Angela's Chemotherapy Flashcards
Calvert Dosing
mg = AUC x (GFR +25)
Cockgroft-Gault Equation for CrCl
[(140-age)(Wt)]/[(SCr x72)] x0.85
x 0.85 for women
Wt in kg
SCr in mg/dL
What affects the rate of absorption of chemo from IP to IV?
size of molecule (molecular weight).
Also: charge, chemical structure
What drugs are alkylating agents? (3 drugs)
- Cyclophosphamide
- Ifosfamide
- Melphalan
Are alkylating agents cell cycle specific?
NO
Antimetabolites (5 drugs)
- Methotrexate
- 5-FU
- Capectabine
- Gemcitabine
- Pemetrexed
Alkylating agent (3 drugs + bonus!)
- Cyclophosphamide
- Ifosfamide
- Alkeran (Melphalan)
- Dacarbazine
Bonus: temozolomide, altretamine
What is amifostine?
Chemoprotective agent - prodrug that is dephosphorylated by alkaline phosphatase into a free thiol. The free thiol binds and detoxifies reactive metabolites of cisplatin and can act as a scavenger of free radicals
Anti-tumor antibiotics (5 drugs)
- Adriamycin (Doxorubicin)
- Bleomycin
- Mitomycin C
- Actinomycin D
- pEgylated Doxorubicin
also: Epirubicin
Think ABCDE
Toposomerase 1 inhibitors (2 drugs)
- Topotecan
- Irinotecan
Topo 2 inhibitor (1 drug)
Etoposide
Vinca Alkyloids (3 drugs)
- Vincristine
- Vinblastine
- Vinorelbine
Methotrexate
1. Most common adverse effect?
2. Clearance?
3. What affects MTX levels? (How does ascites affect MTX)
4. What manipulation of urine can decrease its nephrotoxicity?
Methotrexate
1. Most common adverse effect? Stomatitis / mucositis & myelosuppression (vs high dose = NV)
2. Clearance? Renal
3. What affects MTX levels? Highly protein bound, requires evacuation of ascites & effusions
-prot-bound drugs increase free drug form: salicylate, sulfa, phenytoin
4. What manipulation of urine can decrease its nephrotoxicity? Alkalinization (thiazide, sodium bicarb)
5-FU
- Metabolism?
- Is it a prodrug?
- Where is it activated and cleared?
- Is it dose reduced in renal failure?
- Does it cause PPE?
5-FU
- Metabolism? Hepatic
- Is it a prodrug? YES – F-UMP is active metabolite
- Where is it activated and cleared? LIVER
- Dose reduced in renal failure? No
- Causes PPE? Yes, rare. More with prolonged infusions
Capecitabine
1. Capecitabine is a prodrug of what other antimetabolite?
2. Causes PPE?
Capecitabine
1. Capecitabine is a prodrug of what other antimetabolite? 5-FU
2. Causes PPE? Yes-only SE more freq in Capecitabine than 5-FU
Gemcitabine
- Prodrug?
- If gem is given for >60 mins what happens?
- If gem is given for <60 mins what happens?
- Clearance?
Gemcitabine
- Prodrug? YES
- If gem is given for >60 mins what happens? increased myelosuppression and liver toxicity
- If gem is given for <60 mins what happens? Flu-like symptoms (think: flu is FASTER to get over than myelosuppression)
- Clearance? RENAL
Which chemotherapy causes radiation recall? (3)
- GEMZAR (in chi, also as a risk factor for pulmonary edema in setting of mediastinal RT)
- dactinomycin (listed in Chi)
- doxorubicin (not doxil)
What is the toxicity of amifostene?
Hypotension
Methotrexate MOA
Folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication.
Methotrexate binds to and inhibits dihydrofolate reductase, resulting in inhibition of purine and thymidylic acid synthesis –> interfering with DNA synthesis, repair, and cellular replication.
