Colorectal Cancer An overview Dr. Christina Ng MBBS (Melb) FRACP Consultant Medical Oncologist Pantai Medical Center Sunway Medical Center President and Founder of EMPOWERED

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Colorectal CancerAn overviewDr. Christina Ng
MBBS (Melb) FRACPConsultant Medical
OncologistPantai Medical CenterSunway Medical
CenterPresident and Founder of EMPOWERED
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What is cancer?

• Cancer is a group of diseases characterised by
  uncontrolled growth and spread of abnormal cells
• Cancer is caused by both external factors and
  internal factors that may act together or in
  sequence to initiate or promote carcinogenesis
• The development of most cancers requires multiple
  steps that occur over many years

Garcia M et al. Global Cancer Facts Figures
2007. Atlanta, GA American Cancer Society, 2007
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On average, one in three people will be affected
by cancer at some stage in their life
Cancer isnt one disease but many all have
similar features, but each has distinctive
characteristics that vary according to the type
of cancer and its location in the body
In 2000, there were 330,000 new cases of
colorectal cancer and 155,000 deaths in the five
major European countries and the USA
1.2 million cases of breast cancer are diagnosed
across the world each year
Lung cancer is the major cause of cancer death in
the world, accounting for more than 1.2 million
deathseach year
Five European countries listed as France,
Germany, Italy, Spain, UK
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• LETS TALK ABOUT COLORECTAL CANCER

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What is the burden of cancer in Malaysia?2003
Malaysia Ten Most Frequent Cancer Cases
31 Breast 12.9 Cervix Uteri 10.1 Colon
Rectum 4.3 Uterine corpus 4.1 Ovary
4 Leukemia 3.8 Lung 2.9 Stomach 2.7 Othe
r Skin
Colon Rectum 14.2 Lung 13.8 Nasopharynx 8.8
Leukemia 7.1 Prostate Gland 6.4 Stomach 5.1 Lym
phomas 4.3 Other skin 4 Liver 4
Source National Cancer Registry, 2003.
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5-year survival rates for some cancers have
improved significantly
     
1995-2000
Today
Site
1974-1976
1983-1985

• All sites 50 53 64 gt68
• Breast (female) 75 78 88 gt90
• Colon 50 58 63 gt65
• Leukemia 34 41 46 gt48

These improvements are due to a mix of earlier
detection and advances in treatment, and are
continuing to improve today - especially in more
advanced disease due to new biological therapies
Source (Figures to 2000) Surveillance,
Epidemiology, and End Results Program, 1975-2001,
National Cancer Institute, 2004. 2006 Figures
are estimates based on expert opinion in the
literature
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How does cancer develop?

• Cell division in the body
• All the time, somewhere in our bodies there is a
  need for new cells
• Normal cells divide, get old and die
• This process is usually ordered and highly
  controlled

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Cell division in the body
Normal cell division

• Cancer develops when abnormal cells grow out of
  control.
• These cells grow until a lump or tumour is forms.

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How quickly cancer grows?

• Tumor growth rate is time it takes to double in
  size.
• It takes 30 doublings to produce a 1cm tumor.
• Therefore, if the doubling time of a tumor is
  around 75 days, 30 doublings will take more than
  6 years.
• This means a tumor may have been growing for
  several years before detection. During this
  time, symptoms may be vague and not noticed.

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How Colorectal Cancer Develops

• Cancer of colon and rectum (also called
  colorectal cancer) arise from the inner wall of
  the large intestine.
• The first 6 feet of the large intestine makes up
  the large bowel or colon.
• The final 6 inches make up the rectum and the
  anal canal.
• Cancer cells can break away and spread to other
  parts of the body (liver and lung).

National Cancer Institute Website Colorectal
Cancer
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Risk Factors
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Risk Factors

• Risk factors include the following
• Age 50 or older
• A family history of cancer of the colon or rectum
• A history of polyps in the colon
• A history of ulcerative colitis (ulcers in the
  lining of the large intestine)
• Certain hereditary conditions
• Diet

American Cancer Society Website
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How Is Colorectal Cancer Diagnosed?

• Medical history and physical exam including
  digital rectal exam
• Faecal Occult Blood
• Sigmoidoscopy, barium enema, double-contrast
  barium enema, colonoscopy

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Other Tests

• Blood tests including tumour markers
• substances in the blood that can help tell how
  well treatment is working
• not used to find cancer in people who have not
  had cancer and who appear to be healthy rather,
  they are most often used for follow-up of people
  who have already been treated
• Biopsy
• Ultrasound and Chest x-ray
• Computed tomography (CT)
• Magnetic resonance imaging (MRI)
• Positron emission tomography (PET

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Signs Symptoms

• Early stages of colon cancer may not have any
  symptoms.
• As the polyp grows into a tumor, it may bleed or
  obstruct the colon, causing symptoms. These
  symptoms include
• Bleeding from the rectum
• Blood in the stool or toilet after a bowel
  movement
• Changes in bowel habits such as diarrhea or
  constipation
• Feeling of still needing the toilet after having
  emptied the bowel
• Cramping pain in the abdomen
• General abdomen discomfort (frequent gas pains,
  bloating, fullness, or cramps) or vomiting
• Weight loss with no known reason
• Constant tiredness.

