2. ● WWI Exposure led to the observation that
alkylating agents caused destruction of bone
marrow and lymphatic tissues, which was further
studied in WW II.
● This led to observation to the direct application of
such agents to the patients with Hodgkin’s disease
and lymphocytic lymphomas at Yale Cancer
Centre in 1943.
● Louis Goodman and Alfred Gillman studied it for
the first time.
ORIGIN OF CHEMOTHERAPY
3. 1948, Sydney Farber successfully used Antifolates to induce remission in
children with Leukemias
1955, National Chemotherapy Program begins for drug screening
1958, Roy Hertz and Min Chiu Li demonstrate Methotrexate as a single
best agent for Choriocarcinoma
1959, FDA approve Alkylating agent Cyclophosphamide
1965, began the era of Combination Chemotherapy
4.
5. ● To achieve cure a TOTAL CELL KILL must be tried
● Complete remission is the goal thus, early and intensive
treatment
● Early diagnosis and early initiation of treatment
● Combination chemotherapy
● Intermittent regimens
● Adjuvant and neoadjuvant chemotherapy occasionally
Guiding principles in cancer
chemotherapy
6. • Cytotoxic chemotherapy refers to agents
which kills the rapidly dividing cells.
• Cytotoxic chemotherapy mechanisms of
action may be by either inhibiting mitosis or
DNA damage
• To fully understand chemotherapy it is
important to have an understanding of the
cell cycle.
7. CELL CYCLE
● The cell cycle comprises of four stages. The cell
must progress through these in order to duplicate
its chromosomes and divide.
● G0(Resting Phase) – Normal functions
● G1 phase (Gap 1) During this phase, the cell is
growing and preparing to double its DNA.
● S phase (DNA synthesis) This is the phase in which
the amount of DNA is doubled.
● G2 phase (Gap 2) The cell prepares for mitosis
● M phase (mitosis) Division of the nucleus.
8. ● All cells, normal or neoplastic, must traverse
through cell division
● Malignant cells spend time in each phase - longest
time at G1, but the time may vary
● Many of the effective anticancer drugs exert their
action on cells traversing the cell cycle - Cell Cycle
Specific (CCS) Drugs
● Cell cycle-nonspecific (CCNS) drugs sterilize
tumor cells whether they are cycling or resting in
the G0 compartment
● CCNS drugs can kill both G0 and cycling cells
● CCS are more effective on cycling cells
Cell Cycle and Clinical Importance
17. ● Very irritant drug (potent vesicant)
● MOA:
○ Analog of mustard gas.
○ Classic alkylating agent that forms interstrand and intrastrand cross-links
with DNA resulting in inhibition of DNA synthesis and function.
○ Cell cycle-nonspecific, with activity in all phases of the cell cycle.
● Uses:
● Haematological cancers, lymphomas- Hodgkin’s (as part of MOPP), CML, CLL
● Dose :
○ Hodgkin's lymphoma: 6 mg/m2 IV on days 1 and 8 every 28 days, as part of
the MOPP regimen.
MECHLORETHAMINE (MUSTINE)
18. ● Adverse effects
● Anorexia, nausea, vomiting
● Bone marrow depression, aplasia
● Menstrual irregularities
● Latent viral infection (herpes zoster) - supressed immunity
● Extravasation- (infiltrate with isotonic sodium Thiosulfite to inactivate)
● Estramustine is a combination of estradiol with nitrogen mustard.
MECHLORETHAMINE (MUSTINE)
20. ● Phenylalanine derivative of nitrogen
mustard
● It is an orally active drug; plasma
concentration varies with individual due to
variation in intestinal absorption and
metabolism
● Very effective in MULTIPLE MYELOMA
MELPHALAN
21. ● Dose:
● 9 mg/m2 daily for 4 days every 4-6 weeks
along with prednisone
● Dose should be adjusted by monitoring
platelets and WBCs count
● Adverse Effects :
● Less irritant locally, causes less alopecia
● Bone marrow Depression: Infections (low
WBC), low platelets count bleeding
● pancreatitis
● N/V, oral ulceration
MELPHALAN
22. ● Most commonly used alkylating agent as a prodrug
● Cytotoxic effect generate after formation of their
alkylating species
● Broad spectrum: used single/ as part of a regimen
● Both cyclophosphamide and ifosfamide orally active
● Can be given parenterally also
CYCLOPHOSPHAMIDE
23. ● Good bioavailability of 90% after per oral administration
● After administration, parent drug activated after
phosphorylation with cytochrome p450.
