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Colorectal Cancer
An overview
Dr. Christina Ng MBBS (Melb) FRACP
Consultant Medical Oncologist
Pantai Medical Center
Sunway Medical Center
President and Founder of EMPOWERED
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
On average, one in three people will be affected
by cancer at some stage in their life
Cancer isn’t 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
Lung cancer is the
major cause of
cancer death in the
world, accounting
for more than
1.2 million deaths
each year
In 2000, there were
330,000 new cases of
colorectal cancer and
155,000 deaths in the five
major European countries*
and the USA
*Five European countries listed as France, Germany, Italy, Spain, UK
1.2 million cases
of breast cancer
are diagnosed
across the world
each year
LET’S TALK ABOUT
COLORECTAL CANCER…
What is the burden of cancer in Malaysia?
2003 Malaysia Ten Most Frequent Cancer Cases*
Colon & Rectum
14.2%
31%
Breast
Lung
13.8%
12.9% Cervix Uteri
Nasopharynx
8.8%
10.1% Colon & Rectum
Leukemia
7.1%
4.3%
Prostate Gland
6.4%
4.1% Ovary
Stomach
5.1%
4%
Lymphomas
4.3%
3.8%
Lung
Other skin
4%
2.9%
Stomach
Liver
4%
2.7%
Other Skin
Source: National Cancer Registry, 2003.
Uterine corpus
Leukemia
5-year survival rates for some cancers
have improved significantly
Site
1974-1976
1983-1985
1995-2000
Today*
All sites
50%
53%
64%
>68%
Breast (female)
75%
78%
88%
>90%
Colon
50%
58%
63%
>65%
Leukemia
34%
41%
46%
>48%
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
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
Cell division in the body
Normal cell division
Mutation into cancer
• Cancer develops when abnormal cells grow out of control.
• These cells grow until a lump or tumour is forms.
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.
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
Risk Factors
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
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
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
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
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 1932;35;323-332.
American Joint Committee
on staging for Colorectal Cancer
TNM
Stage I
Duke’s
A,
B1
5-year survival %
85–95
Stage II
B2
60–80
Stage III
C
30–60
Stage IV
D
<5
Macdonald JS. CA Cancer J Clin 1999; 49:202-219
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
Colorectal Cancer Treatment Options
Surgery
Radiotherapy
Systemic Therapies:
• Chemotherapy
• Targeted therapy
Best supportive care
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)
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)
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)
Misconception of cancer treatment
1
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 sideeffects (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
The way cancer is treated is changing
Molecular
biology
Molecular
profile
Old paradigm
Targeted therapies
Future paradigm
Toxic, non selective, chemotherapy drugs
Wider therapeutic index,
derived from molecular
biology discoveries of the
1980s
Integration of molecular
diagnostics with targeted
therapies
= integrated cancer care
Tumour
site
Tumour
histology
24
Development of Systemic Chemotherapy
in Colorectal Cancer
1980
1985
1990
1995
2000
2005
5-FU
UFT
Therapeutic Concepts
Palliative chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Irinotecan
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
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
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.
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, highly
vascularised tumour
Ferrara, Henzel. Biochem Biophys Res Commun 1989, Folkman. NEJM 1971
Growth
factors
28
What is angiogenesis inhibition?
Angiogenesis
inhibition (antiangiogenesis) therefore
means the suppression
of the creation of blood
vessels
An angiogenesis
inhibitor is an agent
that prevents the
formation of new blood
vessels
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)
Colorectal cancer
60–90%
Head & neck cancer
95–100%
Lung cancer (NSCLC)
40–80%
Breast cancer
14–91%
Ovarian cancer
35–70%
Renal cell cancer
50–90%
Cunningham et al. N Engl J Med 2004;351:337-345. Grandis et al. Cancer 1996;78:1284-1292.
Salomon et al. Crit Rev Oncol Hematol 1995;19:183-232. Walker, Dearing. Breast Cancer Res Treat 1999;53:167-176.
EGFR inhibition via monoclonal antibodies
blocking ligand binding
cetuximab
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
Tailored therapy:
Role of Biomarkers in the treatment of
Colorectal cancer
1,2,3
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 2008;26:374–379; 2VDe Roock W, et al. Ann Oncol 2007;Nov 12;
3Tabernero
J, et al. ASCO GI 2008 Abstract No:435
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
KRAS
mutant
35%
Van Cutsem E et al, ASCO 2008
KRAS
normal
65%
Example of Tailored Therapy – Presence of the KRASmutation
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/awareness/treatment/personalizing_treatment/kras_mutations (Accessed 15/03/2013)
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 patient’s 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
QUIZ 1
Colorectal Cancer
1)Cancer of the colon and rectum
2)The commonest cancer in men
3)3rd commonest cancer in women
4)Can be present without any symptons
5)Cannot be cured even it is detected early
QUIZ 2
What are the risk factors of colorectal
cancer?
1) Family history of colorectal cancer
2) Presence of polyps
3) Excessive sunlight exposure
4) Cigarette Smoking
5) Age above 50
QUIZ 3
What are the symptoms of colorectal cancer?
1) Passing blood in the stool
2) Abdominal pain
3) Headache
4) Weight loss
5) Change in bowel habit
QUIZ 4
What are the methods used for picking up
colorectal cancer?
1) Faecal occult blood test
2) Colonoscopy
3) Blood test
4) CT scan
5) Biopsy
QUIZ 5
What are the ways used for treating
colorectal cancer?
1)Surgery
2)Chemotherapy
3)Vegetarian diet
4)Traditional medicine
5)Radiotherapy