chemotherapy.ppt

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CHEMOTHERAPY


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INTRODUCTION

Chemotherapy (sometimes cancerchemotherapy) is the treatment ofcancer with an antineoplastic drug orwith a combination of such drugs into astandardized treatment regimen.

Most commonly, chemotherapy acts bykilling cells that divide rapidly, one ofthe main properties of most cancercells. This means that it also harms cellsthat divide rapidly under normalcircumstances: cells in the bone

marrow, digestive tract and hairfollicles.


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This results in the mostcommon side effects of

chemotherapy:myelosuppression (decreasedproduction of blood cells,

hence alsoimmunosuppression),mucositis (inflammation ofthe lining of the digestivetract), and alopecia (hair loss).


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Newer anticancer drugs act directly

against abnormal proteins in

cancer cells; this is termed targeted

therapy and is technically not

chemotherapy


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The first efforts were in the 1940s to

1950s

,In a german air raid inBari,Italy,one thousand people were

exposed to certain mustard gas

bombs,

Autopsies of the victims suggested thatprofound lymphoid and myeloid

suppression had occurred after

exposure.

MILESTONES IN CHEMOTHERAPY


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Dr. Alexandertheorized that since

mustard gas all but ceased the

division of certain types of Somatic

cells whose nature it was to divide

fast, it could also potentially be put to

use in helping to suppress thedivision of certain types of cancerous

cells


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-Faberin 1948 administered antifolates

to children with ALL , these agents

became the first drugs to be used inchildren with ALL.His reports were

ridiculed during his time.

-Remarkably, a decade later at the

National Cancer Institute, Roy Hertzand Min Chiu Li discovered that the

same methotrexate treatment alone

could cure choriocarcinoma (1958), a

germ-cell malignancy that originates introphoblastic cells of the placenta. This

was the first solid tumour to be cured

by chemotherapy.


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-George Hitchings and Gertrude

Elion, two pharmaceutical chemists

who were working at the Burroughs

Wellcome Co.in Tuckahoe, manypurine analogues were tested,

culminating in the discovery of 6-

mercaptopurine (6-MP), which was

subsequently shown to be a highlyactive antileukemic drug.

-The Eli Lilly natural products group

found that alkaloids of the

Madagascar periwinkle (Vinca

rosea), originally discovered in a

screen for anti-diabetic drugs,

blocked proliferation of tumour cells


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-Combination Chemotherapy- In

1965, a major break-through in cancer

therapy occurred. James Holland,

Emil Freireich, and Emil Freihypothesized that cancer

chemotherapy should follow the

strategy of antibiotic therapy for

tuberculosis with combinations ofdrugs, each with a different

mechanism of action


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This approach was extended to the

lymphomas by Vincent T. DeVita and

George Canellos at the NCI, whoultimately proved in the late 1960s that

nitrogen mustard, vincristine,

procarbazine and prednisone known

as the MOPP regimen

could curepatients with Hodgkin's and non-

Hodgkin's lymphoma


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-The landmark trials ofBernard Fisher, chair of

the National Surgical Adjuvant Breast and

Bowel Project, and ofGianni Bonadonna,

working in the Istituto Nazionale Tumori diMilano, Italy, proved that adjuvant

chemotherapy after complete surgical

resection of breast tumours significantly

extended survival particularly in more

advanced cancer.

-Gordon Zubrod had a particular interest in

natural products, and established a broad

programme for collecting and testing plant and

marine sources, a controversial programme

that led to the discovery oftaxanes (in 1964)

and camptothecins (in 1966).


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After 4 years of clinical testing

in solid tumours, it was found in

1987 (Taxanes,23 years after

its initial discovery) to be

effective in ovarian cancer

therapy.

In 1996 a more stable

analogue, irinotecan, won Food

and Drug Administration (FDA)approval for the treatment of

colon cancer


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Other effective molecules alsocame from industry during the

period of1970 to 1990, including

anthracyclines and

epipodophyllotoxins both ofwhich inhibited the action of

topoisomerase II, an enzyme

crucial for DNA synthesis


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1.The Cells Kill Hypothesis of Skipper

Skipper formulated some principles

while studying tumor cells in mice

suffering from leukemia which showedthat:

The survival of an animal was inversely

related to the Tumor burden.

Asingle leukemic cell is capable ofmultiplying and killing the host.

For most drugs, there is a clear

relationship between dose of the drugs

and eradication of tumor cells.

Principles of Chemotherapy


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-A given dose of a drug kills a constant

fraction of cells and not a constant

number. The same amount of drug isrequired to reduce the burden from one

million cells to 10 cells as from 1 lacks

to 1 cell.

-Implication of this cell kill hypothesis is

that tumors are best treated. when theyare small in volume and the treatment

must continue until the last cell is

eradicated'

-If the treatment is discontinued assoon as the tumor is no longer

clinically detectable, at least 109 tumor

cells will remain unkilled and relapse is

inevitable


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2.The Norton Simon Hypothesis

-In the tumor, which show Gompertizian

type of growth Curves, the rate of

regrowth increases as the tumorshrinks with the therapy.

-Thus, the level of treatment adequate

to initiate a regression maybe

insufficientto maintain the regressionand produce cure.

-So to overcome this, Norton and

Simon hypothesized that to counteract

the slowing rate of regression in a

tumor responding to therapy, it is

necessary to increase the intensity of

treatment as the tumor becomes

smaller.


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-Some time radiotherapy andmarrow transplantation can be

used to intensify the treatment.

-Multidrug regimens are used to

attack residual population of cells,

biochemically resistant to the

initial combination of drugs


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3.The Goldie Goldman Model

-In1979 Goldie and Goldman produceda model to explain the development of

resistance to anticancer drug by the

tumor cells and suggested that the

populationof cells within the tumor

were capable of randomly becoming

resistant to the cytotoxic agents by

means of spontaneous mutation.


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TYPES OF CHEMOTHERAPY


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Induction chemotherapy

-When the disease is locoregionally

advanced or there is potentialsystemic spread, the chemotherapy

initiated as a first line therapy prior

to the main modality of treatment is

known as induction, anterior orneoadjuvant chemotherapy.

