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CHEMOTHERAPY

Presented By: Dr. Joseph John K. Pothanikat


OMFS

he abnormal mass of tissue the growth of which exceeds and


is uncoordinated with that of normal tissue and persists in
the same excessive manner after cessation of the stimuli
which evoked the change
(Rupert Willis)

Neoplasia Greek word new growth

Chemotherapy

The treatment of malignancies and other diseases

with chemical agents; use of cytotoxic chemicals to


destroy rapidly dividing cancer cells throughout the
body; including normal, rapidly dividing cells in the
bone marrow and gastrointestinal tract

The treatment of disease by chemicals especially by


killing micro-organisms or cancerous cells.

INTRODUCTION
Cancer of the oral cavity -most prevalent tumor of the
upper aero-digestive tract (UADT).
Accounts for 3% of all cancers .

In India 80,000 new cases/year

HISTORIC PERCEPTIVE

Mustard Gas (Bis 2 chloro-ethyl sulfide)

World War I mustard gas


studied during WW-II low WBC
damage rapidly growing WBC
effect on cancer
Louis S Goodman and Alfred
Gilmen(1942) recruited by US Dept
of defense to investigate potential
therapeutic applications of chemical
warfare agents autopsy of people
exposed to mustard gas lymphoid
and myeloid suppression

ANTIFOLATES
Farber , Harriett Kilte used folate analogues- first
Aminopterin and then Amethopterin (now
methotrexate)

In 1948 first drug induce remission children


ALL children died in peace
National cancer institute Roy Hertz and Min Chiu
Li choriocarcinoma (1958) first solid tumor
cured by chemotherapy

Combination Chemotherapy
James Holland, Freireich and Frei (1965)
simultaneously methotrexate, vincristine,
mercaptopurine and prednisone POMP
regimen long term remission in children
ALL

Cancer Models

Concepts Of Chemotherapy
SKIPPER-SCHABEL MODEL

ZxT
GOMPERTZ MODEL
NORTON & SIMONS THEORY

Concepts Of Chemotherapy
SKIPPER-SCHABEL MODEL

ZxT
GOMPERTZ MODEL
NORTON & SIMONS THEORY

Gompertzs Model; Implications


1. The initial growth of tumor is rapid and of
first order, later growth being much slower.
2. Small tumors grow slowly but large % of
dividing cells.
3. Medium tumors grow more quickly but
small no of growth fraction.
4. Large tumor has small growth rate & growth
fraction.

Gompertzs Model, Clinical


Presentation

Limitations of Gompertzs Model


Discrepancy exist between the predicted values and the in
vivo results.

NEED FOR A NEW CONCEPT !


MOLECULAR BEAM EXITAXY (MBE)
UNIVERSALITY CLASS

MOLECULAR BEAM EXITAXY (MBE) UNIVERSALITY CLASS

Clinical Implications
All tumors exhibit similar growth dynamics.
Cell diffusion on the border is balanced with the
random duplication.
Movement of cells away from the tumor does
not influence the growth.
The outer cells divide about 30 times more than
the cells in the centre.
The most malignant cells are located at the
border and the degree of malignancy progress
along the radius of the tumor..

THE CELL CYCLE

Clinical Trials

Principles of Clinical Trials


Evaluate efficacy of chemotherapy or combined
modalities
Parameters to be evaluated:
Object survival
disease free survival
duration of response
toxicity

Phases of clinical trial


PHASE I
TRIALS

To determine the toxic effects


To establish - highest dose of drug safely administered.
Pt with different tumor type refractory conventional therapy dose tolerance

PHASE II
TRIALS

to determine if a drug or drug combination


has enough activity to warrant further
testing in a comparative trial.
End point, response rate , efficacy

PHASE III
TRIALS

randomized comparisons of two or more


treatment options
Response rate, disease-free survival, or
response duration and survival are primary
endpoints.

