Colorectal CancerAn overview

Dr. Christina Ng MBBS (Melb) FRACPConsultant Medical Oncologist

Pantai Medical CenterSunway 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

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

LET’S TALK ABOUT COLORECTAL CANCER…

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%

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*

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

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.

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?

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 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

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.

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

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 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)

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

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

24

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

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

Ferrara, Henzel. Biochem Biophys Res Commun 1989, Folkman. NEJM 1971

Small avascular tumour

Tumour

Blood vessels

Large, highlyvascularised tumour

Growthfactors

28

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

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%

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 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

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

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)

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