-Induction chemotherapy

theoretically ensures better drug

delivery and, aims at reduction of

the tumor bulk


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-Higher doses of thechemotherapeutic regimens can be

easily administered as the patient

tolerance is better at the onset of

treatment.

-With the help of this type of

treatment, tumors can be down

staged and the organs can be

preserved such as in oesophagus,bladder and breast cancers


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The neoadjuvant chemotherapy by

producing tumor shrinkage couldtheoretically allow reoxygenation and

reduction of the hypoxic component,

and thereby renders the tumor more

vulnerable to

radiation cell kill.

The possible disadvantage of induction

chemotherapy is that, it delays the

local treatment either by surgery orradiotherapy


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-Secondly, if there is intense

chemotherapy related toxicity, itmay become difficult to administer

the primary mode of treatment.

-Lastly, in a nonresponsive tumor

or where an accelerated

repopulation occurs, there may be

progression of disease during this

protracted course of chemotherapy.


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Adjuvant chemotherapy

-Adjuvant chemotherapy isadministered when the disease is

localized and has been controlled

primarily by another therapeutic

modality "(surgery "or radiationtherapy).

-For a vast majority of solid tumors

where surgery and radiotherapy

remain the local treatment modality,the patient may have the risk of

local recurrence, lymph node or

distant metastasis.


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-The loco-regional relapse rate

can be reduced in these

patients by the adjuvantchemotherapy.

-This form of therapy is given to

reduce the incidence of

systemic micro-metastasis

thereby, increasing the

possibility of disease-free andoverall survival


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-There is a potential advantage in treating

patients with adjuvant chemotherapy, after

the local treatment.

-Total tumor burden is reduced to a sub-

clinical level and the chemotherapeutic

agents are effective in eradicating the

microscopic disease.

-It is also realized that chemotherapy often

fails to cure the disease, once the

recurrence has occurred.

-The benefits of adjuvant systemic

treatment in a particular neoplasm is

critically linked to the properly selected

chemotherapy regimen


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-Suitable and specific, regimens

have been evolved over the

years in certain tumors e.g.osteogenic sarcoma, breast

cancer and colorectal

malignancies.

-On the other hand, the

chemotherapy schedules are not

yet fully standardized in cancersof ovary, lung and esophagus


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Primary chemotherapy

-In certain chemoresponsive ,tumors

chemotherapy is administered as the treatment of

choice such as in leukemias, lymphomas,

choriocarcinoma and non-seminomatous germ

cell tumors;

-Currently, chemotherapy delivered as a curative

approach is usually consisting of a combination of

several drugs. This is commonly known as

combination chemotherapy.

- Drugs that have shown antitumor activity against

the disease are delivered in specific dose

schedules.


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A number of principles have been

recognized for the combination

chemotherapy.

1.Only those agents of, proveneffectiveness should be used.

2. Each agent used should have a

different mechanism of action.

3. Each drug should have a differentspectrum of toxicity.

4. Each drug should be used at

maximum.

5. Drug combination should be

administered in shortest interval

between therapy cycles to allow for

the recovery of normal tissues


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Typically,combination chemotherapy

regimens are given as repetitive

cycles for a defined period (numberof chemotherapy courses or cycles is

designed for a particular neoplasm).

As far as possible the drug dosesare given in a fixed schedule. The

dose modification is needed when

the patient has myelotoxicity (low

blood counts), renal or hepatic

dysfunction or poor tolerance to the

given regimen.


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Certain guidelines are followed forthe drug dose reduction. The

response to the chemotherapy is

periodically evaluated after every 2 -

3 cycles.

The median duration of response is

evaluated after the completion of

chemotherapy schedules in terms of

weeks or months and this is usuallytaken as the end point in evaluation


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Concomitant chemo-radiotherapy

-The main rationale for this strategy is utilization of

direct interaction of radiotherapy and

chemotherapy.

-Generally, drug combinations believed to have

radiation enhancing properties are utilized in this

approach.

-The drugs known to have this property are

hydroxyurea, 5-FU and cisplastin.

-However there are certain drugs which can causedramatic increase in cutaneous and mucosal

reactions and prove deleterious at times. These

are adriamycin, mitomycinC and bleomycin.;


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Simultaneous chemo-radiotherapy is givento improve the local control as well as todecrease the incidence of distantmetastasis.

Several studies have been carried out in thecancers of head and neck region, anal canaland esophagus with encouraging results.

Radiation combined , with hydroxyureaproved more effective than radiation alonein a randomised trial in advanced cervicalcancer.

The chemoirradiation has also been triedas an alternative to the traditional surgeryand radiotherapy combination in advancedlaryngeal cancer.

S l h th


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Salvage chemotherapy

Although objective is tumor regression, duration of

survival and cure rates have also been the objectives

of chemotherapy, there will be a group of patients

who will need chemotherapy with an attempt to

salvage the recurrent disease.

Whenever the first line of therapy, i.e. surgery,

radiotherapy,chemotherapy or combinations fail, thepatient is considered for salvage therapy.

The salvage chemotherapy is generally attempted

when the patient has a good performance status,

there is reasonable expectancy of life, and the

neoplasm is potentially chemosensitive.

The common situations are germ cell tumors,

lymphomas, leukemias and the less common

malignancies are cancer of the breast, head and

neck, colon,rectum and ovary


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The role of chemotherapy as a palliative intent

is not yet well defined and this is usually utilized

in advanced or recurrent solid tumors to

achieve tumor reduction and improve thequality of life.

Radiotherapy and chemotherapy alone can

control about 20-30 % of cancers.

An interdigitation of these modalities in a

logical sequence has led to excellent results in

several tumors.

The multimodal holistic approach in cancer hasresulted in some completely curable cancers,

namely, childhood ALL, Ewing's sarcoma,

testicular tumor and medulloblastoma.