● T ½ : 4-6 hours
● Excreted into feces by biliary transporter
● Parent drug excreted via kidneys exclusively
CYCLOPHOSPHAMIDE
24.
25. Neoplastic conditions
● Hodgkin's and non-Hodgkin's lymphoma
● ALL, CLL, Multiple myeloma
● Burkitt's lymphoma
● Neuroblastoma , retinoblastoma
● Ca breast , adenocarcinoma of ovaries
Non neoplastic conditions
● Control of graft versus host reaction
● Rheumatoid arthritis
● Nephrotic syndrome
USES OF CYCLOPHOSPHAMIDE
26. ● Haemorrhagic cystitis,
● SIADH
● Effects on the germ cells:
● amenorrhea, testicular atrophy, aspermia, sterility
● hepatic damage: Veno-occlusive diseases
● Dose:
● Breast cancer-
● When given orally, the usual dose is 100 mg/m2 PO on days 1-14 given every
28 days.
● When administered IV, the usual dose is 600 mg/m2 given every 21 days as
part of the AC or CMF regimens.
ADVERSE EFFECTS
27. ● Congener of cyclophosphamide
● Longer half life than cyclophosphamide
● T ½ : 3-10 hours
● Only IV form available as Orally it is highly neurotoxic
● Less alopecia and less emetogenic than cyclophosphamide
● Used for germ cell testicular tumors and adult sarcomas; Ewing’s Sarcoma;
bladder cancers
● Dose:
● Testicular cancer: 1,200 mg/m2 IV on days 1-5 every 21 days, as part of the VelP
salvage regimen.
● Soft tissue sarcoma: 2,000 mg/m2 IV continuous infusion on days 1-3 every 21
days, as part of the MAID regimen.
IFOSFAMIDE
28. ● Aromatic analogue of Nitrogen Mustard
● Bifunctional alkylating agent
● Slowest acting and least toxic alkylating agent
● Oral bioavailability is 75% when taken along with food.
● Main action on lymphoid series produces marked
lympholytic action
● DOC for long term maintenance therapy of CLL
● Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for
maintenance
● Adverse Effects: moderate GI upset and haematologic
toxicity
CHLORAMBUCIL (LEUKERAN)
29.
30. ● Triethylene phosphoramide
(TEPA)
● Both thiotepa and its
desulfurated primary metabolite,
TEPA rapidly converted by
hepatic cytochrome P450 to
form DNA cross-links
aziridine rings open after
pronation of the ring-nitrogen
reactive species which gives
cytotoxic effects
THIOTEPA
31. ● Uses
● Active intra-vesicular agent
● Used in superficial bladder cancer
● Not well absorbed orally so given IV
● Dose :
● for bladder instillation 60mg in 60ml sterile water for upto 4
weeks
● Adverse Reactions :
● Myelosuppression; Nausea and Vomiting are dose limiting.
Highly neurotoxic can lead to seizure and coma
THIOTEPA
32. ● Bifunctional alkylating agent
● Cell cycle non specific
● Depresses bone marrow with selective action on myeloid series
● Primarily used in Chronic Myelogenous Leukemia(CML)
● Good oral Bioavailability, T1/2 : 2-3 hours
● Dose: Dose for remission is 4-6 mg/ per day/ PO, and dose for maintenance
is 1-3 mg/ per day/ PO
● Adverse effect:
● Interstitial pulmonary fibrosis
● Impotence and Sterility
● CNS toxicities: seizures - anti convulsant drug - always useful in high dose
regimen of busulfan (0.8mg/kg, every 6hours for 4 days)
BUSULFAN (MYLERAN)
37. ● Oral drugs
● MOA: uncertain, still these are mechanism works:
○ inhibits the synthesis of DNA, RNA, and protein; prolongs interphase; and
produces chromosome breaks.
