Ch. 21. Cancer and the Immune System What is cancer? What is the immune response to cancer?
What is cancer?
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Colorectal CancerAn overview
Dr. Christina Ng MBBS (Melb) FRACPConsultant Medical Oncologist
Pantai Medical CenterSunway Medical Center
President 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 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
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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LET’S TALK ABOUT COLORECTAL CANCER…
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What is the burden of cancer in Malaysia?2003 Malaysia Ten Most Frequent Cancer Cases*
Source: National Cancer Registry, 2003.
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% Other Skin
Colon & Rectum 14.2%
Lung 13.8%
Nasopharynx 8.8%
Leukemia 7.1%
Prostate Gland 6.4%
Stomach 5.1%
Lymphomas 4.3%
Other skin 4%
Liver 4%
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5-year survival rates for some cancers have improved significantly
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
Site 1974-1976 1983-1985 1995-2000
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
Today*
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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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Mutation into cancerNormal cell division
Cell division in the body
• Cancer develops when abnormal cells grow out of control.
• These cells grow until a lump or tumour is forms.
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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 quickly cancer grows?
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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 olderA family history of cancer of the colon or rectumA 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 1932;35;323-332.
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TNM Duke’s 5-year survival %Stage I A,
B185–95
Stage II B2 60–80
Stage III C 30–60
Stage IV D <5
American Joint Committee on staging for Colorectal Cancer
Macdonald JS. CA Cancer J Clin 1999; 49:202-219Macdonald JS. CA Cancer J Clin 1999; 49:202-219
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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 cancerThe 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 diseasePalliative 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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Future paradigm
Integration of molecular
diagnostics with targeted
therapies = integrated cancer care
Molecularprofile
Tumoursite
Targeted therapies
Wider therapeutic
index, derived from molecular
biology discoveries of
the 1980s
Molecularbiology
Tumourhistology
The way cancer is treated is changing
Old paradigm
Toxic, non selective, chemotherapy drugs
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Development of Systemic Chemotherapy in Colorectal Cancer
1980 1985 1990 1995 2000 2005
Therapeutic Concepts
Palliative chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
UFT CapecitabineOxaliplatin
CetuximabBevacizumab
Irinotecan5-FU
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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
Ferrara, Henzel. Biochem Biophys Res Commun 1989, Folkman. NEJM 1971
Small avascular tumour
Tumour
Blood vessels
Large, highlyvascularised tumour
Growthfactors
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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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Lung(NSCLC)
Colorectal(CRC)
Head & neck(SCCHN)
Epidermal Growth Factor Receptor (EGFR)Expression in Solid Tumors
EGFR is expressed in a variety of solid tumors and associated with poor prognosis
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.
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%
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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 2008;26:374–379; 2VDe Roock W, et al. Ann Oncol 2007;Nov 12;
3Tabernero J, et al. ASCO GI 2008 Abstract No:435
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What is KRAS?
KRAS mutant35% KRAS
normal65%
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/awareness/treatment/personalizing_treatment/kras_mutations (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 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
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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
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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
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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
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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
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QUIZ 5
What are the ways used for treating colorectal cancer?
1)Surgery
2)Chemotherapy
3)Vegetarian diet
4)Traditional medicine
5)Radiotherapy