Cancer and Chemotherapy Cancer Although there are many

Cancer and Chemotherapy

Cancer • Although there are many kinds of cancer, they all start because of out of control growth of abnormal cells • Normal body cells grow, divide, and die in an orderly fashion

Cancer • Because cancer cells continue to grow and divide, they are different from normal cells • Instead of dying, they outlive normal cells and continue to form new abnormal cells

Rapid uncontrolled growth • Compresses on surrounding anatomy • Abnormal hormone synthesis • Rapid growth exceeds vascular ability to supply the tumor resulting in necrosis • Cachexia, malnutrition

Cancer • Cancer cells develop because of damage to DNA, and it’s regulatory mechanisms • When DNA becomes damaged, the body is usually able to repair it

Cancer • In cancer cells however, damaged DNA is not repaired • People can inherit damaged DNA, which results in approximately 10 percent of all cancer

Cancer • More often, though, a person’s DNA becomes damaged by exposure to something in the environment or random cellular events

Known causes of cancer • • • Environmental - ultraviolet rays - drugs - asbestos and other occupational hazards - alcohol - smoking

Causes of cancer • Viruses • - HTLV-1 causative agent for T cell leukemia • - oncogenic viruses • - may code for growth factors and may amplify them, may control cell death suppressor gene or tumor suppressor genes

Body defenses • The body is able to launch an immune cytotoxic response to tumors • Once the tumor load has exceeded this system, the tumor grows out of control

Cancer • Most cancers originate almost anywhere in the body and usually form as a solid tumor

Cancer • Others such as leukemia and myeloma, are sometimes referred to as liquid tumors • These cancer cells involve the blood and blood -forming organs (bone marrow) and circulate through other tissues, where they grow

Carcinoma • Carcinomas: the most common type of cancer, these tumors arise from the cells that cover external and internal body surfaces • The most frequent cancers of this type in the US are lung, breast, colon and prostate cancer

Sarcoma • Sarcomas: cancers that arise from cells found in the supporting tissues of the body, such as bone, cartilage, fat, connective tissue, and muscle

Lymphoma • Cancers that arise in the lymph nodes and tissues of the body’s immune system

Leukemia • Leukemias: cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream

Primary • The place where a cancer starts is called the primary site

Metastasis • From the primary site, it can spread (mestastasize) to other parts of the body • The cancer that has spread to other parts of the body are called metastasis or metastases

Primary is name • Regardless of where a cancer may spread, it is always named for the place it began • For instance, breast cancer that spreads to the liver is still called breast cancer not liver cancer

Different Cancers Different Treatments • Different types of cancer can behave very differently. For example, lung cancer and breast cancer are very different diseases. They grow at different rates and respond to different treatments. That is why people with cancer need treatment that is aimed at their particular kind of cancer

Malignant is cancerous Benign is noncancerous • Not all tumors are malignant (cancerous) • Benign, or noncancerous, tumors do not spread to other parts of the body and, with very rare exceptions, are not life-threatening

Biopsy • A biopsy is taking a surgical sample of the suspicious tissue • This is done by a large hollow needle or excision (surgical removal)

Margins • When a tumor is excised surgically, it is sent to the pathologist for examination and diagnosis • The pathologist can tell us if the biopsy is surrounded by normal tissue, or if the biopsy cut through the tumor, meaning part of the tumor has been left in the patient

Biopsy Margin

Biopsy Margin

• Positive margins means that part of the tumor has been left behind • This is not an unusual situation it is not always possible to remove the entire tumor at biopsy

Pathologist • In addition to margins, the pathologist tells us many things about the tumor that we need to know • Gross description (seen with unaided eye) • Microscope description

Pathologist • Gross description • - size (very important) – for staging and treatment • - color • - weight

Pathologist • • • Microscopic description - margins - cellular characteristics - histological grade - special staining techniques

Pathologist Histologic Grade • Histologic grade tells us how abnormal the cancer cell is • Low grade cells are well differentiated • High grade cells are poorly differentiated