○ Oxidative metabolism by microsomal enzymes azo-procarbazine and
H202 DNA strand scissoring.
● Used in Combination regimens to treat Hodgkin's & non Hodgkin's lymphoma, brain
tumor
● Leukemogenic , Teratogenic, Mutagenic
● Variety of this drug's metabolites have cytotoxic activity one metabolite, is act as MAO
inhibitor
● Higher risk to cause secondary cancer as a form of acute Leukemia
Procarbazine (methylhydrazine)
38. ● Initially developed as a purine metabolite
● Metabolic activation by liver microsomal enzymes
oxidative N-demethylation to the monomethyl
derivative Spontaneous decomposes to 5-
aminoimidazole-4-carboxamide (Excreted) and
diazomethan
● Later metabolite forms methyl carbonium ion which
is believed to be cytotoxic.
● Para-enterally active, there is slow and variable oral
absorption
● Non-schedule dependent
● CCNS drug
Dacarbazine
39. ● Uses :
● malignant melanoma; Hodgkin’s diseases; soft tissue sarcoma
● Metabolized by P450 and excreted unchanged via urine
● T ½ : 5-6 hours
● ADR:
● Nausea and vomiting(highly emetogenic)
● flu-like symptoms,
● neuropathy (paraesthesia; ataxia; increased photosensitivity)
● myelosuppression
Dacarbazine
40. ● New alkylating agent
● Imidazole ring analogue structurally and functionally similar to
Dacarbazine
● Approved for use against treatment-resistant gliomas and
anaplastic astrocytomas
● Rapidly absorbed after oral absorption & crosses BBB
● Unlike dacarbazine, temozolamide:
does not not require cytochrome P450 system for metabolic
transformation
● Undergoes chemical transformation under normal physiological
pH
● It has the property of inhibiting the repair enzyme, O6-guanine-
DNA-alkyltransferase
Temozolamide
41. ● Taken orally and has excellent oral bioavailability
● Food reduces the rate and extent of drug absorption
● Able to cross BBB due to lipophilicity
● T 1/2: 2 hours
● Dose :
● Anaplastic astrocytoma: 150 mg/m2 PO daily for 5 days every 28
days.
● Newly diagnosed GBM: 75 mg/m2 PO daily for 42 days along
with radiotherapy (60 Gy in 30 fractions).
Temozolamide
43. ● Inorganic metal complex
● Serendipitous drugs
● Broad activities
● Synergistic action with other anticancer agents
● Used to treat ovarian, head neck, bladder, esophagus, lung and colon cancers
PLATINUM COORDINATION
COMPLEXES
44. ● CDDP : cis-diamine di-chloro platinum
● Non cell cycle specific killing
● Administered IV
● Highly bound to plasma proteins
● Less than 10% remains in plasma after infusion
● T ½ : 20-30 minutes
● Gets concentrated in kidney, intestine, testes
● Poorly penetrates BBB
● Slowly excreted in urine
Cisplatin
45.
46. ● Uses :
● Testicular cancer (85% - 95 % curative rates)
● Head and Neck Cancers
● Nonseminomatous testicular cancer (combination regimens)
● Ovarian cancer, bladder cancer
● Other solid tumors: lung (small & non small), esophagus, gastric
● Adverse effects:
● Highly Emetogenic
● Nephrotoxicity (reduced by hydration with iv saline infusion /saline &
mannitol/ other diuretics)
● Peripheral neuropathy
● Ototoxicity
CISPLATIN
47. ● Second generation platinum analogues with Better tolerability
● Crosses the BBB and enters the CSF
● Less plasma protein binding
● Vigorous I/v hydration not required
● Excreted exclusively via kidneys with 60-70% drug excreted within
24 hours
● T ½: 2-6 hours
● Nephrotoxicity , ototoxicity , neurotoxicity however low
● Less emetogenic, but thrombocytopenia and leukopenia may occur
(dose liming toxicities)
CARBOPLATIN
48. ● Can be Used in place of Cisplatin
● Uses :
● Solid tumours
● Primarily in ovarian cancer of epithelial origin
● Germ cell tumours; Bladder Cancer; Relapsed
Acute Leukemia
● CALVERT formula is used to calculate the dose
● Total dose = Target AUC x (GFR + 25)
● Target AUC is usually between 5-7 mg/ml/min in
previously untreated cases; and 4-6 mg/ml/min
CARBOPLATIN
49. ● 3rd generation diaminocyclohexane platinum analogues
● No cross-resistance to cancer cells that are resistant to cisplatin or
carboplatin on the basis of mismatch repair defects
● 50 times higher volume of distribution than Cisplatin
● About 40% of the drug gets sequestered in RBCs within 2-5 hours of
administration
● Approved for second-line therapy in metastatic colorectal cancer following
treatment with 5-fluorouracil-leucovorin and irinotecan
● First line drug for this disease
● Also used in metastatic pancreatic and Gastro-esophageal cancers
OXALIPLATIN
50. ● Adverse Effects:
● Neurotoxicity : dose-limiting, is seen in acute and chronic forms;
peripheral sensory neuropathy(worsened upon cold exposure)
● Dysesthesias in the upper extremities and laryngopharyngeal region with
episodes of difficulty breathing or swallowing can be observed and usually
within hours or 1-3 days after therapy.
