Colorectal Cancer

Introduction

Cancer is defined as abnormal cells that divide without control and are able to invade other tissues. Lymph and blood systems are the tracks used by cancer cells to spread.

Cancer is not one disease, it is many diseases. More than 100 types of cancer are described. It could be named according to the organ or type of cell where cancer started, such as "colon cancer" that takes place in colon organ, or "lymphoma" that takes place in the lymphocytes cells.

Figure 1: The incidence of Colon cancer worldwide.

I. What is colorectal cancer and the type of cells involved in it?

The large intestine consists of the colon and the rectum. The colon is long tubular muscle of length 6 foots. It connects the small intestine to the rectum. The role of colon is to absorb the water and electrolytes from indigestible food (fibers). It also absorbs vitamins and stores the stool before its elimination. With the help of the bacteria and the mucosa that is secreted from the walls of the colon, the wastes are mixed together to form the feces. Concerning the rectum, it is a muscular tube that connects the colon with the anus, of length 8 inch. Its role is to receive the formed stool from the colon and to hold it until you can evacuate. It lets you know or feel that stool is formed .

Figure 1.1: The place of colon and rectum in the digestive tract 

When the cells in the colon become abnormal, due to certain factors, and these cells proliferate and grow out of 
control, then colon cancer occurs. These cells could pass to the rectum and form colorectal cancer. The type of cells that could become abnormal in such cancer is the epithelial cells that line the colon and the rectum. These epithelial cells line the inner walls of the colon and rectum and secrete the mucosa. So, colon cancer is considered as adenocarcinoma. To be more specific, colorectal cancer arises from polyps which are the localized lesions (benign growth) projecting up the surrounding mucosa. Most colorectal polyps are hyperplastic. Adenomatous polyp or adenoma arising from glandular epithelium with dysplastic morphology and altered differentiation of epithelial cells are the precursor of carcinoma.

II. What are the early common symptoms of this cancer?  How is it detected by the patient?

The symptoms of colorectal cancer don't appear in its beginning. However certain signs accompanied in the development of this cancer such as:

·      Disturbances in the bowel movement, means sometimes having diarrhea or constipation (having a bowel movement fewer than three times per week)

·          Pain during the bowel movement

·    Feeling uncomfortable after each bowel since the bowel has not been emptied completely

·        Rectal bleeding, which can be confirmed by observing dark spots in the stool.

·         Presence of long or thin stool. This kind of stool is termed "pencil stool".

·         Abdominal cramps, bloating and gas

·         Decrease in appetite (An instinctive physical desire, especially one for food or drink)

·         Loss of weight without known reasons.

·         Vomiting sometimes

·         Feeling fatigue and weakness without doing efforts

Figure 2.1: The symptom of abdominal pain

Note that, these symptoms could occur in an individual having problems in colon function, and not necessary having cancer, but in case there is cancer in the colon, these symptoms are available. In addition to these observed signs, the main internal sign is the presence of polyps protruding outside the colon wall.

III. How is it screened and diagnosed?

Colorectal cancer is one of the cancers that can be treated efficiently if detected early. It can be diagnosed by several methods. These methods are:

·         Digital rectal examination (DRE): it's done by the use of gloved finger to detect any abnormalities in the rectum.

·         Fecal occult blood test (FOBT): it is done by taking a sample of stool on slide and detecting the presence of occult (hidden) blood in the stool. Certain diet should be followed before performing this test.

·         Fecal immunochemical test (FIT): it's the same as FOBT but with no need to certain diet .

·         Colonoscopy: it is the use if colonsope machine – long flexible tube with camera and source of light at its end – to examine the rectum and the entire length of the colon and to remove polyps once they are found. Monitor is used to view images from the inside of the large intestine. Colonoscopy duration is 30 minutes, and the patient should be given sedative. It can't be done suddenly, patient should have emptied his colon before 2 days of doing it

Figure 3.1: The colonscope                         Figure 3.2: Removing Polyps

·      

   Flexible Sigmoidoscopy: its function is similar to that of colonoscopy but differences are: optional sedation, observe the rectum and the lower 2 feet of the colon and duration is 10-20 minutes.

