Colorectal cancer

Factsheet

Definition of colorectal cancer

  • Cancer that develops in the large intestine.

Diagnosis

  • Colorectal cancer causes complaints more often when it is advanced. Common symptoms are change in bowel habits, abdominal discomfort, fatigue, weight loss. Blood in stools could be a sign of alert. It could be visible to the naked eye or through a laboratory analysis of stools. 
  • Endoscopy is an examination in which a lighted tube is inserted through the anus into the intestine. It allows seeing the inside of the intestine. When a tumour is found within 15 cm from the anus it is considered rectal tumour, further away it is considered colon tumour.
  • Special radiological tests also help to visualize the localisation and size of the tumour.
  • Blood analysis looking for carcinoembryogenic antigen (CEA), a tumour marker, might be useful in selected situations, but diagnosis should not be relied solely on it.
  • The confirmation of diagnosis is only given by laboratory analysis of the tumour and tissues affected (histopathology).

Treatment according to the extension of the disease

Treatment of malignant polyps

  • Polyps found to be cancerous should be removed from the colon. Depending on the degree of the invasion of malignant cells in the polyp a wider surgical procedure could be recommended.

Treatment according to disease stage

Note: Sometimes after initial treatment and analysis of the tumour removed it could be determined that the cancer is more advanced so that the treatment protocol has to be adapted.

  • In stage 0 the cancer is confined to the most superficial layer of the bowel wall of the mucosa. The tumour should be removed surgically.
  • Stage I involves one layer deeper, the submucosa, and it even reaches the muscle of the colon or rectum. The tumour should be surgically removed as well as local lymph nodes.
  • Stage II involves the muscle of the intestine and invades surrounding organs. The treatment consists of surgical removal of all affected tissues and for some patients additional chemotherapy in case of colon cancer and radiotherapy or radiotherapy combined with chemotherapy for rectal cancer is necessary.
  • Stage III involves structures adjacent to the colon but also regional lymph nodes. The treatment consists of surgical removal of the tumours and other affected tissues and adjuvant therapy i.e. chemotherapy for colon cancer and radiotherapy or chemotherapy plus radiotherapy for rectal cancer.
  • Stage IV involves distant organs, such as liver and lungs. Chemotherapy and biological targeted therapy are treatment options. Chemotherapy helps reducing the size of the metastatic tumours to make them, if possible, operable.

Follow-up

  • There is no follow-up protocol generally accepted. Your doctor will schedule visits after the treatment completed with purpose of monitoring side effects of the treatment, possible recurrence of the disease and to provide you with support to be back to your normal life. The follow-up may last up to 5 years. 
PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of disease. This Guide for Patients in particular has been produced in collaboration with the European Society for Medical Oncology (ESMO) and is disseminated with its permission. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the lead author of the clinical practice guidelines for professionals. It has also been reviewed by patients’ representatives from ESMO’s Cancer Patient Working Group.

Introduction

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

Definition of colorectal cancer

Colorectal cancer is a cancer that develops in the large intestine.

Colon cancer refers to cancer that develops in the colon, the longest part of the large intestine. Rectal cancer develops in the rectum, the final straight part of the large intestine that ends in the anus.

The anus is the opening of the rectum to the exterior. Stool is evacuated through the anus. Cancer may also develop in the anus, but anal cancer is a distinct disease. Anal cancer is not included in this guide.

Anatomy of the digestive system. The consecutive parts of the gastro-intestinal system are the esophagus, stomach, small intestine, large intestine (consisting of the colon and rectum) and the anus. Also shown is the liver.

Frequency

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

Is colorectal cancer frequent?

Colorectal cancer is the most common cancer in Europe and the third most common cancer worldwide. In 2012, approximately 447,000 patients were diagnosed with colorectal cancer in Europe. This accounts for approximately 13% of all cancers in this region.

The majority of colorectal cancers are located in the colon; these are called colon cancer and account for 9% of all cancers in Europe. Approximately one third of colorectal cancers are located only in the rectum, these are called rectal cancer.

Colorectal cancer is more frequent in men than in women. In Europe, around one in every 20 men and around one in every 35 women will develop colorectal cancer at some point in their lifetime. In other words, every year, in Europe, around 35 out of 100,000 men and around 25 out of 100,000 women are diagnosed with colorectal cancer. Overall, the frequency of colorectal cancer is higher in more industrialized and urbanized regions.

Most patients with colorectal cancer are more than 60 years old at the time of the diagnosis, and colorectal cancer below the age of 40 years is rare.

Causes

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

What causes 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.

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.

The main risk factors of colorectal cancer are:

  • Aging: 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.
    • Diabetes mellitus type 2 increases the risk of developing a tumour in the large intestine. This is independent of whether the person is overweight or not.
    • 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. Polyps are therefore recognized as well-determined pre-cancerous lesions. When polyps are found in the large intestine, for example during a screening investigation, they should be removed to prevent them from turning into cancer.
     
  • 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.
     
  • Previous history of other types of cancer: a previous history of other tumours, like lymphoma, testicular cancer or endometrial cancer enhances the risk of developing colorectal cancer.
     
  • 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, a disordered organization 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.

Known hereditary syndromes that predisposes one to colorectal cancer are:

  • 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. To prevent this from occurring, the large intestine should be surgically removed. A variant is the AFAP syndrome: Attenuated FAP syndrome in which polyps are less frequent and occur at a later age, compared to FAP syndrome.
     
  • 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. A consequence hereof is that a benign colorectal tumour may develop into cancer at a faster pace (on average 2 to 3 years) than in individuals who do not have Lynch syndrome. When colorectal cancer occurs in Lynch syndrome, the average age at diagnosis is 45 years. Lynch syndrome also carries an increased risk for certain other types of cancer such as endometrial cancer or ovarian cancer.

Other, less frequent, hereditary syndromes include Turcot syndrome, Peutz-Jeghers syndrome and MYH-associated polyposis. Individuals who have an Ashkenazi Jewish background are at a higher risk of developing colorectal cancer because of certain inherited genetic mutations in this population group.

Some factors may have a protective effect against the development of colorectal cancer:

  • A diet high in vegetables, fruit, and whole grains decrease the risk of colorectal cancer.
     
  • An increase in physical activity may help to reduce this risk of colorectal cancer.
     
  • Long-term intake of anti-inflammatory drugs such as aspirin has been suggested as a way of reducing the recurrence of non-hereditary colorectal polyps. Aspirin has been shown to reduce the risk of colorectal cancer in people with Lynch syndrome. It has also been suggested to support regression of colorectal polyps in FAP patients but, more research is necessary to obtain definitive evidence.
     
  • Intake of female hormones by postmenopausal women has been suggested as a way of reducing the risk of colorectal cancer. However, more research is necessary to obtain definitive evidence.

Diagnosis

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

How is colorectal cancer diagnosed?

The suspicion of colorectal cancer may arise in various circumstances, but most commonly when a patient presents certain complaints or symptoms. Colorectal cancer may also be detected as a result of a screening examination. Many countries offer a systematic screening program to individuals over 50 years old to detect colorectal polyps and to detect colorectal cancer at an early stage. The screening procedure is explained in the next chapter.

Symptoms and signs of colorectal cancer

Symptoms
The principal symptoms of an early colorectal tumour are often vague. Moreover, these symptoms commonly occur in the context of other, non-malignant medical conditions and are therefore not specific for colorectal cancer. In a very early phase, most colorectal cancers do not cause any complaints or symptoms at all.

Signs
The presence of blood in stools can be a sign of colorectal cancer or of a polyp. Blood in the stool can be red, or black when the blood is digested. Dark blood in this context is called melena and often results from lesions bleeding at a larger distance from the anus. The blood loss can sometimes not be visible with the naked eye (microscopic). Blood loss may lead to iron-deficiency and/or anaemia (low red blood cell count and low hemoglobin) and lead to symptoms of fatigue, shortness of breath and pale skin.

