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1.

Getting Diagnosed with Colorectal Cancer

You have recently been diagnosed with colorectal cancer (CRC).

 

The diagnosis of colorectal cancer is based on the examinations that you will have undertaken (colorectaloscopy, clinical, radiological and laboratory investigations).

 

You might have a lot of questions, looking for answers…: What is it? Will I die or survive? Can I survive? What are treatment options? How long will I need treatment?  There is the ‘uncertainty’, that can make you feel emotional and frightened.

 

The diagnosis and treatment approach of colorectal cancer has changed a lot and with today’s modern treatment it is possible to live with CRC. Some even define it as a chronic disease.

 

You will find many medical words in the next chapters. Words that you may not know are defined in the text or in the dictionary. Do ask your oncologist or nurse to explain a word or phrase that you don’t understand or if you need more information.

 

These chapters include information for many patients however keep in mind that you are unique, so talk to your physician to point out what applies to you.

Diagnosing CRC

Our body is made of trillions of cells. These cells are the basic building blocks of all living things...

Read more

How Bad is it?

After someone is diagnosed with colorectal cancer, doctors will ‘rate’ the extent of the cancer. This system is called staging...

Read more

What Now?

Doctors will need to consider many aspects of both the patient and the cancer in order to decide on the best treatment...

Read more

What is CRC?

Colorectal Cancer, also known as bowel cancer, develops in the colorectal or the rectum (the large bowel or the large intestine).

 

The colorectal and rectum are part of the gastrointestinal (GI) or digestive system.  Whilst the first part of the digestive system processes food for energy, the last part (colorectal and rectum) absorbs fluid to form solid waste (stool) that leaves the body.

 

The colorectal is about 1.5 meters long and has four sections:

 

  • Ascending colorectal that starts with a small pouch (caecum) where the small bowel attaches to the colorectal and extends upward (for that reason it is called ascending) on the right side of the abdomen

  • Transverse colorectal goes across the body from the right to the left side in the upper abdomen

  • Descending colorectal continues downward on the left side

  • Sigmoid colorectal is the last section so named because of its “S” (sigmoid) shape

The wall of the colorectal and rectum are made up of several layers.

 

The majority of colorectal cancers begin as a small growth on the bowel wall – a colorectal polyp or adenoma. These, often mushroom-shaped, growths are usually benign but some develop into cancer over time. If left untreated they can grow into the muscle layer underneath and then through the bowel wall.

Development of colorectal cancer

Colorectal cancer is not a rare disease

With almost 1.4 million new cases of colorectal cancer each year worldwide it presents 9.7% of the total global cancer cases.

Colorectal cancer is the third most common cancer in men and the second in women worldwide with almost 55% of the cases occurring in more developed regions.

In Europe it is the second most common cancer with more than 470,000 European citizens being diagnosed every year with the disease.

Colorectal cancer kills 228,000 Europeans every year with the highest estimated mortality rates in both sexes being in Central and Eastern Europe.

This disease is preventable in many cases and highly treatable if diagnosed in its early stages.

Colorectal cancer is a disease that mainly affects the over 50’s and there are more than 175 million citizens in Europe between the 50 to 69 years old.

Colorectal cancer survival rates

Since the mid-1980s the colorectal cancer death rate has been dropping due in part to increased awareness and screening. By finding more polyps and cancer in the earlier (local and regional) stages, it is easier to treat the disease. Improved treatment options have also contributed to a rise in survival rates:
 

  • The five-year survival rate for colorectal cancer found at the local stage is 90%

  • The five-year survival rate for colorectal cancer found at the regional stage is 70%

  • The five-year survival rate for colorectal cancer found at the distant stage today is up to 20%

 

The main risk factors of colorectal cancer

 

Today, it is not entirely clear why colorectal cancer occurs. A number of risk factors have been identified. A risk factor increases the risk of cancer occurring, but is neither necessary nor sufficient to cause cancer. A risk factor is not a cause in itself.

Some people with these risk factors will never develop colorectal cancer and some people without any of these risk factors may nonetheless develop colorectal cancer.