Figure 3.3: Sigmoidscopy verus colonscopy

·         Double-Contrast Barium Enema (DCBE): x-ray here is needed to image the colon and the rectum but without sedation. The mechanism is to introduce barium sulfate (barium is used because it is heavy metal and will absorb the x-rays) into the rectum by flexible tube and to pump air for allowing barium to spread throughout the large intestine. Once barium hits polyps, by the help of x-ray, these polyps can be clearly visualized and may be removed by colonscopy.

·         Virtual colonoscopy: it’s also called Computed Tomography (CT), and x-ray is also needed here. The new in this technique is the obtaining of 3D images by the use of CT scanner. The duration is 10 minutes. Scientists consider this technique as the most efficient one in detecting adenocarcinoma

Figure 3.4: The CT scanner using X-rays

·         Stool DNA Test: by using fecal sample, genetic changes in the DNA sequences can be detected from polyp cell or another colon cell. This technique costs a lot, that's why its use is not widespread .

·         PET scan: this technique is done by injecting labeled glucose (radioactive glucose) through the vein of the patient and noticing the fate of glucose inside the body. Cancer cells will consume large amount of glucose because these cells have a lot of glucose receptors on their cellular membrane. Thus, by PET scan we can view the most consuming cells of glucose by noting the brightest regions.

So at the end, colorectal cancer can be diagnosed using 3 types of diagnosis: biopsy, blood test (maybe blood count test to detect anemia since loss of blood in the stool can cause anemia later on) and imaging tests (CT scan, PET scan, etc) .

The American Cancer Society (ACS), the U.S. Preventive Services Task Force (USPSTF), and the American College of Gastroenterology (ACG) make a schedule for screening after the age of 50 years old. This schedule is as follows:

The test	The time to do it
FOBT	Every year
FIT	Every year
Flexible Sigmoidscopy	Every 5 – 10 years
Colonoscopy	Every 10 years
DCBE	Every 5 years
CT	Every 5 years
sDNA	Every 3 years

Table 3.1: The schedule of screening for colorectal cancer

IV. What are the stages of the disease?

The colon cancer has 4 stages of development. These stages are as follows:

Stage 0: it's also called "carcinoma in situ". In this stage, abnormal mucosal cells (in the innermost layer) are detected in the wall of the colon. Sometimes this abnormality could be uncontrollable and thus cancer will occur and can spread later on if not detected early .

Figure 4.1: Stage 0 of colon cancer

Stage 1: it's also called "Duke's A colon cancer". The abnormality in mucosa becomes cancer, and it passes 

from mucosa to the submucosa (layer under the mucosa)

Figure 4.2: Stage 1 of colon cancer 

Stage 2: it's also called "Duke's B colon cancer". This stage is divided into 3 sub-stages:

       Stage 2A, in which cancer spreads from the submucosa to the serosa (outermost layer) of colon wall.
       Stage 2B, here cancer spreads from serosa but don't reach nearby organs.

       Stage 2C, cancer spreads from serosa but it reaches nearby organs.

Figure 4.3: Stage 2 of colon cancer

Stage 3: it's also called "Duke's C colon cancer". Like stage 2, this stage is divided into 3 sub-stages:

Stage 3A: in this stage, cancer spreads from mucosa, to submucosa, to muscle layer and reaches 1 to 3 lymph nodes. Another case is that cancer spread from mucosa to submucosa and directly reaches 4 to 6 lymph nodes.

Figure 4.4: Stage 3A of colon cancer.

Stage 3B: 3 cases of spreading take place in this stage. The first one is that cancer spread through this

 pathway; mucosa, submucosa, muscle layer, serosa and 1 to 3 lymph nodes. The second case is that cancer 

spread through the same pathway of first case but here it cancer reaches 4 to 6 lymph nodes. The third case is 

that cancer spread through mucosa, to submucosa and finally it reaches 7 or more lymph nodes.

Figure 4.5: Stage 3B of colon cancer.

Stage 3C: also 3 cases are there. The first one is that cancer spread through serosa and reaches 4 to 6 lymph 

nodes, but without reaching any nearby organs. The second case is that cancer reaches 7 or more lymph 

nodes, and the last case is when cancer reaches nearby organs and 1 or more lymph nodes.

Figure 4.6: Stage 3C of colon cancer.