Criteria Or Response
Complete response

Partial response

Minor response
Stable Disease
Progressive disease

Complete disappearance of all evidence of


tumor for at least 4 week.
Disease regression by at least 50% of the
sum of the product of the perpendicular
diameters of all measurable tumor for at least
4 weeks. No simultaneous increase in the
size of any lesions or appearance of new
lesions may occur.
Regression by less than 50% of the sum of
the products of the perpendicular diameters
of all measurable lesions.
No appreciable change in dimensions of all
evaluable lesions.
Increase in the size of any detectable lesions by
at least 25% or the appearance of new lesions.

Performance scales

Performance Scale
Zubrid Scale
Kamofsky Performance Status

Used today :Zubrid scale

PROGNOSTIC FACTORS IN
PLANNING CHEMOTHERAPY

Prognostic factors in planning


chemotherapy
Bulky primary tumors/extensive LN spread
/advanced stage IV /with widespread visceral
metastases
Prior radiation
Prior treatment status
Prior chemotherapy

Prognostic factors in planning


chemotherapy
Bulky primary tumors/extensive LN spread
/advanced stage IV /with widespread visceral
metastases
Prior radiation
Prior treatment status
Prior chemotherapy

Prognostic factors in planning


chemotherapy
Functional status of - kidneys, liver, bone marrow,
heart, and lungs.
Motivation and compliance of the patient.
Performance status and nutritional state
Degree of tumor differentiation

PRINCIPLES OF CHEMOTHERAPY
1. A single cancer cell can multiply and eventually kill the
host
2. Survival and ability to respond to chemotherapy are
inversely related to the numbers of viable tumor cells
3. Generally a direct relationship exists between the dose of
a drug and its ability to kill tumor cells

4. A given dose of drug will kill a constant fraction of tumor


cells regardless of the number present prior to therapy.

INDICATIONS
Metastatic or locally advanced disease not amenable to
curative therapy surgery/radiation
Patient undergone surgery and radiotherapy
Advanced laryngeal carcinoma primary curative
treatment voice preservation
Experimental protocols as primary therapy or combined

with radiotherapy for patients with a high risk of relapse

CONTRAINDICATIONS
First Trimester Pregnancy
Thrombocytopenia
Liver or Kidney Impairment

Recent Surgery

CLASSIFICATION
OF
CHEMOTHERAPEUTIC AGENTS

Chemotherapeutic agents with activity in head


and neck cancers
Agent

Mechanism

Toxicity

Alkylators
Cyclophosphamide

DNA cross-linker

nausea, cystitis,

Ifosfamide
Antimetabolities
Methotrexate

Myelosuppression, cystitis,
confusion, alopecia
Binds dihydrofolate
reductase
Inhibits thymidylate
synthetase

Mucositis,
Myelosuppression
Mucositis,
myelosuppression,diarrhea

Antibodies
Bleomycin

Scission of DNA

Adriamycin

DNA intercalator

Pulmonary fibrosis, rash,


Mucositis
Cardiotoxicity, mucositis,
myelosuppression,
alopecia

5-Fluorouracil

Chemotherapeutic agents with activity in head


and neck cancers
Agent

Mechanism

Toxicity

Vinca Alkaloids
Vincristine

Mitotic arrest

Neurotoxicity, myelosuppression
alopecia

DNA intercalator

Nephrotoxicity, vomiting, otoxicity,


neuropathy Myelosuppression

Microtubule
stabilizer

Myelosuppression, neuropathy
Edema, neutropenia,, neuropathy

Vinblastine
Miscellaneous
Cisplatin
Carboplatin
Taxanes
Paclitaxel
docetaxel

Chemotherapy Approaches
Combination
therapy

Chemoprevention

Induction
chemotherapy

Palliative
chemotherapy

Concomitant
chemoradiotherapy

Adjuvant
chemotherapy

CHEMOPREVENTION
The term was given by Michael B
Sporn in 1976
More than 2000 agents from more
than 20 chemical classes
chemopreventive activity important
ones are:
Retinoids
carotene
tocopherol

Molecular mechanism of retinoids


Nuclear retinoid receptors ligand activated DNA
binding protein modulate gene transcription.
Upto 30-40% premalignant lesion regress
spontaneously.

