chemo agents Flashcards
What are the 8 classes of Chemo agents?
Alkylating, Anti-metabolite, Enzyme Inhibitors, Anti-microtubules, Endocrine Therapies, Targeted therapies, Immunotherapy, Miscellaneous
What are the stages of the cell cycle?
1) Growth (G)
2) Synthesis (S)
3) Growth and preparation for mitosis (G1)
4) Cell division stage (M)
What kind of cells do cell-cycle specific agent kill?
They preferentially kill proliferating cells
How are cell-cycle specific agents administered?
Via continuous infusion to allow for exposure to more cells
What kinds of cells do cell-cycle non specific agents kill?
Malignant and non-malignant cells
Cell kill of cell-cycle non specific agent is proportionate to ____?
Dose
What are the examples of acute toxicities caused by chemo?
Bone marrow suppression, Alopecia, Mucositis
What kind of tissues are most vulnerable to acute toxicities?
Tissues with fast renewal cells such as bone marrow, skin, hair, GI mucosal cells
What cause acute toxicities?
Inhibition of host cell division
What are the examples of delayed toxicities caused by chemo?
Infertility
Anthracycline induced cardiotoxicities
MTX-induced pneumonitis
Examples of alkylating agents?
Platinum analogues, Cyclophosphamide, Ifosfamide
Examples of Platinum analogues?
Cisplatin (1st gen)
Carboplatin (2nd gen)
Oxaliplatin (3rd gen)
MOA of alkylating agents?
1) Formation of positively charged carbonium ion that binds to electron-rich sites on biomolecules
2) Binding to reactive molecules on the DNA (N-7 of guanine)
3) DNA mispairing
4) DNA strand breakage
5) Inhibition of DNA transcription and replication
Dose limiting toxicities of Alkylating agents?
Myelosuppression, nadir in 6-10 days, recovery in 14-21 days
Exception: Nitrosourea demonstrate delayed nadir and recovery.
Do alkylating agent show cross resistance?
No, can switch to different class of alkylating agent if one is ineffective
Alkylating agents differ greatly in?
PK, Lipid solubility, chemical reactivity and properties of membrane transport
Cyclophosphamide is activated in ____?
The liver
What are the products of cyclophosphamide activation?
Enzymatic: Carboxyphosphamide (Inactive)
Non-enzymatic: Acrolein, Phosphoramide mustard
Main cytotoxic agent of cyclophosphamide?
Phosphoramide mustard
Typical dose of cyclophosphamide? Indicated for?
600-750 mg/m^2
Indicated for lymphomas, breast cancer
High dose of cyclophosphamide? Indicated for?
2g/m^2
Indicated for bone marrow transplant
Toxicities of Cyclophosphamide?
N/V
Haemorrhagic cystitis
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Cyclophosphamide is excreted via?
Urine as active/ inactive metabolites
Ifosfamide is activated in ____?
Liver via CYP3A4
MOA of Ifosfamide?
Cytotoxic activity arise from cross-linking of DNA by alkylation at N-7 of guanine. Inter-intra cross links in DNA causes cell death
Active metabolite of Ifosfamide?
Isophosphoramide mustard
Ifosfamide must be co-administered with?
Mesna
What is Mesna?
Mesna is a radical scavenger, must be administered with large dose of Ifosfamide
Toxicities of Ifosfamide?
Dose limiting haemorrhagic cystitis
Nephrotoxicity
N/V
CNS toxicity
MOA of platinum analogues?
Formation of reactive electrophile that covalently binds to DNA
Toxicities of Cisplatin?
1) Dose-limiting acute and delayed CINV
2) Cisplatin-induced Nephrotoxicity
3) Ototoxicity (may be irreversible)
4) Peripheral neuropathy (reversible)
When is the use of Cisplatin not recommended?
When patient’s SCr < 1.5 mg/dl
Preventive measures for Cisplatin-induced nephrotoxicity?