  • Ageing: the risk of colorectal cancer increases as a person gets older

  • Lifestyle-related risk factors:

    • Diet: diet is the most important environmental risk factor for colorectal cancer. A diet that is high in red meat (beef, lamb, or pork) and processed meat (hot dogs and some luncheon meats), high in fat and/or low in fiber can increase the risk of developing colorectal cancer

    • High consumption of alcohol is also a risk factor for colorectal cancer

    • Obesity: overweight increases the risk of developing colorectal cancer

    • Sedentary lifestyle: individuals who are not very physically active are at a higher risk of developing colorectal cancer. This is independent of the person’s weight

    • Smoking: smoking increases the risk of developing large colorectal polyps, which are well-known precancerous lesions       

  • Previous history of colorectal polyps: growths in the bowel, called polyps or adenomas, are not cancerous. However, these growths can develop into cancer over a long period of time

  • Inflammatory bowel disease such as Crohn’s disease or ulcerative colitis: these are conditions in which the large intestine is inflamed over a long period of time. After many years this may cause dysplasia which is a disordered organisation of the cells of the inner lining of the intestine. Dysplasia can evolve into cancer over time. The risk increases with the duration of the inflammatory bowel disease and with the severity and extent of the inflammation. Colorectal cancer in patients with Crohn’s disease or ulcerative colitis accounts for approximately two thirds of all sporadic colorectal cancers

  • Family history: approximately 20 % of colorectal cancers occur in a familial context. If a first-degree relative has colorectal cancer the risk for developing colorectal cancer doubles. This can be due to inherited genes or to shared environmental factors. Investigation into a possible family history of colorectal cancer is important. In selected cases screening at a young age and/or genetic counselling should be considered.

  • Previous history of colorectal cancer: even if the tumour has been completely removed during previous treatment there is an increased risk of developing a new tumour in another part of the large intestine or in the rectum

Colorectal cancer most commonly occurs as a sporadic disease meaning that it is not related to inherited genes that convey a risk for this type of cancer.

Approximately 20% of colorectal cancers occur in a familial context. Less than half of these arise as a result of a known hereditary condition. In the remainder of the familial cases the cause is unknown. The familial occurrence may not only be due to shared inherited genes but also to shared factors in the environment that increase the risk.

Family history (Hereditary colorectal cancer)

A small percent of individuals (approximately 20 %) with colorectal cancer have a hereditary form inherited from one of their parents. In those families the chance of developing colorectal cancer is significantly higher than in the average person. These hereditary cancers typically occur at an earlier age than sporadic (non-inherited) cases of colorectal cancer.

Hereditary cancer is caused by some DNA mutations (changes) that can be passed on in families and are found in all of a person's cells.

Many of these DNA changes and their effects on the growth of cells are now known.

  • Familial Adenomatous Polyposis (FAP)
     

Individuals with this condition have a mutation or a loss of the FAP gene, which causes hundreds or thousands of polyps to grow in the large intestine at a young age. Cancer may develop in one or more of these polyps before the age of 40 and sometimes as early as age 20.

  • Lynch syndrome, also called Hereditary Non-polyposis Colorectal Cancer (HNPCC)
     

Individuals with this condition have certain gene mutations that cause failure of the DNA repair mechanisms, like MLH1, MSH2, MLH3, MSH6, PMS1, and PMS2. These changes can allow DNA errors to go unfixed and cause colorectal cancer.

If you have an inherited syndrome you may be referred to a genetic counsellor. A genetic counsellor can talk with you about the possibilities that your children/siblings/parents have the same gene abnormalities and may recommend that they are screened.

What is cancer exactly?

 

Normal cells

Our body is made of trillions of cells. These cells are the basic building blocks of all living things.

Each cell has a special characteristic and it grows and divides in a controlled manner in order for the organism to function properly. Normal cells have the ability to reproduce correctly, stop reproducing when necessary, remain in a specific location, become specialised for specific functions and self-destruct when necessary.

You can compare a cell with driving a car; you need a key and once you turn that key several mechanisms are activated and finally the engine will start. By using the pedals (gas or brake) you will either drive (grow) or stop (no more reproduction).

