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Cancer Treatment:
Chemotherapy
• Log-kill hypothesis
• Cytotoxic drugs act with first-order
kinetics in a murine model of
leukemia
• A given dose kills a constant
proportion of a cell population
rather than a constant number of
cells.
• A 3-log-kill dose of an effective drug
reduces a cancer cell population of
1012 cells to 109 (a total kill of 999 ×
109 cells)
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The cell cycle
How Drug Therapy Works
• Cell cycle specific
– Works at a specific point in the cell cycle
– Given in divided doses frequently or as a continuous
infusion to “catch” the cells in the specific point in the cell
cycle
• Cell cycle non-specific
– Cancer cells killed directly proportional to dose
– Repeated doses after blood count recovery
• Cyclin-Dependent Kinases Inhibitors
– Interrupt the signals for the cell to reproduce, leading to
cell death
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Chemotherapy- High Risk
Medication
• Narrow therapeutic index
– Small differences in dose may lead to dose dependent
serious therapeutic failures or adverse drug reactions
(including death)
• Height, weight, body surface area (BSA) and all
drug calculations are critical with DOUBLE
CHECKS
Pregnancy & Chemotherapy
• Family planning practices
• Chemotherapy harmful to developing fetus
• If a patient presents with cancer during pregnancy certain
chemotherapy can be given during 2nd and 3rd trimesters
• Chemotherapeutic agents used to combat cancer cross the
placenta and may adversely affect embryogenesis by affecting
cell division.
• Exposure to such agents after the first trimester of pregnancy
has not been associated with increased risk of malformation
but is associated with increased risk of stillbirth, intrauterine
growth restriction, and fetal toxicities.
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Hydration and Pre-medications
• Depending on specific chemotherapy regimen,
pre-medication and/or hydration should be part
of the order set.
• Pre-medications
– Anti-emetics for nausea/vomiting
– Steroids, histamine H2-receptor antagonist to prevent
hypersensitivity reactions
• Drugs that are toxic for the kidney or damaging to
bladder require hydration
– Pre chemo, during chemo and post chemo
Chemotherapy
• Combination chemotherapy
– Several different classifications of drugs
(different side effect profile)
– Several different places in the cell cycle
for increased effectiveness
• Given for multiple cycles
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Combination Chemotherapy
• Many cancers are treated with several
chemotherapy drugs
– CHOP
– ABVD
• Given over a specific time period and at a certain
interval (should be written in the orders)
– Days 1 and 15
– Every 28 days
– For a total of 6 or 8 or 12 cycles
Combination Chemotherapy
• ABVD- for Hodgkin’s lymphoma
– Every 28 days x 6 cycles
• A- Adriamycin (Doxorubicin) 25 mg/m2
IV days 1 & 15
• B- Bleomycin 10 units/m2, IV days 1 & 15
• V- Vinblastine 6 mg/m2 IV days 1 & 15
• D- Dacarbazine 375 mg/m2 IV days 1 & 15
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Combination Chemotherapy
• CA + T: for Breast Cancer
– Cyclophosphamide 600 mg/m2 IV, day 1, every 21
days x 4 cycles
– Doxorubicin 60 mg/m2 IV, day 1, every 21 days x 4
cycles
– Followed by:
– Paclitaxel 175 mg/m2 IV, day 1, every 21 days x 4
cycles
Week
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Chemotherapy Side Effects
• Side effects are dependent on the drug or
drug combination
• Bone marrow suppression • Bladder toxicity
• Skin toxicity • Alopecia (hair loss)
• Hypersensitivity • Neurotoxicity
• Nausea and vomiting • Sexual dysfunction
• Lung toxicity • Liver toxicity
• Renal toxicity • Cardiotoxicity
• Mucositis • Infertility
• Secondary cancers
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Classification of Chemotherapy
• Alkylating Agents
• Antimetabolites
• Antitumor Antibiotics
• Nitrosureas
• Plant Alkaloids
– Camptothecins
– Epipodophyllotoxins
– Taxanes
– Vinca alkaloids
• Miscellaneous
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ALKYLATING AGENTS
• Produce highly reactive carbonium ion intermediates
which transfer alkyl groups to cellular macromolecules
• Position 7 of guanine residues in DNA is susceptible
• This results in cross-linking/abnormal base pairing
• Cross linking of nucleic acids with proteins can also take
place.
• Cell cycle non-specific.
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ALKYLATING AGENTS...
a. Mechlorethamine
– the first nitrogen mustard
– highly reactive and local vesicant: given only by i.v. route
– Produces acute effects like NV and haemodynamic changes
b. Cyclophosphamide
– Produce few acute effects & is not locally
damaging
– Transformation into active metabolites in
the liver
– Has prominent immunosuppressant
property.
– Cause alopecia and cystitis.
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ALKYLATING AGENTS...
C. Ifosfamide
• Congener for cyclophosphamide with a longer t½
• Has found utility in bronchogenic, breast, testicular, bladder, head
and neck carcinomas, osteogeneic sarcoma and some lymphomas.
• Heamorrhagic cystitis is the dose limiting toxicity.
– Mesna reduces this.