Stage 4: it is also called "Duke's D colon cancer". In this stage, cancer has spread through blood or lymph and reaches organs in the body. In stage 4A, cancer reaches one organ that may be near to colon or not such as liver, lung, or ovary via lymph nodes. In stage 4B, cancer reaches more than one nearby or not nearby organs

V. Does this disease have a known common or uncommon cause

The causes of colon cancer are not very known, but they could be related to genetic modifications (mutations in 

certain alleles) or environmental factors or other factors that are considered as risk factors. These latter include:

·         Age of 50 years old and more

·         Life style: Smoking and Obesity

·         Family history including the presence of colon cancer, or Familial Adenomatous Polyposis (FAP)

·         Past medical history which includes inflammatory bowel diseases, pelvic irradiation, cholecystectomy ..

·         Diet includes high dietary fat (saturated and polyunsaturated fats favor the development of 

          adenomatous polyps) and high red meat diet (barbeque, pickled, smoked, salt-cured)

·         Heavy alcohol use

VI. What are the gene mutations that will cause or favor colon carcinoma?

Most of the colorectal cancer occurs sporadically, but about 25% of cases are due to hereditary factors. The risk 

factors are the ones that are able to increase the sporadic of colorectal cancer. The hereditary diseases of colon 

cancer are of two types: the FAP due to mutation in APC gene (adenomatous polyposis coli) on chromosome 5, 

which is a tumor suppressor gene.

Figure 6.1: The position of APC gene that causes FAP once it’s mutated.

Figure 6.2: The inheritance of FAP disease.

The second common hereditary colorectal cancer is Hereditary Nonpolyposis Colon Cancer (HNPCC)/Lynch

 Syndrome (LS). This syndrome is due to mutations in DNA Mismatch Repair (MMR) genes.

Figure 6.3: The percentage of colorectal cancer arising in various family risk settings and that’s of sporadic case.

In the tumor, cells were found that are self renewing and differentiate into transient amplifying cells before

 terminally differentiating. These cells are called cancer stem cells (CSCs). In the colorectal cancer, the CSCs 

have specific surface markers that will help in the diagnosis of the disease. These markers are: CD44, CD166, 

CD133 and ESA (epithelial-specific antigen). Cells expressing these markers have high ability to form tumor.

In addition to tumor formation, CSCs also have ability to metastasize by transforming into epithelial-

mesenchymal transition (EMT), that are characterized by transforming E-cadherin into vimentin (vimentin is an 

effector of Wnt pathway and notch signaling).

Several genetic mutations correlate to colorectal cancer. About 69 genes were found to be a cause of colon 

cancer once they are mutated. The most important of these genes are: KRAS oncogene, p53, PIK3C. In more 

than half of the colon cancer cases, Bax gene is inactivated by several mutations in which Bax is pro-apoptotic 

protein. Losses of portions of chromosomes also can lead to colon cancer if these portions contain important 

regulatory genes. Examples on such losses are: 5q that contains APC gene (APC is tumor suppressor gene), 

18q that contains DCC/MADH2/MADH4 and 17p that contains the p53 gene (tumor suppressor gene).

Epigenetic mutations play role in colorectal cancer. Hypermethylation is a tool for such mutations. An 

example of hypermethylation is the methylation of the antagonist (DKK-1) of wnt. APC promoter methylation is 

acoompanied with metastasized colon cancer.

microRNAs are another tool of epigenetic mutations. The role of miRNAs is to silence its target gene by 

complementary binding with the gene. miRNA-21 targets the tumor suppressor genes tropomyosin 1 (TPM1), 

phosphatase and tension homologue (PTEN) and programmed cell death 4 protein (PDCD4) and also it 

targets genes involved in suppression of invasion and metastasis such as maspin. So inhibition of miRNA-21 

will help in treating colorectal cancer. Note that the expression of this microRNA is induced by IL-6 which in turn 

is increased with aging and tumorigenesis. This shows why age above 50 years old is a risk factor for colorectal 

cancer .

miRNA-34 family is down regulated in colorectal cancer, in which its function is to induce cell-cycle arrest and 

to inhibit invasion and migration. p53 is the transcription factor of this miRNA. So in colon cancer, once p53 is 

mutated, miRNA-34 will not be expressed and cancer will take place .