● Myelosuppression is relatively mild with anemia and thrombocytopenia
more common that neutropenia
OXALIPLATIN
54. ● Analogues related to the normal components of DNA or of
coenzymes involved in nucleic acid synthesis
● Competitively inhibit utilization of the normal substrate or get
themselves incorporated forming dysfunctional
macromolecules
● Folic acid analogue - Methotrexate, Pemetrexed
● Purine analogue - 6-MP, 6-TG, Fludarabine, Cytarabine,
Pentostatin
● Pyrimidine analogue - 5-Fluorouracil, Cytarabine (cytosine
arabinoside), Capecitabine, Gemcitabine
Anti-Metabolites
55. ● Folate antagonist
● Most commonly used and oldest anticancer
drug
● Cell Cycle Specific drug
● Acts during S phase of the cell cycle
● Has Antineoplastic, immunosuppressant
and anti-inflammatory effects
Methotrexate
56. ● Methotrexate structurally resembles folic acid - competitively inhibits dihydrofolate
reductase enzyme and prevents the conversion of DHFA to THFA - depletes
intracellular THFA
● THFA is necessary for synthesis of purines and thymidylate which is necessary for
DNA and RNA synthesis
● Utilizing the folate carrier - enters the cells - transforms into more active
polyglutamate form by enzyme foly-polyglutamate synthase (FPGS)
Methotrexate
57.
58. ● Methotrexate well absorbed after oral
administration, can be given i.m, i.v or
intrathecally
● 50% bound to plasma proteins
● Poorly crosses BBB and most of the drug
excreted unchanged in urine
● DOC - choriocarcinoma; 15-30 mg/m2/day for 5
days orally or 20-40 mg/m2 i.m or i.v twice weekly
● Also used in Acute Leukemia, Burkitt's Lymphoma
and Breast Ca.
● Low dose Methotrexate ( 7.5-30 mg once weekly)
– Rheumatoid Arthritis (DMARDS)
● Other Uses - Psoriasis, IBD and in Organ
transplantation
Methotrexate
59. ● Toxic effects of Methotrexate on normal cells can
be minimized by giving folinic acid
● Availability of folinic acid has helped the use of
very high doses of Methotrexate for better
antineoplastic effect
● A nearly 100 times higher dose (250-1000
mg/m2) of Methotrexate infused i.v over 6 hrs,
followed by 3-15 mg i.v calcium leucovorin within
3 hrs, repeated as required
● Can be repeated weekly
● Folinic acid (Active CoA) - bypasses the block
produced by Methotrexate and rapidly reverses
the toxicity
Folinic acid rescue/ Leucovorin rescue
60. ● Newer congener of Methotrexate
● Primarily targets the enzyme Thymidylate
synthase
● Though not a DHFRase inhibitor, the pool of
THFA is not markedly reduced
● Like Methotrexate, it utilizes the folate carrier to
enter cells and requires transformation into
polyglutamate form by FPGS for activity
enhancement
● Adverse effects - Mucositis, Diarrhoea,
Myelosuppression (same as Methotrexate)
● Painful, itching erythematous rash, mostly
involving the hands and feet 'hands foot
syndrome’ is common
Pemetrexed
61. ● Only administered IV, peak plasma levels reach at about 30 mins
● Dose - 500 mg/m2 i.v every 3 weeks
● All patients should receive vitamin supplementation with 350 mcg/day
of folic acid PO and 1,000 mcg of vitamin B12 IM every 3 cycles to
reduce the risk and incidence of toxicity while on drug therapy.
