency ablation

· Ethanol (alcohol) ablation

· Cryosurgery (cryotherapy)

Embolization:

During an embolization procedure, substances are injected to try to block or reduce the blood flow to cancer cells in the liver. The liver is unusual in that it has 2 blood supplies. Most normal liver cells get blood from branches of the portal vein, whereas cancer cells in the liver usually get their blood supply from branches of the hepatic artery. Blocking the branch of the hepatic artery feeding the tumour helps kill off the cancer cells, but it leaves most of the healthy liver cells unharmed.

Embolization can be used for tumours that are too large to be treated with ablation– usually larger than 5 cm (about 2 inches) across. It can also be used with ablation. Embolization does reduce some of the blood supply to the normal liver tissue, so it may not be a good option for patients with liver damage from diseases such as hepatitis or cirrhosis. There are 3 main types of embolization procedures used to treat cancer in the liver:

· Arterial embolization

· Chemoembolization

· Radioembolization

Radiation Therapy:

Radiation therapy uses powerful energy sources, such as X-rays, to kill cancer cells, to shrink large tumors before an operation so that they can be removed more easily, or to relieve symptoms of colon cancer and rectal cancer. Radiation therapy either alone or combined with chemotherapy is one of the standard treatment options for the initial management of rectal cancer followed by surgery [2]. These techniques include [13]: External-beam radiation therapy, Internal radiation therapy (brachytherapy), Endocavitary radiation therapy, Interstitial brachytherapy.

Chemotherapy:

Chemotherapy uses drugs to destroy cancer cells. Chemotherapy for colon cancer is usually given after surgery if the cancer has spread to lymph nodes. In this way, chemotherapy may help reduce the risk of cancer recurrence and death from cancer. Sometimes chemotherapy may be used before surgery as well, with the goal of shrinking the cancer before an operation. Chemotherapy before surgery is more common in rectal cancer than in colon cancer [2].

Systemic Chemotherapy:

Drugs are injected into your vein or you take them by mouth. These drugs enter your bloodstream and reach all areas of your body [13].

Regional Chemotherapy:

Drugs are injected directly into an artery that leads to a part of the body with a tumour. This method concentrates the dose of chemo reaching the cancer cells in that area. It reduces side effects by limiting the amount of drug reaching the rest of your body. Hepatic artery infusion, or chemo given directly into the hepatic artery, is an example of regional chemotherapy sometimes used for cancer that has spread to the liver [13].

Adjuvant chemo:

Chemo can be given after surgery. The goal is to kill any cancer cells that may have been left behind at surgery because they were too small to see, as well as cancer cells that might have escaped from the main tumour and settled in other parts of the body (but are too small to see on imaging tests). This helps lower the chance that the cancer will come back [13].

Neoadjuvant chemo:

For some cancers, chemo is given (sometimes with radiation) before surgery to try to shrink the cancer and make surgery easier. This is often used in treating rectal cancer [13].

Chemo for advanced cancers:

For cancers that have spread to other organs, such as the liver, chemo can also be used to help shrink tumours and relieve symptoms. Although it is not likely to cure the cancer, it often helps people live longer. Drugs used for chemotherapy are as follows:

· 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug leucovorin (also called folinic acid) or a similar drug called levo-leucovorin, which helps it work better.

· Capecitabine (Xeloda), which is in pill form. Once in the body, it is changed to 5-FU when it gets to the tumor site.

· Ieinotecan (Camptosar)

· Oxaliplatin (Eloxatin)

· Trifluridine and Tipiracil (Lonsurf), a combination drug in pill form [13].

Targeted Therapy Drugs for Colorectal Cancer [13]:

As researchers have learned more about the gene and protein changes in cells that cause cancer, they have developed newer drugs to specifically target these changes. Targeted drugs work differently from standard chemotherapy (chemo) drugs. They sometimes work when standard chemo drugs don’t, and they often have different (and less severe) side effects. They can be used either along with chemo or by themselves if chemo is no longer working.

Drugs that target blood vessel formation (VEGF):

Vascular endothelial growth factor (VEGF) is a protein that helps tumours form new blood vessels to get nutrients (a process known as angiogenesis). Drugs that stop VEGF from working can be used to treat some colon or rectal cancers. These include:

· Bevacizumab (Avastin)

· Ramucirumab (Cyramza)

· Ziv-aflibercept (Zaltrap)

These drugs are given as infusions into your vein (IV) every 2 or 3 weeks, typically along with chemotherapy. When combined with chemo, these drugs can often help patients with advanced colon or rectal cancers live longer.