Pathologist Special Stains • Pathologists are able to use special stains to reveal characteristics of cancer

Staging • Although the pathology report is important to staging the cancer, there are many other factors involved • Different types of cancer have different staging systems

Staging • Staging reflects the amount and location of cancer in the body to make sure a person gets the proper treatment for his or her specific treatment

Staging • The treatment for Stage 1 breast cancer may be surgery and radiation, while a more advanced stage of breast cancer, stage 2 or 3 may require treatment with chemotherapy as well

Staging • Staging helps predict the course of cancer is likely to take • Staging implies prognosis

TNM staging • Some caners of the blood such as leukemias are not staged TNM because they are assumed to be in all parts of the body

TNM staging • Cancers in or around the brain are not staged using the TNM, since these cancers can interfere with vital functions of the brain and body before they even begin to spread

TNM staging • For most cancers, the stage is based on 3 main factors: • - T. the original (primary) tumor’s size and whether or not the tumor has grown into other nearby areas. • - N. whether or not the cancer has spread to the nearby lymph nodes • - M. whether or not the cancer has metastasized to distant areas of the body

TNM • The T category describes the original (primary) tumor and it’s size

TNM • The numbers T 1 - T 4 describes the tumor size and/or level of invasion into nearby structures. The higher the T number, the larger the tumor and/or the further it has grown into nearby structures

TNM • T 0 means there is no evidence of primary tumor (the primary tumor cannot be found). • Tx means the tumor can’t be measured or evaluated • Tis means the cancer is in situ (the tumor has not started growing into the structures around it)

TNM • The N category describes whether or not the cancer has reached lymph nodes

TNM • N 0 means nearby lymph nodes do not contain cancer • N 1 -N 3 describe the size, location and/or the number of lymph nodes available. The higher the N number, the more lymph nodes are available • Nx means the nearby lymph nodes can’t be measured or evaluated

TNM • The M category tells whethere are distant metastases (spread of cancer to other parts of the body)

TNM • M 0 means that no distant metastases were found • M 1 means that distant metastases were found • Mx means mestastasis can’t be measured or evaluated

Each primary type has it’s own systems • Each cancer type has it’s own version of this classification system, so letters and numbers don’t always mean the same thing for every kind of cancer. For example, for some cancers, classification may have some subcategories, such as T 3 a and T 3 b, while others may not have an N 3 category

Why is each staging different from each other? • Staging helps predict the course a cancer is likely to take • Staging implies prognosis

Cancer Chemotherapy • • Cancer chemotherapy Basic drug subclasses - alkylating agents - antimetabolites - plant alkaloids - antibiotics - hormones - biologic response modifiers

Many cancer chemotherapy agents are described by how they affect the cell cycle

• • • M phase – mitosis which is cellular division - drugs that block mitosis are: M phase CCS (Cell Cycle Specific) Antimitotic

• The G 1 phase is the first growth phase

• The S phase is the DNA synthesis phase • drugs that block DNA synthesis are: • S phase • CCS (Cell Cycle Specific)

• The G 2 phase is the second growth phase • drugs that block the growth after DNA synthesis are: G 2 phase CCS (Cell Cycle Specific)

• Many drugs are Cell Cycle NON Specific (CCNS) • Meaning they are cytotoxic during the entire cell cycle

Alkylating Agents • The first alkylating agents were derived from nitrogen mustards • Nitrogen mustards were used in WWI as chemical warfare agents (mustard gas) causing blistering of the skin (vesicants)

Mustard gas in the battlefield

Mustard gas

Alkylating agents • Nitrogen mustards were later found to be very effective in treating cancer

Alkylating agents • The alkylating agents form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine

Alkylating agents • Alkylating agents cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis

Alkylating agents • The alkylating agents are cell cycle nonspecific agents that damage DNA

Alkylating agents • Cell Cycle NON Specific • CCNS • Meaning they are cytotoxic during the entire cell cycle

Alkylating agents • Because they are vessicants, causing blistering of the skin, these agents can be very damaging if they are not properly administered