● Folic acid supplementation should begin 7 days prior to initiation of
pemetrexed treatment, and the first vitamin B12 injection should be
administered at least 1 week prior to the start of pemetrexed.
● Prophylactic use of steroids may ameliorate and/or completely
eliminate the development of skin rash.
● Dexamethasone can be given at a dose of 4 mg PO bid for 3 days
beginning the day before therapy.
Pemetrexed
64. ● Highly effective anti-neoplastic drugs synthesised in the body
● Mono-ribonucleotides : inhibit the conversion of Inosine
monophosphate to adenine and guanine nucleotides which are the
building blocks for DNA and RNA
● Also cause Feedback inhibition of de novo purine synthesis, get
incorporated into RNA and DNA rendering them dysfunctional
● Indicated in ALL only
● Especially useful in childhood acute leukemias, choriocarcinoma
and few solid tumors
6-MERCAPTOPURINE and 6-
THIOGUANINE
65. ● CCS with activity in S phase
● Absorbed orally , poor penetration BBB
● Plasma half life after oral administration is 1.5 hours only
● Does not cross BBB
● Metabolized in Liver exclusively vis oxidation by xanthine oxidase.
● Allopurinol inhibits xanthine oxidase and the catabolic breakdown of
6-MP, resulting in enhanced toxicity.
● Dose of mercaptopurine must be reduced by 50%-75% when given
concurrently with allopurinol.
6-MERCAPTOPURINE and 6-
THIOGUANINE
66. ● Newer purine anti-metabolite
● Phosphorylated intracellularly active triphosphate form which inhibits
DNA polymerase and ribonucleotide polymerase interferes with DNA
repair as well as gets incorporated to form dysfunctional DNA
● Indicated in Chronic Lymphatic Leukemia and Non-Hodgkin's lymphoma
that have recured after treatment
● Adverse effects - chills, fever, myalgia, arthralgia and vomiting after
injection, myelosuppression and oppurtunistic infections
● Dose - 25 mg/m2 daily for 5 days every 28 days by i.v infusion
Fludarabine
69. ● Mechanism of the cytotoxic action of 5-FU
● 5-FU is converted to 5-FdUMP, which competes with
deoxyuridine monophosphate (dUMP) for the enzyme
thymidylate synthetase.
● Causes Thymidine-less death of the cells
● Resistance is due to decreased activation of 5-FU and
decreased thymidylate synthase activity
5-FU
70. ● Uses :
● Mainly used in treatment of slowly growing tumours
● Colorectal, Upper GIT, Breast and Ovarian carcinomas
● Oral absorption of 5-FU is unreliable, primarily used by i.v
infusion
● 5-FU rapidly metabolized by dihydro-pyrimidine dehydrogenase
(DPD) which is already present in plasma
● Thus; T1/2 : 15-20 mins after i.v infusion
● Genetic deficiency of DPD - severe 5-FU toxicity
5-FU
71. ● Adverse Reactions –
● Myelosuppression
● Peripheral Neuropathy (Hand-foot Syndrome)
● Nausea, Vomiting, Diarrhea
● Alopecia,
● Severe Ulceration Of The Oral And GI Mucosa,
● Bone Marrow Depression (With Bolus Injection),
● Allopurinol Mouthwash: Used To Reduce Oral Toxicity
5-FU
72. ● palmar-plantar erythrodysesthesia
● It is a side effect of
some chemotherapy drugs that can cause
redness, swelling and blistering on the
palms of the hands and soles of the feet.