• Mesna is a-SH compound, excreted in urine
– binds and inactivates the vasicotoxic metabolites of Ifosphamide and
cyclophosphamide.
• Ifosphamide causes less alopecia and is less emetogenic than
cyclophosphamide
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ALKYLATING AGENTS...
d. Chlorambucil
– Specially active on lymphoid tissue
– Drug of choice for long term maintenance therapy for
chronic leukemia; Hodgkin’s disease
e. Melphalan
– Effective in multiple myeloma and has been used in
advanced ovarian cancer.
– Bone marrow depression is the most important toxicity
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f) Nitrosoureas
• Cross blood-brain barrier
• Delayed myelosuppression 4-6 weeks after
therapy
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Alkylating Agents & Diseases
• Cyclophosphamide: breast and ovarian, multiple
myeloma, lymphomas
• Chlorambucil: CLL, lymphomas
• Carmustine: lymphomas, multiple myeloma,
Brain tumors
• Lomustine: Brain tumors, lymphoma
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Alkylating Agents- General Side
Effects
• Myelosuppression
– Nitrosoureas: Treatment should not be given any
more frequently than 6 weeks due to delayed
myelosuppression
• Nausea & Vomiting
• Anorexia
• Gonadal dysfunction and infertility
• Secondary malignancies
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Alkylating Agents - Specific Side
Effects
• Cyclophosphamide: hemorrhagic cystitis
• Chlorambucil: pulmonary fibrosis
• Dacarbazine: hepatoxicity, local irritation
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Important Facts About Alkylating
Agents
• Hypersensitivity may occur with late doses of
carboplatin
• Tumor Lysis Syndrome high tumor burden, hydration
and allopurinol
• Nephrotoxic assess BUN/creatinine
• Myelosuppressive monitor CBC with differential
• Nausea/vomiting highly emetogenic
– If oral route is given, administer in morning
• Mesna (bladder protectant) is required for doses of
ifosfamide, cyclophosphamide
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ANTIMETABOLITES
1. Folate antagonist: Methotrexate (Mtx)
• Inhibits dihydrofolate reductase
• Has cell cycle specific action- kills cells in S-phase
• Exerts major toxicity on bone marrow
– Low dose: megaloblastic anemia
– High dose: pancytopenia
• Methotrexate is absorbed orally; 50% PPb
• Largely excreted unchanged in urine.
• Folinic acid, but not folic acid, rapidly reverses toxicity.
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• Folate antagonist: methotrexate...
– Curative in choriocarcinoma
– Used to maintain remission in children with acute leukemia
– Other clinical uses: rheumatoid arthritis, psoriasis, and as
immunosuppressant.
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2. Purine antagonists
a) Mercaptopurine (6-MP)
• Mechanism: They are converted in the body to
monoribonucleotides, which inhibit the conversion of inosine
monophosphate to adenine & guanine nucleotide
• Clinical use:
– Childhood acute leukemia
– Choriocarcinoma
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b) Azathioprine
– Has marked effect on T-lymphocytes
– Azathioprine & 6-MP are metabolized by xanthine oxidase.
(reduce dose of 6-MP/azathioprine if allopurinol is given
concurrently.)
– Main toxicity of antipurines: bone marrow depression.
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3. Pyrimidine antagonists
Fluorouracil (5-FU)
• Blocks the conversion of dUMP to dTMP
• 5-FU gets incorporated into nucleic acids
this may contribute to its toxicity.
• Used for many solid tumors (breast,
colon, urinary bladder, liver)
• Topical use: cutaneous basal cell
carcinoma
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Antimetabolites & Diseases
• Capecitabine: breast, colon
• Cytarabine: leukemias, lymphomas
• Fluorouracil: colorectal, breast, pancreatic,
stomach
• Gemcitabine: pancreatic, breast, ovarian, NSCLC
• Methotrexate: lymphomas, leukemias, lung,
breast, head and neck
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Antimetabolites: General side
Effects
• Myelosuppression (bone marrow suppression)
• Mucositis, stomatitis
• Nausea and vomiting
• Diarrhea
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Important Facts About
Antimetabolites
• Myelosuppression- monitor CBC with diff
• Renal and liver toxicity
• Ensure adequate hydration and allopurinol
for high tumor burden to prevent tumor lysis
syndrome
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VINCA ALKALOIDS
• Bind to microtubular protein- tubulin
• Cell cycle specific & act in mitotic phase.
Vincristine
• Rapidly acting drug
• Clinical use:
– Useful for inducing remission in childhood acute leukemia
– Other indications hodgkin’s disease, wilm’s tumour, Ewing’s sarcoma
and carcinoma lung.
• Prominent ADR: peripheral neuropathy & alopecia.
• Bone marrow depression is minimal.
Vinblastine
• Used with other drugs in Hodgkin’s disease & testicular carcinoma.
• Bone marrow depression is more prominent.
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Tall Man Lettering
• To avoid errors with drugs that have “look alike and
sound alike” names, tall man lettering is used for the
letters that are different:
– VinCRIstine,
– VinBLAstine
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TAXANES
Paclitaxel
• Mechanism: Enhances polymerization of tubulin
– Abnormal bundles of microtubules are produced
throughout the cell cycle cell cycle specific.