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The Classification ofAnticancer Drugs


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According to chemical

structure and resource ofthe drug;

According to biochemistry

mechanisms of anticanceraction;

According to the cycle or

phase specificity of thedrug


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According to chemical

structure and resource of

the drug:

Alkylating Agents,

Antimetabolite,Antibiotics,

Plant Extracts

Hormones

Others


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According to biochemistry mechanisms of

anticancer action:

Drugs that Block nucleic acidbiosynthesis

Drugs that Directly influence the

structure and function of DNA

Drugs that Interfere the transcriptionand block RNA synthesis

Drugs that Interfere with proteinsynthesis and function

Drugs that Influence hormonehomeostasis

Others


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Drugs that Block Nucleic Acid (DNA, RNA) Biosynthesis

Antimetabolites:

Folic Acid Antagonist:inhibit

dihydrofolate reductase (methotrexate)

Pyrimidine Antagonist:inhibit thymidylate

synthetase (fluorouracil) ; inhibit DNA

polymerase (cytarabine)

Purine Antagonist:inhibit interconversion

of purine nucleotide (mercaptopurine)

Ribonucleoside Diphosphate Reductase

Antagonist:(hydroxyurea)


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Drugs that Interfere with ProteinSynthesis

Antitubulin:vinca alkaloidsand

taxanes;

Interfere the function ofribosome:harringtoninesInfluence amino acid supply:L-

asparaginaseBind tubulin, destroy spindle to

produce mitotic arrest


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Drugs that InterferewithTranscription and Block RNA

Synthesis

They bind with DNA to

block RNA production.

For eg: doxorubicin


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Drugs that Influence theStructure and Function of DNA

Alkylating Agent:mechlorethamine,cyclophosphamide and thiotepaPlatinum:cis-platinium

Antibiotic:bleomycin andmitomycin C

Topoismerase inhibitor:camptothecine and

podophyllotoxin


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Drugs that Influence HormoneHomeostasis

These drugs bind to hormone receptors toblock the actions of the sex hormones whichresults in inhibition of tumor growth.

Estrogens and estrogen antagonistic drug

Androgens and androgen antagonistic drug

Progestogen drug

Glucocorticoid drug

gonadotropin-releasing hormone inhibitor:leuprolide, goserelin

aromatase inhibitor: aminoglutethimide,anastrazole


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According to the cycle or

phase specificity of the

drug:

cell cycle nonspecificagents (CCNSA)

cell cycle specific agents(CCSA)


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The Basic Concept ofCell Generation Cycle


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The cycle of cell replication

includes:

MMitosisphase G1Gap1, period before Sphase SDNA synthesisphaseo G2Gap2,period after Sphase

Growth Fraction (GF


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d h l d


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According to chemical structure andresource of the drug

Alkylating Agents

-Alkyl SulfonateBusulfan

-Nitrogen MustardsMustine HCL,

Cyclophosphamide,

Melphalan and Chlorambucil

-NitrorsoureasCarmustine (BCNU), Lomustine

(CCNU),Semustine (Methyl-CCNU)

-TriazineDacarbazine

-EthylenimineThio- TEPA


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They produce their effect by linking an alkylgroup (R-CH2) covalently in protein andnucleic acid. Some of them are described

below:

Alkyl Sulfonate

BusulfanIt is highly specific for myeloidelements, granulocyte precursors beingmost sensitive, followed by those ofplatelets and RBCs.

UseIt is the drug of choice of chronicmyeloid leukemia.

Dose2-6 mg/day orally.


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Nitrogen Mustards

Mechanismit has two chloroethyl sidechains. One of them forms a cyclical highlyreactive ammonium ion which binds tonucleic acids, i.e. 7-nitrogen group ofguanine. The other chloroethyl sides of

nitrogen mustards can crosslink with DNAstrands, either within a strand or betweenstrands. Although alkylating agents maybind to variety of cellular components likecytoplasmic proteins and RNA at

therapeutic doses, impairment of DNAreplication is the major mechanism ofcytotoxicity of these drugs. Damage toDNA is more serious during the 'S' phase ofcell cycle probably because the cell has lesstime to excise the damage to DNAfragment.

M ti HCl It i th fi t it t d


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Mustine HClIt is the first nitrogen mustard,highly reactive and local vesicant. Dose0.4 mg/kg IV in 1-4 days.

Cyclophosphamideit has prominentimmunosuppressant property. Dose2-3mg/kg/day orally, 10-15 mg/kg IV every 7-10 days.

Chlorambucilit is the slow actingalkylating agent, especially active onlymphoid tissue. It is drug of choice forchronic lymphatic leukemia. Dose4-10mg daily for 3-6 weeks, then 2 mg daily for

maintenance.

Melphalanit is very effective in multiplemyeloma. Dose10 mg daily for 7 days or6 mg/day for 2-3 weeks and after 4 weeks'gap, 2 -4 mg daily for maintenance orally.


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Nitrosoureas

Mechanismthey act partly asalkylating agents linking to an alkylgroup or carbonyl group of cellproteins and form compounds

which are unstable in water anddecompose to form alkylatinggroups, which are able to damagethe cell proteins.

DoseBCNU50-200 mg/m2,CCNU100-130 mg/m2, methylCCNU100-200 mg/m2.

i i


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Triazine

Dacarbazineit is different fromother alkylating agents inhaving primary inhibitory

action on RNA and proteinsynthesis. It is activated in theliver. It is used in malignantmelanoma.

Dose3.5 mg/kg/day IV for 10days, repeat after 4 weeks.

h l i i


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Ethylenimine

Thio-TEPAit does notrequire formation of an activeintermediate. It has high

toxicity and seldom usedtoday.

Dose0.3-0.4 mg/kg IV at 1-4

weeks intervals.

Antimetabolites


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Antimetabolites

Purine antagonist - 6-Mercaptopurine,

6-Thioguanine

-Folate antagonist Methotrexate

-Pyrimidine antagonist 5-Fluorouracil, Cytarabine (cytosinearabinoside).

i A i


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Purine Antagonist

Mechanism of actionMercaptopurine andthioguanine are highly effective anticancerdrugs. It inhibits conversion of inosinemonophosphate to adenine and guaninenucleotides.

Usethey are useful in childhood acuteleukemia and choriocarcinoma

Toxic effectmain toxic effects ofantipurines are bone marrow depressionwhich develops slowly.