Cell cycle specific for the S phase
5-FU MOA
Pyrimidine analog antimetabolite that interferes with DNA and RNA synthesis
- FU activates to F-UMP (active metabolite) which inhibits thymidylate synthase to deplete DNA nucleoside base thymidine
- incorporation of FUTP into RNA to replace uracil and inhibit cell growth.
- incorporation of FUTP into DNA
Cell cycle specific to S phase
For 5-FU. I think as if it has 5-floors. Many floors like a pyramid. So it’s a pyrimidine antagonist. The liver is shaped like a pyramid. So it’s metabolized by the liver
Gemcitabine MOA
Antimetabolite
Gem is phosphorylated into gem-diphosphate and gem-triphosphate
1. Gem-diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase (think di-phosphate is two Ps which inhibits RR [ribonucleotide reductase = two Rs])
2. Gem-triphosphate incorporates into DNA (pyrimidine analog) and inhibits DNA polymerase
It’s active triphosphate inserts itself as a “fraudulent base pair” and causes “masked-chain termination”
Cell cycle-specific for S phase, also blocks G1-S progression
Gemzar. Gems for short 💎. Gem can be found on a chain around the neck. So it does masked chain termination.
Gems are found in pyramids, so gem-triphosphate is a pyrimidine analog
3 chemotherapy drugs that cause radiation recall
Gemcitabine
Dactinomycin
Doxorubicin
Which order should cis and gem be given in?
CIS THEN GEM
Gem 1st: twofold decrease in AUC
Cis 1st: increases Gem activity
**this is opposite of taxol=taxol before carbo
What is the least effective IP chemo?
- adriamycin
- cis
- carbo
- taxotere
- gem
GEMZAR -rapid inactivation?
Chemos that require liver activation CANNOT:
Ifosfamide and cyclophosphamide (require activation by P450 system)
Excess toxicity given IP (per Chi):
- mitoxantrone
- doxorubicin
Docetaxol? (Large size)
Which drug cannot be given as IP chemotherapy?
- cyclophosphamide
- 5-FU
- doxorubicin
- paclitaxel
cyclophosphamide because it requires activation by liver P450 microsomal oxidase system
Not 5FU - it can be used in IP and discussed as such in Chi
Others that require liver activation CANNOT:
Ifosfamide (also requires activation by P450 system)
Excess toxicity given IP (per Chi):
- mitoxantrone
- doxorubicin
What is the cardiac toxicity of cyclophosphamide?
cardiomyocyte necrosis
What chemotherapy causes SIADH?
Cyclophosphamide
What premedication should be avoided with cyclophosphamide and ifosfamide, and why?
Duplicate
Cimetidine (weak inhibitor of CP450, may worsen myelotoxicity by increasing concentrations of cyclophos/ifos)
When barbiturates and cyclophosphamide OR ifosfamide are given together, what is the primary adverse effect?
Duplicate
Sedation and possible accumulation of toxic metabolites
Barbiturates are CY450 INDUCERS —> increased metabolism of cyclophos/ifos, which increases the rate of these drugs to their toxic metabolites
Cyclophosphamide may block metabolism of barbiturates, increasing their sedative effects
Cyclophosphamide
1. Metabolism?
2. Main toxicity?
3. Excretion?
4. When do you dose-reduce?
5. Prodrug?
- Metabolism? Hepatic
- Main toxicity? Myelosuppression
- Excretion? Urinary
- When do you dose-reduce? Hemorrhagic cystitis (also renal impairment)
- Prodrug? YES - 4-hydroxycyclophosphamide. Peripheral tiss convers to toxic phosphoramide mustard and acrolein)
FYI: During hepatic metabolism of both cyclophosphamide and ifosfamide, acrolein is generated, filtered by the kidneys, and concentrated in the bladder–> Hemorrhagic cystitis. Acrolein is a reactive, unsaturated aldehyde that causes cell death through upregulation of reactive oxygen species, and that activates inducible nitric oxide synthase, leading to the production of nitric oxide.