Diagnosis

A combination of the following complaints, particularly if persistent over a longer period of time, should raise the suspicion of colorectal cancer and should warrant further investigation:

  • a change in bowel habits
  • general abdominal discomfort
  • unexplained weight loss
  • prolonged fatigue

The diagnosis of colorectal cancer is based on the examinations detailed below. Of note, in women, it is important to rule out presence of synchronous breast, ovarian and endometrial cancers.

  1. Clinical examination

This includes a physical examination of the abdomen and a rectal examination. By palpating the abdomen the doctor determines whether the tumour has caused the liver to enlarge, and whether it has caused excess fluid in the abdomen, called ascites. During a rectal examination, the doctor will use the finger of a gloved hand to examine the interior of the anus and the rectum in order to detect abnormal swellings or traces of blood.

  1. Endoscopy

During endoscopy of the large intestine, a fine lighted tube with a camera is inserted through the anus into the large intestine. This allows the doctor to inspect the interior of the bowel for abnormal areas or growths in the inner lining of the intestine. Insertion of fine instruments through the endoscope also allows the doctor to perform a biopsy of an abnormal area, or - if a polyp is found - to remove the entire polyp. This tissue is sent to the laboratory for histopathological examination (see below).

Endoscopy can be performed in different areas, by inserting the relevant instrument at varying distances into the colorectal area. A rectoscope is a short, rigid instrument that is inserted into the rectum only (the procedure is called rectoscopy). A sigmoidoscope is a somewhat longer flexible instrument that is inserted in the lowest part of the large intestine, above the rectum (the procedure is called sigmoidoscopy). A colonoscope is a long and flexible instrument that can be passed through the entire large intestine (the procedure is called colonoscopy).

Tumours found within 15 cm of the anus are classified as rectal tumours, whereas any tumour further away from the anus is called a colonic tumour.

When a rectal tumour is found during rectoscopy, a complete colonoscopy is also required, either preoperatively or postoperatively.

  1. Radiological investigation.
  • CT colonography. This examination involves a CT scan of the abdomen, after which a computer produces 3-dimensional images from the interior wall of the large intestine. This procedure is also called a virtual colonoscopy. It is not a routine procedure but may be helpful when colonoscopy is difficult, for example in obstructive tumours. It may also be helpful for surgeons to accurately locate the tumour before an operation.
  • Double contrast barium enema. During this examination, barium sulphate (a chalky liquid commonly used in radiological examinations) and air are introduced into the colon via the anus. Both barium and air will be visible on X-ray film and this will visualize an outline of the interior wall of the colon and rectum. This examination is used only occasionally, typically when the right-sided part of the colon is difficult to reach with the colonoscope, but today it is usually replaced by a CT colonography.
  • For the colonoscopy and virtual colonoscopy adequate preparation of the bowel is needed.
  1. Laboratory investigations
  • Routine blood tests are performed and include complete blood count, liver function and kidney function tests.
  • Tumour markers are factors that are produced by tumours and that can be measured using a blood test. Together with results from the routine investigations, tumour markers may help to diagnose a recurrence of cancer after initial treatment at an early stage or to follow the evolution of cancer during or after therapy. A great deal of research effort is being spent in search of tumour markers for colorectal cancer. Except for carcinoembryonic antigen (CEA, see below), which may be useful in selected situations, so far no such test is available.
  • Carcinoembryonic antigen (CEA). Colorectal cancer cells may produce the factor CEA and this can be measured using a blood test. However, not all colorectal cancers produce CEA, and CEA may also be elevated in other cancers and in non-malignant conditions. Therefore, in colorectal cancer, CEA is not useful as a screening test. In patients with colorectal cancer who have elevated CEA at diagnosis, however, it may be useful for evaluation of prognosis and for follow-up after treatment.
  1. Histopathological examination.

This is the laboratory investigation of the tumour tissue. It is performed using a microscope on the biopsy or the polyp obtained via endoscopy. The histopathological information will confirm the diagnosis of colorectal cancer and reveals specific characteristics of the tumour.

If surgery is done, a histopathological examination is performed not only on the tumour tissue itself, but also on lymph nodes that are routinely removed, and on organs that have been invaded by tumour and resected during surgery. It may also be necessary to perform a histopathological examination on metastases. Histopathology is part of a diagnostic process called staging. Staging means that the doctor defines the extent to which the colorectal tumour has invaded other organs or has caused metastases. Staging allows the doctors to direct the optimal treatment.

The chapter ‘What is important to know to define the optimal treatment’ explains how histopathological information is used to direct treatment.

 

Screening for colorectal cancer

Many countries offer a systematic screening program to individuals over 50 years of age to detect colorectal polyps and to detect colorectal cancer at an early stage. The reasons for this are firstly, that early colorectal cancer often produces vague or no symptoms, secondly, that polyps are well determined precancerous lesions, and third, that aging is an important risk factor.

The screening program usually includes a Faecal Occult Blood Test (FOBT), and a colonoscopy for confirmation. The FOBT is used by doctors to examine the patient’s stool for traces of blood: a colorectal tumour may shed small amounts of blood that may not be visible to the naked eye.
During a colonoscopy, a fine lighted tube with a camera is inserted through the anus into the large intestine: this allows the doctor to inspect the interior of the colon and rectum, and to detect polyps or other colorectal tumours.

In Europe, screening is recommended to men and women aged 50 or older, with an interval of 1 to 2 years, until the approximate age of 74 years. The screening programme considers a FOBT and a colonoscopy for individuals who have a positive FOBT.

 

 

Treatment

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

What is important to know to get 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.

Relevant information about the patient
  • Gender
  • Age
  • Personal medical history, previous illnesses and treatments
  • Family history of colorectal cancer, colorectal polyps and other forms of cancer
  • General wellbeing and general performance status
  • Specific physical complaints
  • Results of the clinical examination
  • Results of laboratory tests on blood counts, kidney and liver function, CEA
  • Results of endoscopic and radiological investigations

Relevant information about the cancer

When doctors determine the stage of the cancer, they use different methods to assess the extent to which the cancer has spread locally and at a distance in the body. This process is called staging.

The stage is fundamental in order to make the right decision about the treatment. The stage also determines the prognosis of the patient: the lower the stage, the better the prognosis.

Staging is usually performed twice. After clinical and radiological examination the doctors estimate the stage of the cancer. If surgery is performed, staging is influenced by the histopathological examination of the removed tumour, lymph nodes and/or other organs that may have to be surgically removed. This process is called surgical staging. The histopathological examination should include examination of all the resection margins of the surgical specimen, to determine if the tumour has spread beyond the resected tissue. At least 12 lymph nodes should be removed to allow accurate staging. Also, the histopathological examination should verify whether the tumour has invaded blood vessels or nerves.

The TNM staging system is commonly used. The combination size of the tumour and invasion of nearby tissue (T), involvement of lymph nodes (N), and metastasis or spread of the cancer to other organ of the body (M), will classify the cancer as being at one of the stages explained in the table below. The definitions are somewhat technical and refer to the anatomy of the intestine and the abdominal cavity. It is recommended to ask doctors for more detailed explanations.