Palliative Chemotherapy
Primary goal - improve quality of life.
Accomplished by

relieving pain,
preserving or improving organ function,
preventing obstruction of the airway or esophagus.

Single Agent Methotrexate Therapy


The standard palliative therapy for head and neck
cancer.
Well tolerated, convenient, and inexpensive.

Response rates range from 15% to 30%, with a


median duration that has generally been less than 6
months

METHOTREXATE
It is one of the oldest and highly
efficacious antineoplastic drugs;

Relatively nontoxic, inexpensive,


and convenient.

MECHANISM OF ACTION
Folic acid analog that is
S-phase specific.

Binding to the enzyme


dihydrofolate
reductase,

Tetrahydrofolic acid is
necessary for the
synthesis of thymidine
and purine synthesis.

Blocks the reduction of


dihydrofolate to
tetrahydrofolic acid.

Interrupts the synthesis


of DNA, RNA, and
protein.

Methotrexate is absorbed orally, 50% plasma protein bound


little metabolized and largely excreted unchanged in urine.

Methotrexate can be administered by intramuscular injection


or subcutaneous, intravenous oral routes.-- 2.5mg tabs,5 15
,50 mg/vial inj..
Aspirin and sulfonamides decrease its renal tubular secretion.
These drugs enhance the toxicity of Mtx.
Mechanisms for resistance to methotrexate include ,
decreased transport of methotrexate into cells and increased
dihydrofolate reductase activity.

Toxicity
Moderate dose

Mild stomatitis.
Exfoliate maculo-papular rash

Renal dysfunction -because of precipitation of


the drug, especially in acid urine.
Hydration and alkalinization of the urine
before and after methotrexate administration
can reduce risk.

CISPLATIN
inorganic metal coordination complex
with major anti-tumor activity in a
number of diseases.

behaves as a bi-functional alkylating


agent binding to DNA to cause interstrand and intra-strand cross-linking.
also binds to nuclear and cytoplasmic
proteins.

CISPLATIN

Resistance is believed to develop through increased


metabolic inactivation.
Cisplatin is administered by the intravenous route
and requires hydration and diuresis to prevent renal
tubular damage.
The major toxic reaction is renal dysfunction,

Nausea and vomiting are almost universal.


Ototoxicity can occur. Hematologic toxicity,
including neutropenia and thrombocytopenia, is
mild ,bone marrow suppression

CISPLATIN

Resistance is believed to develop through increased


metabolic inactivation.
Cisplatin is administered by the intravenous route
and requires hydration and diuresis to prevent renal
tubular damage.
The major toxic reaction is renal dysfunction,

Nausea and vomiting are almost universal.


Ototoxicity can occur. Hematologic toxicity,
including neutropenia and thrombocytopenia, is
mild ,bone marrow suppression

Taxanes
New class of compounds
include paclitaxel (taxol) and docetaxel (taxotere).
active against a variety of solid tumors
prolonged infusions - more effective.
response rates of approximately 30% to 40%.

Mechanism Of Action
Binding to the Bsubunit of tubulin,

Stabilizing
microtubules

Cell cycle arrest at


G.

Inhibiting
microtubule depolymerization,

Dosage
Paclitaxel - 135 to 250 mg/m2 given
over 3 or 24 hours.

Docetaxel - 60 to 100 mg/m2 by


bolus injection every 3 weeks.

IFOSFAMIDE
Congener of cyclophosphamide.
DNA interstrand and intrastrand
cross-linking that disrupts DNA
replication.
its metabolites are excreted in the
urine.

Dosage
Total doses of 7 to 10 g/m2 usually is administered
as a 5-day continuous infusion or over 3 to 5 days in
equally divided doses.
Need to be well hydrated before drug
administration.

