Cancer Chemo

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