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Chemotherapy
INTRODUCTION
Cancer of the oral cavity -most prevalent tumor of the
upper aero-digestive tract (UADT).
Accounts for 3% of all cancers .
HISTORIC PERCEPTIVE
ANTIFOLATES
Farber , Harriett Kilte used folate analogues- first
Aminopterin and then Amethopterin (now
methotrexate)
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
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..
Clinical Trials
PHASE II
TRIALS
PHASE III
TRIALS
Criteria Or Response
Complete response
Partial response
Minor response
Stable Disease
Progressive disease
Performance scales
Performance Scale
Zubrid Scale
Kamofsky Performance Status
PROGNOSTIC FACTORS IN
PLANNING CHEMOTHERAPY
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
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
CONTRAINDICATIONS
First Trimester Pregnancy
Thrombocytopenia
Liver or Kidney Impairment
Recent Surgery
CLASSIFICATION
OF
CHEMOTHERAPEUTIC AGENTS
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
5-Fluorouracil
Mechanism
Toxicity
Vinca Alkaloids
Vincristine
Mitotic arrest
Neurotoxicity, myelosuppression
alopecia
DNA intercalator
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
Palliative Chemotherapy
Primary goal - improve quality of life.
Accomplished by
relieving pain,
preserving or improving organ function,
preventing obstruction of the airway or esophagus.
METHOTREXATE
It is one of the oldest and highly
efficacious antineoplastic drugs;
MECHANISM OF ACTION
Folic acid analog that is
S-phase specific.
Tetrahydrofolic acid is
necessary for the
synthesis of thymidine
and purine synthesis.
Toxicity
Moderate dose
Mild stomatitis.
Exfoliate maculo-papular rash
CISPLATIN
inorganic metal coordination complex
with major anti-tumor activity in a
number of diseases.
CISPLATIN
CISPLATIN
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
Inhibiting
microtubule depolymerization,
Dosage
Paclitaxel - 135 to 250 mg/m2 given
over 3 or 24 hours.
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
produces
mixture
of
which is a
glycopeptides.
superoxide ions - intercalates between
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
which
synthetase.
inhibits
thymidylate
5-FLUOROURACIL (5-FU)
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
ALKYLATING AGENTS
These compounds produce highly reactive carbonium ion.
This results in cross linking/ abnormal base pairing/scission
of DNA strand.
Alkylating
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.
Vinca Alkaloids
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
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.
SWOG Study
Carboplatin and 5-FU
Methotrexate.
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.
Other studies
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.
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.
Intra-arterial Chemotherapy
Based on delivering an increased drug concentration
to the tumor bed, with possible avoidance of
systemic toxicity
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).
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
Methotrexate
CHEMO CYCLES
6 CYCLE SINGLE DOSE
CHEMO CYCLES
6 CYCLE DOUBLE DOSE
Sore Mouth
Loss / Change Of Taste
Nausea / Vomiting
Loss Of Appetite
Constipation
Diarrhoea
Lymphedema
Hair Loss ( Alopecia)
Infertility
Sore Mouth
Nausea / Vomiting
Loss Of Appetite
Constipation
Diarrhoea
Lymphedema
Hair Loss
Infertility
BEFORE CHEMOTHERAPY
DURING CHEMOTHERAPY
AFTER CHEMOTHERAPY
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.
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.
BIBLIOGRAPHY
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