 

Stage

Definition

Category

Stage 0

Carcinoma in situ: a malignant tumour that is confined to the mucosa, and that does not invade the submucosa

Localized colorectal cancer

Stage I

The tumour invades the submucosa or the muscularis propria

Stage IIA

The tumour invades through the muscularis propria into the subserosa or into neighboring tissues in the intraperitoneal space

Stage IIB

The tumour penetrates the visceral peritoneum and/or directly invades organs or structures in the intraperitoneal space

Stage III

The tumour has produced metastasis in regional lymph nodes. Stage III is divided into 3 different stages depending on the invasion of the local tumour and the number of lymph nodes with metastasesa

  • Stage IIIA: The tumour invades the submucosa or muscularis propria and has spread to 1-3 regional lymph nodes
  • Stage IIIB: The tumour invades the subserosa, visceral peritoneum or neighboring organs, and has spread to 1-3 regional lymph nodes
  • Stage IIIC: The tumour, irrespective of the degree of local invasion, has spread to 4 or more regional lymph nodes

Stage IV

The tumour has spread to distant organs, irrespective of the degree of local invasion and/or spread to regional lymph nodes

Advanced colorectal cancer

a during surgical staging, at least 12 lymph nodes should be removed to accurately determine the number of lymph nodes involved.

  • Radiological investigations

Radiological investigations may help to determine the local spread of the tumour and the presence of metastases. These may include:

  • Computed tomography (CT) of chest and abdomen are routinely performed preoperatively to detect metastatic spread of the tumour.
  • Intra-operative ultrasound of the liver may help in determining the presence of liver metastases and in determining whether they are suitable for resection.
  • Nuclear magnetic resonance imaging (MRI) is useful to accurately visualize the extent of tumour spread, and to detect or confirm the presence of metastases. MRI of the rectum is a routine staging procedure in rectal cancer.
  • Endoscopic ultrasound can be used as an alternative for MRI in early stage rectal cancer to determine the extension of the tumour.
  • Positron emission tomography (PET) is not performed as a routine investigation, but may be useful to visualize metastases. PET can help to determine whether a distant lesion is malignant in nature, particularly if it is used in combination with computed tomography (CT). PET also helps to accurately visualize liver metastases that may be suitable for surgical resection. PET may also be useful to help visualize residual or recurring tumours after radiotherapy and/or surgery.
  • Histopathological examination

During colonoscopy, a biopsy is taken from suspicious areas, and– if possible – polyps are entirely removed. These tissues are examined in the laboratory. This examination is called histopathology. When surgery is indicated, a second histopathological examination involves the examination of the tumour tissue and the lymph nodes after surgical removal. This is very important to confirm the first histopathology results and to provide more information on the cancer.

Results of the histopathological examination should include:

  • Histological type of the lesion
    The histological type refers to the type of cells that compose the lesion. Most of the colorectal cancers are adenocarcinomas or subtypes of adenocarcinomas (mucinous or signet-ring). Other rare types of colorectal cancers include squamous cell carcinomas, adenosquamous carcinomas, undifferentiated carcinomas, and medullary carcinomas.

    Neuroendocrine carcinomas are cancers that develop from neuroendocrine cells of the colon or rectum. These cancers exhibit different behavior, making their treatment different. The information in this guide does not apply to this form of colorectal cancer.

  • Grade
    The grade is determined on the basis of how different the tumour cells look from the cells normally found in the healthy colorectal lining. The abnormal features indicate the rate at which the cells multiply and the degree to which they are invasive.

    In colorectal cancer, four grades are distinguished. In grade 1, the tumour tissue closely resembles normal colorectal tissue, whereas in grade 4, the tumour cells look very abnormal. Grades 2 and 3 are intermediate grades. The grade of colorectal cancer is often referred to more generally, as low grade (grade 1-2) and high grade (grade 3-4). Signet-ring cell carcinomas, small cell carcinomas, and undifferentiated carcinomas are always classified as high grade.

  • Level of invasion in malignant colorectal polyps
    Colorectal cancer usually develops from a benign colorectal polyp. When a colorectal polyp is removed and examined for the presence of invasive carcinoma, the pathologist will specifically look for features that may predict the aggressiveness of the cancer.

    Several systems have been proposed to stage these so-called ‘malignant polyps’ to direct treatment. One of these is the ‘level of invasion’, referring to how far the carcinoma has invaded the structure of the polyp. In pedunculated polyps (polyps attached to the bowel lining by a narrow elongated stalk) four levels of invasion have been defined. In sessile polyps (polyps that do not have a stalk) three levels of invasion have been defined.

    Other histological findings that predict an aggressive outcome are the presence of cancer cells in the excision margins of the resected polyp, invasion of the blood or lymphatic vessels by cancer cells, and a high grade lesion.

  • Molecular profiling

Cancer develops when genes responsible for regulating cell growth and differentiation are altered. Such gene alterations 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) and a change in the length of specific repeat sequences in the DNA (called microsatellite instability).

Molecular profiling is a technique that reveals the entire set of genes 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. By comparing these so-called molecular profiles amongst cancers, and by relating them to clinical information, it helps doctors to understand the origin of the cancer, its potential to metastasize, its responsiveness to treatment, and the likelihood of recurrence.

For colon cancer, a number of gene alternations have been described, such as RAS mutations, BRAF mutation, MLH1 mutation, chromosomal instability and microsatellite instability. The presence or absence of these molecular profiles helps to classify colorectal tumours and helps to determine the optimal treatment. This is particularly true for RAS mutations (either KRAS or NRAS) which will determine whether two specific drugs might be effective or not.

 


What are the treatment options?

Planning of the treatment involves an interdisciplinary 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 therapy

The extent of the treatment will depend on the stage of the cancer, on the characteristics of the tumour and on the risks for the patient.

Below, the general principles of treatment in colorectal cancer are listed first. Colorectal cancer is usually found within a polyp; the treatment of so-called malignant polyps is described separately. This is followed by a description of the treatment plans per stage. Colon cancer and rectal cancer are described separately.

All treatments have their benefits, their risks and their contraindications. It is recommended that patients ask their 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.

 

Principles of treatment

Surgery

Surgery aims to remove the primary tumour. In patients with advanced disease, surgery may also be performed to remove metastatic lesions.

The extent of surgery on the primary tumour will depend on the local spread of the tumour. In a simple excision, the tumour is removed locally from superficial inner layer of the bowel wall. When the cancer develops from a polyp, the entire polyp is removed, a procedure called polypectomy. In a segmental resection, the bowel segment where the tumour is located is surgically removed and the bowel ends are reconnected.

Standardized resections are now considered more appropriate than segmental resections in the treatment of colon cancer. Depending on the location of the tumour, such standardized resection consists of removing either the ascending colon (right hemicolectomy) or the descending colon (left hemicolectomy) or the sigmoid colon (sigmoid resection). Right and left hemicolectomy are sometimes extended to the transverse colon and are then called extended (right or left) hemicolectomy. The corresponding segment of the bowel is removed as well as the regional lymph nodes and any part of the adjacent organs that are invaded by the tumour. It is necessary to remove at least 12 regional lymph nodes to perform accurate staging. The surgeon will also need to take the structure of the blood supply into account and the margins may therefore be wider. When in the case of rectal cancer the entire rectum, along with the mesorectum containing the regional lymph node is removed, the procedure is called total mesorectal excision (TME).

Usually, the healthy ends of the bowel are surgically reconnected during the initial operation (called anastomosis). When a total mesorectal excision is performed for rectal cancer, a colo-anal anastomosis is performed. However, in selected patients, the surgeon needs to create a temporary connection between the small or large bowel and the wall of the abdomen, called an ileostoma or colostoma, respectively (the procedure is called ileostomy and colostomy, respectively, see below). The stoma is usually temporary, but in some patients it may be permanent, especially in patients operated on because of a cancer in the lower part of the rectum.

For rectal cancer, local excision can be performed using a magnifying scope that is inserted via the anus into the rectum. This procedure is called transanal endoscopic microsurgery and requires specific expertise. For colon tumours, simple excision and polypectomy can be performed using a colonoscope.

Surgical resections can be performed by laparotomy, but also by laparoscopy. Laparotomy refers to open surgery, meaning that the surgeon makes a large incision in the abdomen to perform the operation. During laparoscopy, fine lighted tubes and instruments are inserted through 3 or 4 small incisions in the abdomen. After laparoscopy, patients experience a quicker and easier recovery then after laparotomy.