Dose6-Mercaptopurine (2.5 mg/kg/day)and 6-Thioguanine (2 mg/kg/day).

F l A id A i


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Folate Acid Antagonist

ActionMost commonly used folic acid antagonistmethotrexate. It inhibits the conversion ofdihydrofolate to tetrahydrofolic acid which inturn is converted to a variety of coenzymes. Itblocks thymidylate monophos-phate synthesisand thus inhibiting RNA synthesis and so

methotrexate is 'S' phase specific

Absorptionit is well absorbed from the gut atlow doses (up to 100 mg) but higher dosesshould be given intravenously. After IVinjection, there is a rapid early half life of 45

minutes, a slower phase of renal excretion: ofabout 3 hours and then a very long terminalhalt Methotrexate does not penetrate the CSFat conventional doses. To ensure adequatelevels in CSF, methotrexate may be givenintrathecally at a dose of 10 mg/m2.

Toxicity the prolonged clearance of


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Toxicitythe prolonged clearance ofmethotrexate is responsible for thetoxicity to marrow gut and mucous

membrane which leads to bonemarrow depression, diarrhea andoral ulceration. The toxicity ofmethotrexate can be reversed byfolic acid.

Contraindicationsit should be

avoided in patients withascites orpleural effusion as the drug mayaccumulate in fluid reservoirs andwill release slowly causing toxicity.

Indications Used in treatment of


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IndicationsUsed in treatment ofacute leukemia, non-Hodgkin'slymphoma, breast cancer and

osteogenic sarcoma.

Dosein choriocarcinoma 1 5-30mg/day for 5 days orally or 20-40

mg/m2

IM or IV twice a week. Inmaintaining remission in childrenwith acute leukemias. 2,5-15mg/day is useful.

P i idi A i


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Pyrimidine Antagonists

Actionmost commonly used are 5-fluorouracil and cytarabine. Itinterferes with nucleic acid synthesisby antagonizing or mimickingpyrimidine metabolites.

Absorptionit may be given orally butits absorption is unpredictable. So, theIV route is often used because theplasma clearance is rapid.

Toxicitynausea, vomiting, stomatitis,alopecia and myelosuppression.

Indications it is given in the


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Indicationsit is given in thetreatment of breast and GITcancer, Hodgkin's lymphoma,

non-Hodgkin's lymphoma,acute leukemia to induceremission,

Dosefluorouracil1 gm

orally on alternate day for 6days followed by 1 gm weekly

or 12 mg/kg/day IV for 4 days.Cytarabine1.5-3 mg/kg IVBD for 5-10 days.

A tibi ti


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Antibiotics

-Actinomycin-D-Mitoxantrone

-Bleomycin

-Daunorubicin-Doxorubicin

-Mithramycin

-Mitomycin C

A tibi ti


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Antibiotics

Practically all of theantibiotics intercalate betweenDNA strands and interfere

with template functioning

A ti i D


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Actinomycin-D

It is isolated from streptomyces. Itis intercalated with guanine andcytosine base pairs and blocks thetranscription of DNA and DNA

related RNA Synthesis. It inhibits division of rapidly

dividing cells. It is givenintravenously and plasma

clearance is within a few- minutes.

Toxicity nausea vomiting


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Toxicitynausea, vomiting,mucositis, diarrhea andmyelosuppression.

Indicationsit is active againstrhabdomyosarcoma, Wilm's

tumor ,Ewing's sarcoma, andteratoma.

Doseit maybe given as a singleinjection of 15 g/kg IVdailyfor 5 days or in combinationwith cyclophosphamide and

vincristine.

Mit t


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Mitoxantrone

Actionit binds to DNA and is givenintravenously and has a longterminal half life of 36 hours.

-Toxicityit may causemyelosuppression, cardiomyopathyand alopecia.

Indicationsacute non-hemolyticleukemia, chronic Myelogenousleukemia, non-Hodgkin lymphomaand Carcinoma of breast:12 mg/m2

single IV dose repeat at 3 weeks

Bl i


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Bleomycin

ActionIt consists of a mixture of closelyrelated glycopeptide antibiotics. It inhibitsDNA synthesis and causes a break in DNAand is active in G2 phase of the cell cycle

AbsorptionIt is given by parenteral,subcutaneous,intramuscular route becauseit is non-vesicant. It has initial half life of30 minutes and elimination from plasmatakes 2-9 hours. It is excreted by kidney

and does not cross the CSF.

Toxicityskin pigmentatic


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Toxicityskin pigmentatic ,erythema, vesiculation orfibrosis.

Indicationsit is used incombination with otherchemotherapeutic drugs in

testicular carcinoma, headand neck cancer andHodgkin's lymphoma.

Dose30 mg per injection

twice weekly IV

Doxorubicin and Daunorubicin


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Doxorubicin and Daunorubicin

ActionThese are antitumor antibiotics andare produced by streptomyces fungus. Theyare capable of causing breaks in DNAstrands by activating topoiso-merase II andgenerating quinone type radicals.

Absorptionthey are given by IV route andcleared from plasma, metabolized in liverand excreted in bile. So should be taken

while prescribing in liver dysfunctionpatients.

Toxicitynausea, vomiting,


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y , g,alopecia and diarrhea occur.Cardiotoxicity can occur whichmanifests as ECG changes,arrhythmias and hypotension.

Indications-doxorubicin is givenin lymphoma (Hodgkin's disease),small cell cancer, breast cancer and

daunorubicin is given in acutemyeloid and lymphatic leukemia.Daunorubicin used is limited toacute leukemia.

Dosedoxorubicin60-75 mg/m2IV every 3 weeks anddaunorubicin30-60 mg/m2 IVdaily

Mitramycin


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Mitramycin

Actionits use is restricted toembryonal testicular tumor,disseminated cancers, especiallythose with bony metastasis and

hypercalcemia. It reduces serumcalcium levels, probably by directaction on bone inhibiting calciumrelease.

Dose25 g/kg by slow IV infusiondaily or on alternate days.