1Cancer Facts Figures, 2007. American Cancer
Society
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Stages1

• Stage I The cancer is in the inner layers of the
  colon
• Stage II The cancer has spread through the
  muscle wall of the colon
• Stage III The cancer has spread to the lymph
  nodes
• Stage IV The cancer that has spread to other
  organs (metastasis)

1Dukes, C. The classification of cancer of the
rectum. J Pathol and Bacteriol 193235323-332.
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American Joint Committee on staging for
Colorectal Cancer
TNM Dukes 5-year survival
Stage I A, B1 8595
Stage II B2 6080
Stage III C 3060
Stage IV D lt5
Macdonald JS. CA Cancer J Clin 1999 49202-219
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Is Colorectal Cancer Curable?

• Early detection increase the potential for cure

Most patients who have their cancer diagnosed
early in stage I and 2 (confined to the organ of
origin) or stage 3 (only the first station of
nodes are involved) are cured by existing
modalities and technologies1
1www.radiologymalaysia.org
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Colorectal Cancer Treatment Options

• Surgery
• Radiotherapy
• Systemic Therapies
• Chemotherapy
• Targeted therapy
• Best supportive care

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Chemotherapy

• Compared to most normal cells, cancer cells
  divide much more rapidly
• Chemotherapy enters the bloodstream and damages
  dividing cells
• Therefore cancer cells, which are often in the
  process of dividing, are more at risk of being
  damaged by chemotherapy.
• Chemotherapy kills cells by damaging or
  interrupting the process of cell division.

Reference http//www.cancerresearchuk.org
(Accessed 28/02/2013)
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Chemotherapy

• The main ways chemotherapy is administered 
• An injection into the bloodstream
• A drip (intravenous infusion) into the
  bloodstream 
• By mouth (tablets or capsules)
• The chemotherapy drugs circulate all round the
  body in the bloodstream and can reach cancer
  cells almost anywhere in the body (systemic
  therapy).

Reference http//www.cancerresearchuk.org
(Accessed 28/02/2013)
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Objectives of Chemotherapy

• Chemotherapy can be administered at various
  stages of cancer
• The objectives of chemotherapy can differ
  according to the stage of disease at which it is
  given.
• Chemotherapy given in the setting of earlier
  stages of disease
• Neoadjuvant chemotherapy Chemotherapy given
  before surgery to shrink the cancer so that the
  surgical procedure may not need to be as
  extensive
• Adjuvant chemotherapy Chemotherapy given to
  destroy left-over (microscopic) cancer cells that
  may be present after the tumour is removed by
  surgery.  Adjuvant chemotherapy is given to
  prevent a cancer from coming back. 
• Chemotherapy given in the setting of advanced
  stage of disease
• Palliative chemotherapy Chemotherapy given
  specifically to manage symptoms, to optimise
  quality of life and prolong survival

Reference http//chemocare.com (Accessed
11/03/2013)
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Misconception of cancer treatment1

• Myth Cancer treatment kills bad cells and good
  cells as well
• Truth
• Doctors have several methods of treating cancer
  such as surgery, radiotherapy, chemotherapy and
  targeted therapy.
• Along with the beneficial effects, all medicines
  may cause side-effects (for any disease,
  including cancer).
• Most side effects of cancer therapy are
  temporary, reversible and manageable. The
  side-effects can be reduce or control by
  medications.
• Without treatment, cancer progresses and causes
  great pain, suffering and eventually death.
• Myth Alternative therapies can cure cancer
• Truth Cancer treatments need to be rigorously
  tested and scientifically verified to be
  effective. Alternative therapies are not tested
  nor verified to be effective against cancer.

1www.radiologymalaysia.org
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The way cancer is treated is changing
Tumour site
Tumour histology
Old paradigm Toxic, non selective, chemotherapy
drugs
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Development of Systemic Chemotherapy in
Colorectal Cancer
1980
1985
1990
1995
2000
2005
5-FU
Irinotecan
UFT
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
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Targeted Therapy

• Monoclonal antibodies, block the growth of cancer
  cells by interfering with specific molecules
  needed for tumour growth and division
• More effective and tolerable than current
  treatment options as they specifically attack
  cancer cells, leaving the majority of healthy
  cells unharmed
• Cetuximab is an monoclonal antibody that
  specifically targets a receptor on the cell,
  called the epidermal growth factor receptor EGFR.
• Bevacizumab exerts an inhibitory effect on tumour
  cell growth, survival, motility, invasion and
  tumour ANGIOGENESIS (blood vessel growth).

