chemotherapy

Cancer Chemotherapy 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 ProliferationDedifferentiation and loss of functionInvasiveness (Spreading)Metastasis (spread of cancer from its primary site to other places in the body ) Cancer


Management of Cancer SurgicalRadiationChemotherapyThe 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 cancerColorectal cancerOsteosarcomaWilms' tumorStage II-III gastric cancerStage II-III non-small cell lung cancerStage 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 cancerLarynx cancerEsophageal cancerBladder cancerAnal cancerOsteosarcomaSoft tissue sarcoma



Larynx cancer Esophageal cancerCervical carcinomaPNS CarcinomaRectal 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 G0 : A resting phase,the cell has stopped dividing.G1 : Cells increase in size.S : DNA replication occurs.G2 : 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 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 ChoriocarcinomaHodgkin's lymphomaNon-Hodgkin's lymphoma (some types)Testicular cancerAcute lymphoid leukemiaAcute myelogenous leukemiaOvarian cancerSmall cell lung cancer


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

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.


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 toxicitiesDrugs 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) AcquiredToxicities: Effects on normal rapidly proliferating cells i.e. Buccal mucosa, Bone marrow, GI mucosa, Hair. Principles of cancer chemotherapy



Bone marrow suppressionAnemiaNeutropeniaThrombocytopeniaEffects on GITNausea & VomitingStomatitis & mucositisDysphagiaConstipationDiarrhea Side Effects


Effects on skin:Skin drynessPhotosensetivitySkin pigmentationHair lossEffects on reproductive system:AzospermiaAmenorrhea Side Effects


Side Effects Effects on Cardiovascular System:Heart failurecardiomyopathyIHDEffects on CN system:Periphral neuropathyFitParasthesiaLoss of hearing


Side Effects Effects on Respiratory System:Respiratory failurePulminary fibrosisRDSChemical pneumonitisEffects on GU system:nephropathyHaemoragic cystitisRenal papillary necrosisRenal fialure


OthersSecond Malignancies After ChemotherapyHepatic toxicityCataractElectrolites imbalanceTeratogenicity in pregnancyHypersensetivity reactionsextravasation Side Effects


ROUTES OF ADMINISTRATION Intravenous Most chemotherapeutic agents are available only in an intravenous preparation, requiring venous accessOral A number of agents are available in oral form, making intravenous access unnecessary. Intraperitoneal TherapyIntrathecal 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 TherapyIntra-arterial Therapyprimary and metastatic to the liverIntravesical therapyBCG for T1 Ca BladderWafers eluting BCNU surgically implanted into resection sites have been used as part of multimodality therapy for gliomasIntrapleurally for sclerosis of malignant pleural effusions



Cell Cycle Specific Drugs:AntimetabolitesBleomycin peptide antibioticsVinca alkaloidsCell Cycle non-Specific Drugs:Alkylating agentsAntibiotics (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 effectsCell cycle Agents Cell cycle nonspecific Nitrogen mustards, aziridines, nitrosoureas, alkyl alkanesulfonates, nonclassic alkylating agents, anthracyclines,actinomycins, anthracenedionesCell cycle specificS Bleomycin, antimetabolites, camptothecins, epipodophyllotoxinsG2 Bleomycin, epipodophyllotoxinsM Vinca alkaloids, taxanes

Chemotherapeutic Agents

Alkylating agents:Major interaction: Alkylation of DNA Binds to nucleophilic groups on various cell constituents. Including DNAThese 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 CyclophosphamaideCarboplatinCisplatinOxaliplatinDacarbazine


Antimetabolites:Folic Acid AnalogsMethotrexateinhibitor of dihydrofolate reductase, the enzyme that catalyzes conversion of folic acid to tetrahydrofolate.Pyrimidine AnalogsTwo 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-specificPurine AnalogsTwo 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 UracilGemcitabineCyterabineMethotrexate


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 AlkaloidsVincristine VinblastineVinorelbineTaxanesPaclitaxelDocetaxel


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 BleomycinDoxorubicinDactinomycinDaunorubicin



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 PrednisoloneTamoxifenEstrogensFlutamideNilutamideBicalutamide


Biologic response modifiers (e.g., interferon خ± and interleukin 2,) antibodies, and targeted agents of several types. In addition, gene therapy and antisense approachesAntibodies 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 TrastuzumabCetuximabBevacizumabInterleukinInterferoneimatinibe 6. Targeted therapy:


Three types of monoclonal A-bodies: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).Carry cancer drugs or radiation to directly to cancer cells These are called conjugated MABs. E.g. Ibritumomab (Zevalin) Chemotherapeutic Agents Rituximab TrastuzumabCetuximabBevacizumab


CANCER CHEMOTHERAPEUTIC DRUGS WITH RADIATION SENSITIZER PROPERTIES 5-FluorouracilGemcitabineCisplatin, carboplatinPaclitaxelCPT-11, topotecan5-bromodeoxyuridine, 5-iododeoxyuridine

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