Possible side effects of drugs that target VEGF:

Common side effects of these drugs include high blood pressure, tiredness, bleeding, low white blood cell counts (with increased risk of infections), headaches, mouth sores, loss of appetite, and diarrhoea. Rare but possibly serious side effects include blood clots, severe bleeding, holes forming in the colon (called perforations), heart problems, kidney problems, and slow wound healing. If a hole forms in the colon it can lead to severe infection and may require surgery to correct. Another rare but serious side effect of these drugs is an allergic reaction during the infusion, which could cause problems with breathing and low blood pressure.

Drugs that target cells with EGFR changes:

Epidermal growth factor receptor (EGFR) is a protein that often appears in high amounts on the surface of cancer cells and helps them grow. Drugs that target EGFR can be used to treat some advanced colon or rectal cancers. These include:

· Cetuximab (Erbitux)

· Panitumumab (Vectibix)

Both of these drugs are given by IV infusion, either once a week or every other week.

Some colorectal cancers have mutations (defects) in the KRAS, NRAS or BRAF gene, which make these drugs ineffective. Doctors now commonly test the tumor for these gene changes before treatment, and only use these drugs in people who do not have these mutations.

Possible side effects of drugs that target EGFR:

The most common side effects of these drugs are skin problems such as an acne-like rash on the face and chest during treatment, which can sometimes lead to infections. A topical antibiotic may be prescribed to help limit the rash and related infections. The skin problems with panitumumab can be more serious and might lead to the skin peeling off. Other side effects can include headache, tiredness, fever, and diarrhea. A rare but serious side effect of these drugs is an allergic reaction during the infusion, which could cause problems with breathing and low blood pressure. You may be given medicine before treatment to help prevent this.

Other targeted therapy drugs:

Regorafenib (Stivarga) is a type of targeted therapy known as a kinase inhibitor. Kinases are proteins on or near the surface of a cell that carry important signals to the cell’s control center. Regorafenib blocks several kinase proteins that either help tumour cells grow or help form new blood vessels to feed the tumour. Blocking these proteins can help stop the growth of cancer cells.

This drug is used to treat advanced colorectal cancer, typically when other drugs are no longer helpful. It is taken in pill form. Common side effects include fatigue, loss of appetite, hand-foot syndrome (redness and irritation of the hands and feet), diarrhoea, high blood pressure, weight loss and abdominal pain. Less common but more serious side effects can include severe bleeding or perforations (holes) in the stomach or intestines [13].

Immunotherapy:

Some patients with advanced colon cancer have a chance to benefit from immunotherapy with antibodies such as pembrolizumab (Keytruda) and nivolumab (Opdivo). Whether a colon cancer has the chance to respond to these immunotherapies can be determined by a specific test of the tumor tissue.

Vitamins, Calcium and Magnesium:

Some studies suggest that taking a daily multi-vitamin containing folic acid, or folate, may lower colorectal cancer risk, but not all studies have found this. In fact, some studies have hinted that folic acid might help existing tumours grow. More research is needed in this area.

Some studies have suggested that vitamin D, which you can get from sun exposure, in certain foods, or in a vitamin pill, might lower colorectal cancer risk. Because of concerns that excess sun exposure can cause skin cancer, most experts do not recommend this as a way to lower colorectal cancer risk at this time. More studies are needed to determine if vitamin D can help prevent colorectal cancer.

Low levels of dietary calcium have been linked with an increased risk of colorectal cancer in some studies. Other studies suggest that increasing calcium intake may lower colorectal cancer risk. Calcium is important for a number of health reasons aside from possible effects on cancer risk. But because of the possible increased risk of prostate cancer in men with high calcium intake, the American Cancer Society does not recommend increasing calcium intake specifically to try to lower colorectal cancer risk. Calcium and vitamin D might work together to reduce colorectal cancer risk, as vitamin D aids in the body’s absorption of calcium. Still, not all studies have found that supplements of these nutrients reduce risk. A few studies have found a possible link between a diet that is high in magnesium and reduced colorectal cancer risk, especially among women. More research is needed to determine if this link exists [5].

Non-steroidal anti-inflammatory drugs (NSAIDs):

Many studies have found that people who regularly take aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Motrin, Advil) and naproxen (Aleve), have a lower risk of colorectal cancer and polyps.

But aspirin and other NSAIDs can cause serious or even life-threatening side effects such as bleeding from stomach irritation or stomach ulcers, which may outweigh the benefits of these medicines for the general public. For this reason, most experts don’t recommend taking NSAIDs just to lower colorectal cancer risk if you are someone at average risk.

