Wk 3 Chemotherapy Flashcards
Adjuvant chemotherapy
also known as adjunct therapy, adjuvant care, or augmentation therapy, is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness
– Reduce local and distant recurrence after surgery
Neoadjuvant chemotherapy
Prior to surgical resection to improve results
Primary Chemotherapy
– Palliative in advanced (incurable) disease
– Curative in select diseases (primarily hematologic)
-first chemo
What are 4 types of primary chemotherapy?
- Induction: treatment of disease to
achieve remission - Consolidation chemotherapy: given after induction to control microscopic disease
- Maintenance chemotherapy: given over long-term basis to maintain remission
- Salvage chemotherapy: chemotherapy given after relapse or refractory to previous therapy
What is the gompertzian model?
response to chemo depends on position on growth curve
-how many cells are in rapid growth phase
What is the log-kill hypothesis?
Curability dependent on if you can give enough cycles of chemotherapy before resistance ensues
-a given chemotherapy is predicted to kill a constant fraction of cells as opposed to a constant number – 1st order kinetics
– Inverse relation between cell number and curability – Race of time to cure versus resistance
What are the 3 phases of chemotherapy?
- induction
- consolidation
- maintenance
What is the limit of detection?
Determined by scans, BM biopsies, etc, below which cancer cannot be detected
How much kill is the goal after one cycle of chemotherapy in logarithmic theory?
~99.9%
BIggest toxicities w/ chemo?
-huge decrease in rapidly dividing cells:
-WBC -> infection
-platelets -> bleeding
-RBC -> anemia
-GI tract -> vomiting
What are microtubule chemo agents and what part of the cell cycle do they interupt?
Mitotic phase
-taxanes
-Vincas
What are 3 cell cycle non-specific chemotherapies?
1.Alkylating agents
2. platinums
3. nitrosoureas
What chemotherapies are antimetabolites and what cell cycle phase do they interupt?
S phase:
1. antifolates (methotrexate)
2. antipyrimidines
3. antipurines
4. misc - hydroxyurea, procarbazine
IMP cell cycle chemo target meds
Therapeutic index
- Efficacy—maximize cell kill
- Toxicity—minimize host damage
- Therapeutic Index is narrow (<10x) for many chemotherapies
What are 4 dosage factors that can be manipulated in chemotherapy?
- Dose escalation
- Reduce the interval: “dose dense”
- Sequential scheduling
- Combination Chemotherapy - don’t have overlapping toxicities
3 principles of combination chemo
- Drugs should be effective against the cancer type – Goal of additive or synergistic activity
- Each agent should act through a different mechanism
– Avoid resistance - Drugs with different dose-limiting toxicities should be
combined
– Use of full or nearly full therapeutic doses
Cisplatin
MOA
ADE
- MOA: cross-linking DNA
- ADE: nephrotoxicity, ototoxicity
Etoposide
- MOA: topoisomerase inhibitor
- ADE: bone marrow suppression
Radiation
- MOA: DNA damage via free radical formation * AE: local burn/irritation
Common combination regime
Cisplatin + Etoposide + radiation
Common combination regime
Cisplatine + Etoposide + radiation
Timeframe for myelosuppression w/ myeloablation
Timeframe for myelosuppression w/ mild chemotherapy
Timeframe for myelosuppression w/ strong chemotherapy
- most pts get sick w/ infection and those infections come from norm bacteria w/in GI tract
4 resistant tx failures
- Pharmacologic
– Inadequate drug dose – Suboptimal scheduling - Host determinants (physiologic): – Patient general status
– Immunocompetence
– Sanctuary sites
– Poor drug penetration - Primary resistance: absence of initial response to chemotherapy
- Acquired resistance: develops in response to anticancer therapy
– Goldie-Coleman hypothesis predicts tumor cells mutate to a resistant phenotype at a rate dependent on their intrinsic genetic instability
7 mechanisms of acquired resistance
- Expression of drug transport proteins – Efflux: P-glycoprotein / MDR1
– Influx: OATP, OCT - Altered expression of molecular targets
- Intracellular redistribution of drug
- Detoxification of drug
- Decreased activation
- Enhanced DNA repair
- Altered apoptotic pathways
What are alkylating agents?
Exert cytotoxic effects by binding directly to DNA
-nitrogen on guanine is most common target
-not cell cycle specific
-damaged DNA can be repaired, primarily targets rapiding dividing tumors
What are 5 alklyating agent subclasses
- nitrogen mustards
- nitrosoureas
- triazenes and methylhydrazine
- misc
- platinums (alkylator-like, less effective)
How do alkylators work?
They develop crosslinks in DNA
-monoalkylated
-crosslinked (interstrand..bigger effect…ER more serious)
-crosslinked (intrastrand…platinums)
Can we gain resistance to alkylators?
Yes, via various mechanisms
What are 3 alkylating agent toxicities?
