CancerChemotherapy Dr. Khdair Al-Rawaq

It is basically a disease of cells characterized by the shift in the control mechanism that govern cell proliferation and differentiation. Special Characteristics of Cancer Cells Uncontrolled Proliferation Dedifferentiation and loss of function Invasiveness (Spreading) Metastasis (spread of cancer from its primary site to other places in the body ) Cancer

Management of Cancer Surgical Radiation Chemotherapy The neoplastic cell burden is initially reduced either by surgery and /or radiation followed by chemotherapy or combination therapy.

Chemotherapy Adjuvant: Additional treatment after the primary treatment to lower the risk that the cancer will come back. Neo-Adjuvant therapy :Treatment as a first step to shrink a tumor before the main treatment. Concurrent therapy: When two or more therapies are given together, such as chemotherapy and radiation. Types of Therapis :

CANCERS WITH ESTABLISHED OR PROBABLE BENEFIT FROM ADJUVANT CHEMOTHERAPY Breast cancer Colorectal cancer Osteosarcoma Wilms' tumor Stage II-III gastric cancer Stage II-III non-small cell lung cancer Stage III melanoma

The rationale of neoadjuvant therapy is The immediate exposure of local and possible distant disease to effective chemotherapy, avoiding the delay introduced by surgery and recovery; Immediate in vivo assessment of chemotherapy responsiveness of the primary tumor, and therefore, of possible nodal or distant micrometastatic disease; Bulk reduction of local disease to allow for a subsequent less anatomically destructive surgical procedure. In responding patients, chemotherapy is carried out in a flexible number of cycles to the best or complete response, followed by definitive surgery.

CANCERS WITH ESTABLISHED BENEFIT FROM NEOADJUVANT CHEMOTHERAPY Locally advanced breast cancer Larynx cancer Esophageal cancer Bladder cancer Anal cancer Osteosarcoma Soft tissue sarcoma

Larynx cancer Esophageal cancer Cervical carcinoma PNS Carcinoma Rectal Carcinoma CANCERS WITH ESTABLISHED BENEFIT FROM Concurrent Chemoradiation

Chemotherapy It is the treatment of disease by chemicals especially by killing micro-organisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a regimen.

Cell Cycle G 0 : A resting phase,the cell has stopped dividing. G 1 : Cells increase in size. S : DNA replication occurs. G 2 : Gap between DNA synthesis and mitosis, the cell will continue to grow. M : Cell growth stops,and cellular energy is focused on the orderly division into two daughter cells.

Principles of cancer chemotherapy 1.Goal of treatment: The ultimate goal of chemotherapy is cure. i.e. long term disease free survival. If cure is not attainable, then the goal becomes pallitation i.e. alleviation of symptoms and avoidance of life-threatening toxicity.

2. Indications for treatment: Chemotherapy is indicated when neoplasms are disseminated (Spread over a large area)and are not cured by surgery. Chemotherapy is also used as a supplimental treatment to attack micrometastasis following surgery and radiation treatment. Principles of cancer chemotherapy

CANCERS POTENTIALLY CURABLE WITH CHEMOTHERAPY ALONE 1.Choriocarcinoma 2.Hodgkin's lymphoma 3.Non-Hodgkin's lymphoma (some types) 4.Testicular cancer 5.Acute lymphoid leukemia 6.Acute myelogenous leukemia 7.Ovarian cancer 8.Small cell lung cancer

3.Tumor susceptibility and growth cycle: Rapidly dividing cells are generally more sensitive to anti cancer drugs. therefore the fraction of tumor cells that are in replicative stage of their cycle are most susceptible. Non proliferating cells (those are in Go phase) usually survive the toxic effects of many of these agents. Principles of cancer chemotherapy

4. Cell cycle specificity of drugs: The normal and tumor cells differ in the number of cells that are in various stages of the cycle. Chemotherapeutic agents that are effective only against replicating cells are called cell cycle specific (CCS) drugs. Others are said to be cell cycle non specific (CCNS) drugs. The non specific drugs have more toxicity in cycling cells and are useful against tumors that have low percentage of replicating cells. Principles of cancer chemotherapy

