Colorectal Cancer

What is Colorectal Cancer?

• Third most common type of cancer and second most frequent cause of cancer-related death

• A disease in which normal cells in the lining of the colon or rectum begin to change, grow without control, and no longer die

• Usually begins as a noncancerous polyp that can, over time, become a cancerous tumor

Each year around 289,000 people are newly diagnosed with cancer and breast, lung, colorectal and prostate cancer account for over half of all the new cases (ONS, 2008a; ISD online, 2008a, WCISU, 2008; Northern Ireland Cancer Registry, 2008)

United Kingdom (2008)

Colorectal Cancer

Epidemiology

• peak incidence: 60 to 70 years of age• < 20% cases before age of 50• adenomas – presumed precursor lesions for

most tumors• males affected ≈ 20% more often than females

Epidemiology

• worldwide distribution• highest incidence rates in United States,

Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries

Etiology

• genetic influences:– preexisting ulcerative colitis or polyposis

syndrome– hereditary nonpolyposis colorectal cancer

syndrome (HNPCC, Lynch syndrome) → germ-line mutations of DNA mismatch repair genes

Etiology

• environmental influences:– dietary practices• low content of unabsorbable vegetable fiber• corresponding high content of refined carbohydrates• high fat content• decreased intake of protective micronutrients (vitamins

A, C, and E)– use of Aspirin® and other NSAIDs: protective effect

against colon cancer?• cyclooxygenase-2 & prostaglandin E2

Carcinogenesis

• chromosome instability pathway

Carcinogenesis

• mismatch repair (microsatellite instability) pathway

What Are the Risk Factors for Colorectal Cancer?

• Polyps (a noncancerous or precancerous growth associated with aging)

• Age• Inflammatory bowel disease (IBD)• Diet high in saturated fats, such as red meat• Personal or family history of cancer• Obesity• Smoking• Other

Hereditary Colorectal Cancer Syndromes: HNPCC

• Hereditary non-polyposis colorectal cancer (HNPCC), sometimes called Lynch syndrome, accounts for approximately 5% to 10% of all colorectal cancer cases

• The risk of colorectal cancer in families with HNPCC is 70% to 90%, which is several times the risk of the general population

• People with HNPCC are diagnosed with colorectal cancer at an average age of 45

• Genetic testing for the most common HNPCC genes is available; measures can be taken to prevent development of colorectal cancer

Hereditary Colorectal Cancer Syndromes: FAP

• Familial adenomatous polyposis (FAP) accounts for 1% of colorectal cancer cases

• People with FAP typically develop hundreds to thousands of colon polyps (small growths); the polyps are initially benign (noncancerous), but there is nearly a 100% chance that the polyps will develop into cancer if left untreated

• Colorectal cancer usually occurs by age 40 in people with FAP • Mutations (changes) in the APC gene cause FAP; genetic testing is

available• Yearly screening for polyps is recommended• Attenuated familial adenomatous polyposis (AFAP) is related to FAP;

people have fewer polyps

Hereditary Colorectal Cancer Syndromes

• Several other less common syndromes can increase a person’s risk of colorectal cancer

Morphology

• 25% of colorectal carcinomas: in cecum or ascending colon

• similar proportion: in rectum and distal sigmoid

• 25%: in descending colon and proximal sigmoid

• remainder scattered elsewhere• multiple carcinomas present → often at widely

disparate sites in the colon

Morphology

• all colorectal carcinomas begin as in situ lesions• tumors in the proximal colon: polypoid, exophytic

masses that extend along one wall of the cecum and ascending colon

Morphology

• in the distal colon: annular, encircling lesions that produce “napkin-ring” constrictions of the bowel and narrowing of the lumen

• both forms of neoplasm eventually penetrate the bowel wall and may appear as firm masses on the serosal surface

Morphology• all colon carcinomas - microscopically similar• almost all - adenocarcinomas• range from well-differentiated to undifferentiated,

frankly anaplastic masses• many tumors produce mucin• secretions dissect through the gut wall, facilitate

extension of the cancer and worsen the prognosis• cancers of the anal zone are predominantly squamous

cell in origin

Clinical Features • may remain asymptomatic for years• symptoms develop insidiously• cecal and right colonic cancers:

– fatigue– weakness– iron deficiency anemia

• left-sided lesions:– occult bleeding– changes in bowel habit– crampy left lower quadrant discomfort

• anemia in females may arise from gynecologic causes, but it is a clinical maxim that iron deficiency anemia in an older man means gastrointestinal cancer until proved otherwise

Clinical Features

• spread by direct extension into adjacent structures and by metastasis through lymphatics and blood vessels

• favored sites for metastasis:– regional lymph nodes– liver– lungs– bones– other sites including serosal

membrane of the peritoneal cavity

• carcinomas of the anal region → locally invasive, metastasize to regional lymph nodes and distant sites

TNM Staging of Colon Cancer

Tumor (T)T0 = none evidentTis = in situ (limited to mucosa)T1 = invasion of lamina propria or submucosaT2 = invasion of muscularis propriaT3 = invasion through muscularis propria into

subserosa or nonperitonealized perimuscular tissue

T4 = invasion of other organs or structures

Lymph Nodes (N)0 = none evident1 = 1 to 3 positive pericolic nodes2 = 4 or more positive pericolic nodes3 = any positive node along a named blood vessel

Distant Metastases (M)0 = none evident1 = any distant metastasis

5-Year Survival RatesT1 = 97%T2 = 90%T3 = 78%T4 = 63%Any T; N1; M0 = 66%Any T; N2; M0 = 37%Any T; N3; M0 = data not availableAny M1 = 4%

Clinical Features

• detection and diagnosis:– digital rectal examination– fecal testing for occult blood loss– barium enema, sigmoidoscopy and

colonoscopy– confirmatory biopsy– computed tomography and other

radiographic studies– serum markers (elevated blood

levels of carcinoembryonic antigen)

– molecular detection of APC mutations in epithelial cells, isolated from stools

– tests under development: detection of abnormal patterns of methylation in DNA isolated from stool cells

Colorectal Cancer and Early Detection

• Colorectal cancer can be prevented through regular screening and the removal of polyps

• Early diagnosis means a better chance of successful treatment

• Screening should begin at age 50 for all “average risk” individuals or sooner if you have a family history of colorectal cancer, symptoms, or a personal history of inflammatory bowel disease

Screening Methods for Colorectal Cancer

• Colonoscopy (currently the best way to prevent and detect colorectal cancer)

• Virtual colonography

• Sigmoidoscopy

• Fecal occult blood test

• Double contrast barium enema

• Digital rectal examination

What Are the Symptoms ofColorectal Cancer?

• A change in bowel habits: diarrhea, constipation, or a feeling that the bowel does not empty completely

• Bright red or dark blood in the stool

• Stools that appear narrower or thinner than usual

• Discomfort in the abdomen, including frequent gas pains, bloating, fullness, and cramps

• Unexplained weight loss, constant tiredness, or unexplained anemia (iron deficiency)

How is Colorectal Cancer Evaluated?

• Diagnosis is confirmed with a biopsy

• Stage of disease is confirmed by pathologists and imaging tests, such as computerized tomography (CT or CAT) scans

• Endoscopic ultrasound and magnetic resonance imaging (MRI) may also be used to stage rectal cancer

Cancer Treatment: Surgery

• Foundation of curative therapy

• The tumor, along with the adjacent healthy colon or rectum and lymph nodes, is typically removed to offer the best chance for cure

• May require temporary or (rarely) permanent colostomy (surgical opening in abdomen that provides a place for waste to exit the body)

Cancer Treatment: Chemotherapy

• Drugs used to kill cancer cells

• Typical medications include fluorouracil (5-FU), oxaliplatin (Eloxatin), irinotecan (Camptosar), and capecitabine (Xeloda)

• A combination of medications is often used

Types of Chemotherapy

• Adjuvant chemotherapy is given after surgery to maximize a patient’s chance for cure

• Neoadjuvant chemotherapy is given before surgery

• Palliative chemotherapy is given to patients whose cancer cannot be removed to delay or reverse cancer-related symptoms and substantially improve quality and length of life