Cyclophosphamide MOA
Alkylating agent that prevents cell division by cross-linking DNA strands (Intra>interstrand) and decreasing DNA synthesis (DNA adducts).
Cell cycle phase nonspecific but causes arrest and death in G2.
Also possesses potent immunosuppressive activity.
Which chemotherapeutic drugs should not be given with Cimetidine?
Cyclophosphamide
Ifosfamide
Why can’t cyclophosphamide be administered IP?
Prodrug - requires hepatic metabolism for an active metabolite
Cyclophosphamide
1. Metabolism?
2. Excretion?
3. Prodrug?
4. Main toxicity?
- Metabolism? Hepatic
- Excretion? Urine
- Prodrug? YES - acrolein, chloracetaldehyde
- Major toxicity? Myelosuppression
Ifosfamide
1. Metabolism?
2. Excretion?
3. Prodrug?
4. Main toxicity?
- Hepatic
- Urinary
- Yes - acrolein, chloracetaldehyde
- Myelosuppresion
Ifosfamide MOA
Alkylating agent. Causes cross-linking of strands of DNA by binding with nucleic acids and other intracellular structures, resulting in cell death. Inhibits protein synthesis and DNA synthesis.
Cell cycle non-specific
In what situation is ifosfamide neurotoxicity more common?
What is the mechanism of ifosfamide neurotoxicity? What is the antidote?
- Hypoalbuminemia or elderly
- Chloracetaldehyde, methylene blue
What is the mechanism of ifosfamide cystitis? What is the antidote?
Acrolein, Mesna (sodium-2-mercaptoethane sulfonate/ 2-MercaptoEthane Sulfonate Na)
Mesna is oxidized to dimesna in blood, which in turn is reduced in the kidney back to mesna, supplying a free thiol group which binds to and inactivates acrolein
Uremia occurs in what percentage of people on ifosfamide?
66% if >150 mg/kg
Does cimetidine increase or decrease cyclophos/ifos levels?
INCREASE - CY450 inhibition
Does phenobarbital increase or decrease cyclophos/ifos levels?
DECREASE - CY450 inducer
It causes faster accumulation of toxic byproducts. may block metabolism of barbs leading to greater neurotoxicity/sedating effects of phenobarbital
What is the treatment for extravasation of Ifosfamide at the primary IV site?
Nothing, it is activated in the liver
Remember vesicants DAMN TV
Doxorubicin (also Epirubicin/ idarubicin/ daunorubicin)
ActinomycinD
Mitomycin C
Nitrogen mustard
Trabectedin
vincas (Vinblastine, vincristine, vinorelbine)
Is alopecia a common side effect with ifosfamide?
Yes
Most common here are: microtubule agents (taxanes), anthracyclanes, topoisomerase inhibitors, and alkylating agents
Is ifosfamide processed more rapidly or more slowly than cyclophosphamide? What does this result in?
More slowly. Resulting in more chloracetaldehyde and neurotoxicity
What is the DLT of Melphalan?
Prolonged myleosuppression with nadir at 30 days and 40 day recovery
*alkylating agent.
What class of chemotherapy drug is Melphalan? is it cell cycle specific?
Alkylating agent
Not cell cycle specific
Bleomycin
1. Metabolism?
2. Excretion?
3. Prodrug?
4. Main acute toxicity? Chronic toxicity?
- Metabolism? Enzymatic inactivation by bleomycin-hydrolase, found in most normal tissues except lungs and skin
- Excretion? Urinary
- Prodrug? No
- Main acute toxicity? Mucocutaneous - rash, striae, pruritis, hyperpigmentation. Pulmonary fibrosis.
—> bc bleomycin-hydrolase not in lungs and skin, this is where toxicity is!
Bleomycin DLT
Max lifetime dose?
Pulmonary fibrosis when >
400 units
Per SGO handbook, max cumulative dose should be capped at 270u
What is the most sensitive way to diagnose bleomycin-induced pulmonary toxicity? What is the cheapest way?