Gene	Syndrome	Hereditary Pattern	Predominant Cancer
Tumor suppressor genes
APC	FAP	Dominant	Colon, intestine, etc.
AXIN2	Attenuated polyposis	Dominant	Colon
TP53 (p53)	Li-Fraumeni	Dominant	Multiple (including colon)
PTEN	Cowden	Dominant	Multiple (including intestine)
Repair/stability genes
MLH1 , MSH2, MSH6 ,PMS2	Lynch	Dominant	Multiple (including colon, uterus, and others)
EPCAM (TACSTD1)	Lynch	Dominant	Multiple (including colon, uterus, and others)
MYH (MUTYH)	Attenuated polyposis	Recessive	Colon
BLM	Bloom	Recessive	Multiple (including colon)

Table 6.1: the main genes that are mutated in colorectal cancer ⁽²⁴⁾

VII. Does it affect any particular group of people (based on ethnicity, geographical distribution)?

According to several studies, it was detected that colorectal cancer affects group of people more than others 

depending on race and geographical distribution.

Table 7.1: colorectal cancer incidence and mortality rate.

Colorectal cancer incidence and mortality rates are highest in African American men and women (Table 3); 

incidence rates are 20% higher and mortality rates are about 45% higher than those in whites. Incidence and 

mortality rates among other major racial/ethnic groups are lower than those among whites. For example, 

incidence rates among American Indians/Alaska Natives (AI/AN) living in Alaska are 102.6, compared to 21.0 

among AI/ANs residing in the Southwest. So here environmental factors play role in causing colorectal cancer. 

Also colorectal cancer incidence differs between men and women as shown in the following graphs:

 

Figure 7.1: The incidence of colorectal cancer in men and women at different ages.

It's concluded that as age increases, the incidence of colon cancer increases, and colon cancer incidence is 

higher in men than in women.

VIII. Who are the people that least suffer from this form of cancer and why?

According to what stated about the causes of colon cancer, it becomes obvious that if decreasing these causes 

(the causes that can be controlled, and not such as genetic causes), colorectal cancer probability will decrease. 

So, by decreasing the red meat diet and the high fat diet, colorectal cancer incidence will decrease. Diet rich in 

fibers from whole grain cereals, legumes, fruits and vegetables (water insoluble fibers maybe best) is a good 

way to avoid colorectal cancer since Fibers assist the colon in two ways. Fibers are important to the colon 

health because insoluble fibers have the ability to absorb water (as the colon) and helps in the formation of stool. 

In addition, the soluble fibers are broken down by the bacteria to form gel, which is beneficial for waste 

elimination.

High physical activity is good for colon. Physical activity may protect against colon cancer and tumor 

development through its role in energy balance, hormone metabolism, insulin regulation, and by decreasing the 

time the colon is exposed to potential carcinogens. Physical activity has also been found to induce a number of 

inflammatory and immune factors, some of which may influence colon cancer risk.

In addition, folate or `methionine intake could protect the DNA from being methylated in colon cells, and thus 

decrease the chance of gene modifications and the forming of colon cancer.

High calcium intake also can reduce the risk of having colorectal cancer since calcium prevents adenomas 

recurrence which will lead later on to cancer .

Certain medications play a role in decreasing the risk of colorectal cancer. NSAIDs (Non Steroidal Anti 

Inflammatory Drugs) are one of these drugs. Its mechanism of action as follows :

Figure 8.1: The effect of NSAIDs on colorectal cancer risk.

High doses of NSAIDs will induce apoptosis. a) NSAIDs can inhibit the activity of I B kinase

 (IKK ). This leads to antagonism of the NF- B signaling pathway by blocking the destruction of the NF- B

 inhibitor I B, preventing NF- B from translocating to the nucleus and regulating key target genes. b) Certain

 NSAIDs can activate peroxisome proliferator-activated receptor (PPAR) subtypes   and  , and the NSAID

 sulindac has been shown to inhibit the DNA-binding activity of PPAR . PPARs activate transcription in 

conjunction with the retinoid X receptor RXR. Overexpression of PPAR  can partially rescue sulindac-induced

 apoptosis in a colorectal cancer cell line. c) NSAIDs can decrease the levels of the anti-apoptotic gene BCL-XL,

 thereby increasing the cellular ratio of BAX: BCL-XL;BAX-/- cells are resistant to NSAID-induced apoptosis .

