3 mustard alkylators
cyclophosphamide
Ifosfamide
melphalan
Cell cycle specificity of Mustard Alkylators
cell cycle non-specific
MOA of mustard alkylators
crosslink DNA strands decreasing DNA synthesis (active Cl- groups)
common toxicity for cyclophosphamide
hemorrhagic cystitis
The byproduct of cyclophosphamide/ifosfamide metabolism that causes hemorrhagic cystitis
acrolein
Rescue therapy for high dose cyclophosphamide
MESNA
Metabolism of Ifosfamide
metabolized by two pathways - one causes neurotoxicity and one causes nephrotoxicity
Doses of ifosfamide that require MESNA
all doses - makes 4x as much Acrolein than cyclophosphamide
drugs to avoid with ifosfamide
anticoagulants and anti-platelets
Common ADE associated with melphalan
patients feeling very hot
dose limiting toxicity for all mustard alkylators
myelosuppression
Mustard alkylators are _____ emetogenic
moderately-highly
ifosfamide causes wasting of these electrolytes
potassium
magnesium
phosphate
dacarbazine
temozolomide
carmustine (BCNU)
Lomustine (CCNU)
4 non-mustard alkylators
MOA of non-mustard alkylators
causes DNA double strand breaks and apoptosis
cell cycle specificity of non-mustard alkylators
cell cycle non specific
non mustard alkylator
IV only
poor CNS penetration
HIGHLY EMETOGENIC
dacarbazine
non mustard alkylator
IV administration
needs ethanol vehicle
crosses BBB (CNS penetration)
pulmonary toxicity
delayed nadir
carmustine (BCNU)
non mustard alkylator
PO administration only
crosses BBB (CNS penetration)
pulmonary toxicity
delayed nadir
Lomustine (CCNU)
Carmustine and Lomustine are commonly used for ___
brain cancers (bc they cross the BBB)
test performed after each cycle of carmustine or lomustine
chest x ray
treatment of choice for brain cancer
temozolomide
most commonly used non-mustard alkylator
temozolomide
how temozolomide is converted to active form
spontaneous hydrolysis
dose limiting toxicity for temozolomide
myelosuppression
type of prophylaxis needed for temozolomide and when
PCP when used in combo with radiation
3 platinum derivatives
cisplatin
carboplatin
oxaliplatin
MOA of platinum derivatives
inhibit DNA synthesis disrupts DNA function, blocks DNA crosslinks
dose limiting toxicity for cisplatin
nephrotoxicity
max dose of cisplatin per dose or per cycle
100 mg/m2
cisplatin causes wasting of these electrolytes
K, Mg, Phos
cisplatin is ____ emetogenic
highly
____ is another common ADE associated with cisplatin
ototoxicity
dose limiting toxicities of carboplatin
myelosuppression and thrombocytopenia
carboplatin is ____ emetogenic
moderately
formula that needs to be used to calculate carboplatin dose
calvert formula: dose (mg) = AUC x CrCl
AUC target for carboplatin
5-6
risk of anaphylaxis with carboplatin increases with __
exposure (6+ cycles)
place in therapy for oxaliplatin
for tumors resistant to cisplatin and carboplatin
Dose limiting toxicity of oxaliplatin
neurotoxicity
acute phase of neurotoxicity caused by oxaliplatin
extreme cold intolerance for 4 days post infusion
delayed phase of neurotoxicity caused by oxaliplatin
peripheral neuropathy
specificity of platinum derivatives
cell cycle non specific
methotrexate
pemetrexed
fludarabine
cytarabine
5-FU
capecitabine
Gemcitabine
6-MP
antimetabolites
cell cycle specificity of antimetabolites
s-phase specific
MOA of methotrexate
inhibits dihydrofolate reductase to interfere with DNA synthesis
ADEs from CHRONIC mtx therapy
hepatic fibrosis and pneumonitis
ADEs from ACUTE mtx therapy
myelosuppression, mucositis, hepatotoxicity
2 common routes of administration of MTX utilized with chemotherapy
IV and IT
PO absorption is saturable at doses of MTX above ____ and these doses are mostly used for chemo
> 25 mg/m2
the 7 drugs that interact with MTX and MUST be held for 48 hrs after last MTX dose
Penicillins
sulfonamides
tetracyclines
ciprofloxacin
NSAIDs
Saliciylates
PPIs
Creatinine clearance cut off for high dose MTX
> 50 mL/min
A patient's urine needs to be _____ with ___ in order to excrete MTX
alkalized, with Na bicarb or Na acetate
Goal urine pH for patients on MTX
? 7
rescue therapy for MTX
leucovorin
When to start leucovorin rescue
48 hours after dose of MTX
MOA premetrexed
inhibits thymidylate synthetase to interfere with DNA synthesis
Pemetrexed works on the same pathway as __
MTX
rescue therapy for pemetrexed
folic acid (not leucovorin!)