Mitomycin C


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Mitomycin-C

Action-it is derived from streptomycesspecies and inhibits DNA synthesis byboth cross linking and alkylating DNA.

Toxicitymyelosuppression, cumulative

thrombocytopenia and renal toxicity.

Indicationsusedin combination in cancerof breast, stomach, cervix, pancreas andthose of head and neck.

Dose10 mg/m2 IV.


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Plant Extracts

Vinca alkaloids-Vinblastine

-Vincristine

Taxanes- Paclitaxel

- Docetaxel


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Epipodophyllotoxin

-Etoposide

- Teniposide

The Vinca Alkaloids


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The Vinca Alkaloids

They are mitotic inhibitors, which bind to'tubulin'(proteins of the cellularmicrotubules) to cause disruption ofmitotic spindle and interfere withcytoskeletal function.

The vinca alkaloid blocks assembly of Aand B subunit of the tubulin preventingthe formation of the microtubules.

Vinblastine


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Vinblastine

-Absorptionthese drugs aregiven IV and are vesicants ifextravasated. Plasmaclearance occurs in 3 phaseswith half life of 4 minutes, 1hour and 16 hours.

-Tissue binding is extensive and

prolongs the actions and thedrug binds to platelets, redcells and plasma proteins.

Indicationsit is used in


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Indications it is used incombination for treatment oftesticular tumors and

lymphoma.

Toxicityit causes alopecia,neurotoxicity and

myelosuppression. Dose0.1-0.15 mg/kg IV

weekly in 3 doses.

Vincristine


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VincristineUse.it is a rapidly acting drug, very

useful for inducing remission inchildhood acute leukemia.

Toxicityit causes peripheral

neuropathy, alopecia.

Indicationsit is medicated inlymphoma (Hodgkin's disease),

acute lymphatic leukemia, small cellcancer of bronchi and breast cancer.

Dose1.5 mg/m2 IV weekly.

Taxanes


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Taxanes

Paclitaxel

Actionit is a complex diterpintaxane from bark of the

Western yew tree.It enhances polymerization oftubulin. The microtubules arestabilized and their

depolymerization isprevented.


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Indicationsit is used in metastaticovarian and breast carcinoma afterfailure of first line chemotherapyand in relapse cases. It can be used

in head and neck cancer, small celllung cancer.

Dose175 mg/m2 by IV infusion

over 3 to 24 hours repeated every 3weeks

Docetaxel


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Docetaxel

It is a congener of paclitaxelwith the same mechanism ofaction.

It has been found to haveefficacy in metastatic breastcancer refractory to first linedrugs.

Major toxicity is neutropenia.

Epipodophyllotoxin


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Epipodophyllotoxin

Actionthese are phase specific and preventcells from entering mitosis from G2 phase.

Absorptionthe drugs are absorbederratically from the gut with the plasma

availability up to 50%, rapid clearancefrom plasma occurs when givenintravenously followed by a slower phase.

Etoposideit is highly protein bound and isexcreted in the urine in 72 hours.

Teniposideit is active as a single agent insmall cell lung cancer.

Toxicitythey cause alopecia,


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y y p ,myelosuppression, mucositisand neuropathy.

Indicationsit is used intreatment of testicular tumors,

leukemia and lymphoma.

Dose100 mg in 5 mlinjection or 120 mg/m2 IVinfusion for 30 minutes.


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Others

Enzymes:L-Asparaginase

Miscellaneous:

- Hydroxyurea

- Procarbazine

- Cisplatin

-Hexamethylamine

-Carboplatin

Enzymes


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Enzymes

L-Asparaginasethis enzyme is producedbyE. coli.

Actionit acts by removing asparaginefrom the circulation, thus depressing those

tumor cells which are unable to synthesizeasparagine due to lack of or have very lowlevels of asparagine synthetase.

Route of administrationdrug is usuallygiven intravenously after a skin test forhypersensitivity.

Indicationsit is used in the


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remission period in acutelymphocytic leukemia.

Toxicityanaphylaxis, pancreatitis,hypoglycemia, hypoproteinemia,encephalopathy and nausea.

Dose50-200 KU / kg IV daily for

2-4 weeks

Miscellaneous Agents


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Miscellaneous Agents

Hydroxyurea Actionit blocks the conversion ofribonucleotides to deoxyribonucleotides byinhibiting the enzyme ribonucleosidediphosphate reductase interfering with

DNA synthesis. It is'S' phase specific. It iswell absorbed orally and crosses the CSF.

Toxicityit causes neutropenia and gutdisturbance. There is also

myelosuppression.


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Indicationsit is used inchronic granulocytic leukemia,polycythemia vera.

Dose20-30 mg/daily for 8

weeks.

Procarbazine


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Actionthis is a weak mono-aminoacid oxidase inhibitor

which inhibits action of DNAand RNA and depressesproline synthesis. It alsocauses chromosomal damage.

Absorptionit is well absorbedfrom the gut and is one of the

few drugs which penetrate theCSF.

Indicationsit is used mainly


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in Hodgkin's disease and braintumor.

Toxicityit includes nausea,vomiting and leukopenia.

Dose: 100 -300 mg orally daily

for 2 weeks.

Cisplatin

A i hi d i h l i i


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Actionthis drug is the only active cytotoxicagent in its cis form. Chloride ions are lostfrom the molecule after it diffuses into the

cell and the compound crosslinks mainly toguanine groups like an alkylating agent. Itshould be protected from light and is givenintravenously with an early half life of about40 minutes with a later slower phase of

clearance i.e. about 60 hours.

Absorptionabout 90% of cisplatin bound toplasma protein is taken up in the kidney,gut, liver, testis and ovary, but it does not

cross the blood-brain barrier. It is excretedby the kidney.

Toxicityit is nephrotoxic, ototoxicd d


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and may cause severe nausea andvomiting. Renal damage may be

cumulative. Magnesium wastingmay occur as a result of renaldamage. If it is given in large dosesit is associated with peripheralneuropathy, predominately

affecting sensory nerve endings. it is very effective in testicular

tumors and ovarian cancer. It isalso effective in bladder, head neck

tumors, small cell cancer of bronchiand Htensarcoma. DMP50-100mg/m2 every 3-4 weeks.

