Principles of chemotherpy in oncology

Click to edit Master subtitle style Dr ganesh

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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

Cance It is basically a disease of cells r

Click to edit Master subtitle style

places in the body )

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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.

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Chemotherapy
Types of Therapis: 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 5/20/12 chemotherapy and radiation.

Chemother apy It is the treatment of disease by

chemicals especially by killing microorganisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a regimen.

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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 5/20/12 is focused on the orderly division into two

1.

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 lifethreatening toxicity.

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Principles of cancer chemotherapy

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 5/20/12 radiation treatment.

3.

Principles of cancer chemotherapy 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.

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4. Cell cycle specificity of drugs:

Principles of cancer chemotherapy

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

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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.

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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 Click to edit Master subtitle style than single drug treatment. In combine therapy the drugs must have different toxicities, Mechanism of action.

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Principles of cancer chemotherapy on the Effects of various treatments

cancer cell burden:

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Problems associated with chemotherapy:

Principles of cancer chemotherapy

Resistance:
a) Inherent b) Acquired

Toxicities:

Effects on normal rapidly proliferating cells i.e. Buccal mucosa, Bone marrow, GI mucosa, Hair.
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Dosage

In most cases, the dose is adjusted for the patient'sbody surface area. In others given as /body wt. The BSA is usually calculated with a mathematical formula or anomogram, using a patient's weight and height.

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Delivery

Intravenous Oral ( melphalan, busulfan, capacitabine) isolated limb perfusion(melanoma), or isolated infusion

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A Hickman line in aleukemiapati ent. It is tunnelled under the skin to thejugular vein
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Port-a-Cath with needle assembly inserted.

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Advantages

These have a lower infection risk Much less prone tophlebitisorextravasation Abolish the need for repeated insertion of peripheral cannulae.

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New experimental approches

Isolated infusion approaches Targeted delivery mechanisms Nanoparticles Electrochemotherapy

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Isolated infusion approaches

Isolated limb perfusion(often used inmelanoma) isolated infusion of chemotherapy into the liver or the lung purpose of these approaches is

to deliver a very high dose of chemotherapy to tumor sites without causing overwhelmingsystemicdamage
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Targeted delivery mechanisms

Targeted delivery vehicles have a differentially higher affinity for tumor cells by interacting with tumorspecific or tumor-associated antigens. Aim to increase the maximum effective dose that can be delivered to the tumor cells
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Nanoparticles

Useful vehicle for poorly soluble agents such aspaclitaxel. Protein-bound paclitaxel(e.g. Abraxane)

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Electrochemotherapy

injection of a chemotherapeutic drug is followed by application of high-voltage electric pulses locally to the tumor enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells, to enter the cancer cells e.g.bleomycin and cisplatin
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Adverse affects

Chemotherapeutictechniques have a range of side-effects that depend on the type of medications used. The most common medications affect mainly thefast-dividing cellsof the body, such as blood cells and the cells lining the mouth, stomach, and intestines.
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Contd

Depression of theimmune system, which can result in potentially fatalinfections. Fatigue( mild to severeanemia.) Tendency to bleed easily.( platelets) Gastrointestinal distress . Nauseaand vomitingare common can also producediarrheaorconstipation

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Contd.
Damage to specific organs is possible:

Cardiotoxicity Hepatotoxicity Nephrotoxicity Ototoxicity Encephalopathy

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Chemotherapeutic

Cell Agents Cycle Specific Drugs:

Antimetabolites Bleomycin peptide antibiotics Vinca alkaloids
Effective for high growthfractionmalignancies, such as hematologic cancers.

Cell Cycle non-Specific Drugs:

agents

Alkylating 5/20/12

Effective for both lowgrowth (solid tumors) and high growth fraction malignancies

Chemotherapeutic

Agents

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Chemotherapeutic
1.

Agents Alkylating agents:

Major interaction: Alkylation of DNA

Cyclophosphamaid e Carboplatin Cisplatin Oxaliplatin Dacarbazine

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) Toxicity: bone marrow suppression

Major 5/20/12
.

Chemotherapeutic
2.

Agents 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.

5-Fluoro Uracil Gemcitabine Cyterabine Methotrexate

Their maximal cytotoxic effects are in Sphase and therefore are cell-cycle specific.

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Chemotherapeutic

Agents
3.

Microtubule Inhibitors:

Vinca Alkaloids Vincristine Vinblastine Vinorelbine Taxanes Paclitaxel Docetaxel

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 5/20/12

Chemotherapeutic
4.

Antineoplastic Antibiotics:

Agents

Interacts with DNA, leading to disruption of DNA function. Also Inhibit topoisomerases (I and II) and produce free radicals. Cell-cycle nonspecific.

Bleomycin Doxorubicin Dactinomyc in Daunorubici n

Eg: Actinomycin D binds with doublestranded DNA and blocks the action of RNA polymerase, which prevents DNA 5/20/12 transcription.

Chemotherapeutic

Agents
5.

Hormonal Agents:

Commonly involves the use of glucocorticoids.

Prednisone Tamoxifen Estrogens Flutamide Nilutamide Bicalutami de

Direct antitumor effects are related to their lympholytic properties;.

Glucocorticoids can inhibit mitosis, RNA synthesis, and protein synthesis in sensitive lymphocytes.
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Considered cell-cycle nonspecific .

Chemotherapeutic
6. Monoclonal Antibodies: Antibodies 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. monoclonal antibody recognizes

Agents

Rituximab Trastuzuma b Cetuximab Bevacizuma b

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Chemotherapeutic

Agents

Different types of monoclonal A-bodies: Trigger the immune system to attack and kill cancer cells. E.g. Rituximab 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.

Rituximab Trastuzuma b Cetuximab Bevacizuma b

1.

2.

3.

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