Alkylating Agents Nitrogen Mustards • Chlorambucil • Cyclophosphamide (Cytoxan®) • Mecloethamine

Alkylating Agents • • • Busulfan Dacarbazine Procarbazine Carmustine Lomustine

Alkylating Agents Platinum Analogs • Ciplastin • Carboplastin • Oxaplatin

Cancer Chemotherapy Basic Drug Subclasses • • • Alkylating Agents Antimetabolites Plant Alkaloids Antibiotics Hormones Biologic Response Modifiers

Antimetabolites • Antimetabolites interfere with DNA and RNA production • Antimetabolites • S phase • Cell Cycle Specific • CCS • Meaning they interfere with the S phase

Antimetabolites • Methotrexate (meh-thuh-TREK-sayt) (MTX) • Folic acid antagonist that binds to dihydrofolate reductase • Interferes with DNA and RNA synthesis by preventing nucleoside production

Antimetabolites • Purine antagonists • - mercaptopurine (mer-CAP-to-pur-een) (6 MP) • - Thioguanine (thio-GWA-neen) (6 -TG) • Interferes with DNA and RNA synthesis by preventing nucleotide production

Fluoropyrimidine Antimetabolites • Pyrimidine antagonists • - stops DNA and RNA synthesis by preventing nucleoside production • Fluorouracil (floor-oh-YOOR-ul-sil) (5 -FW) • Capecitabine (ka-peh-SITE-uh-been) (Xeloda®) • - 5 -FU prodrug

Plant Alkaloids • • Taxanes Taxane (TAK-sayn) The taxanes are produced by Yew trees Taxanes interfere with microtubules and are mitotic inhibitors

• • • Taxane Alkaloids M phase Cell Cycle Specific CCS Meaning they interfere with mitosis

• Yew Trees Produce Taxanes

Taxanes • Paclitaxel (PA-klih-TAK-sil) (Taxol®) • Docetaxel (doh-she-TAK-sil) (Taxotere®)

Vinca Alkaloids • • M phase Cell Cycle Specific CCS Meaning they interfere with mitosis

• Periwinkles produce Vinca Alkaloids

Taxanes • - Paclitaxel (PA-klih-TAK-sil) (Taxol®) • - Docetaxel (doh-she-TAK-sil) (Taxotere®)

Vinca Alkaloids • • Vinblastine (vin-BLAS-teen) Vincristine (vin-KRIS-teen) - from Vinca rosea, periwinkle plant) - binds to tubulin and causes mitosis to stop

Vinca Alkaloids • • M phase Cell Cycle Specific CCS Meaning they interfere with mitosis

• Periwinkles produce Vinca Alkaloids

Plant Alkaloids Captothecins • • Camptothecin (KAMP-toh-THEK-in) - from Camptotheca acuminate tree) Topotecan (toh-poh-TEE-kan) Irinotecan (I-rih-noh-TEE-kan)

Captothecins are Topoisomerase Inhibitors • Topoisomerase (TOH-poh-i-SAH-meh-rays) • Topoisomerase is an enzyme required for DNA reproduction. • Inhibiting topoisomerase interferes with DNA replication

• • • Comptothecins are: S phase Cell Cycle Specific CCS Meaning they interfere with DNA synthesis

• Camptotheca Acuminata Trees or happy tree produce camptothecins

Plant Alkaloid Topoisomerase Inhibitors • Epipodophyllotoxin (EH-pih-POH-doh-FIH-loh. TOK-sin) • Epipodohphyllotoxin is extracted from the mandrake root of the Podophyllym peltatum. It is a type of topoisomerase inhibitor

• • • Podophyllotoxins S phase Cell Cycle Specific CCS Meaning they interfere with DNA synthesis

• Podophyllum peltatum • “Mayapple” produces epipodophyllotoxin

Antibiotics • Anthracyclines (AN-thruh-SY-klin) • A type of antibiotic that comes from Streptomyces bacteria. Anthracyclines are used to treat many types of cancer. Anthracyclines not only block DNA synthesis, they damage DNA during all phases of the cell cycle. They are too toxic to use for bacterial infections.