5. Tumor growth rate: The growth rate of most solid tumors in vivo is initially rapid, but growth rate decreases as tumor size increases. Because of unavailability of nutrients and oxygen. By reducing the tumor burden through surgery or radiation promotes the remaining cells growth into active proliferation and increases their susceptibility to chemotherapeutic agents. Principles of cancer chemotherapy

6. Treatment regimens and scheduling: Drugs are administered on the bases of body surface area. Destruction of cancer cell by chemotherapeutic agent follows first order kinetics, i.e. given dose destroys constant fraction of cells.(Log kill) Combine drug therapy is more successful than single drug treatment. In combine therapy the drugs must have different toxicities, Mechanism of action. Principles of cancer chemotherapy

The principles of choosing combinations of chemotherapy are as follow: Each drug is active against the tumour as a single agent. There are no clinically important drug interactions between the agents. Combinations should avoid drugs of the same class or those with similar modes of action. The drugs should have different dose-limiting toxicities Drugs should have different mechanisms or patterns of resistance Chemotherapy scheduling and regimens:

Principles of cancer chemotherapy Effects of various treatments on the cancer cell burden:

Problems associated with chemotherapy: Resistance: a) Inherent b) Acquired Toxicities: Effects on normal rapidly proliferating cells i.e. Buccal mucosa, Bone marrow, GI mucosa, Hair. Principles of cancer chemotherapy

Bone marrow suppression Anemia Neutropenia Thrombocytopenia Effects on GIT Nausea & Vomiting Stomatitis & mucositis Dysphagia Constipation Diarrhea Side Effects

Effects on skin: Skin dryness Photosensetivity Skin pigmentation Hair loss Effects on reproductive system: Azospermia Amenorrhea Side Effects

Effects on Cardiovascular System: Heart failure cardiomyopathy IHD Effects on CN system: Periphral neuropathy Fit Parasthesia Loss of hearing

Side Effects Effects on Respiratory System: Respiratory failure Pulminary fibrosis RDS Chemical pneumonitis Effects on GU system: nephropathy Haemoragic cystitis Renal papillary necrosis Renal fialure

Others Second Malignancies After Chemotherapy Hepatic toxicity Cataract Electrolites imbalance Teratogenicity in pregnancy Hypersensetivity reactions extravasation Side Effects

ROUTES OF ADMINISTRATION Intravenous Most chemotherapeutic agents are available only in an intravenous preparation, requiring venous access Oral A number of agents are available in oral form, making intravenous access unnecessary. Intraperitoneal Therapy Intrathecal Leptomeningeal seeding and/or free tumor cells in the cerebrospinal fluid (CSF) most commonly occur with acute lymphocytic, and myelogenous leukemia, lymphomas, and carcinomas

ROUTES OF ADMINISTRATION Intraventricular Therapy Intra-arterial Therapy primary and metastatic to the liver Intravesical therapy BCG for T1 Ca Bladder Wafers eluting BCNU surgically implanted into resection sites have been used as part of multimodality therapy for gliomas Intrapleurally for sclerosis of malignant pleural effusions

Cell Cycle Specific Drugs: Antimetabolites Bleomycin peptide antibiotics Vinca alkaloids Cell Cycle non-Specific Drugs: Alkylating agents Antibiotics (Dactinomycin) Cisplatin Chemotherapeutic Agents Effective for high growth-fraction- malignancies, such as hematologic cancers. Effective for both low-growth (solid tumors) and high growth fraction malignancies

Drugs according to cell-cycle effects Cell cycle Agents Cell cycle nonspecific Nitrogen mustards, aziridines, nitrosoureas, alkyl alkane sulfonates, nonclassic alkylating agents, anthracyclines, actinomycins, anthracenediones Cell cycle specific S Bleomycin, antimetabolites, camptothecins, epipodophyllotoxins G2 Bleomycin, epipodophyllotoxins M Vinca alkaloids, taxanes

Chemotherapeutic Agents

1.Alkylating agents: Major interaction: Alkylation of DNA Binds to nucleophilic groups on various cell constituents. Including DNA These drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and phosphate groups of cellular constituents. Primary DNA alkylation site: N7 position of guanine (other sites as well) Major Toxicity: bone marrow suppression Chemotherapeutic Agents Cyclophosphamaide Carboplatin Cisplatin Oxaliplatin Dacarbazine