Cox-2 is an enzyme that converts arachidonic acid to prostaglandin (the hormone that causes the pain feeling, 

inflammation, etc.) NSAIDs target cox-2 inorder to reduce pain and fever. Cox-2 inhibitors are called coxibs. 

Certain studies reveal that cox-2 promotes colorectal cancer development. So cox-2 inhibitors are able to 

minimize the risk of colorectal cancer. The mechanism by which cox-2 promotes colorectal cancer is :

Figure 8.2: The effect of Cox-2 on colorectal cancer.

In colorectal tumors, COX-2 presents in epithelial cells, macrophages, fibroblasts and vascular endothelial cells. 

COX-2 may act on epithelial cells (autocrine effect) or other cells in stroma (landscape effect) to promote 

cancer. a) Cell-autonomous effects. The expression of COX2 in colorectal cancer cell lines causes mutations in 

specific genes that regulate cell death, so Cox-2 will cause resistance to apoptosis and enhance migration. b) 

Landscaping effects. COX-2 is primarily found in the stromal fibroblasts within a tumor. COX-2 promotes 

neovascularization within the cells and thus helps tumor cells to grow and metastasize and several groups have 

shown that COX-2 inhibitors can block the migration of endothelial cells .

IX. How is colorectal cancer treated?

Adenomatous polyps are main cause or risk for colorectal cancer. They are detected by colonoscopy or 

sigmoidscopy. Once they are found, these polyps are removed by colonoscopy and the patient should repeat 

colonoscopy every 1 to 3 years.

Figure 9.1: Adenomatous polyp

Now in the case of Familial Adenomatous Polyposis (FAP), (which is hereditary disease that causes 

formation of polyps in the colon) total colonectomy is the suitable way for treating this disease .

Inflammatory bowel diseases can lead to colon cancer if inflammation became chronic. So, patients with 

such diseases should always be subjected to colonoscopy to detect any abnormalities such as polyps. Some 

people who have chronic inflammation in their colon undergo prophylactic colectomy to preserve the healthier 

parts in their colons and remove the highly inflammatory ones .

All what is stated above are treatments to avoid colon cancer, but in case cancer occurs, different treatments 

have been investigated: Surgery, chemotherapy, biological therapies and radiations. They can be done in 

combination .

Surgery:

There are 3 main options of surgery depending on metastasis.

1)      Bowel Resection: in this technique, surgery is done by cutting into the abdomen to reach the cancer area in the colon or rectum. After cutting this area, the healthy parts are rejoined together.

2)      Liver Resection: when colon cancer spread to other organs, it can reach the liver. More than half of the liver can be removed and the person will stay healthy. In case the tumor is large in the liver, chemotherapy can be used to decrease its size .

3)      Other Resection: lung, ovarian and adrenal organs can be removed also if cancer spread in them.

Chemotherapy:

This therapy depends on drugs that can tumor-cidal. These drugs can be delivered into the patient by 

intravenously injections or orally by mouth in the form of pill.

Table 9.1: Schedule for adjuvant chemotherapy with specific doses

The side effects:

Table 9.2: The side effects of chemotherapy and the supportive care option

Biological therapies:

The other name is immunotherapy. The aim of this treatment is to let the body fight cancer using its immune 

system. There are 4 types of immunotherapy:

·         Biological response modifiers: these contain the cytokines (secreted by certain cells of the 

immune system and having an effect on other cells) such as interferons and interleukins. This treatment aim 

to introduce large amount of cytokines and thus activate the immune system to fight more against cancer 

cells.

·         Colony-stimulating factors: they are factors that stimulate the bone marrow to synthesize bone 

marrow cells (white blood cells for fighting pathogens, red blood cells to exchange O₂ and CO₂ and platelets 

and fragments for blood clotting). These factors don't affect tumor directly, but help the body to stay strong 

while treating cancer with other treatments that decrease such cells .

·         Tumor vaccines: the aim of such vaccines is not to treat cancer, but to let the body able to 

recognize cancer cells and to activate more the immune system.  The vaccine role is to prevent cancer from 

returning to body and to reject the tumor lumps. These vaccines are not as known vaccines, they are given to 
the patient after having cancer and not before it as in ordinary vaccine treatments .