Hexamethylamine


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Hexamethylamine

Indications-it is active against ovarianand cervical cancer

Absorption-it is well absorbed from

the gut.

Toxicity it causes abdominalcramps, diarrhea and leucopenia.

CNS toxicity includes alteredmental state aid convulsions.DOSE it is given orally at a dose of12 mg/kg/day for 14 days

Carboplatin


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p

Actionit is a less reactive

second generation platinumcompound that is bettertolerated.

Toxicity nephrotoxicity,ototoxicity and neurotoxicityare low. The dose limitingtoxicity is thrombocytopenia,

aids less often, neutropenia.

Indicationsit is primarily


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indicated in ovariancarcinoma of epithelial origin,

squamous cell carcinoma ,head and neck, small lungcancer and seminoma.

Dose 400 mg/m2 as an IVinfusion over 15-60 minutesto be repeated only after 4

weeks

COMPLICATIONS


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COMPLICATIONS

Many cytotoxic drugs areassociated with side effectsat commonly used

therapeutic doses. Long term side effect of

chemotherapy result in an

increased risk of secondarymalignancy and infertilityin some cases.

Local Toxicity


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Local Toxicity

Some cytotoxic drugs causesevere local reaction whenextravasated, e.g.daunorubicin, mitomycin andmustine HCl.

The use of trained personnelfor injection of cytotoxic drugs

reduces the hazards ofadministration

Hematological Toxicity


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Hematological Toxicity

Bone marrow suppression is the mostimportant dose limiting toxicity.Myelosuppression is expected to bemaximum in 10-14 days after treatment.

Certain drugs such as mitomycin and

nitrosoureas have a delayed effect at 4-5weeks. Hence, these drugs cannot be givenmore than once in week.

Some of the alkylating agents have acumulative effect on the bone marrow stem

cells, e.g. chlorambucil, busulphan andmelphalan. So the count may fall graduallyfor several weeks and recovery is slow.

Gastrointestinal Toxicity


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Gastrointestinal Toxicity

The precise cause of nausea and vomitingwhich is commonly seen with cytotoxicdrugs is uncertain; but it is probably due toa combination of stimuli from thechemoreceptor trigger zone.

The timing of onset of vomiting varies andmay occur within 2 hours. Prophylacticanti-emetics are used to abolish vomitingand reduce nausea.

Vinca alkaloids may cause constipation

and paralytic ileus which will usuallyresolve spontaneously

Alopecia


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Alopecia

Generally, the head hair is lost butthe whole of the body hair may beaffected. The hair follicles areaffected because of the high rate of

cell turnover. Hair loss due to daunorubicin may

be reduced by scalp cooling "whichby causing local vasospasm reducesthe amount of drug reaching thefollicles.

Pulmonary Toxicity


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Pulmonary Toxicity

It is associated with only a fewcytotoxic agents such asbleomycin, busulphan,cyclophosphamide and metho-

trexate. The pulmonary changes with

infiltrate may be transient or mayprogress to pulmonary fibrosis

Cardiac Toxicity


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Ca d ac o c y

Cadiomyopathy may be seenwith certain drugs. The exactcause is uncertain.

Cardiac arrhythmias maybeseen during or recently afterthe injection of daunorubicin

Renal and Bladder Toxicity


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y

Cisplatin may cause nephrotoxicityleading to fall in glomerular filtration rateand tubular dysfunction with subsequenthypocalcemia and hypomagnesemia.

High doses of methotrexate may causerenal damage. The damage may beavoided by treating only those patientswith satisfactory renal function.

Neurological Toxicity


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g y

The most common toxicity associated withcytotoxic drugs is peripheral neuropathyas seen with vinca alkaloids.

Loss of tendon reflexes, paresthesia andnumbness in the finger and toes may be

noted only and are an indication to reducethe dosage.

Development of myalgia, neuritic painand peripheral sensory loss is anindication to stop the treatment.

Drowsiness, confusion andencephalopathy may be seen withcyclophosphamide, procarbazine anddacarbazine.

Indirect RiskFactors

Direct Risk FactorComplication

-Decreased-Mucosal cytotoxicityOral mucositis


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Decreasedlocal/systemicimmunity-local infections

Mucosal cytotoxicity-Physical/chemicaltrauma-Re-activation of HSV

Oral mucositis

-Decreased systemicimmunity

Oral infections Viral

-Decreased systemicimmunity-Salivary glanddysfunction-Altered oral flora(decreased bacterialflora)

Fungal

-Decreased systemic

immunity-Salivary glanddysfunction

-Inadequate oral

hygiene-Mucosal breakdown-Acquired pathogens

Bacterial

Taste receptor toxicityTaste dysfunction

-Anticholinergic drugs-Salivary gland toxicityXerostomia

Vinca alkaloid druguse

Neuropathies


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Nausea and vomitingGastrointestinalmucositis

ThrombocytopeniaOral mucositisHemorrhage

Cancer Chemotherapy Agents Which Cause Mucositis


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MechlorethamineDocetaxelAmsacrine

MercaptopurineDoxorubicinBleomycinMethotrexateEpirubicinBusulfanMitoxantrone

Etoposide

Carboplatin

Mitomycin5-FluorouracilChlorambucilPaclitaxelFludarabineCisplatin

ProcarbazineGemcitabineCyclophosphamide

VinblastineIdarubicinCytarabine

VincristineIrinotecanDacarbazineVinorelbineHydroxyurea

LomustineDactinomycinDaunorubicin

MANAGEMENT


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Current management of mucositis inpatients includes an emphasis on good oralhygiene, the use of frequent oral rinses forwetting the surfaces and diluting oralcontents, avoidance of irritating foods and

oral care products, avoidance of tobaccoproducts, and the use of benzydamine (incountries where available).

The management of oropharyngeal pain incancer patients frequently requires

systemic analgesics, adjunctivemedications, physical therapy, andpsychological therapy, in addition to localmeasures, oral care, and topicaltreatments.