1) Avoid in patients with renal dysfunction
2) Hydration with at least 1.2L 0.9% NaCl IV pre and concurrent with Cisplatin, with Potassium and Magnesium supplementation
3) Use of osmotic diuretics (Mannitol/ Furosemide)
4) Maintain urine output >100ml/h
5) Prolong infusion time
6) Use amifostine (radical scavenger)
Disadvantages of Amifostine?
1) Expensive and myelosuppressive.
2) Might affect efficacy of Cisplatin
How is Carboplatin dosed?
Based on Calvert’s equation
State the Calvert’s equation
Dose = AUC * (GFR +25), where AUC=2 for weekly dosing, AUC= 5 or 6 for every 3 weekly dosing
Toxicity of Carboplatin?
Dose limiting myelosuppression, hypersensitivity
Benefits of Carboplatin over Cisplatin?
Carboplatin has lower incidence of Nephrotoxicity, delayed N/V, Ototoxicity
Indication of Cisplatin, Carboplatin, Oxaliplatin?
Cisplatin/ Carboplatin: Large range of solid tumour
Oxaliplatin: Colorectal cancer
Oxaliplatin is only stable in?
D5W
Toxicity of Oxaliplatin
1) Cumulative peripheral neuropathy
2) Myelosuppression
3) Nephrotoxicity
4) Hypersensitivity
What are the enzymes that enzyme inhibitors anatagonise?
Topoisomerase I and II
Topoisomerase I inhibitors?
Irinotecan (CPT-11)
Which stage of the cell cycle does Irinotecan affects?
S phase
Active metabolite of Irinotecan
SN-38
MOA of Irinotecan
Binds to Topoisomerase I-DNA complex, prevents the relegation of DNA. Resulting in DNA breakage and cell death
Indication of Irinotecan?
Metastatic colorectal cancer
Excretion of Irinotecan?
Biliary and urinary
Toxicities of Irinotecan?
1) Dose-limiting Diarrhoea
2) Cholinergic syndrome
3) UGT1A1 deficiency
Management of Irinotecan dose-limiting diarrhoea?
Use Loperamide 4mg at earliest sign, 2mg q2h until diarrhoea free for 12 hours
Describe UGT1A1 deficiency
Patient with homozygosity for UGT1A1*28 allele has problem clearing the active metabolite SN-38
Management of Irinotecan cholinergic syndrome?
Routinely pre-med with IV/SC Atropine (0.25-1 mg)
Topoisomerase II inhibitors?
Etoposide, Anthracyclines
Examples of Anthracyclines?
1) Doxorubicin
2) Daunorubicin
3) Epirubicin
4) Idarubicin
5) Liposomal Daunorubicin
6) Mitoxantrone
Indication for Etoposide?
Wide range of solid tumour?
Availability of Etoposide?
IV (100mg injection), Oral (50mg Caplet)
Administration instructions for IV Etoposide?
1) Infused for at least 1 hour to avoid hypotension
2) Use non-PVC tubing
3) Diluted to concentration of <0.4mg/ml
Toxicities of Etoposide?
1) Dose-limiting myelosuppression
2) Hypotension if infused too quickly
MOA of Anthracyclines?
1) Induce formation of covalent topoisomerase II-DNA complexes, preventing relegation of DNA
2) Intercalation of base pairs in DNA
3) Metabolized in liver to form oxygen rich radicals
Toxicities of Anthracyclines?
1) Anthracycline-induced cardiotoxicity
2) Dose-limiting myelosuppression (primarily neutropenia)
3) Alopecia
4) Acute N/V
5) Vesicant
6) Red discolouration of urine
Before initiation of Anthracyclines what test must be performed?
Baseline MUGA/ECHO performed to evaluate left ventricular ejection fraction (LVEF).
If LVEF <40%, do not start
What causes Anthracycline-induced cardiotoxicity?
Formation of free radicals
Risk factors of Anthracycline-induced cardiotoxicity?
1) Cumulative doses
2) Age
3) Pre-existing cardiac disease
4) Administration schedule
5) Mediastinal radiation
Prevention of Anthracycline-induced cardiotoxicity?
