Colorectal CancerAn overviewDr. Christina Ng MBBS (Melb) FRACPConsultant Medical OncologistPantai Medical CenterSunway Medical CenterPresident 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 deathseach 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 1.2 million cases of breast cancer are diagnosed across the world each year *Five European countries listed as France, Germany, Italy, Spain, UK
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% 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% Source: National Cancer Registry, 2003.
5-year survival rates for some cancers have improved significantly All sites 50% 53% 64% >68% Breast (female) 75% 78% 88% >90% Colon 50% 58% 63% >65% Leukemia 34% 41% 46% >48% 1995-2000 Today* Site 1974-1976 1983-1985 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
Mutation into cancer 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.
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 rectumand the analcanal. • 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 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 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 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
The way cancer is treated is changing Future paradigm Integration of molecular diagnostics with targeted therapies = integrated cancer care Targeted therapies Wider therapeutic index, derived from molecular biology discoveries of the 1980s Molecular biology Molecular profile Tumour site Tumour histology Old paradigm Toxic, non selective, chemotherapy drugs 24
Therapeutic Concepts Palliative chemotherapy Adjuvant chemotherapy Neoadjuvant chemotherapy Development of Systemic Chemotherapy in Colorectal Cancer 1980 1985 1990 1995 2000 2005 5-FU Irinotecan UFT 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.
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 Angiogenesis is essential to tumour development Small avascular tumour Tumour Blood vessels Growthfactors Large, highlyvascularised tumour Ferrara, Henzel. Biochem Biophys Res Commun 1989, Folkman. NEJM 1971 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
EGFR is expressed in a variety of solid tumors and associated with poor prognosis Epidermal Growth Factor Receptor (EGFR)Expression in Solid Tumors Colorectal (CRC) Lung (NSCLC) Head & neck(SCCHN) 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 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 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 • 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
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
QUIZ 3 What are the symptoms of colorectal cancer? • Passing blood in the stool • Abdominal pain • Headache • Weight loss • Change in bowel habit
QUIZ 4 What are the methods used for picking up colorectal cancer? • Faecal occult blood test • Colonoscopy • Blood test • CT scan • Biopsy
QUIZ 5 What are the ways used for treating colorectal cancer? • Surgery • Chemotherapy • Vegetarian diet • Traditional medicine • Radiotherapy