However, for some people in their 50s who have an elevated risk of heart disease, where low-dose aspirin is found to be beneficial, the aspirin may also have the added benefit of reducing the risk of colorectal cancer.

Because aspirin or other NSAIDs can have serious side effects, check with your doctor before starting any of them on a regular basis [5].

Hormone replacement therapy for women:

Taking oestrogen and progesterone after menopause (sometimes called menopausal hormone therapy or combined hormone replacement therapy) may reduce a woman’s risk of developing colorectal cancer, but cancers found in women taking these hormones after menopause may be at a more advanced stage.

Because taking oestrogen and progesterone after menopause can also increase a woman’s risk of heart disease, blood clots, and cancers of the breast and lung, it is not commonly recommended just to lower colorectal cancer risk [5].

Supportive (Palliative) care:

Palliative care is specialized medical care that focuses on providing relief from pain and other symptoms of a serious illness. Palliative care specialists work with you, your family and your other doctors to provide an extra layer of support that complements your ongoing care. When palliative care is used along with all of the other appropriate treatments, people with cancer may feel better and live longer. Palliative care is provided by a team of doctors, nurses and other specially trained professionals. Palliative care teams aim to improve the quality of life for people with cancer and their families. This form of care is offered alongside curative or other treatments you may be receiving [2].

Patients suffering from colon cancer have to undergo frequent checkup and tests to monitor the therapy and progression of cancer. As already discussed, early detection and identification can help treat the colorectal cancers successfully, but there are chances to re-develop cancer or secondary cancers. The fully cured and suffering patients has to go under proper medication regimen along with healthy diet and physical activity to be a healthy cancer survivor. The post treatment follows an array of healthy lifestyle along with frequent medical consultations. [15]

Second Cancers after Colorectal Cancer:

Colorectal cancer survivors can be affected by a number of health problems, but often a major concern is facing cancer again. Cancer that comes back after treatment is called a recurrence. But some cancer survivors develop a new, unrelated cancer later. This is called a second cancer.

Table 6 Second Cancers for Colorectal Cancer [15]

FOR COLON CANCER	FOR RECTAL CANCER
A second colon cancer (This is different from the first cancer coming back.	Colon cancer
Stomach cancer	Small intestine cancer
Small intestine cancer	Anal cancer
Anal cancer	Lung cancer
Bile duct cancer	Vaginal cancer
Rectal cancer	Kidney cancer
Uterine cancer
Kidney cancer
Cancer of the ureter

CONCLUSION:

Colorectal Cancer is the leading health problem and accounts for a major number of deaths occurring due to cancers. Colorectal cancer results from the development of outgrowths in the colon and rectum called polyps which differ with respect to anatomy and physiology according to the mutations inherited or caused. Colorectal has been reported to be caused due to various lifestyle changes and is mostly found in people with ages above 50. Being the cancer of alimentary canal, it is related what kind of food we intake and working of our digestive system

Colorectal cancers invade and spread to other organs through morphologic and molecular progression. It is important to diagnose colorectal cancer as early as possible, to start treatment and control its spread. The treatment of CRC has markedly changed in recent years due to the development of new predictive biomarkers that facilitate optimized, tailored therapy. The discovery of new biologic techniques, such as the liquid biopsy approach, elucidate the increasingly complex heterogeneity of this disease and can be used to monitor minimal residual disease, track tumor clonal evolution and design novel therapeutic strategies to overcome the emergence of drug resistance. Despite this exceptional progress, a large subset of patients continues to be unresponsiveness. In the immediate future, further clinical investigations, such as clinical trials, are needed to guarantee to all patients a genetically determined treatment strategy. Treatment of colorectal cancer is done through surgery, radiotherapy, chemotherapy, hormone replacement therapy and other preventive and palliative measures. The best way to avoid colorectal cancer and its spread towards chronic stages is early detection and measures to treat it. Chemotherapy has helped treating colorectal cancers but with the expense of number of side effects and challenges. Targeting drugs at various factors like vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) has shown some outstanding results. Thus, it has become a challenge for health professionals to treat such a cancer of large intestine and colon where people fear and shy to share their health problems regarding the same. Measures are taken worldwide to create awareness regarding Colorectal Cancer and the month of march is declared as the Colorectal Cancer awareness month.

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Received on 25.04.2020 Modified on 23.05.2020

Asian J. Res. Pharm. Sci. 2020; 10(3):211-223.

DOI: 10.5958/2231-5659.2020.00040.5