1) Limit cumulative dose, involves lifetime tracking
2) Adjust administration schedule. Fractionate doses and prolong infusion
3) Use less cardiotoxic alternative such as Liposomal Daunorubicin, Mitoxantrone
4) Use Dexrazoxane, a cardiac protectant
Examples of Antimetabolites?
Anti-folate agent: MTX
Pyrimidine analogues: 5-FU, Capecitabine
MOA of MTX?
Binds to Dihydrofolate reductase, prevents formation of tetrahydrofolate from folic acid. Hence, preventing formation of thymidylate and purines.
Lesser DNA synthesis, repair and cellular replication
Indication of MTX?
All cancers
Administration instructions for high dose (>1g/m^2) MTX?
Requires therapeutic drug monitoring and folinic acid rescue.
What kinds of drugs should be avoided with MTX?
1) NSAIDs
2) Penicillins
3) Salicylates
4) Omeprazole
5) Ascorbic acid (Vit C)
6) Probenecid, Sulfonamides
Excretion of MTX
Primarily renal via glomerular filtration and active tubular secretion
Toxicities of MTX?
1) Dose limiting myelosuppression
2) MTX-induced pneumonitis
3) Nephrotoxicity
4) Hepatitis
5) Diarrhoea
6) Mucositis
7) CNS toxicities
8) MTX can escape into third spaces. Patients with ascites, pleural effusion are at high risk for MTX toxicity
MOA of 5-FU?
Acts as a “false pyrimidine”, inhibits the enzyme Thymidylate synthase, thus inhibiting formation of the DNA base thymidine
Indication of 5-FU?
Solid tumour cancers
Excretion of 5-FU
As respiratory CO2, and via biliary system
Toxicities of 5-FU
Depends on the duration and rate of administration
1) Dose-limiting leukopenia, thrombocytopenia, anemia in bolus administration
2) Dose-limiting hand-food symptoms and diarrhoea in continuous infusion
3) Skin discolouration
4) Nail changes
5) Photosensitivity
6) Neurologic toxicities
7) Vasospastic angina
MOA of Capecitabine?
Undergoes 3-step conversion to fluorouracil. Last step being phosphorylation by thymidine phosphorylase (TP). TP is found in higher levels in tumour cell
Indication of Capecitabine?
Solid tumour cancers
Toxicities of Capecitabine?
1) Dose-limiting hand foot syndrome (more in Capecitabine), mucositis, diarrhoea
2) CINV
3) Fatigue
4) Rash
Examples of Anti microtubule drug?
Vinca alkaloids, Taxanes
Examples of Vinca alkaloid?
Vincristine, Vinblastine, Vinorelbine
Examples of Taxanes?
Paclitaxel, Docetaxel
MOA of Vinca?
Inhibition of polymerisation by binding to Tubulin
MOA of Taxanes?
Inhibition of depolymerisation by binding to microtubules
Toxicities of Vinca (general)?
1) Alopecia
2) Vesicants
Benefit of Vinca?
Low emetogenic potential
Toxicities of Vincristine?
1) Peripheral neuropathy
2) Ileus
3) Constipation
Toxicities of Vinblastine, Vinorelbine?
1) Dose-limiting neutropenia, thrombocytopenia
2) Neurologic toxicity
3) Constipation
Premedication for Paclitaxel? Indicated for?
To prevent Hypersensitivity. Anti-histamines (H1 & H2), Corticosteroids
Premedication for Docetaxel? Indicated for?
To prevent Edema. Dexamethasone 8mg PO BD, start 1 day prior to treatment, continuing for 2 additional days
Toxicities of Paclitaxel?
1) Hypersensitivty
2) Myelosuppression (Less significant than Docetaxel)
3) Myalgias
4) Peripheral neuropathy
5) Mucositis (Seen more with prolonged infusion)
Toxicities of Docetaxel?
1) Myelosuppression (Neutropenia more significant than Paclitaxel)
2) Less peripheral neuropathy
3) Less hypersensitivity
4) Less asthenia
Examples of Endocrine therapies?