Cancer Treatment: Radiation Therapy

• The use of high-energy x-rays or other particles to destroy cancer cell

• Used to treat rectal cancer, either before or after surgery

• Different methods of delivery

• External-beam: outside the body

• Intraoperative: one dose during surgery

New Therapies: Antiangiogenesis Therapy

• “Starves” the tumor by disrupting its blood supply

• This therapy is given along with chemotherapy

• Bevacizumab (Avastin) was approved by the U.S. Food and Drug Administration (FDA) in 2004 for the treatment of stage IV colorectal cancer

New Therapies: Targeted Therapy

• Treatment designed to target cancer cells while minimizing damage to healthy cells

• Cetuximab (Erbitux) was approved by the FDA in 2004 for the treatment of advanced colorectal cancer

Colorectal Cancer Staging• Staging is a way of describing a cancer, such as the

depth of the tumor and where it has spread• Staging is the most important tool doctors have to

determine a patient’s prognosis • Staging is described by the TNM system: the size (the

depth of penetration of the Tumor into the wall of the bowel), whether cancer has spread to nearby lymph Nodes, and whether the cancer has Metastasized (spread to organs such as the liver or lung)

• The type of treatment a person receives depends on the stage of the cancer

Stage 0 Colorectal Cancer• Known as “cancer in situ,”

meaning the cancer is located in the mucosa (moist tissue lining the colon or rectum)

• Removal of the polyp (polypectomy) is the usual treatment

Stage I Colorectal Cancer• The cancer has grown

through the mucosa and invaded the muscularis (muscular coat)

• Treatment is surgery to remove the tumor and some surrounding lymph nodes

Stage II Colorectal Cancer• The cancer has grown beyond

the muscularis of the colon or rectum but has not spread to the lymph nodes

• Stage II colon cancer is treated with surgery and, in some cases, chemotherapy after surgery

• Stage II rectal cancer is treated with surgery, radiation therapy, and chemotherapy

Stage III Colorectal Cancer• The cancer has spread to the

regional lymph nodes (lymph nodes near the colon and rectum)

• Stage III colon cancer is treated with surgery and chemotherapy

• Stage III rectal cancer is treated with surgery, radiation therapy, and chemotherapy

Stage IV Colorectal Cancer• The cancer has spread outside

of the colon or rectum to other areas of the body

• Stage IV cancer is treated with chemotherapy. Surgery to remove the colon or rectal tumor may or may not be done

• Additional surgery to remove metastases may also be done in carefully selected patients

The Role of Clinical Trials for the Treatment of Colorectal Cancer

• Clinical trials are research studies involving people• They test new treatment and prevention methods to

determine whether they are safe, effective, and better than the best known treatment

• The purpose of a clinical trial is to answer a specific medical question in a highly structured, controlled process

• Clinical trials can evaluate methods of cancer prevention, screening, diagnosis, treatment, and/or quality of life

Clinical Trials: Patient Safety

• Informed consent: Participants should understand why they are being offered entry into a clinical trial and the potential benefits and risks; informed consent is an ongoing process

• Participation is always voluntary, and patients can leave the trial at any time

• Other safeguards exist to ensure ongoing patient safety

Clinical Trials: Phases

• Phase I trials determine safety and dose of a new treatment in a small group of people

• Phase II trials provide more detail about the safety of the new treatment and determine how well it works for treating a given form of cancer

• Phase III trials take a new treatment that has shown promising results when used to treat a small number of patients with cancer and compare it with the current, standard treatment for that disease; phase III trials involve a large number of patients

Clinical Trials Resources

• Coalition of Cancer Cooperative Groups (www.CancerTrialsHelp.org)

• CenterWatch (www.centerwatch.com)

• National Cancer Institute (www.cancer.gov/clinical_trials)

Coping With the Side Effects of Cancerand its Treatment

• Side effects are treatable; talk with the doctor or nurse

• Fatigue is a common, treatable side effect• Pain is treatable; non-narcotic pain relievers are

available• Antiemetic drugs can reduce or prevent nausea and

vomiting• For more information, visit www.plwc.org/sideeffects

Follow-Up Care

• Doctor’s visits• Serial carcinoembryonic antigen (CEA)

measurements are recommended• Colonoscopy one year after removal of colorectal

cancer• Surveillance colonoscopy every three to five years

to identify new polyps and/or cancers • More information can be found in the ASCO Patient

Guide: Follow-Up Care for Colorectal Cancer