BLEOMYCIN
Anti-neoplastic antibiotic
closely

related

Chelates copper or iron -

produces

mixture

of

which is a

glycopeptides.
superoxide ions - intercalates between

DNA strands - Causes chain scission


and inhibits repair

Mechanism Of Action
Binds to DNA and produces DNA strand breaks
by generating oxygen free-radicals.

DOSAGE
10 to 20 units/m2 or twice weekly IM/IV
continuous 24-hour infusion over 5 or 7 days at
a dose of 10 units/m2 each 24 hours.

5-FLUOROURACIL (5-FU)
PYRIMIDINE ANTAGONISTS
Converted

in

the

body

to

corresponding nucleotide 5 ~ fluoro 2 -deoxyuridine monophosphate, -

which
synthetase.

inhibits

thymidylate

5-FLUOROURACIL (5-FU)

Fluorouracil itself gets incorporated into nucleic


acids and this may contribute to its toxicity.
Even resting cells are affected though rapidly
multiplying ones are more susceptible
response rates of 15%,
used in combination with other agents,
particularly cisplatin.

Dose
Conventional intravenous dose -10 to 15 mg/kg
weekly
Alternate method of delivery -loading dose of 400 to
500 mg/m.sq daily for 5 days, followed by a weekly
intravenous dose of 400 to 500 mg/m.sq

NO MORE THAN 800 MG GIVEN AS A SINGLE BOLUS.

ALKYLATING AGENTS
These compounds produce highly reactive carbonium ion.
This results in cross linking/ abnormal base pairing/scission
of DNA strand.

Alkylating

agents have cytotoxic and radiomimetic(like

ionizing radiation) actions

Cyclophosphamide
It has prominent immunosuppressant property. Thus
it is one of the most popular anti cancer drugs.
Mechanism Of Action
cross-linking DNA strands, preventing further
division.
Can be given orally or intravenously.

single dose of 500 to 1500 mg/m2 repeated every 3 or 4


weeks.

Vinca Alkaloids

Vinblastine and Vincristine

MECHANISM OF ACTION
These are mitotic inhibitors, bind to
microtubular protein tubulin , prevent its
polymerization and assembly of microtubules.
Cause disruption of mitotic spindle and
interfere with cytoskeletal function .
The chromosomes fail to move apart during
mitosis, metaphase arrest occurs.

Dose
Vinblastine (Velban)
given weekly at 5 mg/m2 or it may be given by
continuous infusion over several days.

Vincristine (Oncovin)
1.0 to 1.5 mg/m2 once or twice monthly.
single dose not exceed 2 mg.

Hydroxyurea
MECHANISM OF ACTION
Inhibits Ribonucleotide Reductase

Interfering with the conversion of ribonucleotide to


deoxyribonucleotide

Causing inhibition of DNA synthesis.

New Single Agents

New Single Agents

Topotecan

Gemcitabine

Vinorelbine

Analogs of
methotrexate

COMBINATION THERAPY
Median duration of response ranges from 2 to
6 months.
ECOG study
SWOG Study

ECOG Study
Cisplatin
Bleomycin & Methotrexate

Methotrexate.

Response to single agent therapy with methotrexate was


35%, and to the combination 48%.
Toxicity was greater-for the combination with no
difference in survival time.

SWOG Study
Carboplatin and 5-FU

Cisplatin and 5-FU

Methotrexate.

Cisplatin and 5-FU arm was associated with


significantly more toxicity than methotrexate.
Carboplatin and 5-FU were intermediate in toxicity.
Median survival times were not different, varying
between 4.7 and 6.6 months.

Ways Of Combined Chemotherapy

Induction Chemotherapy
Benefits
Increased compliance
Better tolerance of therapy.
Reduce tumor burden
Resulting in the preservation of organ function
by obviating the need for surgery.
Reduce metastatic seeds
Eliminate problems with poor vascularity that
often occur after surgery or radiation, thus
reducing a potential pharmacologic sanctuary.