1) Antiestrogen
2) Anti-aromatase
Example of Antiestrogen agent?
Tamoxifen, a selective estrogen receptor modulator.
Indications for Tamoxifen?
1) Indicated for pre menopausal women with Estrogen-receptor positive breast cancer.
2) Advanced endometrial cancer
MOA of Tamoxifen?
Inhibits nuclear binding of the estrogen receptor, prevent estrogen from stimulating breast cancer cells
Antagonist and Agonist activity of Tamoxifen?
Antagonist: Breast epithelial cells (Cancer/ Non cancer)
Agonist: Bone, Lipids, Endometrium (Can increase risk for endometrium cancer)
Examples of Anti-aromatase agent?
1) Anastrozole
2) Letrozole
3) Exemestane
Group of patient anti-aromatase agent is used in?
Post-menopausal women
SEs of Anti-aromatase agents?
1) Hot flashes
2) Fatigue
3) Myalgia/ Arthralgia
4) Bone Loss
Two major classification of Targeted Therapies?
1) Small molecular drug
2) Monoclonal antibodies
TT-induced toxcities?
1) Cardiotoxicity
2) Neurotoxicity
3) Immunotoxicity
4) Hepatotoxicity
5) Pulmonary toxicity
6) GI toxicity
7) Dermatological toxicity
Examples of Small molecule drugs?
Epidermal growth factor tyrosine kinase inhibitors:
1) Gefitinib
2) Erlotinib
3) Afatinib
MOA of Epidermal growth factor tyrosine kinase inhibitors
Inhibits cell proliferation by blocking intracellular signals that stimulate gene expression.
1) Decrease proliferation
2) Decrease cell survival
3) Decrease growth factor
4) Decrease angiogenesis
5) Decrease metastasis
6) Increase Chemo/Radio sensitivity
Epidermal growth factor tyrosine kinase inhibitors are indicated for?
EGFR positive cancers (Lung, pancreatic (erlotinib only))
Toxicities of small molecule drugs?
1) Dermatological toxicities (Mild)
2) Diarrhoea
Management principle for toxicities of small molecule drugs?
1) Should not interfere with anti-tumour effects of EGFR-inhibitors
2) Minimal SEs
3) Tailored to type of clinical presentation
What are the agents used for dermatological toxicities?
1) Anti-microbials
2) Emollients/ Skin protectant
3) Antihistamines
4) Retinoids
5) Corticosteroids/ Immunomodulators
Examples of Monoclonal antibodies?
1) Rituximab
2) Bevacizumab
3) Trastuzumab
MOA of Rituximab?
Binds to CD20 receptors on malignant/ normal B cells leading to:
1) Apoptosis
2) Complement Dependent Cytotoxicity
3) Antibody-dependant cell-mediated cytotoxicity
Toxicities of Rituximab?
1) Infusion related reactions (Fever, chill/rigor, bronchospasm, hypotension)
2) N/V
3) Myelosuppression
4) Infections
Management of Infusion related reactions?
1) Pre-medicate with paracetamol, diphenhydramine
2) Start infusion slow and increase rate overtime
MOA of Bevacizumab?
Vascular endothelial growth factor inhibitor
Bevacizumab should be avoided in _____?
Patient with bleeding risk, CNS metastasis
MOA of Trastuzumab?
HER2/ Neu receptor antagonist
Indication for Trastuzumab?
Cancer with HER2 overexpression (Breast/ Gastric)
Toxicities of Trastuzumab?
Cardiotoxicity, hypersensitivity
Toxicities of Bevacizumab?
1) Increased risk of thrombotic events (Stroke)
2) Haemorrhage
3) Gastrointestinal perforation
4) Proteinuria
5) Wound healing complication
Examples of Immunotherapies?
1) Ipilimumab
2) PD-1 inhibitor
3) PD-L1 inhibitor
MOA of Ipilimumab?
Blocks cytotoxic T-cell lymphocyte associated antigen (CTLA-4) inhibitory signal, allowing CTL to kill cancer cells