Hand-foot syndrome
73. ● Newer, Oral Fluoro-pyrimidine Carbamate
● Unlike 5-FU, orally well absorded
● After being absorbed it undergoes a series of
enzymatic reactions, the last of which is hydrolysis to
5-FU
● Thus, Oral Prodrug of 5-FU
● Metabolised into fluoro-b-alanine and CO2
Excreted in urine
● Peak plasma levels are reached in 1.5 hours but rate
and amount of absorption decreases with food.
CAPECITABINE
74. ● FDA approved drug for metastatic breast cancer that
is resistant to first-line drugs
● Currently used in colorectal cancer Treatment
● DOSAGE RANGE
● Recommended dose is 1,250 mg/m2 PO BD (morning
and evening) for 2 weeks with 1 week rest.
● May decrease dose of capecitabine to 850-1,000
mg/m2 BD to reduce risk of toxicity without
compromising efficacy
CAPECITABINE
75. ● Adverse Reactions:
● Peripheral Neuropathy (Hand-foot Syndrome)
● Myelosuppression
● Nausea and Vomiting, Diarrhoea
● Caution with renal & kidney function impaired patients
CAPECITABINE
76. ● Cytidine analogue
● Originally isolated from the sponge
Cryptotethya crypta
● Single most effective agent for induction
of remission in AML
● Drug is activated and phosphorylated by
deoxy-cytidine kinases to Ara C - inhibitor
of DNA polymerases
● Of all antimetabolites - Cytarabine is the
most specific for the S phase of the cell
cycle
CYTARABINE
77. ● Crosses BBB
● T ½ : 2-6 hours but in CSF, T ½ is prolonged 2-11 hours
● Can be administered iv, as oral bioavailability <20%
● Highly schedule dependent and should be given by continuous
infusion or every 8-12 hours for 5-7 days
● Adverse Reactions
● Thrombocytopenia and leukopenia
● Mild to moderate emetogenic
● High dose - Neurotoxicity (Cerebellar Ataxia and peripheral
neuropathy)
CYTARABINE
78. ● Ara-C syndrome
● Seen in paediatric patients and represents an allergic reaction to
cytarabine.
● Characterized by fever, myalgia, malaise, bone pain, maculopapular
skin rash, conjunctivitis, and occasional chest pain.
● Usually occurs within 12 hours of drug infusion.
● Steroids appear to be effective in treating and/or preventing the onset
of this syndrome.
CYTARABINE
79. ● Deoxy-Cytidine analogue
● Converted to active diphosphate and triphopshate nucleotide form
● Gemcitabine diphosphate - inhibits ribonucleotide reductase -
diminish pool of deoxyribonucleoside triphosphates required for
DNA synthesis
● Can be incorporated into DNA and leads to chain termination
● Administered only via IV route as extensively deamination takes
place in GI tract
● Elimination mainly by metabolism
● Uses: initially Pancreatic Ca, nowadays widely Non-Small Cell
Lung Ca, Bladder Ca, and Non-Hodgkin's lymphoma
GEMCITABINE
81. ● Most important of these plant derived, CCS drugs are
● Vinca Alkaloids( Vinblastine, Vincristine, Vinorelbine),
● Podophyllotoxins( Etoposide, Teniposide),
● The Camptothecins (Topotecan, Irinotecan),
● The Taxanes(Paclitaxel, Docetaxel)
Mitotic Spindle Inhibitors
82. ● Vinblastine and Vincristine are derived from
the periwinkle plant
● CCS agent, act during M phase of the cycle
● Block the formation of Mitotic Spindle by
preventing the assembly of tubulin dimers into
microtubules
● These drugs block the formation of mitotic
spindle by preventing the assembly of tubulin
dimers into microtubules
VINKA ALKALOIDS
83.
84. ● DISTRIBUTION
● Widely and rapidly distributed into body tissues within 30 minutes of
administration.
● Poor penetration across the blood-brain barrier and into the CSF.
● Given parenterally
● METABOLISM
● Metabolized in the liver by the cytochrome P450 microsomal system.
● The majority of vinka alkaloids are excreted in bile and feces.
● Only 15%-20% of the drug is recovered in urine.