Anthracyclines • • • Daunorubicin Doxorubicin (Adriamycin®) Epirubicin (Ellence®) Idarubicin Mitoxantrone (analog)

• Anthracyclines are Cell Cycle NON Specific • CCNS • Meaning they are cytotoxic during the entire cell cycle

Bleomycin • Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus • Bleomycin not only interferes with DNA synthesis and damages DNA and is especially active during the G 2 phase

• • Bleomycins G 2 phase CCS Meaning they interfere with DNA synthesis mostly during S and G 2

Hormones • • • Glucocorticoids – Prednisone Gonadal Hormone Antagonists - Estrogen Antagonist - Androgen Antagonists Gonadotropin Releasing Hormone Analogs Aromatase Inhibitors

Glucocorticoids • Prednisone is a glucocorticoid commonly used in combination with other agents in the treatment of leukemias and lymphomas

Estrogen Antagonist • Tamoxifen Nolvadex ® is an estrogen receptor modulator commonly used to treat breast cancer

Androgen Antagonist • Flutamide, Eulixin® is an androgen antagonist commonly used to treat prostate carcinoma

Gn. RH analogs • Leoprolide, Lupron® • Goserelin, Zoladex® • Gn. RH analogs commonly used to treat prostate carcinoma

Aromatase Inhibitors • Aromatase is an enzyme important in estrogen formation • Aromatase inhibitors are used to treat breast carcinomas

Aromatase Inhibitors • Anastrozole, Arimidex® (ANAS) • Letrozole, Femara® (LTZ)

Biologic Response Modifiers Interferons • Interferons are naturally occuring endogenous glycoproteins with antiviral and antineoplastic activity • Interferon A is effective against certain leukemias and lymphomas

Biologic Response Modifiers Monoclonal Antibodies • • Alemtuzumab Campath® Bevacizumab Avastin® Gemtuzumab Mylotarg® Ibritumomab Zevalin® Rituximab Rituxan ® Tositumomab Bexxar ® Trastuzumab Herceptin®

Biologic Response Modifiers Monoclonal Antibodies • Trastuzumab (tras-TOO-zuh-mab) Herceptin® • A monoclonal antibody that binds to HER 2 (human epidermal growth factor receptor 2) and can kill HER 2 – positive cancer cells • Trastuzumab (Herceptin) is used to treat breast cancer that HER 2 – postive and has spread after treatment with other drugs

Biologic Response Modifiers Monoclonal Antibodies • Bevacizumab (beh-vuh-SIH-zoo-mab) Avastatin® • Bevacizumab (Avastatin) binds to vascular endothelial growth factor (VEGF) preventing angiogenesis (the growth of new blood vessels that tumors need to grow).

Biologic Response Modifiers Tyrosine Kinase Inhibitors • Imantinib Gleevic® inhibits the tyrosine kinase activity of the protein product of the Bcr-Abl gene commonly expressed in Chronic Myelogenous Leukemia

Biologic Response Modifiers Tyrosine Kinase Inhibitors • Gefitinib, Iressa® • Erlotinib, Tarceva® • Inhibits the tyrosine kinase activity of the epidermal growth factor required for angiogenesis

Adjuvant Chemotherapy • Systemic therapy given to patients with no evidence of cancer after surgery is called adjuvant therapy • While surgery is used to remove all of the cancer that can be seen, adjuvant therapy is used to kill any cancer cells that may have been left behind that can’t be seen

Neoadjuvant Chemotherapy • Chemotherapy given before surgey is called neoadjuvant therapy • Neoadjuvants can shrink tumors and reveal responsiveness to tumors before surgery allowing for less aggressive therapy

Rescue therapy • Rescue therapy is any agent that prevents or lessens the toxicity of cancer chemotherapeutic agents

• National Cancer Institute / cancer. org • American Cancer Society Cancer. org