Cells communicate with other cells through proteins (chemical signals).

These signals help normal cells to know when to reproduce and when to stop reproducing (remember the gas or brake pedal in our car). Cell signals are usually transmitted into a cell by specific proteins.

Cells provide structure for the body, take in nutrients from food, convert those nutrients into energy and carry out specialised functions. Cells also contain the body’s hereditary material and can make copies of themselves.

Cells have many parts each with a different function. The cell’s command centre, let’s say the engine, is called the nucleus. This control centre will send directions to the cell to grow, mature, divide or die.

The nucleus contains chromosomes that houses DNA (deoxyribonucleic acid) the cell’s hereditary material. The structure of DNA is described as a ‘double helix’, a spiral staircase. Within DNA are coded instructions for building new cells and controlling how cells behave and these are called genes.

Genes are instruction manuals in our body. They are molecules in our body that explain the information hidden in our DNA and supervises our bodies to grow in line with that information.

Let’s compare this to a library: you have a bookshelf (nucleus), containing 46 books (chromosomes).

In these books sentences (genes) are written with letters (DNA).  Normally these books are tightly

packed on the bookshelf. Imagine that by accident (sporadic) the book is damaged (pages are torn,

letters are missing, …).

Cancer is a disease of cells - This is what happens when you get cancer.

Cancer develops when genes responsible for regulating cell growth and differentiation are altered. Such gene alterations (changes in the books or inside a book) include for example:

  • a change in the DNA sequence of a gene (called a mutation)

  • a change in the number or breakage of chromosomes (called chromosomal instability)

  • a change in the length of specific repeat sequences in the DNA (called micro satellite instability).
     

It actually takes a number of mutations before a cell becomes cancerous.

Some types of mutation that are linked to cancer are present in all cells. Other mutations are present only in cancer cells. Mutations cause cancer cells to not behave like normal cells and sometimes to look different from normal cells:

  • Cancer cells grow more quickly and live longer than normal cells, they don’t die, they form a mass(tumor).

  • They can grow into surrounding tissue and even travel to another part of the body and start growing there(metastases)

  • Cancer cells send out chemical signals that promote the formation of new blood vessels(angiogenesis)

 

During previous investigations, your physician will have collected small samples of tissues cells (biopsy) and sent these for testing to a pathologist.

The pathologist will have examined your tissue with a technique called molecular profiling. This technique  reveals a subset of specific genes  (specific pages of the books) expressed in a cell or a tissue. This technique is increasingly being used to determine the profile of genes and gene alterations expressed in cancers.

The molecular profile of your cancer together with the clinical information (e.g. stage of your tumour)  helps doctors to identify the possibility of underlying genetic predisposition of the cancer, its potential to metastasize, its responsiveness to treatment and the likelihood of recurrence.

Mutation for colorectal cancer

A number of gene alternations have been described:

  • RAS mutations (KRAS, BRAF and NRAS mutation)

  • Mismatch repair (MMR) and Micro satellite instability (MSI)

 

RAS mutations (KRAS, NRAS) - BRAF

RAS is a family of related proteins that are involved in transmitting signals within cells. Mutation in RAS can lead to the production of permanently activated RAS proteins with overactive signaling inside the cell with ultimately activation of genes involved in cell growth, differentiation and survival. 

Mutations of KRAS are most common in colorectal cancers with a frequency of 30–50%, BRAF are 10–20% and NRAS mutations are found in about 3–5%.

The presence or absence of these mutations helps to determine the optimal treatment and whether specific drugs might be effective or not. (see section on treatment)

MMR and MSI

The biologic function of mismatch repair (MMR) genes is to repair  transcription mistakes that sometimes occur in the DNA when cells divide. 

Remember our book, try to envision typing a lengthy but important document on a computer with a broken spell‐check function; for most of us the longer we type the higher the number of spelling errors. In many ways the MMR genes serve as a “spell‐check” protein for DNA. The proteins produced by the MMR genes analyse the DNA looking for any “spelling” errors in the genetic  sequence.  If an error is detected the proteins can remove the faulty segment of DNA and replace it with the correct sequence.