Gold standard: Carbon monoxide diffusing capacity (DLCO) - needs to be done with each cycle of bleo
Cheapest is physical exam (crackles)
What phase of the cell cycle is bleomycin most active in?
G2 phase
Chi: G1, G2, S
What is an iron chelator?
Which chemo drugs are iron chelators?
duplicate
- Iron chelators enter cells, bind free iron, and remove it from the body
- Doxorubicin and bleomycin (chelation causes free-radical formation that results in cardiac or pulmonary toxicity)
Bleomycin MOA
Binds to DNA leading to single and double strand breaks –> inhibits synthesis of DNA, RNA, and protein synthesis.
Binds to guanosine-cytosine-rich portions of DNA via association of the “S” tripeptide and by partial intercalation of the bithiazole rings
Also is an iron chelator which results in ROS
Angela’s says single-strand breaks, UpToDate says single and double
Which chemo is least myelosuppressive?
Bleomycin
Which two tissues lack bleomycin-hydrolase?
Duplicate
Skin, lungs
Doxorubicin DLT
Cumulative cardiac toxicity
PharmD: Risk for cardiomyopathy increases at cumulative dose 550 over 18.
Test answer on pharmacy exams is usually 550 but no one ever pushes that high since the recommendation to start dexrazoxane is at 300mg/m2 which is probably why you’re seeing that range!
SGO states some centers limit the lifetime cumulative dose to no more than 450 mg/m2.
Doxorubicin
1. Metabolism?
2. Major toxicity?
3. Max dose?
- Hepatic (think: Hepatic metabolism for Heart toxicity)
- Cardiac - CHF
- 450mg/m2 (there is conflicting info between 400-550)
From PharmD: Risk for cardiomyopathy increases at cumulative dose 550 over age 18.
Incidence is 1 to 20% from 300mg/m2 to 500mg/‘m2 if given every 3 weeks.
Test answer on pharmacy exams is usually 550 but no one ever pushes that high since the recommendation to start dexrazoxane is at 300mg/m2 which is probably why you’re seeing that range!
How do you treat doxorubicin extravasation?
Dexrazoxane but if not available, then DMSO
DMSO and cold packs
Dimethylsulfoxide (DMSO)
Dmso for Doxorubicin (D for D)
Which chemotherapies cause radiation recall?
dactinomycin (Actinomycin D), doxorubicin, gemcitabine
How does phenobarbital interact with doxorubicin?
increases hepatic clearance of doxorubicin and decreases serum concentration by inducing P450 system
Is Doxorubicin cell-cycle specific?
No, but it is most active in S-phase
Doxorubicin MOA
1) Inhibits DNA and RNA synthesis by intercalation between DNA base pairs
2) Inhibition of topoisomerase II
3) Steric obstruction - intercalates at points of local uncoiling of the double helix
4) Iron chelator - produces free radicals that cleave the DNA and cell membranes.
Pegylated liposomal doxorubicin DLT
PPE
Paclitaxel DLT
Neutropenia (nadir day 10-12)
In what order do you administer cisplatin and paclitaxel? Why?
Taxol first then cis - avoids increased myelosuppression
What is the difference in toxicity between 24h vs 3h paclitaxel infusions?
24h - increased myelosuppression
3h - increased neurotoxicity
Paclitaxel MOA
1) Promotes microtubule assembly by enhancing action of tubulin dimers, then stabilizes and inhibits disassembly at G2-M transition –> inhibits cell replication
2) Can distort mitotic spindles, resulting in the breakage of chromosomes
3) May also suppress cell proliferation and modulate immune response
M-phase specific
Paclitaxel
1) Metabolism?
2) Adverse effects?