When the cancer has caused obstruction of the bowel, it may be necessary for the surgeon to relieve the obstruction and let the bowel heal by inserting a stent, or by performing a colostomy. A stent is a tube that is placed in the bowel at the level of the tumour to open the natural passage. When a colostomy is performed, the healthy bowel above the level of the tumour is connected directly to the skin of the abdomen and the lower end of the bowel is closed; stool can now leave the body through this new path and is collected in a plastic bag attached to the skin. This new opening is called a stoma. Usually, the stoma is temporary, meaning that - when the tumour is resected and the bowel has had time to heal - a second operation is performed to join the two ends of the bowel together (anastomosis), and to close the stoma. The stoma may be permanent in some patients (e.g. those with very low position of tumour in the rectum).

Chemotherapy

Chemotherapy aims to kill or harm the tumour cells. Chemotherapy is given orally or through a vein, and therefore acts systemically. The mainstay of chemotherapy for colorectal cancer is treatment with drugs called fluoropyrimidines, given either as single therapy (called monotherapy), or in combination with other drugs (called combination therapy).

The fluoropyrimidines that are used are 5-fluorouracil (5-FU), given intravenously, and capecitabine or tegafur-uracil (UFT), given orally. Fluoropyrimidines are usually given in combination with leucovorin (LV), also known as folinic acid, a drug that enhances the efficiency of the fluoropyrimidine. Commonly, 5-FU is given with LV, abbreviated 5-FU/LV.

In combination chemotherapy, fluoropyrimidines are combined with other chemotherapeutic drugs such as oxaliplatin or irinotecan.

Biologic therapy

Biological targeted therapy refers to the therapeutic use of substances that are specifically designed to interfere with the growth of cells.

Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), a growth factor for blood vessels. Colorectal cancer cells produce high amounts of VEGF, which stimulates the formation of new blood vessels in and around the tumour (that feed the tumour). Blocking VEGF using bevacizumab therefore may prevent this from occurring.

Cetuximab and panitumumab are monoclonal antibodies which act against epidermal growth factor receptor (EGFR), a structure on the surface of all normal cells that helps them grow. Colorectal cells carry high amounts of EGFR on their surface, and binding of cetuximab or panitumumab to EGFR interferes with the growth of tumour cells and causes them to die.

Aflibercept is a recombinant fusion protein that binds to circulating VEGF and inhibits activity of different molecules belonging to VEGF family. It inhibits the growth of blood vessels in the tumour.

Regorafenib is an oral targeted therapy, a multi-kinase inhibitor. It targets receptor tyrosine kinases, high affinity cell surface receptors that are key regulators of normal processes in the cell, but also have a critical role in development and progression of tumours.

Radiotherapy

Radiotherapy aims to kill tumour cells through ionizing irradiation. Radiotherapy is used either alone or in combination with chemotherapy (chemoradiotherapy), prior to surgery in selected stages of rectal cancer. Surgery is usually performed 6-8 weeks after termination of chemoradiotherapy.

In rectal cancer, radiotherapy or chemoradiotherapy is recommended to be given preoperatively whenever possible. Postoperative radiotherapy or chemoradiotherapy is reserved for selected patients with rectal cancer who have a high risk of recurrence and who had not received radiotherapy preoperatively.

In experienced centers, brachytherapy or special contact techniques can be used as an alternative to local surgery (with or without adjuvant chemoradiotherapy) for selected forms of rectal cancer.

 

Treatment of malignant polyps

When a carcinoma is found in a colon or rectal polyp, it is known as a malignant polyp. The treatment of this lesion depends on the extent to which the carcinoma has invaded the polyp itself or beyond the polyp into the bowel wall, and whether unfavourable histological features are present (see: Histopathological examination).

Malignant polyps in the colon

If the carcinoma in the polyp shows no invasion or a low/intermediate level of invasion (level 1-3 in pedunculated polyps, level 1-2 in sessile polyps), a polypectomy is sufficient. If a high level of invasion (level 4 in pedunculated polyps, level 2-3 in sessile polyps) or unfavorable histological features are present, a segmental or standardized surgical resection, as described in the previous section (and therefore including lymph nodes), is indicated.

Malignant polyps in the rectum

If the carcinoma in the polyp shows no invasion or a low/intermediate level of invasion (level 1-3 in pedunculated polyps, level 1-2 in sessile polyps), a local excision procedure using the transanal endoscopic microsurgery technique is sufficient.

If the carcinoma in the resected polyp shows a high level of invasion (level 4 in pedunculated polyps, level 2-3 in sessile polyps) or unfavorable histological features, it is recommended to perform a more extensive surgical resection, called total mesorectal excision (TME), in which the entire rectum is removed as well as the regional lymph nodes that are located in the mesorectum. In patients who are not fit for a more extensive surgical intervention, postoperative chemoradiotherapy is recommended.

If the invasive carcinoma is diagnosed on a biopsy of the polyp and if a local treatment is envisaged using the transanal endoscopic microsurgery approach, chemoradiotherapy should be given preoperatively.

In selected patients, doctors may consider to give local radiotherapy (also called brachytherapy) or local contact therapies as an alternative to local surgery either with or without chemoradiotherapy.

 

Treatment plans according to disease stage

 

Treatment plan for Stage 0

At this stage, the cancer is confined to the mucosa and does not invade the submucosa. Since the tumour is confined to the most superficial layer of the bowel wall, the main goal of the treatment is to remove the local tumour by surgery, and additional treatment is not needed.

A clinical stage is attributed to the cancer before surgery based on the clinical and radiological examinations. Actually, the definitive stage is only known after examination of the tumour tissue resected during surgery. Therefore, the treatment plan may be modified after surgery.

The colon or rectal tumour is removed by simple surgical excision. Larger lesions in the colon are more difficult to excise, and in these cases, the bowel segment containing the tumour is removed (called segmental resection), followed by anastomosis. For rectal cancer the doctor will use the transanal endoscopic microsurgery technique.

 

Treatment plan for Stage I

At this stage, the cancer has grown into the submucosa and may have grown into the muscle layer of the bowel. Since the tumour has grown deeper into the bowel wall, the treatment requires a wider surgical resection of bowel tissue, as well as resection of the regional lymph nodes. However, since the tumour is still considered to be local, no further treatment is necessary.

A clinical stage is attributed to the cancer before surgery based on the clinical and radiological examinations. The definitive stage is only known after examination of the tumour tissue resected during surgery. Therefore, the treatment plan may be modified after surgery.

For colon cancer the doctor performs a surgical resection of the bowel, thereby removing the segment of the colon where the cancer is localized, as well as the regional lymph nodes. For rectal cancer the procedure is a total mesorectal excision, during which the entire rectum is removed, as well as well as the regional lymph nodes located in the mesorectum.

 

Treatment plan for Stage II

At this stage the cancer has grown beyond the muscle layer of the bowel and may have invaded the organs surrounding the colon or rectum. The primary treatment consists of surgery, which aims to remove the tumour and the adjacent organs invaded by the tumour. However, for selected patients, additional treatment could be recommended since it decreases the risk that the tumour may come back. For colon cancer this consists of chemotherapy, for rectal cancer this consists of radiotherapy or chemoradiotherapy.

A clinical stage is attributed to the cancer before surgery based on the clinical and radiological examinations. The definitive stage is only known after examination of the tumour tissue resected during surgery. Therefore, the treatment plan may be modified after surgery.

Colon Cancer

The doctor performs a surgical resection of the bowel, thereby removing the segment of the bowel where the cancer is localized, the regional lymph nodes, as well as the adjacent organs that are invaded by the tumour.