·         Monoclonal antibodies: these are used for "targeting therapy"; means the ability to target 

specifically the cancer cells. These antibodies are produced at the lab and used to detect the location of 

tumor in the body. An important use of such antibodies is attaching drugs, toxins or radioactive substances 

to these antibodies that will specifically recognize the cancer cells and deliver the drugs or toxin for these 

cells only. The FDA (Food and Drug Administration) approved some of these antibodies to treat specifically 

the colorectal cancer such as: Erbitux (cetuximab), Avastin (bevacizumab) and Vectibix (panitumumab).

Erbitux (cetuximab): it targets epidermal growth factor receptors (EGFR) that are highly expressed on cancer 

cells membrane to support their growth and development. It's delivered intravenously usually once a week. 

Certain side effects are accompanied with Erbitux usage, such as skin problems, headaches, fever, diarrhea, etc. 

this drug is not recommended for patients having KRAS mutation.

Figure 9.3: the mechanism of action of Cetuximab

Avastin (bevacizumab): it targets vascular endothelial growth factors (VEGF), which is needed for angiogenesis;a 

process that helps tumor cells to form new blood vessels to get the nutrients they need, and grow more. It's also 

delivered intravenously once every 2 or 3 weeks.

Figure 9.4: The role of Avastin

Vectibix (panitumumab): like Erbitux, Vectibix is used to target EGFR but here it's used in patients that have 

KRAS mutation. It’s given intravenously once every 2 weeks. 

Radiation:

This technique is used sometimes in association with chemotherapy. It's used to target internal cancer such as 

the colon cancer in which doctors can't be sure 100% that cancer has been removed at all, so by using high 

energy x-rays or particles that damage cancer cells. Radiation therapy is advised to be done before surgery, in 

order to decrease the size of tumor and not to let it return back again.

Radiation treatments are given 5 days a week for several weeks, but the length of time may be shorter if it is 

given before surgery.

The side effects of radiation therapy are:

·         Skin irritation at the site where radiation beams were aimed

·         Nausea

·         Rectal irritation, which can cause diarrhea, painful bowel movements, or blood in the stool

·         Bowel incontinence (stool leakage)

·         Bladder irritation, which can cause problems like feeling like you have to go often (called frequency), burning or pain while urinating, or blood in the urine

·         Fatigue/tiredness

·         Sexual problems (impotence in men and vaginal irritation in women)

X. What is the prognosis of this disease?

Prognosis is a prediction of the chance of recovery or survival from a disease. Most physicians give a prognosis 

based on statistics of how a disease acts in studies on the general population. For colorectal cancer, prognosis 

varies depending on the stage of the cancer. The prognosis percentage in each stage is as follows :

Stage of colorectal cancer	Relative 5-years survival rate
Stage 0	95%
Stage 1	74%
Stage 2	37-67%
Stage 3	28-34%
Stage 4	6%

Table 10.1: The relative 5-years survival rate depending on the stage of the colorectal cancer

To improve prognosis, patient should follow up a schedule for monitoring after treating the colorectal cancer. 

General guidelines include:

·         Physical examination: in general cancer can re-occur within 3 years after the surgery. So for the 

first 2 years, the patient should visit his doctor every 3-6 months for just physical examination and every 6 

months after 5 years of surgery .

·         Colonoscopy: it's required after 1 year of surgery, and if results are good, then it should be repeated 

after 3 years and then after 5 years. If results were not good, the patient should make colonoscopy more.

·         Flexible sigmoidoscopy: it should be done every 6 months after surgery for patients with stage 2 or 

3 colorectal cancer and didn't receive radiation therapy.

·         Carcinoembryonic Antigen levels: CEA should be measured every 3 to 6 months after surgery for 2 years. However for patients with stage 2 or 3 colorectal cancer, CEA should be measured every 6 months up to 5 years. If CEA is high, then may be cancer has recurred or spread to other organs .

·         Imaging test: CT scan is recommended for the first 3 years to determine if cancer has spread to lung, ovaries or liver, in patients with high risk for cancer recurrence. Patients diagnosed ate stage 1 or 2 are not asked to do usual CT scan.

·         Other tests: blood test can be done to determine the blood count and liver function test is beneficial to monitor any abnormalities in liver function. In addition, blood occult test can be accomplished to detect any blood drops in the stool.

Conclusion:

colorectal cancer is one of the cancers that can be treated efficiently if detected early, so always check your colon health.