1. Committee for Medicinal Products for Human Use
EMEA/CHMP/280402/2008 2NCCN Guideline V.1.2009
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ANGIOGENESIS

• Angiogenesis is the growth of new blood vessels
• Normal angiogenesis
• Occurs primarily during embryonic development but
  also in some adult physiological processes,
  including wound healing and female reproduction
• Characterized as focal and of brief duration
• Tumor angiogenesis
• Growth of blood vessels from surrounding tissue
  to the tumour
• Initiated by the release of chemicals from the
  tumour.

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Angiogenesis is essential to tumour development

• An independent blood supply is required for a
  tumour to grow beyond 2mm in diameter
• Larger tumours rely on their vasculature for
  survival and further growth

Small avascular tumour
Tumour
Blood vessels
Large, highlyvascularised tumour
Growthfactors
Ferrara, Henzel. Biochem Biophys Res Commun 1989,
Folkman. NEJM 1971
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What is angiogenesis inhibition?

• Angiogenesis inhibition (anti-angiogenesis)
  therefore means the suppression of the creation
  of blood vessels
• An angiogenesis inhibitor is an agent that
  prevents the formation of new blood vessels

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Epidermal Growth Factor Receptor
(EGFR)Expression in Solid Tumors

• EGFR is expressed in a variety of solid tumors
  and associated with poor prognosis

Colorectal (CRC)
Lung (NSCLC)
Head neck(SCCHN)
Cunningham et al. N Engl J Med 2004351337-345.
Grandis et al. Cancer 1996781284-1292. Salomon
et al. Crit Rev Oncol Hematol 199519183-232.
Walker, Dearing. Breast Cancer Res Treat
199953167-176.
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EGFR inhibition via monoclonal antibodies
blocking ligand binding
cetuximab
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Biomarker in Cancer Treatment

• Biomarker Definition
• A measurable DNA and/or RNA characteristic that
  is an indicator of normal biologic processes,
  pathogenic processes, and/or response to
  therapeutic or other interventions1

1FDA biomarker definitions
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Tailored therapy Role of Biomarkers in the
treatment of Colorectal cancer1,2,3

• Identification of the presence of specific
  molecules, biomarker in colorectal cancer can
  predict the effectiveness of targeted therapies
  
• This breakthrough enable oncologists to select
  the most appropriate treatment for patients from
  the beginning and thus improve their overall
  long-term outcomes.

1Lièvre A, et al. J Clin Oncol 200826374379
2VDe Roock W, et al. Ann Oncol 2007Nov 12
3Tabernero J, et al. ASCO GI 2008 Abstract
No435
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What is KRAS?

• KRAS is the first and important biomarker for
  metastatic colorectal cancer. KRAS is the
  predictive marker for cetuximab efficacy
• Higher response rate
• Trend towards improved survival

Van Cutsem E et al, ASCO 2008
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Example of Tailored Therapy Presence of the
KRAS-mutation

• Approximately 40 of colorectal cancer have a
  mutated KRAS gene
• When the disease progresses, the normal gene may
  change and alters the way signals are
  communicated inside the cancer cell
• Certain targeted therapies have demonstrated
  improved benefit when combined with standard
  chemotherapy in patients without this mutation
  (known as KRAS wild type)
• On the other hand, patients with this mutation
  will not benefit from these targeted therapies
• As such, KRAS testing is often done in patients
  with advanced colorectal cancer to determine the
  best course of treatment for patients

Reference http//fightcolorectalcancer.org/awaren
ess/treatment/personalizing_treatment/kras_mutatio
ns (Accessed 15/03/2013)
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Conclusion

• Patients have more treatment choices today
• Early detection increases the chance of cure
• The evolving colorectal cancer treatments improve
  the survival in colorectal cancer patients
• Biomarker can predict the patients response to
  targeted therapies
• Future studies to explore more predictive
  biomarkers in the cancer treatment to identify
  the right patient to receive tailored targeted
  therapy

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QUIZ 1

• Colorectal Cancer
• Cancer of the colon and rectum
• The commonest cancer in men
• 3rd commonest cancer in women
• Can be present without any symptons
• Cannot be cured even it is detected early

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QUIZ 2

• What are the risk factors of colorectal cancer?
• Family history of colorectal cancer
• Presence of polyps
• Excessive sunlight exposure
• Cigarette Smoking
• Age above 50

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QUIZ 3

• What are the symptoms of colorectal cancer?
• Passing blood in the stool
• Abdominal pain
• Headache
• Weight loss
• Change in bowel habit

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QUIZ 4

• What are the methods used for picking up
  colorectal cancer?
• Faecal occult blood test
• Colonoscopy
• Blood test
• CT scan
• Biopsy

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QUIZ 5

• What are the ways used for treating colorectal
  cancer?
• Surgery
• Chemotherapy
• Vegetarian diet
• Traditional medicine
• Radiotherapy