In some colorectal cancers, MMR mutations cause one or more MMR proteins to be absent. DNA errors are not corrected and the number of gene mutations (typos) increases. Doctors call this dMMR (defective mismatch repair).

The DNA errors caused by defective mismatch repair often occur in microsatellites. These are tiny little parts of the DNA code that due to dMMR cause the micro satellites to be shorter or longer. This is called MSI (micro satellite instability).

Testing for loss of MMR proteins or MSI is needed for all people with colorectal or rectal cancer as this may affect your treatment plan.

 

How bad is it?

After being diagnosed with colorectal cancer doctors will ‘rate’ the extent of the cancer. This system is called staging.

The stage of a cancer describes how much cancer is present in the body and where it is located. It helps determine how serious the cancer is and which treatments are best. Doctors also use a cancer's stage when talking about survival statistics.

Scoring and staging of colorectal cancer

The clinical staging  of colorectal cancer is based on the results of radiological, biochemical and endoscopic tests and is done before surgery or treatment.

It guides the decision to optimal treatment of colorectal cancer with or without surgery.

When trying to determine the extent of the cancer in the body clinicians first look at the primary (main) tumour for its size, location and whether it has grown into nearby areas.

They might also look at nearby lymph nodes to find out if cancer has spread into them. Lymph nodes are small, bean-shaped collections of immune cells. Many types of cancer often spread to nearby lymph nodes before they reach other parts of the body.

Doctors might also look at other parts of the body to see if the cancer has spread there. When cancer spreads to parts of the body far from the primary tumour it is known as metastasis.

The staging system most often used for colorectal cancer is the American Joint Committee on Cancer (AJCC) TNM system,  where the three letters T, N and M describe the areas of cancer growth.

A number after T,N and M (0-4) will describe size and/or amount of spread into nearby structures, nodes or organs. The higher the number, the larger the tumour and/or the more it has grown into or spread to nearby tissues or organs.

Once the values for T, N, and M have been determined, they are combined to assign an overall stage.

For most cancers, the stage is a Roman numeral from I to IV, where stage IV (4) is the highest.

As a rule, the lower the number, the less the cancer has spread. A higher number such as stage IV means cancer has spread more. And within a stage an earlier letter means a lower stage. So the stage determines the prognosis: the lower the stage the better the prognosis.

The stage is fundamental in order to make the right decision about the treatment.

Pathology staging

During surgery the primary tumour and its locoregional lymph nodes are removed.

After examination of this resection specimen under the microscope the pathologist will determine the pathological staging with an exact (final) interpretation of the depth of invasion into the bowel wall and the number of lymph nodes involved with the tumour.

 

To summarise

The prognosis of colorectal cancer is clearly related to:

  • The staging features of the TNM classification including the degree of penetration of the tumour through the bowel wall

  • The presence, or absence, of nodal involvement

  • The presence, or absence, of metastasis

 

The system in the link below is the most recent AJCC system effective January 2018.

Click here to read more about the AJCC system.

Cancer staging can be complex, so ask your doctor to explain it to you in a way you understand.

Are there words that you find difficult to understand? Click here to see the dictionary of words we have chosen throughout the site explained.

 

What Now?

What is the optimal treatment?

Doctors will need to consider many aspects of both the patient and the cancer in order to decide on the best treatment.

Planning of treatment involves a multidisciplinary team of medical professionals. This usually implies a meeting of different specialists, called multidisciplinary opinion or tumour board review. In this meeting the planning of treatment will be discussed according to the relevant information mentioned before.

The treatment will usually combine therapies that:

  • Act on the cancer locally, such as surgery or radiotherapy

  • Act on the cancer cells systemically (all over the body) such as chemotherapy and biologic targeted therapy

 

All treatments have their benefits, their risks and their contraindications. It is recommended that you ask your doctors about the expected benefits and risks of every treatment in order to be informed about the consequences of the treatment. For some patients, several possibilities are available and the choice should be discussed according to the balance between benefits and risks.