• Indicated in metastasis ovarian and breast carcinoma
• Has shown efficacy in advanced cases of:
– Head & neck cancer
– Small cell lung cancer
– Esophageal adenocarcinoma
– Hormone refractory prostate cancer.
Docetaxel
• Potent congener of paclitaxel
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EPIPODOPHYLLOTOXINS
Etoposide
• Semisynthetic derivative of podophyllotoxin
• Affect DNA topoisomerase II function
– block cell division in the late S-G2 phase of the cell cycle
• Primarily used in testicular tumors, lung cancer,
hodgkin’s and other lymphoma
• Main toxicity: alopecia, leucopenia & GIT disturbance.
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CAMPTOTHECIN ANALOGUES
Mechanism: inhibit topoisomerase I
– Act in the S-phase and arrest cell cycle at G2 phase
Topotecan:
• Used in metastatic carcinoma of ovary & small cell lung cancer
• Major toxicity: bone marrow depression
Irinotecan
• Inhibits AchEcholinergic effect: Needs prior atropinization
• Indicated in metastatic /advanced colorectal carcinoma, cancer
lung/ cervix/ovary etc.
• Toxicity: diarrhoea, neutropenia, thrombocytopenia,
haemorrhage, bodyache and weakness.
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ANTIBIOTICS
Intercalate between DNA strands & interfere with its template function.
Actinomycin D (Dactinomycin)
• Efficacious in wilm’s tumor and rhabdomyosarcoma
• Prominent adverse effects: vomiting, stomatitis, erythema,
desquamation of skin, alopecia and bone marrow depression.
Doxorubicin
• Causes breaks in DNA strands by activating topoisomerase II and
generating quinine type free radicals
• Maximum action is exerted at S-phase, others phases are also
affected.
• Used in acute leukemia and in many solid tumors.
• Both produced cardiotoxicity, (ECG changes)
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ANTIBIOTICS...
Bleomycin
• Mixture of closely related glycopeptide antibiotics
• It chelates copper or iron, produces superoxide ions and
intercalates between DNA strands
• Effective in squamous cell carcinoma of skin, head & neck, GI
tract & esophagus, and testicular tumor; also useful in
hodgkin’s lymphoma.
• Mucocutaneous toxicity & pulmonary fibrosis
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Antitumor Antibiotics: General Side
Effects
• Myelosuppression
• Stomatitis
• Cardiac toxicity
• Nausea and vomiting
• Alopecia
• Hyperpigmentation
• Skin and nail changes
• Hypersensitivity reactions
• Diarrhea
• Electrolyte imbalance
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Antitumor Antibiotics: Specific Side
Effects
• Bleomycin: Pneumonitis, pulmonary fibrosis
• Mitomycin: Pulmonary fibrosis
• Doxorubicin: radiation recall, lifetime
cumulative dose 400 mg/m2, discolored urine
(drug is red in color)
• Doxorubicin liposomal: hand foot syndrome
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MISCELLANEOUS CYTOTOXIC DRUGS
Hydroxyurea
• Inhibits the enzyme ribonucleotide reductase
• Blocks conversion of ribonucleotide to deoxyribonucleotide
• interferes with DNA synthesis, S-phase specific action
• Used in chronic myeloid leukemia, psoriasis, polycythemia vera & in
some solid tumor
• Myelosuppression is major toxicity.
Procarbazine (prodrug)
• generates free radicals that cause DNA strand scission
• Component of MOPP regimen for Hodgkin’s disease
• It is week MAO inhibitor.
• With alcohol: disulfirum like reaction.
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MISCELLANEOUS CYTOTOXIC DRUGS
L-aspraginase
• Convert L-asparagine (Asn) to L-aspartic acid and ammonia
• Used in acute lymphocytic leukemia.
• However, It is ineffective in solid tumors.
• No leucopenia, alopecia, or mucosal damage
• L-asparaginase may cause anaphylaxis,
Cisplatin
• Produce highly reactive moiety which causes cross linking of DNA
• It can also react with -SH groups in proteins & has radiomimetic property.
• Effective in metastatic testicular and ovarian carcinoma.
• It is emetic drug, causes renal impairment
Carboplatin
• Less reactive second-generation platinum compound; better tolerated.
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• Cisplatin: renal damage, hearing loss(ototoxicity),
electrolyte imbalance, peripheral neuropathy,
• Carboplatin: hypersensitivity reactions
• Oxaliplatin: peripheral neuropathy especially
reaction to cold temperatures
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Selectivity of anticancer drugs
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Summary
• Drug therapy in cancer:
– Radical treatment to cure
– Adjuvant treatment
– Neo-adjuvant
– Palliative treatment to control symptoms
• Common and drug specific ADR
• Chemotherapy drugs are “high risk” drugs
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Issues in chemotherapy
• Chemosensitivity – chemoresistance
• The importance of dose
• Dose intensity, dose density
• The need of cyclic therapy
• The importance of combinations
• Toxicity management
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Thank you
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