1) Hepatic - highly protein-bound
2) Hypersensitivity (urticaria, angioedema) - usually due to solvent castor oil [Cremaphor]), alopecia, peripheral neuropathy (cumulative dose-dependent), bradycardia
Cisplatin MOA
1) Inhibits DNA synthesis by forming DNA cross-links (inter-strand and intra-strand by binding two adjacent guanines) –> strand breakage
2) Denatures the double helix
3) Covalently binds to DNA bases and disrupts DNA function; may also bind to proteins
Cisplatin
1) Metabolism?
2) Excretion?
3) Adverse effects?
1) Nonenzymatic - inactivated by glutathione and thiosulfate
2) Urine
3) Neurotoxicity, nausea/vomiting, nephrotoxicity, ototoxicity, dose-dependent ovarian failure
What is the mechanism of resistance to cisplatin?
1) Decreased uptake: Downregulation of CTR1 (Copper transporter 1)
2) Inactivation by glutathione: Elevated levels of enzymes involved in GSH synthesis (gamma-glutamylcystein synthestase) and glutathione S transferase (binds to platinum inactivating it)
3) Nuclear excision repair (NER) pathway : expression of ERCC1 leads to increased repair of platinum-DNA adducts (THIS most common)
4) DNA MMR: loss of function of MMR contributes to developing DNA damage tolerance
5) loss of pro apoptotic factors or over expression of anti-apoptotic factors
Increased damage tolerance, decreased drug accumulation, increased glutathione levels, enhanced DNA repair, May be related to ERCC1 (excision repair cross complementation group 1)
Which platinum agent is most associated with sodium wasting nephropathy?
Cisplatin
Electrolyte disturbances with cisplatin?
Hypomagnesemia
Hyponatremia
Which platinum agent is most associated with high-frequency hearing loss?
Cisplatin (30%)
What are symptoms associated with Cisplatin neurotoxicity?
Stocking-glove neuropathy, focal encephalopathy, cortical blindness
What is cisplatin aquation?
The process by which chloride is displaced by H2O, activating cis and carboplatinum
What is Lhermittes’s sign?
Electrical-like pain or shock with neck flexion. Is seen with RT to the spine and some chemo (platinum).
(Lhermitte’s syndrome is eye issues).
Cisplatin DLT
Nephrotoxicity
What is the mechanism of platinum electrolyte disturbance?
Interfere with loop of henle and distal convoluted tubule
Carboplatin DLT
Thrombocytopenia
Why do we use AUC instead of BSA to calculate carboplatin?
Better in predicting myelosuppression than BSA
When does carboplatin hypersensitivity manifest?
Usually after 6+ cycles
Carboplatin MOA
1) Alkylating agent which covalently binds to DNA
2) Interferes with the function of DNA by producing interstrand DNA cross-links
not cell-cycle specific
Carboplatin
1) Metabolism?
2) Excretion?
3) Adverse effects?
1) Minimally hepatic - aquation
2) Urine
3) Myelosuppression esp thrombocytopenia, nephrotoxicity, electrolyte disturbance (decreased Ca, Mg, K, Na), nausea/vomiting
What is the function of topoisomerase 1?
Causes single strand DNA breaks followed by religation
Topoisomerase I: cleaves ONE DNA strand and pass either one or two strands through the break before resealing it
Topoisomerase II: cleaves TWO DNA strands in concert and pass another double strand through the break followed by religation of the double strand break
What is the function of topoisomerase 2?
Causes double strand DNA breaks followed by religation
Topoisomerase I: cleaves ONE DNA strand and pass either one or two strands through the break before resealing it,
Topoisomerase II: cleaves TWO DNA strands in concert and pass another double strand through the break followed by religation of the double strand break
Topotecan MOA
Inhibition of topoisomerase-1, stabilizing the cleavage complex so that re-ligation of DNA breaks cannot occur –> accumulation of ssDNA breaks
(topoteCan Cleavage Complex)
S phase specific
I thought it specific to G2 and S - Jenny
Megan: Chi says S
Topotecan DLT
Myelosuppression
Topotecan
1) Metabolism?