ADE of pemetrexed
myelosuppression
3 pretreatments for pemetrexed
folic acid
vitamin b12
dexamethasone
CrCl cutoff for pemetrexed
avoid if CrCl < 45 mL/min
Main DDI for pemetrexed
NSAIDs - avoid 2-3 days before/after premetrexed
MOA of fludarabine
purine agonist that inhibits DNA polymerase to cause double strand breaks
CrCl cutoff for fludarabine
30 mL/min
main ADE with fludarabine
myelosuppression
Fludarabine causes a prolonged ___
nadir (period of immunosuppression)
Pyrimidine antagonist
IV. IT, SQ
causes cerebellar toxicity and commonly causes conjunctivitis
cytarabine
the ___ dose regimen on cytarabine is used more often
high
risk factors for cerebellar toxicity with cytarabine
elderly and renal failure
PO form of cytaranine
pyrimidine antagonist
20x higher conc inside the cell than cytarabine
dose limiting toxicity = myelosuppression (specifically a decrease in platelets)
gemcitabine
treatment for conjunctivitis caused by cytarabine
dexamethasone eye drops
MOA of 5-FU when given as a continuous infusion
pyrimidine antagonist that inhibits thymidylate synthetase
MOA of F-5U when given as a bolus
pyrimidine antagonist that falsely incorporates into DNA
PO prodrug of 5-FU
Capecitabine
reason leucovorin is used with 5-FU/capecitabine
enhances stability and helps drug work better
The IV form of 5 FU is metabolized by ___
dihydropyrimidine dehydrogenase (DPD)
main DDI with 5-FU/capacitabine
warfarin (leads to increase in INR)
main ADE for bolus of F-5U/capecitabine
myelosuppression
Main ADEs of continuous infusion 5-FU
GI toxicity and mucositis
CrCl cutoff for capecitabine
30 mL/min
MOA of 6MP or AZ
purine analog that interferes with DNA synthesis
enzyme that converts azathioprine to active form and that converts 6MP to inactive form
TMPT
6MP or azathiaprine is contraindicated in ___
patients with TMPT enzyme deficiency
a drug that could interact with 6MP or AZ due to xanthine oxidase
allopurinol
two types of antimicrotubule agents
taxanes and vinca alkaloids
taxanes MOA
prevent microtubule assembly
Vinca Alkaloids MOA
prevent microtubule DISassembly
Paclitaxel, Docetaxel
Taxanes
Vincrsitine; vinblastine, vinorelbin
vinca alkaloids
cell cycle specificity of antimicrotubule agents
G1 & G2 specific - M phase
Routes of Administration for paclitaxel
IV or intraperitoneal
dose limiting toxicity of paclitaxel
peripheral neuropathy
Premedication with these 3 agents when giving paclitaxel to prevent hypersensitivity rxn
dexamethasone
diphenhydramine
H2RAs
why is paclitaxel given before cisplatin?
cisplatin impairs the clearance of paclitaxel
Docetaxel DLT
myelosuppression
Hypersensitivity rxns
causes capillary leak syndrome, full body hair loss, and nail changes
DLT = myelosuppression
Docetaxel
drugs that cannot be administered intrathecally
vinca alkaloids
dose cap of vincristine
2 mg
vincristine DLT
peripheral neuropathy
vincristine does NOT cause ___
myelosuppression
vinblastine, vinorelbine DLT
myelosuppression
irinotecan
topotecan
2 topoisomerase I inhibitors
MOA of topoisomerase I inhibitors
Inhibit topoisomerase I leading to single strand DNA breaks
enzyme responsible for inactivating irinotecan
UGT1A1
DLT of irinotecan
diarrhea
treatment of acute (< 24 hours) irinotecan-induced diarrhea
atropine
treatment of chronic (> 24 hours) irinotecan-induced diarrhea
loperamide
etoposide
doxorubicin
mitoxantrone
topoisomerase II inhibitors
cell cycle specificity of topo 2 inhibitors
S and G2
topo 2 inhibitors MOA
Inhibit topoisomerase II leading to double strand DNA breaks & apoptosis
etoposide DLT
myelosuppression
conc of etoposide must be less than 0.4 mg/mL to avoid...
precipitation
topo 2 inhibitor
IV and PO (saturable at doses above 200 mg)
causes Hypotension due to EtOH diluent
Metallic taste
etoposide
the rubicins + mitoxantrone
anthracyclines
DLT of anthracyclines
cardiac toxicity
counseling point for anthracyclines
red urine
due to this, cold caps should never be used with anthracyclines
increases metastases in brain
DLT of mitoxantrone
myelosuppression
preferred agent for pre-existing cardiomyopathy
mitoxantrone
counseling point for mitoxantrone
blue green urine
MOA bleomycin
creates DNA single strand breaks via free-radical formation
2 drugs that are not myelosuppresive
vincristine and bleomycin
DLT of bleomycin
pulmonary toxicity
rituximab
cetuximab
bevacizumab
Trastuzumab
monoclonal antibodies
imatinib
sorafenib
crizotinib
erlotinib
TK inhibitors
MOA of rituximab
anti CD20 (on B cells)
MOA of cetuximab
binds to EGFR to block angiogenesis
patients with this mutation DO NOT benefit from cetuximab
K-ras
Bevacizumab MOA
binds to VEGF to decrease angiogenesis
Imatinib MOA
inhibits BCR-ABL gene, tyrosine kinase
imatinib interacts with ___
3A4 inhibitors/inducers
most common ADE with imatinib
nausea
TK inhibitor
inhibits VEGF, PDGFR, cKIT, or FLT3
causes HTN (need antihypertensive agent)
Sorafenib
ALK inhibitors
crizotinib
EGFR & HER1 inhibitor
Avoid H2 and PPIs
Erlotinib
ipilimumab MOA
cytotoxic t-lymphocyte antigen (CTLA-4) antagonist to activate T cells to kill cancer
Nivolumab and pembrolizumab MOA
inhibit programmed cell death (PD-1) to lead to enhanced T cell response