First use of induction chemotherapy

methotrexate with leucovorin rescue given twice


before surgery.
77% of patients had some tumor shrinkage,

Other studies

methotrexate and bleomycin.


response rate was approximately 5%

Disadvantages
Delay in potentially curative surgery or radiotherapy, or
both, in tumors with chemoresistant cells. -can result in selective
proliferation of clones, which are less responsive to
radiotherapy.

Patients may refuse potentially curative follow-up


radiotherapy or surgery because of tumor response to initial
chemotherapy.

Increased morbidity and costs of treatment.

Concomitant Chemoradiotherapy :
Primarily in patients with unresectable disease to
improve local and regional control.
Theoretic rationale and mechanism for the
interaction between cytotoxic drugs and radiation
that results in additive or synergistic enhancement mechanisms.
Net effect - improve cellular cytotoxicity.

Adjuvant (Maintenance) Chemotherapy


Subsequent to definitive locoregional therapy, adjuvant
chemotherapy has been given to control microscopic residual
disease and micrometastatic disease.

Although there appears to be some reduction in the incidence


of distant metastases, adjuvant therapy has not been
demonstrated to improve survival.
At this time, adjuvant chemotherapy has not been shown to
have a role in management of carcinomas of the head and
neck

Intra-arterial Chemotherapy
Based on delivering an increased drug concentration
to the tumor bed, with possible avoidance of
systemic toxicity

Intra-arterial cisplatin given before surgery or


radiation has produced responses in the 70% to 80%
range.

Intralesional Chemotherapy
Intralesional injection of vinblastine, vincristine, or
interferon has been shown to be effective in the local
control of epidemic Kaposis sarcoma and can be
used in combination with systemic chemotherapy or
radiotherapy.
If necessary, lesions are reinjected at 3-to-6-week
intervals.

TOPICAL CHEMOTHERAPY
Actinic keratotic lesions have been effectively treated with the
application of 5% fluorouracil cream--applied twice daily
until the area exhibits a significant inflammatory reaction
(usually 3 to 4 weeks).

Similar topical application of fluorouracil in selected cases of


multiple superficial basal cell carcinomas, as may be seen in
basal cell nevus syndrome, has been effective.
Topical therapy, however, is not effective for invasive lesions
and results in needless delay in definitive therapy

Chemotherapy Regimen
Concurrent chemoradiation for stage III, IVA and IVB
cancer
Cisplatin + RT
Cisplatin (CDDP) 100 mg/m2 iv d1, 22 and 43
Concurrent radiotherapy 2 Gy/d to a total of 70 Gy

5-FU + Carboplatin + RT

Carboplatin (Paraplatin) 70 mg/m2/d iv d1-4, 22-25 and 43-46


5-FU 600 mg/m2/d civi d1-4, 22-25 and 43-46
Concurrent radiotherapy 2 Gy/d to a total of 70 Gy

NEOADJUVANT CHEMOTHERAPY FOLLOWED BY


CHEMORADIATION OR RADIATION FOR STAGE III,
IVA AND IVB CANCER
TPF Carboplatin + RT
Docetaxel (Taxotere) 75 mg/m2 iv over 1 hour d1
Cisplatin (CDDP) 100 mg/m2 iv over 30 min-3 hours
d1
5-FU 1000 mg/m2/d civi d1-4
Q3w x 3 cycles
3-8 weeks later:
Carboplatin (Paraplatin) AUC 1.5 iv over 1 hour qw x
7 weeks during RT
Concurrent radiotherapy 2 Gy/d to a total of 70-74 Gy
6-12 weeks later:
Surgical resection as needed

CHEMOTHERAPY FOR STAGE IVC


(METASTATIC) CANCER
5-FU + Cisplatin + Bleomycin

Cisplatin (CDDP) 100 mg/m2 iv d1


5-FU 650 mg/m2/d civi d1-5
Bleomycin 15 mg iv d1 followed by 16 mg/m2/d civi d1-5
Q4w x 3 cycles