2) Excretion?
3) Best pH to function?
4) Water soluble?
1) Metabolism? Renal
—> 35% protein bound
DECIM TDP
2) Excretion? Renal and hepatic - dose reduce only for renal impairment
3) Best pH to function? Acidic (low pH)
4) Water soluble? Yes
Irinotecan DLT
Diarrhea
Etoposide MOA
Topo-2 inhibitor causing dsDNA strand breaks
Forms a complex with topoisomerase II and DNA. Etoposide Poisons topoisomerase II by stabilizing an otherwise transient form of topoisomerase II by covalent linking to DNA. normal topoisomerase II activity is blocked. This causes protein linked DNA strand breaks
May also generate O2 free radicals
G2-phase specific
Etoposide
1) Metabolism
2) Excretion
3) Vesicant?
1) Hepatic - highly protein bound
—> DECIM TDP
2) Urine (requires renal dosing)
—> A BICC THE MMP
3) NO - it’s an IRRITANT
- If extravasation - but treat with HEAT and hyaluronidase
Irritants: TICE
Taxol, ifosfamide, cisplatin, etoposide
Actinomycin-D MOA
Binds to the guanine portion of DNA intercalating between guanine and cytosine base pairs –> inhibiting DNA and RNA synthesis and protein synthesis
G1 max killing, but non-cell cycle specific
Vesicant vs irritant and treatment?
Vesicant - potential to cause tissue necrosis with a more severe and/or lasting injury
Irritants - inflammation but rarely result in direct toxicity to the tissue
Apply COLD to promote vasoconstriction
EXCEPT vinca alkaloids, taxanes and etoposide - apply HEAT
Vesicants: DAMN TV
Doxorubicin (Anthracyclines - dexrazoxane > DMSO),
ActinomycinD, no treatment
Mitomycin C, DMSO
Nitrogen mustard,
Trabectedin,
vincas (Hyaluronidase)
Irritants: TICE
Taxol, Hyaluronidase
ifosfamide, Hyaluronidase
cisplatin, Sodium thiosulfate
etoposide Hyaluronidase
What is the chromosomal abnormality associated with leukemia in patients on etoposide?
11q22-23
Etoposide caused therapy-related leukemia is a chromosomal rearrangement involving the MLL gene on chromosome 11q23
Total cumulative Dose above 2.0g/m2 associated with Leukemia
Anastrazole adverse effects
Hotflashes and osteoporosis
Anastrazole-asthenia
Letrozole-hot flashes, arthralgias
What is the cardiac toxicity of trastuzumab?
CHF - need echo before treatment
Vinca alkaloids MOA
(vincristine, vinblastine, vinorelbine)
Bind tubulin, preventing microtubule polymerization during assembly of the mitotic spindle apparatus –> resulting in mitotic arrest
“spindle poison”
UTD: M and S phase specific
Chi: M and G2
What is the most common side effect of vinca alkyloids?
Notes say: Constipation
Chi: Nausea 38%, constipation 31%
DLT: BM suppression
Vinca alkaloids
1) Metabolism?
2) Treatment of extravasation?
1) Hepatic
2) Vesicant - HEAT and hyaluronidase
Ondansetron MOA
Selective 5HT3 antagonist (blocks serotonin)
Aprepitant
1) MOA
2) Metabolism
1) Neurokinin-1 antagonist
2) Hepatic cp450
What drugs should not be given with aprepitant?
These drugs are also metabolized by cp450:
Warfarin - increased INR
Cyclophosphamide - increased toxicity
Steroids - increased corticosteroid levels (need to reduce dose if premedicating)
Promethazine (phenergan) MOA
- blocks dopaminergic receptors in the brain
- alpha-adrenergic blocking effect
- competes with histamine for the H1-receptor
- muscarinic-blocking effect may be responsible for antiemetic activity
Metoclopramide
1) MOA
2) Side effect and how to treat?