Topical antimicrobials, includingchlorhexidine and systemic


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yantimicrobials, have little effect inpreventing mucositis in patients

but may be used for effect uponplaque levels, caries and gingivitisrisk, and candidiasis.

Amifostine provides salivary gland

protection but requires furtherstudy to document a potential rolein prevention of oral mucositis.

Innovative new products are in

clinical trials and low-energy lasersand (possibly) anti-inflammatorymedications require further study.

Amifostine, administered bythe intravenous or


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the intravenous orintramuscular route prior to

radiation exposure, has beenapproved by the PDA forprevention of salivary glanddysfunction and may reduce

the severity of oral mucositis;however, additional study isneeded to determine its impacton mucositis and its costeffectiveness

HyposalivationSTIMULATION OF SALIVARY FUNCTION


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STIMULATION OF SALIVARY FUNCTION

For patients with residual gland function,

high fluid intake and the use of sugarlessgum or candies also may assist thestimulation of residual gland function.

Systemic sialagogues offer the advantage ofstimulating saliva secretion that includes

all normal components and protectivefunctions of saliva.

Measurement of saliva flow rates todetermine the amount of residual functionshould be conducted before prescribing asialagogue.

If no saliva is collected under resting orstimulated conditions, it is unlikely that asystemic agent will be effective.

Pilocarpine is the best studied sialagogue.Pilocarpine is a parasympathomimetic


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agent and has its major effects at themuscarinic cholinergic receptor of salivary

gland acinar cells. In doses of 5 to 10 mg tid, increased

secretion of saliva occurs, and fewcardiovascular side effects have beennoted.

Other agents have been studied, includingbethanechol and civemiline.

Bethanechol (75-200 mg/d in divided doses),which stimulates the parasympathetic nervoussystem, has been reported to have potentialbenefits without causing gastrointestinal upset.

Anetholetrithione (not available in the UnitedStates; Paladin Laboratories Inc, Montreal,Canada) has been reported to be beneficial inthe management of dry mouth .

.The mechanism of action may be due to anincrease the number of cell surface


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receptors on salivary acinar cells.

Because pilocarpine stimulates the

receptors and because anetholetrithionemay act by stimulating the formation ofreceptor sites, synergistic effects may resultwith the combined use of these drugs

SYMPTOMATIC TREATMENT


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Mouth-wetting agents or saliva

substitutes may be used when it isnot possible to stimulate salivaryfunction.

Frequent sipping of water and amoist diet are mandatory.

The desired characteristics of salivasubstitutes are excellent lubrication,surface wetting, inhibition ofovergrowth of pathogenic

microorganisms, maintenance ofthe hardness of dental structure,pleasant taste, long duration ofeffect, extended shelf life, and low

cost.

The majority of products currentlyavailable are based on carboxyl


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available are based on carboxylethyl cellulose. Complex moleculesand animal mucins have beenincorporated into some products.

Most commercial products aremore viscous than saliva and donot simulate the viscoelastic

properties of saliva.

They also do not contain thecomplex enzyme systems andantibodies of natural saliva.

Many of the commercial productsbeing marketed have not beensubjected to controlled clinicalstudy

Patients who receive radiationtherapy/chemotherapy can be managed


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with topical antifungals because oralcandidiasis produces oral discomfort but

does not lead to systemic infection unlessthe patient is immunocompromised.

Systemic azoles are used for infection thatoccurs while using topicals and ifcompliance with topical oral therapy ispoor.

When prescribing topical antifungal drugs,the presence of sucrose in the productmust be known because frequent use ofsucrose-sweetened products may promotecaries, particularly in patients with drymouth.

CARIES


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Caries associated with hyposalivationtypically affect the gingival third and theincisal cusp tips of the teeth .

The etiology is related to a lack ofproduction of saliva, loss of remineralizing

potential, loss of buffering capacity,reduced pH, and change in the bacterialflora.

Treatment of each component of the cariesprocess must be addressed to prevent

demineralization and rampant caries.

MANAGEMENT


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The tooth structure may be hardened bythe use of fluorides, and remineralizationmay be enhanced by the use of fluoridesand remineralizing products

The effects of topical products maybe

enhanced by increased contact time on theteeth, which can be achieved by applyingthem with occlusive vacuform splints or gelcarriers, which should extend over thegingival margins of the teeth.

Custom vinyl trays are useful for theapplication of fluoride to prevent andcontrol caries in high-risk patients.

However, until controlled studies areavailable, treatment should remainfl id li i i l i f


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fluoride application in gel carriers; forthose who do not comply with carrier

application, high-potency brush-onfluoride dentrifice may be suggested as itis simpler and may reducedemineralization and caries.

Continuing reinforcement of topicalfluoride use is needed and will enhancepatient compliance.

Topical fluorides and chlorhexidine rinsesmay reduce levels ofStreptococcus

t


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mutans.

A 2% chlorhexidine gel applied in mouth

guards demonstrated an enhanced abilityto control cariogenic flora in cancerpatients with xerostomia

Taste and Smell impairment


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Zinc supplementation (zinc sulfate, 220 mgtwice daily) may be useful for somepatients who experience taste disturbances.

Nutritional counseling in which the focus ison the maintenance of caloric and nutrient

intake may be required during andfollowing cancer therapy.

Long-term complications includehyposalivation, altered ability to chew,difficulty in forming the food bolus, and

dysphagia. Consideration must be given to taste,

texture, moisture, and caloric and nutrientcontent.

Drug Resistance


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De novo Resistance

Acquired Resistance

Multidrug Resistance(MDR)

De novo resistance:


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De novo resistance can be

de novo genetic (i.e. the

cells are initially inherently

resistant), or can arise

because drugs are unableto reach the target cells

because of permeability

barriers such as the blood-brain barrier.

Acquired Resistance:


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Acquired drug resistancemay result from genomicmutations, such as theinduction or deletion ofenzymes involved in druginactivation or drugactivation, respectively.