Methotrexate

Methotrexate (MTX) 40 mg/m2 iv


Qw

CHEMO CYCLES
6 CYCLE SINGLE DOSE

CHEMO CYCLES
6 CYCLE DOUBLE DOSE

BLOOD TEST AND CHEMOTHERAPY


Leukopenia
Thrombocytopenia.
Anemia.
CHEMOTHERAPY REGIME
CBC should be done before and 7 days after starting
Chemo drugs as well as after any dose increase.
Thereafter, the blood counts can be monitored every
2 to 4 weeks.

SIDE EFFECTS OF CHEMOTHERAPY


1.
2.
3.
4.
5.
6.
7.
8.
9.

Sore Mouth
Loss / Change Of Taste
Nausea / Vomiting
Loss Of Appetite
Constipation
Diarrhoea
Lymphedema
Hair Loss ( Alopecia)
Infertility

Sore Mouth

Loss / Change Of Taste

Nausea / Vomiting

Loss Of Appetite

Constipation

Diarrhoea

Lymphedema

Hair Loss

Infertility

Dental treatment considerations in the


chemotherapy patient
1.Infections
2.Neurological & Dental Alterations
3.Dysgeusia
4.Hyposialia & Xerostomia
5.Bleeding Tendency
6.The Development Of Osteonecrosis.

BEFORE CHEMOTHERAPY
DURING CHEMOTHERAPY
AFTER CHEMOTHERAPY

BEFORE CHEMOTHERAPY

Exhaustive examination of the oral cavity


Denture fitting should be checked
Radiological study
General prophylactic measures
Teeth that are Non-viable or Poor prognosis:

Minor surgery: al least two weeks before


chemotherapy.
Major surgery: 4-6 weeks before chemotherapy.

DURING CHEMOTHERAPY
Treatment of the oral complications of
chemotherapy.
Continued patient reminder of the need to
maintain strict dental hygiene
No elective dental treatment should be carried
out.
ONLY emergency dental care.

AFTER CHEMOTHERAPY
Insist on the need for routine systematic oral
hygiene.
Use of chlorhexidine rinses and fluorization.

Elective dental treatment.

Tooth Extraction In Chemotherapy


PRIOR TO CHEMO

DURING CHEMO

CHEMOTHERAPY SAFETY
They can cause abnormal changes in DNA. (They are
mutagenic.)
They may be able to alter development of a fetus or
embryo, leading to birth defects.
They may be able to cause another type of cancer.
Some may cause skin irritation or damage.

Wear double gloves, goggles, and gowns.


Proper ventilation systems to avoid spattering
and/or inhaling the droplets that can form
while mixing.
Special precautions when handle urine and
stool.
Use of separate plastic containers to dispose of
sharp items, syringes, IV tubing & medicine
bags.

Recent Advances InChemotherapy


Bacterial treatments clostridium novyi
HAMLET (human alpha-lactalbumin made
lethal to tumor cells)
Insulin potentiation therapy
Telomerase therapy Inositol hexaphosphate
Electrochemotherapy

BIBLIOGRAPHY
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

CANCER-PRINCIPLE AND PRACTICE OF ONCOLOGY- DE-VITA, ROSENBERG


HEAD AND NECK CANCER J.P SHAH
CANCER OF FACE AND MOUTH- IAN MCGREGOR
MEDICAL PHARMACOLOGY- K.D TRIPATHI
MAXILLOFACIAL SURGERY- PETER WARD BOOTH
HEAD AND NECK CANCER EMERGING PERSPECTIVES-JOHN.F ENSLEY
HEAD AND NECK CANCER- FEE, GOEFERT
Myers, Suen cancer of the head and neck 2003, 4th edition
WWW.WIKIPEDIA.ORG
WWW.CANCER.COM