For patients presenting high-risk disease, adjuvant chemotherapy is recommended. It is given in addition to primary, initial surgical treatment to prevent that tumour occurs again. In general, patients with stage IIB are considered to be at high risk, as well as patients presenting at least one of the following features: the tumour causes obstruction, the tumour penetrates the visceral peritoneum and/or invades adjacent organs, the surgeon could not remove sufficient (minimum 12) regional lymph nodes to determine lymph node involvement, the tumour is poorly differentiated, or the tumour invades vascular, lymphatic or perineural tissues.

Chemotherapy consists of oxaliplatin and 5FU/LV, given intravenously. This combination is known as FOLFOX. This can also be replaced by the combination of oral capecitabine with intravenous oxaliplatin. Alternatively, a regimen with 5FU/LV by the intravenous route or with capecitabine by mouth can be considered. Chemotherapy is given for 6 months.

In patients older than 70, one should be cautious in advising combination chemotherapy drugs such as with oxaliplatin.

Participation in clinical trials is encouraged so as to help develop the optimal treatment for patients in this category.

Rectal Cancer

In rectal cancer, an MRI of the pelvis is fundamental to determine the local spread of the tumour before initiating treatment. In some selected cases, no pre-operative treatment is required since surgery alone is sufficient. For all other cases, it is recommended to give radiotherapy or chemoradiotherapy before surgery. The recommended regimen depends on the local spread of the tumour.

If the tumour can be entirely removed by total mesorectal excision and the tumour has spread only to organs that can be readily resected, pre-operative radiotherapy or chemoradiotherapy is indicated.

If a total mesorectal excision does not allow removing the tumour completely, and/or if the tumour has spread to organs that cannot be resected, chemoradiotherapy should be given.

The radiotherapy regimen consists of 25 Gray, given in 5 fractions of 5 Gray, over 1 week, followed immediately by surgery. The chemoradiotherapy regimen consists of radiotherapy with 46 - 50.4 Gray given in fractions of 1.8 to 2 Gray, together with chemotherapy with 5FU (intravenously or by mouth), or capecitabine or UFT (by mouth), followed by surgery 6-8 weeks later. In patients older than 80 or patients unfit for chemoradiotherapy, the radiotherapy regimen with 5 fractions of 5 Gray may be considered and surgery should be delayed for 6-8 weeks after the end of the radiotherapy.

During surgery, the doctor performs a total mesorectal excision, thereby removing the entire rectum, the regional lymph nodes located in the mesorectum. The surgeon also removes the adjacent organs that are invaded by the tumour, if that is possible.

 

Treatment plan for Stage III

At this stage, the cancer has metastasized to regional lymph nodes. The primary tumour may be limited to the bowel or may have invaded the adjacent organs. Since the cancer has spread beyond the bowel, the treatment not only consists of surgery to remove all tumour tissue but also of adjuvant therapy since it decreases the risk that the tumour may come back. For colon cancer this consists of chemotherapy, for rectal cancer it consists of radiotherapy or chemoradiotherapy. 

A clinical stage is attributed to the cancer before surgery based on the clinical and radiological examinations. Actually, the definitive stage is only known after examination of the tumour tissue resected during surgery. Therefore, the treatment plan may be modified after surgery.

Colon Cancer

The doctor performs a surgical resection, thereby removing the segment of the bowel where the cancer is localized, the regional lymph nodes, as well as the adjacent organs that are invaded by the tumour.

The standard adjuvant chemotherapy consists of oxaliplatin and 5FU/LV, given intravenously. This combination is known as FOLFOX. A combination of capectabine and oxaliplatin (a combination known as CAPOX) can also be proposed. Oxaliplatin in some patients is contraindicated: in these cases, the standard regimen is therapy with 5FU/LV by the intravenous infusion or capecitabine by mouth. Chemotherapy is given for 6 months.

Rectal Cancer

In rectal cancer, an MRI of the pelvis is fundamental to determine the local spread of the tumour before initiating treatment. Unfortunately, neither MRI nor any other radiological exam can accurately tell if the cancer has spread to regional lymph nodes. In most cases, it is recommended to give radiotherapy or chemoradiotherapy before surgery. The recommended regimen depends on the local spread of the tumour.

If the tumour can be entirely removed by total mesorectal excision and the tumour has spread only to organs that can be readily resected, pre-operative radiotherapy or chemoradiotherapy is indicated.

If a total mesorectal excision does not allow for complete removal of the tumour, and/or if the tumour has spread to organs that cannot be resected, chemoradiotherapy should be given.

The radiotherapy regimen consists of 25 Gray, given in 5 fractions of 5 Gray, over 1 week, followed immediately by surgery. The chemoradiotherapy regimen consists of radiotherapy with 46 - 50.4 Gray given in fractions of 1.8 to 2 Gray, together with chemotherapy with 5FU (intravenously or orally), or capecitabine or UFT (orally), followed by surgery 6-8 weeks later. In patients older than 80 or patients unfit for chemoradiotherapy, the radiotherapy regimen with 5 fractions of 5 Gray may be considered and surgery should be delayed for 6-8 weeks after the end of the radiotherapy.

During surgery, the doctor performs a total mesorectal excision, thereby removing the entire rectum and the regional lymph nodes located in the mesorectum. The surgeon also removes the adjacent organs that are invaded by the tumour, if possible.

 

Treatment plan for metastatic colorectal cancer: Stage IV

At this stage, the tumour has spread significantly and caused metastasis in distant organs such as the liver and lungs. The treatment therefore not only aims to remove the tumour by surgery, but also to target the tumour cells systemically with chemotherapy, or with a combination of chemotherapy and biological targeted therapy.

Metastatic disease should be confirmed by adequate radiological investigations. Usually it is necessary to obtain histopathological confirmation of metastases before chemotherapy is started.

The treatment plan should be individually optimized for each patient. It is determined by a multidisciplinary team and should take several factors into account. Most patients present unresectable metastases. However, careful staging allows doctors to identify metastases that may become suitable for surgical removal when their volume is reduced by chemotherapy. It is therefore critical to determine whether the patient has resectable disease, unresectable disease, or disease that is unresectable but may become amenable to resection after chemotherapy. Furthermore, the patient’s general condition, the patient’s organ function, the presence of possible other illnesses and the patient’s preference also direct the decision-making in designing the optimal individual treatment.

The principles of treatment are discussed below. Chemotherapy and biological targeted therapy are discussed according to whether or not the metastases are resectable. Surgery includes resection of the primary tumour, but may also include operative removal of metastases.

During treatment, follow-up is recommended in order to evaluate the response to chemotherapy. A possible regimen recommends a 2- to 3-month evaluation of history, general condition, side effects of chemotherapy, impact of chemotherapy on quality of life, physical examination, laboratory investigation of the CEA level (if it was initially elevated), and CT of the involved regions.

 

Treatment options
 

The main therapies used at this stage of the disease are briefly introduced in this section. Reading this section will help understanding the next section which describes the best treatment strategy depending on the characteristics of the disease and the general health status of the patient.


Surgery

Surgery on primary tumour
The doctor performs a surgical resection, thereby removing the segment of the bowel where the cancer is localised, the regional lymph nodes, as well as the adjacent organs that are invaded by the tumour.

Resection of metastases
The most frequent location of metastases of colorectal cancer is in the liver. Surgical resection should be considered for solitary or confined liver metastases, since it offers these patients the best chance of long-term survival even if, in about 3 out of 4 patients, liver metastases can come back after resection. Radiofrequency ablation, in combination with systemic treatment, is under investigation as an alternative, or a complement, to surgical resection of liver metastases in cases where this is not possible or complete.

Selected metastases in the lungs can also be surgically removed. This may be useful only if there are no other poor prognostic signs.