1) Dopamine antagonist
2) Extrapyramidal symptoms (EPS) [akathisia, dystonia, tardive dyskinesia, Parkinsonism] - treat with benadryl
Also enhances response to acetylcholine of upper GI tract causing enhanced motility and accelerated gastric emptying
What is the MOA of tamoxifen in the breast?
SERM - binds estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects
What is the least likely side-effect of tamoxifen?
A) osteoporosis
B) vaginal bleeding
C) cervical and endometrial polyps
Osteoporosis - tamoxifen is protective for BMD for post-menopausal patients
Which is NOT a side effect or effect of tamoxifen?
A) ovarian cysts
B) increased LDL
C) decreased DCIS
D) increased uterine sarcoma
Increased LDL
Ovarian cysts - 3%
Decreased LDL [increases HDL and triglycerides. Lowers LDL vs AI, which raises LDL!]
Uterine neoplasm < 1%
VTE < 1%
Is endometrial cancer more common in tamoxifen or raloxifene?
Tamoxifen
What does MTORC1 inhibition cause?
Decreases phosphorylation of MTOR, so it is not activated. Prevents subsequent overexpression of oncogenes.
What are some MTOR inhibitors?
Rapamycin, Temsirolimus, Everolimus
G1 phase specific
Which of the following is least emetogenic?
A) cytoxan
B) cisplatin
C) Act D
D) adriamycin
E) vincristine
Vincristine
Highly emetic (>90%)
- Cisplatin
- Anthracycline and cyclophosphamide
- Cyclophosphamide >=1500 mg/m²
Minimally emetic (<10%)
- Bev
- Bleo
- Nivo, pembro
- Trastuzumab
- Vinblastine, vincristine, vinorelbine
Emetogenicity classifcations
High >90%
Moderate 30-90%
Low 10-30%
Minimal < 10%
Which are high-risk emetogenics?
*Angela’s says “NCCN Risk 5” emetogenics but I think that is old lingo
Cisplatin, high-dose cyclophosphamide (>1500mg/m2), dacarbazine, anthracycline/cyclophos combo
Angela’s listed doxorubicin and ifos but these are moderate risk
Which are moderate risk emetogenics?
*Angela’s says “NCCN Risk 4” emetogenics but I think that is old lingo
Carbo, anthracyclines (doxo, dauno, epi-rubicin), ifosfamide, oxaliplatin, temozolamide, trabectidin
Angela also says: ACT-D, megadoses of MTX, melphalaln
Which are low risk emetogenics?
Docetaxel, etoposide, 5FU, gemcitabine, methotrexate, nab-paclitaxel, paclitaxel, PLD, pemetrexed, temsiroliums, topotecan
Skinny: Taxanes, folate antagonists / anti metabolites, Topoisomerase inhibitors, temsirolimus, doxil
Which are minimal risk emetogenics?
Bleomycin, bevacizumab, vincas, trastuzumab, monoclonal antibodies (other -mabs)
Which renally cleared chemotherapies causes alopecia?
Ifosfamide, cyclophosphamide, topotecan
Which agents cause peripheral neuropathy?
Vinca (dose-limiting), taxol, cisplatin (dose-limiting)
JS- Chi states cis DLT is nephrotoxicity
Which agents cause peripheral neuropathy and motor disturbances?
Vincas
Why can you not give 3 hour paclitaxel with cisplatin?
Dose-limiting neurotoxicity
Which agent can cause a significant number of patients to have permanent neuropathy?
Cisplatin
Which agents are classic vesicants?
mitomycin C, doxorubicin, dactinomycin, vinca alkaloids
Can also use DAMN TV for Nitrogens and Trabectedin
Which vesicants are treated with hyaluronidase?
Vincas and taxol
*only these per UTD label
What agents are prodrugs that need to be activated for cytotoxicity?
cyclophosphamide, gemcitabine, mitomycin C, ifosfamide, capcitabine, irinotecan, 5-FU
Which agents cause leukemia?