Antimetabolites: Folic Acid Analogs Methotrexate inhibitor of dihydrofolate reductase, the enzyme that catalyzes conversion of folic acid to tetrahydrofolate. Pyrimidine Analogs Two pyrimidine analogs, 5-fluorouracil and cytarabine, are commonly used. 5-Fluorouracil must be converted to an active 5-fluoro−2′-deoxyuridine-5′-phosphate form to bind the enzyme thymidylate synthetase and block or inhibit DNA and RNA synthesis. This drug is considered S phase-specific. Cytarabine (cytosine arabinoside) is an analog of 2′- deoxycytidine and must be activated by conversion to a 5′- monophosphate nucleotide. The nucleotide analog, AraCTP, inhibits DNA synthesis by substitution of arabinose for deoxyribose in the sugar moiety of DNA; cytarabine may also inhibit DNA repair enzymes. This drug is S phase-specific Purine Analogs Two purine analogs, 6-mercaptopurine (6-MP) and 6- thioguanine (6-TG), are used occasionally. 6-MP is a sulfhydryl-substituted analog of hypoxanthine that must be converted to an active form by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The active drug inhibits synthesis and metabolism of purine nucleotides and thus disrupts synthesis and function of DNA and RNA. This S phase- specific drug Chemotherapeutic Agents 2. Antimetabolites: Structurally related to normal compounds that exist within the cell. Interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase and therefore are cell-cycle specific. 5-Fluoro Uracil Gemcitabine Cyterabine Methotrexate

3. Microtubule Inhibitors: These are plant-derived substances. Cause cytotoxicity by affecting the equilibrium between the polymerized and depolymerized forms of the microtubules. Vinca alkaloids inhibit microtubule polymerization and increase microtubule disassembly. The mitotic spindle apparatus is disrupted, and segregation of chromosomes in metaphase is arrested. Chemotherapeutic Agents Vinca Alkaloids Vincristine Vinblastine Vinorelbine Taxanes Paclitaxel Docetaxel

4. Antineoplastic Antibiotics: Interacts with DNA, leading to disruption of DNA function. Also Inhibit topoisomerases (I and II) and produce free radicals. Cell-cycle nonspecific. Eg: Actinomycin D binds with double-stranded DNA and blocks the action of RNA polymerase, which prevents DNA transcription. Chemotherapeutic Agents Bleomycin Doxorubicin Dactinomycin Daunorubicin

5. Hormonal Agents: Commonly involves the use of glucocorticoids. Direct antitumor effects are related to their lympholytic properties;. Glucocorticoids can inhibit mitosis, RNA synthesis, and protein synthesis in sensitive lymphocytes. Considered cell-cycle nonspecific. Resistance to a given glucocorticoid may develop rapidly and typically extends to other glucocorticoids. Chemotherapeutic Agents Prednisolone Tamoxifen Estrogens Flutamide Nilutamide Bicalutamide

Biologic response modifiers (e.g., interferon خ ± and interleukin 2,) antibodies, and targeted agents of several types. In addition, gene therapy and antisense approaches Antibodies or molecules that are made in the lab rather than by a person's own immune system. Directed at specific targets and often have fewer adverse effects. Designed to recognise and find specific abnormal proteins on cancer cells. Each monoclonal antibody recognizes one particular protein. Chemotherapeutic Agents Rituximab Trastuzumab Cetuximab Bevacizumab Interleukin Interferone imatinibe 6. Targeted therapy:

Three types of monoclonal A-bodies: 1.Trigger the immune system to attack and kill cancer cells. E.g. Rituximab (Mabthera) 2. Stop cancer cells from taking up proteins E.g. Trastuzumab (Herceptin). 3.Carry cancer drugs or radiation to directly to cancer cells These are called conjugated MABs. E.g. Ibritumomab (Zevalin) Chemotherapeutic Agents Rituximab Trastuzumab Cetuximab Bevacizumab

CANCER CHEMOTHERAPEUTIC DRUGS WITH RADIATION SENSITIZER PROPERTIES 5-Fluorouracil Gemcitabine Cisplatin, carboplatin Paclitaxel CPT-11, topotecan 5-bromodeoxyuridine, 5- iododeoxyuridine

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