In general, resection of metastases may be successful on the condition that the location of the metastasis does not create an operative risk, and on the condition that resection would leave sufficient functional tissue (for example at least 30% of the liver tissue). Hence multiple resections may be performed. Some metastases may become resectable if they are downsized during chemotherapy; such patients should receive specific chemotherapeutic regimens (see above).
 

Chemotherapy and biological targeted therapy

The list of drugs approved in the treatment of stage IV colorectal cancer has grown gradually during the past 10 years. In addition, clinical trials have brought useful information regarding several combination of drugs and their respective efficacy. The main drugs and combinations available are presented below.

Individual chemotherapy drugs

  • 5-fluorouracil (abbreviated 5-FU)
    • 5-FU is always used in combination with leucovorin (abbreviated LV). Leucovorin is reduced folinic acid and increases the efficacy of 5-FU. The combination of the two is abbreviated 5-FU/LV or FOLF.
    • 5-FU is given in the veins and is either administered as a shot in a short period of time (<60 min) or infused slowly over 24 hours. Slow infusions should be preferred as they are better tolerated.
  • Capecitabine (abbreviated CAP)
    • Capecitabine is transformed into 5-FU in the body.
    • Capecitabine is given orally.
  • Oxaliplatin (abbreviated OX)
    • Oxaliplatin is usually given in combination with other drugs in the treatment of colorectal cancer.
    • Oxaliplatin is infused into a vein usually over 2 hours.
  • Irinotecan (abbreviated IRI)
    • Irinotecan is rarely given alone in the treatment of colorectal cancer.
    • Irinotecan is infused into a vein usually over 90 minutes.

Chemotherapy combinations for the treatment of colorectal cancer

  • FOLFOX is the combination of 5-FU, LV and oxaliplatin.
  • FOLFIRI is the combination of 5FU, LV and irinotecan.
  • FOLFOXIRI is the combination of 5-FU, LV, oxaliplatin and irinotecan.
  • CAPOX is the combination of capecitabine and oxaliplatin.

Biological targeted therapies

  • Aflibercept
    • Aflibercept is only given in combination with FOLFIRI in patients who already received oxaliplatin-based therapy.
    • Aflibercept is infused into a vein usually over 60 minutes.
  • Bevacizumab (abbreviated BEV)
    • Bevacizumab can be given together with any of the chemotherapy combinations.
    • Bevacizumab is infused into a vein usually over 30 to 90 minutes.
  • Cetuximab
    • Cetuximab can be given either alone or in combination with chemotherapy.
    • Its use is limited to patients whose tumour does not present a RAS mutation. A RAS mutation is detected after analysis of a tumour sample in the lab.
    • Cetuximab is infused into a vein over 1 to 2 hours.
  • Panitumumab
    • Panitumumab can be given either alone or in combination with chemotherapy.
    • Its use is limited to patients whose tumour does not present a RAS mutation. A RAS mutation is detected after analysis of a tumour sample in the lab.
    • Panitumumab is infused into a vein over 1 hour.
  • Regorafenib
    • Regorafenib is given as a single drug. It can be proposed to patients who already received all other treatment options.
    • Regorafenib is given orally.
       
Radiotherapy

Radiotherapy should be considered (possibly combined with chemotherapy) for patients with metastatic rectal cancer to alleviate symptoms from the primary tumour. Radiotherapy can also be used to relieve symptoms caused by metastases in the bones. Types of radiation therapy that use radiation from an external source (radiotherapy machine) are called external radiotherapy.

Selective internal radiation therapy involves injecting tiny microspheres or radioactive material into arteries that supply the tumour. This radioembolisation could be proposed when patients have metastases in the liver only and received all available chemotherapeutic options. Radioembolisation using Yttrium 90 particles aims to embolize as well as to bring radiation therapy very close to the tumour. A small tube is placed in the main artery going to the liver (hepatic artery), through which microscopic balls are released. These balls reach the tumour through the blood vessels of the liver and contain a radioactive substance called Yttrium 90. They block the supply of blood to the tumour, and at the same time emit radiation that destroys the tumour cells surrounding them. Since the radiation is delivered directly into the blood vessels supplying the tumour, the radiation is more potent than the usual external radiation therapy. The radioactivity of the balls is gone after 2 weeks.

 

Treatment strategy or how to decide what the best treatment is

Decision about the best treatment has become complex as the list of drugs approved in the treatment of metastatic colorectal cancer has become longer. In some cases direct comparison between treatments have been performed and it can guide decisions.

Whenever possible, resection of the tumour(s) by surgery is recommended. Answering the question about the “possibility” of removing the tumour(s) will actually guide the treatment strategy by grouping patients in several groups.

  1. Patients for whom removing metastases is deemed feasible by the multidisciplinary team. These patients have what is called resectable metastastic disease.

For patients who present liver and/or lung metastases that can be operatively removed, the treatment consists of surgical resection of the metastases and combination chemotherapy. Chemotherapy consists of a 6-month regimen of 5-FU/LV with oxaliplatin (FOLFOX). FOLFOX can be given either perioperatively, meaning that it is given for 3 months before and for 3 months after surgery or, after the operation, for 6 months.

  1. Patients for whom removing metastases is deemed not immediately feasible by the multidisciplinary team, but may become feasible if shrinkage of the metastases is obtained. These patients have what is called unresectable disease that may become resectable after chemotherapy.

Selected patients may present liver metastases that initially are unresectable, but that can become resectable when they are downsized by chemotherapy. Such patients are treated with standard combination chemotherapy consisting of 5-FU/LV and irinotecan (FOLFIRI) or 5-FU/LV and oxaliplatin (FOLFOX). The addition of a third chemotherapeutic drug (FOLFOXIRI), or the biologic agents bevacizumab, cetuximab or panitimumab increases the toxicity of the treatment but may be considered in selected patients. Cetuximab and panitumumab seems to provide better results than bevacizumab in this specific situation, but cannot be given to patients whose tumour presents a RAS mutation.

The patient is closely monitored during chemotherapy. Surgery is indicated as soon as the metastases are considered to have become resectable. However, this needs to be delayed allowing at least 4 weeks after the last cycle of cetuximab, and at least 6 week after the last cycle of bevacizumab, before surgery is undertaken. This delay reduces the risk of complications of the surgery.

  1. Patients for whom removing metastases is deemed never feasible by the multidisciplinary team. These patients have what is called disseminated disease technically never or unlikely resectable.

Depending on the general health condition of the patients, a more or less intensive treatment will be proposed. Treatment will rely on chemotherapy and biological targeted therapy.

Doctors are trying to continually improve the treatment for unresectable metastatic disease and the optimal treatment is therefore rapidly evolving. The goal of the treatment and the different options to reach this goal are tailored to the individual patient and may thus vary between patients. In case of symptomatic disease, combination therapy is the preferred choice, and a sequential approach remains a valid option in selected and frail patients.

Several first-line chemotherapeutic regimens can be proposed. If a patient fails to respond to first-line chemotherapy, and the general condition allows, further treatment in the form of second-line chemotherapy should be considered.

Biological targeted therapy should be considered for selected patients. The optimal treatment regimen is tailored to the individual patient and the type of first-line therapy received.

The duration of the treatment can vary between individual patients. Options are either a fixed treatment period of 3 to 6 months, or treatment until doctors document that the disease progresses. After an initial period of combination chemotherapy, maintenance treatment can improve outcome in comparison to treatment break, and restart of combination chemotherapy is recommended if progression occurs. The principle behind a maintenance treatment is to continue using a drug that has been well tolerated. This usually consists of 5-FU or capecitabine, in combination with bevacizumab can be considered. Combination chemotherapy may be discontinued or changed to a less intensive regimen if increasing toxicity occurs, when the disease is controlled, or when metastases have become surgically resectable.