Melphalan, etoposide, cyclophosphamide, nitrosureas, chlorambucil, alkylators
melphalan is most leukemogenic
Etoposide - 11q23 mutation
Which chemotherapy agents cross the blood-brain-barrier?
Nitrosureas: CCNU, BCNU, DTIC
(carmustine and lomustine)
Also topotecan, niraparib, ipilimumab, nivolumab (ipi and nivo bind peripheral T cells and cross), cyclophos/ifosphamide, Bev, temezolamide
Which agents are topoisomerase I inhibitors?
topotecan
irinotecan
Which agents are topoisomerase II inhibitors?
doxorubicin, mitoxantrone, etoposide, teniposide
Which drugs cause PPE?
Chi: Capecitabine > 5-FU, Doxil, pemetrexed
Also Multitargeted tyrosine kinase inhibitors sorafenib, sunitinib
Which drugs are very heavily protein bound?
MTX, Adriamycin, cisplatin, etoposide
“MACE”
Which drug does not need reduction in renal failure?
A) capecitabine
B) Doxorubicin
C) Topotecan
D) MTX
Doxorubicin
Most common side effect with G-CSF?
Bone pain, followed by fever
Which drug is not affected by p-170 glycoprotein MDR1?
A) paclitaxel
B) vinca alkaloids
C) anthracyclines
D) cisplatin
cisplatin
“MDR1 has at least three major areas where its activity impacts clinical outcomes and toxicity. First, MDR1 confers resistance to cancer chemotherapeutic agents and is a major cause of treatment failures. Because MDR1 transports a wide range of chemotherapy drugs, such as the anthracyclines, vinca alkaloids, taxanes, etoposide, mitoxantrone, bisantrene, and the histone deacetylase inhibitor depsipeptide”
What is p-170 glycoprotein MDR1?
P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs.
Significance
MDR1 has at least three major areas where its activity impacts clinical outcomes and toxicity. First, MDR1 confers resistance to cancer chemotherapeutic agents and is a major cause of treatment failures. Because MDR1 transports a wide range of chemotherapy drugs, such as the anthracyclines, vinca alkaloids, taxanes, etoposide, mitoxantrone, bisantrene, and the histone deacetylase inhibitor depsipeptide
What drug can overcome MDR I (p-170 glycoprotein system)?
Verapamil
What is not protein bound?
MTX, Cisplatin, Etoposide, Doxorubicin, Gemcitabine, Bleomycin
(multiple)
Gemcitabine, Bleomycin
G1 phase specific
mTOR (everolimus, temserolimus), tamoxifen
Act-D max kiling in G1 but NOT cell cycle specific
G2 phase specific
Etoposide, Bleomycin
S phase specific
5FU, capecitabine, MTX
M phase specific
Vincas, Taxol, (and Radiation)
Vincas: both M and S
Drugs causing radiation recall
this appears multiple times
Actinomycin D, doxorubicin (Adria), gemcitabine
Think: It was AAGonizing going through radiation once, I don’t want to recall it again!
Where is the gene locus encoding progesterone receptors?
PRA and PRB: Chromosome 11q22-23
Chemotherapy and Cell Cycle picture (from the internet)
Chemotherapy and immunotherapy that crosses blood-brain-barrier
Topotecan
Etoposide
Cyclophosphamide
Ifosfamide
Temozolamide
Lomustine
Carmustine
Nivolumab (bound to T cells)
Ipilimumab (bound to T cells)
Difference between docetaxel and paclitaxel?
Docetaxel has:
- LESS neuropathy
- MORE fluid retention / peripheral edema (must give extra steroids)
- Caution in diabetics due to need for extra steroids
Difference between nab-paclitaxel and paclitaxel?
Nab-paclitaxel is albumin bound. It does not contain crempahor (also known as kolliphor - polyoxyethylated castor oil), which is the agent responsible for hypersensitivity reactions.
