Treatment for Lung Cancer Flashcards
What are the localised symptoms and signs of lung cancer?
Cough and fatigue
Breathing problems
Blood in phlegm
Chest pain and tightness
Hoarseness & hiccups
What are the generalised signs and symptoms of lung cancer?
Bone pain
Headaches
Weight loss
Abdominal pain
Hepatomegaly
GI disturbances
What are the available treatment methods for lung cancer?
Surgery
Radiation
Pharmacotherapy
What are the two options under pharmacotherapy of lung cancer?
Chemotherapy
Targeted or Biologic therapy
What are the kinds of drugs given in chemotherapy?
Alkylating agents
Antimetabolites
Topoisomerase inhibitors
Microtubule inhibitors
What are the examples of alkylating agents?
Cisplatin (1st gen)
Carboplatin (2nd gen)
What is the mechanism of action of alkylating agents?
Kill tutor cells at all stages of cycle
Form intra-strand and inter-strand crosslinks –> inhibition of DNA synthesis
Bind both to cytoplasmic and nuclear proteins
Pharmacokinetics of alkylating agents?
Administered via IV
What is a contraindication of cisplatin?
Aluminium, it reacts and inactivates it
What are the adverse effects of alkylating agents?
Nephrotoxicity
Ototoxicity
Neurotoxicity
Nausea & Vomiting
Myelosuppression
What are the examples of antimetabolites (folate antagonists)?
Pemetrexed and Pralatrexate
What is the mechanism of action for antimetabolites (folate antagonists)?
Inhibits DHFR and enzymes involved in de novo purine nucleotide biosynthesis
Inhibits thymidylate synthase –> lower risk of resistance
What is the function of the DHFR enzyme?
Converts folic acid into DHF which is then converted into THF
What is the function of thymidylate synthase?
Converts dUMP into dTMP
What are the pharmacokinetics of antimetabolites (folate antagonists) ?
Excited in urine
Dose modification is required if renal dysfunction
What are the adverse effects of antimetabolites (folate antagonists)?
Myelosuppression
Skin rash
Neutropenic sepsis leading to death
What is an example of antimetabolites (pyrimidine analogs)?
Gemcitabine
What is the mechanism of action of Gemcitabine?
Gemcitabine diphosphate inhibits ribonuclease reductase required to convert ribonucleotides into deoxyribonucleotides
Gemcitabine triphosphate inhibits DNA polymerase –> blockade of DNA synthesis and repair
How does Gemcitabine triphosphate go by unrecognised?
It is incorporated into DNA and it is followed by one more normal nucleotide
What are the adverse effects of Gemcitabine?
Myelosuppression
Hepatic toxicity
Flu-like symptoms !!
GI disturbances
Elevations of serum transaminases
Proteinuria
What does inhibition of DNA repair by Gemcitabine do to the other agents?
It may increase cytotoxicity
What are examples of topoisomerase inhibitors?
Irinotecan and Topotecan
What is Irinotecan?
It is a prodrug that is converted mainly in the liver to a more potent metabolite
What is Irinotecan converted into?
SN-38 metabolite
What are the pharmacokinetics of camptothecins?
Irinotecan and SN-38 mainly eliminated in the bile and feces
Dose reduction is required in liver dysfunction
Mecanism of action of camptothecins?
Inhibit topoisomerase I –> S phase
What are the adverse effects of camptothecins?
Myelosuppression
Diarrhea
What is an example of topoisomerase inhibitor (epipodophylolotoxins)?
Etoposide
What is etoposide?
A semisynthetic derivative of podophyllotoxin
What is the mechanism of action of Etoposide?
Inhibits DNA enzyme topoisomerase II
Cell - cycle phase specific and arrests cells in S phase (or early G2)
Pharmacokinetics of Etoposide?
Administered IV or orally
Excreted in urine,
Dose reduction in patients with renal dysfunction
Adverse effects of Etoposide?
Myelosuppression
GI disturbances
Alopecia
What is an example of microtubule stabilisers?
Texans
What are examples of taxanes?
Paclitaxel and Docetaxel
Which is more potent: Paclitaxel or Docetaxel?
Docetaxel
What does the original taxmen drug contain?