First-line chemotherapy:
Possible regimens are:

  • Therapy with 5-FU/LV given intravenously, or monotherapy with capecitabine given orally.
  • Combination therapy of 5-FU/LV plus oxaliplatin (FOLFOX) or 5-FU/LV plus irinotecan (FOLFIRI), given intravenously. This is the preferred treatment. These regimens are given as 48-hour treatment infusions every two weeks. Both are equally effective but have different side effects.
    An alternative regimen, based on a fluoropyrimidine given orally (namely capecitabine), is the combination of capecitabine plus oxaliplatin (CAPOX) which is given in three weeks regimen. The combination of capecitabine plus irinotecan is less frequently used because of higher toxicity but it seems to be better supported than was previously thought.
  • Combination of 3 drugs (5-FU, oxaliplatin and irinotecan called FOLFOXIRI) has not been extensively studied but suggest that, even though patients experience more side effects, this combination could prolong survival of the patients. In frail patients these agents may be given sequentially rather than as a combination, in order to reduce toxicity.

Second-line chemotherapy
The choice of second-line chemotherapy depends on the regimen given as first-line therapy:

  • If a therapy with 5-FU/LV or capecitabine was administered in first-line, it can be followed by 5-FU/LV plus oxaliplatin (FOLFOX) or 5-FU/LV plus irinotecan (FOLFIRI)
  • If a combination therapy with 5-FU/LV plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX) was administered in first-line, it can be followed by combination therapy with 5-FU/LV plus irinotecan (FOLFIRI)
  • If a combination therapy with 5-FU/LV plus irinotecan (FOLFIRI) was administered in first-line, it can be followed by capecitabine plus oxaliplatin (CAPOX), or 5-FU/LV plus oxaliplatin (FOLFOX)

Biological targeted therapy
Biological targeted therapy should be considered in combination with selected chemotherapy regimens:

  • Bevacizumab should be considered in combination with first-line therapy with 5-FU, capecitabine, 5-FU/LV plus oxaliplatin (FOLFOX) and 5-FU/LV plus irinotecan (FOLFIRI). It can also be considered in combination with second-line 5-FU/LV plus oxaliplatin (FOLFOX) or FOLFIRI therapy. Treatment with bevacizumab can be continued in combination with chemotherapy until disease progression, toxicity or metastases become resectable.
  • Cetuximab can be considered in combination with 5-FU/LV plus irinotecan (FOLFIRI), 5-FU/LV plus oxaliplatin (FOLFOX) and in combination with irinotecan. Panitumumab can be considered in combination with 5-FU/LV plus oxaliplatin (FOLFOX) and with 5-FU/LV plus irinotecan (FOLFIRI).
    Molecular profiling of the tumour helps determining the appropriate choice of combination therapy. Approximately 50% of metastatic colorectal cancers have a genetic mutation in RAS and 5-10% have the BRAF mutation. The combination of cetuximab and FOLFIRI is the recommended treatment in medically fit patients who have a tumour without a RAS mutation. Cetuximab and panitumumab are not active against colorectal tumours with the RAS mutation, and it is unclear whether they are active against tumours with the BRAF mutation. Cetuximab and panitumumab should therefore only be used for tumours that do not have RAS mutations.
    If first- and second-line therapy has failed, cetuximab with irinotecan is the preferred treatment, although cetuximab or panitumumab monotherapy may also be considered.
  • Aflibercept is given in combination with FOLFIRI in patients who already received   oxaliplatin-based therapy.
  • Regorafenib can be considered after all the above options have been used. It is an oral drug given alone.

 

 

What are the possible side effects of the treatment?

 

Surgery

General risks and side effects

Some risks are common for every surgical intervention performed under general anesthesia. These complications are unusual and include deep vein thrombosis, heart or breathing problems, bleeding, infection or reaction to the anesthesia. These are maximally prevented by thorough medical evaluation before surgery.

After a surgical intervention on the colon, it is frequent to experience problems of the intestinal motility. This includes colicky pain, diarrhoea, constipation and nausea. Intestinal obstruction is not an uncommon complication that requires immediate medical care. Vomiting or loss of any bowel movement (no stool, no gas) may be signs of intestinal obstruction and should be immediately reported.

Rapid oral intake of food after surgery is recommended and can be done by using a nasogastric tube in some patients. Nutritional advice should be given by health professionals to minimize intestinal discomfort.

The colon is located in the abdomen and extends throughout the entire abdomen. It is located partly in the intraperitoneal space, and partly in the retro- and infraperitoneal space. The lower two thirds of the rectum are located in the infraperitoneal space. The colorectal bowel therefore lies in close proximity to several organs, lymph nodes and major blood vessels. During the surgical intervention, depending on the extent of tumour spread and the extent of surgical resections needed to obtain the best results, some of these structures may become damaged. Accurate preoperative staging and imaging will help to minimize such risk.

Colostomy

If the cancer has caused obstruction of the bowel, it may be necessary for the surgeon to relieve the obstruction and let the bowel heal by performing a colostomy. In this procedure, the healthy bowel above the level of the tumour is connected directly to the skin of the abdomen, and the lower end of the bowel is closed. Stool can now leave the body through this new path and is collected in a plastic bag attached to the skin. This new opening is called a stoma. The stoma is usually temporary, meaning that - when the tumour is resected and the bowel has had time to heal - a second operation is performed to surgically join the two ends of the bowel together (anastomosis), and to close the stoma. In some patients the stoma may be permanent.

Chemotherapy

Side effects of chemotherapy are frequent, even if progress has been made in controlling them using adequate supportive measures. They will depend on the drug(s) administered, on the doses and on individual factors. If a patient has suffered from other medical problems in the past, some precautions should be taken and/or adaptation of the treatment should be made.

Listed below are the side effects that are known to occur with one or several of the chemotherapy drugs currently used for colorectal cancer. The nature, frequency and severity of the side effects vary for every chemotherapeutic drug combination used.

The most frequent general side effects of chemotherapy are:

  • Decreased blood cell counts, which may lead to anaemia, bleeding, bruising, and infections
  • Fatigue, which may be prolonged
  • Nausea or vomiting
  • Diarrhea
  • Sore mouth or mouth ulcers

Listed below are other more specific side effects that may occur with chemotherapeutics used for colorectal cancer. For some of the side effects it may be necessary to adjust treatment.

  • Treatment with 5-Fluorouracil (5-FU )
    • Severe side effects may occur in individuals who have the inborn condition dihydropyrimidine dehydrogenase (DPD) deficiency: these individuals have low levels of the enzyme dihydropyrimidine dehydrogenase needed by the body to break down this drug
    • Skin sensitivity to sunlight: sun exposure should be avoided for at least one year following completion of treatment
    • Hand and foot syndrome (see below)
  • Treatment with capecitabine:
    • Hand and foot syndrome (also called palmo-plantar erythema): the skin of palms and soles shows reddening and feels sore; the skin may peel. The syndrome is usually mild.
    • Dihydropyrimidine dehydrogenase (DPD) deficiency (see above) may cause severe side effects
    • Capecitabine may interact with other treatments, increasing the risk of side effects of medications. All additional medications, especially folic acid, warfarin and St John’s wort should be disclosed and discussed upfront with the doctor.
  • Treatment with tegafur-uracil (UFT)
    • Skin rashes
    • Skin sensitivity to sunlight
  • Treatment with irinotecan
    • Sweating
    • Watery eyes
    • Increased production of saliva
    • Cramping pain in the abdomen
    • Diarrhea starting the day after treatment
    • Hair loss or hair thinning
  • Treatment with oxaliplatin
    • Numbness of the lips, hands or feet
    • Tingling of hands or feet
    • Sensitivity to cold
    • These specific side effects may be persistent after treatment with oxaliplatin.
Biological targeted therapy

Listed below are the most frequent side effects of the biologics used in colorectal cancer. The combination of biologic therapies with chemotherapy increases the risk of chemotherapy side effects, particularly with cetuximab and panitumumab.