● T 1/2 is long, on the order of 85 hours (VINCRISTINE)
● T ½ for VinBlastine is 25 hours
Vinca alkaloids
85. ● Special caution to be taken during administration as they cause
EXTRAVASCATION
● Clinical use:
● Vincristine - Acute leukemias, lymphomas, Wilm's Tumor and
Neuroblastoma
● Vinblastine - Lymphomas, Neuroblastomas, Testicular cancers and
Kaposi's sarcoma
● Vinorelbine - non-small cell lung carcinoma and breast Ca
Vinca alkaloids
86. Vinca alkaloids
VinBlastine
VinCristine
(oncovin)
MOPP(Hodgkin's disease)
Childhood leukemias
Childhood tumors-Wilm's tumor,
Neuroblastoma
Toxicity:
Peripheral neuritis with
Paresthesia, Muscle weakness,
Foot Drop
*Vincristine has marrow sparing
effect
Hodgkin's disease(ABVD)
Lymphomas
Carcinoma Breast
Testicular tumors
Toxicity:
Bone marrow suppression,
nausea and vomiting,
Diarrhea, Alopecia
Use with Bleomycin increases risk
for Reynaud’s Syndrome
87. ● The inappropriate or accidental infiltration of chemotherapy into the
subcutaneous tissue or subdermal tissues surrounding the administration
site.
● VESICANTS : Drugs which have corrosive properties and have the
potential to cause tissue destruction if extravasated.
● Varying degrees of pain, oedema, erythema, blistering and necrosis may
occur.
EXTRAVASCATION
88. ● Vesicants (Paclitaxel; Vinblastine; Vincristine; Vinorelbine )
● First step is always to STOP the infusion and try to aspirate the leaked
solution through the catheter.
● Firmly apply a heat pack to the extravasated area for 20 minutes every 6
hours for the first 24 hours.
● For extravasations of <5ml, infiltrate the site with 1500 units of
hyaluronidase in 1ml water for injection.
● Inject subcutaneously at several areas around site.
● Gently massage area to facilitate dispersion.
● For Paclitaxel extravasations, follow this with application of 1%
hydrocortisone cream every 6 hours for 7 days.
EXTRAVASCATION
91. ● Plant derivative of Podophyllum
peltatum (Mayapples)
● Etoposide is a semisynthetic derivative
of podophyllotoxin
● Induces DNA breakage through its
inhibition of topoisomerase lI
● Teniposide is an analogue with similar
properties
● Most active in late S and early G phase
of the cell cycle
ETOPOSIDE and TENIPOSIDE
92. ● Oral bioavailability is 50% which means
it requires twice the oral dose as the of
IV dose
● Well absorbed and distributes to most
body tissues
● Elimination is mainly via kidneys
● T ½ : 3- 10 hours
● Clinical use :
● Germ cell tumours
● Testicular cancer
● Lung cancer
● Non-hodgkin's lymphoma and
● AIDS related Kaposi's Sarcoma
ETOPOSIDE
93. ● Adverse Drug Reactions:
● Myelosuppression
● Alopecia with podophyllotoxins is well
documented and seen in approximately
2/3rd of the patients.
● Increases risk of secondary malignancies
(associated with translocation 11:23 )
ETOPOSIDE
95. ● Obtained from Camptotheca acuminata tree
● Camptothecins, Topotecan and Irinotecan, produce
DNA damage by inhibiting Topoisomerase I
● Irinotecan is a prodrug - converted to active
metabolite (SN 38) in Liver
● Topotecan is a semisynthetic derivative of
Camptotheca acuminata tree.
● Only IV route of administration
TOPOTECAN and IRINOTECAN
96. ● Irinotecan and its metabolite are eliminated via bile
and feces
● Topotecan is eliminated renally
● Clinical use:
● Topotecan - 2nd line agent - Advanced Ovarian Ca
and Recurrent/ relapsed/ stage IV B Cervical
Cancer and for small cell lung Ca.
● Irinotecan - Metastatic Colorectal Ca and Lung
carcinoma
TOPOTECAN and IRINOTECAN
97. ● Toxicity :
● Myelosuppression
● Moderately emetogenic
● “Early Diarrhoea” which is a cholinergic response
and happens within 24 hours of drug administration
and is managed with Atropine
● Late diarrhoea typically 3-10 days after treatment.
TOPOTECAN and IRINOTECAN