Cremophor and ethanol –> hypersensitivity reaction and myelosuppression
What does docetaxel contain?
Paclitaxel bound to albumin –> lower incidence of hypersensitivity reactions
Mechanism of action of taxanes?
Stabilise microtubule formation
Inhibit angiogenesis
How does resistance develop with taxanes?
Alteration in tubular or tubular binding sites or P-glycoprotein mediated multi drug resistance
Pharmacokinetics of taxanes?
Infused
Large distribution –> cannot enter CNS
Metabolised by liver
Excreted in bile
What are the adverse effects of taxanes?
Myelosuppression
Peripheral neuropathy
Fluid retention
Hypersensitivity reactions
What are the examples of targeted or biologic therapy?
VEGF inhibitors
EGFR inhibitors
Immunomodulatory monoclonal antibodies
ALK inhibitors
What is an example of VEGF inhibitors?
Bevacizumab
What is the mechanism of action of Bevacizumab?
Binds to and inhibits VEGF A –> inhibiting angiogenesis
Pharmacokinetics of Bevacizumab?
IV infusion
What are the adverse effects of Bevacizumab?
Hypertension
Bleeding !!
Thrombotic Events !!
GI perforation
Proteinuria
What are examples of the EGFR inhibitors?
Erlotinib and Gefitinib
What is the mechanism of action of EGFR inhibitors?
Inhibition of EGFR kinase
Pharmacokinetics of EGFR inhibitors?
Metabolised by the liver by the CYP3A4 enzyme
What are the adverse effects of EGFR inhibitors?
Skin rash
Diarrhea
Anorexia
Fatigue
What is the difference between Afatinib and the other EGFR inhibitors?
Afatinib irreversibly blocks all kinases of the ErbB family –> binding to kinase domain –> inhibition of tumor growth
What is Osimertinib?
Another EGFR inhibitor which also binds irreversibly
When is OSimertinib used?
1st option for patients who develop resistance to first line therapy (erlotinib and gefitinib)
What are the adverse effects of Osimetinib?
GI toxicities
Dermatologic toxicities
Pulmonary toxicities
What is Necitumumab?
An EGFR inhibitor which binds to the human EGFR and blocks the binding of EGFR to its ligands
What are the adverse effects of Necitumumab?
Cardiopulmonary arrest
Hypomagnesemia
Thromboembolytic event
Dermatologic toxicities
Infusion reactions
What happens if necitumumab is given with pemetrexed and cisplatin?
Higher morbidity
What are the examples of the monoclonal antibodies?
Nivolumab and Pembrolizumab
What is the mechanism of action of nivolumab and pembrolizumab?
PD1 receptor is expressed by activated T cells and serves as checkpoint
PD1 ligand is expressed on numerous human tumours
Through the interaction, T cell activity becomes limited and tumour evades
Nivolumab and pembrolizumab block PD1 from interacting with its receptor –> restoration of T-cell activity
Pharmacokinetics of Pembrolizumab?
Half life of 22 days
Very minimal drug interactions
What is a contraindication of Pembrolizumab?
Use of systemic corticosteroids or immunosuppressants should be avoided before the use of drug
pharmacokinetics of Nivolumab?
Half life of 27 days
Adverse effects of Nivolumab?
Headache, URTI, abdominal pain
General adverse effects of monoclonal antibodies?
Immune-mediated toxicities, pneumonitis, colitis and thyroid dysfunction
Depending on severity corticosteroids should be started
What is an example of ALK inhibitors?
Crizotinib (1st gen)
Alectinib & Ceritinib (2nd gen)
Mechanism of action of Crizotinib?
Binds to the ATP intracellular domain of activated ALK –> inhibiting phosphorylation and downstream signaling
Adverse effects of Crizotinib?
Visual disorders
QT prolongation
Mechanism of action of Alectinib and Ceritinib?
Inhibit autophosphorylation of ALK and downward signalling
General adverse effects of Alectinib and Ceritinib?
Fatigue
Bradycardia
Hepatotoxicity
Visual disturbances
Specific adverse effects of Alectinib?
Anemia, constipation, edema and myalgia (alectinib)
Specific adverse effects of Ceritinib?
QT interval prolongation GI toxicity, pancreatitis, hyperglycemia