  • Treatment with cetuximab and panitumumab
    • Acneiform rash occurs in most patients
    • Hypomagnesaemia
    • Allergic reactions, slightly more frequent after cetuximab than after panitumumab.
  • Treatment with bevacizumab
    • Hypertension and proteinuria are rather frequent
    • Other rare but severe side effects include arterial thrombosis, mucosal bleeding (mouth, nose, vagina, rectum), gastrointestinal perforation and problems with wound healing.
  • Treatment with aflibercept
    • Headaches
    • Fatigue
    • Liver problems which will be monitored by looking at the level of liver enzymes
    • Hypertension and proteinuria
    • Diarrhoea
    • Decreased blood cell counts, which may lead to anaemia, bleeding, bruising, and infections
    • Bleeding
  • Treatment with regorafenib
    • Hand and foot skin reaction: the skin of palms and soles shows reddening and feels sore, very characteristically localised to areas of pressure or friction on the skin
    • Skin rash
    • Fatigue
    • Liver problems which will be monitored by looking at the level of liver enzymes
    • Hypertension and proteinuria
    • Diarrhoea
    • Bleeding
Radiotherapy

During radiotherapy, side effects may occur in organs that are directly targeted, but also in healthy organs that lie close to the region that needs to be irradiated and that cannot be avoided by the X-rays. Side effects are more intense when radiotherapy is administered together with chemotherapy. Use of radiotherapy in addition to surgery also increases the risk of surgical complications.

Effects of radiation on the lower digestive tract include rectal discomfort, diarrhea, and mucus and blood rectal discharge.

Effects of radiation on the urinary tract are rarer. They include painful urination, an urgent need to urinate, presence of blood in the urine, urinary tract obstruction, and ulceration or necrosis of the bladder lining.

In women, vaginal narrowing is a possible late effect of pelvic radiotherapy.

Strategies to maximally prevent and relieve post-radiation reactions are provided by the radiation oncologist.

 

What happens after treatment?

It is not unusual for cancer patients to experience treatment-related symptoms after the treatment has been completed.

  • Patients may experience anxiety, sleeping difficulty or depression, and may need psychological support.
  • During and after treatment, nutrition may become problematic due to reduced appetite, nausea and general malaise
  • Difficulties in concentrating and memory loss are not uncommon side effects of systemic chemotherapy
Follow-up with doctors

After completion of treatment the doctor will propose a follow-up aiming to:

  • Detect and prevent adverse effects of the treatment
  • Detect possible recurrence as soon as possible and direct appropriate treatment
  • Provide medical information, psychological support and referral to specialized support providers to optimize returning to normal daily life.

The follow-up protocol will include regularly timed office visits and investigations. The protocol depends on the staging of the cancer that was treated, and on the type of treatment given. In general, follow-up visits may include a combination of the following investigations:

  • Questions on general physical health and colorectal cancer-related symptoms
  • Physical examination
  • Laboratory test for carcinoembryonic antigen (CEA) level may help in detecting recurrence
  • Colonoscopy to detect recurrence
  • Radiological investigations to detect progression or recurrence of the primary tumour, or the appearance of metastasis

For patients who have had a colorectal polyp removed, it is necessary to follow-up with history and colonoscopy.

Patients treated for colorectal cancer should be followed up intensively. However, there is not one generally accepted follow-up protocol.

The following is a possible follow-up protocol after treatment for localized colon cancer.

  • History and physical examination every 3 to 6 months for 3 years, and every 6 to 12 months in year 4 and 5.
  • During these follow-up visits, CEA could be determined
  • Colonoscopy at 1 year, and thereafter every 3 to 5 years to detect new cancerous or non-malignant tumours. It is important to note that when colon cancer is diagnosed, the entire colon should be visualised prior to surgery, so as to detect other simultaneous colon tumours.
  • In patients who are considered to be at high risk of recurrence, a CT scan of the chest and abdomen every 6 to 12 months for the first 3 years can be considered
  • Abdominal CT scan can be replaced by contrast enhanced ultrasound
  • In patients presenting specific symptoms that raise concern for recurring disease, appropriate additional laboratory or radiological investigations should be performed

In patients with rectal cancer, the follow-up protocol is similar to the one for colon cancer described above.

Returning to normal life

Returning to a normal daily life may be difficult knowing that the cancer may come back. If any of the known risk factors for colorectal cancer are present, it is advised to eliminate these to a maximal extent.

Follow-up visits with the doctor provide an opportunity for the patient to obtain medical information, psychological support and referral to specialized support providers. Additional expert psychological advice may be valuable, and some patients may find support from patient groups or patient-targeted information media. Dieticians may provide advice on adequate nutrition. Social workers may help in finding resources to ensure successful rehabilitation..

What if the cancer comes back?

If the cancer returns, it is called ‘recurrence’. The extent of the recurrence will direct the treatment decision, and this should be carefully determined for each individual patient.

If after being treated for primary colon cancer, a patient presents local or distant recurring disease, he/she will be treated according to the treatment plan for advanced disease (see ‘what are the treatment options’). Patients with advanced disease failing to respond to first-line treatment with either chemotherapy or chemotherapy with biological targeted therapy will be treated with second-line treatment; if second-line therapy fails, treatment with biological targeted therapy (like regorafenib) is recommended (see ‘what are the treatment options’).

The treatment for patients who present local recurrence of rectal cancer depends on whether the prior treatment included radiotherapy and whether salvage surgery is possible.

If radiotherapy was not given in the primary situation, radiotherapy should be given along with chemotherapy. If the previous treatment included radiotherapy, additional radiotherapy can be considered in the form of either external, intraoperative, or local radiotherapy. However, if radiotherapy was already administered, additional radiotherapy can rarely achieve appropriate control of the cancer growth.

Surgery is indicated 6-10 weeks after radiotherapy. If salvage surgery is not an option, chemotherapy should be considered.

In colon cancer, the lung is the first site of recurrence in approximately 20% of patients and pulmonary resection could be considered if feasible. Lung metastases are more frequent in rectal cancer.

If the cancer returns in the form of metastasis in the liver, surgical resection of the metastases can be considered in selected patients, as described in the paragraph “Treatment plan for advanced colorectal cancer: stage IV”.

 

Synonyms

Colorectal cancer

Colorectal tumour

Colorectal tumor

Cancer of the colon and rectum

Tumour of the colon and rectum

Tumor of the colon and rectum

Large bowel cancer

Large bowel tumour

Large bowel tumor

Cancer of the large bowel

Tumour of the large bowel

Tumor of the large bowel

Colon cancer

Colon tumour

Colon tumor

Cancer of the colon

Tumour of the colon

Tumor of the colon

Rectal cancer

Rectal tumour

Rectal tumor

Cancer of the rectum

Tumour of the rectum

Tumor of the rectum

Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Surgical interventions

Procedures involving instrumental means to investigate or treat a cancer, or to improve the body’s functions or appearance. Generally, a surgical intervention involves an incision. More

Radiotherapy

Medical use of high-energy radiation to kill cancer cells and reduce tumor size. More

Registered drugs

Anti-cancer drugs with market authorization in the USA or in countries of the European Union. More

Cell-based therapies

Administration to patients of their own or someone else’s manipulated human cells. More

Synthetic products (excluding registered drugs)

Synthetically produced substances or modified natural products that are not registered as anti-cancer drugs.

Natural products (excluding registered drugs)

Substances found in nature that usually have a pharmacological or biological activity. More

Diets

Controlled consumption of carefully selected foods and beverages with the intent to influence disease outcome.

Energy based therapies

Use of electromagnetic energy including electricity, magnetic fields, radio waves, microwaves, infrared rays and light to diagnose or treat disease.

Body-based & Manipulative therapies

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.

The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for colorectal cancer is available here.