Multidrug Resistance (MDR):


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P-glycoprotein transports many

naturally occurring drugs out of

neoplastic cells, and its induction

may lead to multidrug

resistance. As scientific understanding of

the mechanisms of drug

resistance increases, new

treatments may be developed tocounteract resistance


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Current concepts for themanagement of head and neck

cancers in chemotherapy

Locoregionally advanced squamous cellcarcinoma of the head and neck


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carcinoma of the head and neck

Two-thirds of the SCCHN are in a LA stageat time of diagnosis. Treatment paradigmsin that setting include various forms ofcurative combined modality therapies,including concurrent chemoradiation (or

biochemoradiation), inductionchemoradiation followed by irradiationand sequential therapy (inductionchemotherapy followed by concurrentchemoradiation).

Concurrent chemoradiation


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Concurrent chemoradiation waswidely adopted as standard of carefor LA-SCCHN after thepublicationof a large meta-analysis based on

individual data of 10,741 patients in63 randomized trials.

The meta-analysis was recentlyupdated and extended to 6,640patients treated in 87 trials.aConcurrent chemoradiationconferred an absolute survivalbenefit of 8% at 2 and 5 years.

Chemotherapy even improvessurvival when added toh f ti t d l t d


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hyperfractionated or acceleratedracliotherapy which itself is

superior to conventional radiationalone.

The best studied and most widelyused regimen, which can be

considered the standardcomparator for randomized trials, iscisplatin 100mg/m2 0n days 1,22and 43

A survival benefit in single randomized trialshas also been suggested with daily low dosecisplatin weekly intermediate dose of cisplastin


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p y p20 mg/m2 day 1-5 and day 29-33 and 5-flurouracil combined with either

cisplatin,carboplatin or mitomycin C.

Promising results in non-randomized studieswere reported with multiple single agentsincluding weekly low dose gemcitabine,weeklydocetaxel,weekly paclitaxel,carboplatin andwith combinations as TFHX (paclitaxel, 5fluorouracil and hydroxyurea).

Induction chemotherapy


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Rationale Induction chemotherapy has some

appealing theoretical advantages such asoptimal drug delivery to the tumor throughundisrupted vasculature, early eradication

of micrometastases and improvedtolerance of cytotoxic drugs.

Moreover, induction chemotherapy offersthe opportunity of assessing tumor

response and thereby selecting the patientsfor organ preservation.

Combination of cisplatin, (7 5- 1 00 mg/m2 )and 5-flurouracil (5-FU, 750 - 1000 mg/m2)every three weeks is the most commonly used


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regimen (pF) for induction treatment.

the pF regimen yields a 5% improvement in 5-

year survival There have been three randamised trial adding

taxans to standard approach

In one trial by Hitts Et al paclitaxel added tocisplastin and 5Fu in exp arm

Although the response rates were better in theexperimental arm there was no significantdifference in the ovetall survival (51% versus43%p=0.063).

In the two recently published studies(EORT24971/TAX323 and TAX324 study),

docetaxel was added to cisplatin and 5-FU(TPF) in the experimental arm for inductiontreatment


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Post operative induction chemotherapy hasalso been investigated the RadiotherapyOncology Croup(RTOG) study , a Phase IIstudy of paclitaxel followed bv paclitaxeland cisplatin for CRT in resected SCCHNpatients showed comparable toxicity andimproved outcome compared to historicalcontrols (RTOG study 9501) receiving post-operative CRT alone.

In spite of the published evidence,induction chemotherapy is not consideredthe standard of care


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the standard of care

There are several reasons

The induction therapy delays CRT which isthought to be the definite treatment inadvanced SCCHN.

The toxicity resulting from inductionchemotherapy may preclude the delivery of

adequate doses of chemotherapy andradiation during CRT

In some cases chemotherapy did deliverconcomitant chemotherapy if they did itwas thought to be sub-optimal

Randamised studies of inductionchemotherapy followed by CRT verses CRTalone are ongoing

Recurrent disease


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While the vast majority of the patientspresenting with stage I and II SCCHN willremain disease free after surgery and/orradiotherapy, the majority of patientspresenting in a more advanced diseasestage will eventually relapse eitherlocoregionally and/or at distant sites.

A few patients with a locoregionalrecurrence can be salvaged by surgery or

reirradiation.

However, most patients withrecurrent or metastatic disease

l lif f lli i


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only qualify for palliativetreatment.

Treatment options in these patientsinclude supportive care only, singleagent chemotherapy, combinationchemotherapy or targeted

therapies either alone or incombination with cytotoxic agents.

Treatment choice - hormone status,comorbidity, prior treatment,

symptoms and patient preference.

Single agent cytotoxics


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The 4 most extensivelystudied single cytotoxic agentsare - bleomycin, methotrexate.5-fluorouracil ancl cisplatin

Combination chemotherapy


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Standard combinations The PF combination

gradually emerged as the

most commonly usedcombinationchemotherapy regimen in

SCCHN,

The combination of cisplatin,bleomycin and methotrexate


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was compared to weekly

methotrexate in a randamisedprospective trial in 163patients

combination - 48% response

to 35% for methotrexate

Median survival was the same(5.6 months) both arms

SOME OTHER STUDIES


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Cirauvergne et al. reportedthat cisplatin can be aloneor in combination withvincristine, bleomycin andmethotrexate. Theresponse rate was higherwith combination(30% vs,

15%). however, thetolerance was significantlybetter with cisplatin alone.


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The Liverpool Head and Neck OncologyGroups-reported that in a randomizedstudy of 200 pts,were made to receiveeither cisplatin alone or methotrexatealone or cisplatin plus methotrexate or PF.No difference in the response rates wasfound.

They reported a survival benefit for thecispiatin alone arm compared with

metotrexate alone

REFERENCES


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Current concept in the management ofhead and neck cancer, pol Specenier, oraloncology,2009.(49)400-415

Oral cancer treatment: developments in

chemotherapy and beyond British Journalof Cancer (2002) 87, 933 937

Advances in chemotherapy for head andneck cancerS.A. Bhide, C.M. Nutting

Oral Oncology 46 (2010) 436-438

Textbook of RadiationOncology,Principles and


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gy, ppractice ,Gaura K

Rath,BidhuMohanti,Thirdedition,2007

Internet


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THANK YOU

chemotherapy.ppt

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