- premature ovarian failure and azoospermia
- alopecia
- leukemogenic (peaks 5-7 yrs after therapy, similar to myelodysplastic syndrome) - accumulation of DNA damage
What kind of drug is cyclophosphamide?
Where is it activated?
Nitrogen mustard
-must be activated by CP450 in liver
- -> development of cytotoxic acrolein (which is also bladder toxic)
What is acrolein?
a substrate of cyclophosphamide that is toxic to the bladder, ruining the bladder wall -> hematuria
How are nephrotoxic and urotoxic metabolites from cyclophosphamide managed?
Acrolein is the toxic metabolite
-prevented by hydration and coadministration of mesna, which binds to acrolein so it gets peed out w/o damaging the bladder
What are 3 platinums?
- cisplatin
- carboplatin
- oxaliplatin
-slightly less potent and less toxic
What are platinum side effects?
- nephrotoxicity (cisplatin)
- nausea/vomiting
- ototoxicity
- neurotoxicity (acute -cold-induced distal dysesthesia, cummulative - irreversible sensory peripheral neuropathy)
- hypersensitivity
What are antimetabolites?
Drugs that are structurally similar to naturally occurring compounds (AA, DNA, RNA, etc)
-damage DNA via:
1. competitive enzyme inhibitors
2. incorporating directly into DNA or RNA
All are cell cycle specific: S-phase
3 subclasses of antimetabolites
- Folic acid analogs
- Purine analogs
- Pyrimidine analogs
MOA of methotrexate (MTX)
-modified form of folic acid, which is necessary for synthesis of purine nucleotides
-folic acid converted to active form by DHFR
-MTX binds to DHFR as a competitive inhibitor, prevents folic acid’s contribution to DNA synthesis by blocking conversion of FH2 to FH4
When is Methotrexate used?
-anything in brain b/c it has good penetration into CSF
-IV, PO, IM, Intra-thecal (IT)
-active transport into cells, actively secreted in proximal tube for renal excretion (~80%)
-hydration is key
-alkalinization is key to prevent MTX precipitation in renal tubule and prevent nephrotoxicity
-use leucovorin 12-24 hrs after end MTX (high exposure 24-36 hrs)
-antidote = glucarpidase - enzymatically inactivates MTX & VERY expensive
-monitor serum concentrations until clear
What is leucovorin?
Activated folic acid
-administered 12-24 hrs after high does MTX
-directly converted to THFR 4 for purine and pyrimidine synthesis bypassing MTX inhibition
-used to rescue BM and GI mucosal cells
MTX toxicity
Dependent on exposure duration:
-myelosupporession
-mucositis
-hepatotoxicity
nephrotoxicity
What kind of drug is fluorouracil?
A pyrimidine analog, mimics uracil
-5-FU
-gets incorporated into RNA, impairs RNA/DNA
-suicide inhibitor of thymidylate synthase (converst 5,10 methylene THF to dihydrofolate)
5-FU delivery methods and associated toxicities
- Continuous infusion -> hand-foot syndrome (palmar-plantar erythrodysethesia)
- Bolus -> myelosuppression (BM)
Other side effects: mucositis, stomatitis, diarrhea, N/V
If pt has dihydropyrimidine dehydrogenase (DPD) deficiency (~8% population) -> increased toxicity
Antidote = uridine triacetate
How is leucovorin used w/ 5-FU?
MOA: folinic acid -> enhanced FdUMP inhibition of thymidylate synthase
-also for MTX rescue
What is capecitabine?
Oral prodrug of 5-FU
-0 to 80% bioavailability
-Toxicity:
1. hand-foot syndrome
2. mucositis (less than bolus 5-FU)
3. myelosuppression (“)
4. diarrhea
Management of hand-foot syndrome
- Skin care - wash w/ cool water, use moisturizers/keratolytic
- avoid tight clothes (belts, bras, shoes)
- avoid activities that cause sweating/abrasions
What kind of drug is cytidine?
Pyrimidine/nucleoside analog
-can be incorporated into DNA
What is cytarabine?
A cytidine analog
-has good CNS penetration across BBB
-IV, SQ, or IT
-elimination: urine (inactive metabolites)
-> myelosuppression, neurotoxicity (cerebellar: ataxia), ocular, skin rash, PE, N/V/D/mucositis
What are purine analogs?
-either look like adenine or guanine
-damage DNA
What are ABC transporters?
ATP binding cassettes on the membrane like MDR1 (multidrug resistance 1) that use ATP to pump toxins (or drugs) out of cells
-a way that cells become resistant to chemotherapeutic agents
T cell markers
CD3
CD5
<10 usually T cells
B-cell associated markers
CD19
CD20 - target of rituximab
Stem-cell and progenitor cell-assocated
CD34 = immature/precursor leukemia and lymphoma
What is TdT used for?
To ID stem cell and progenitor cell
-specialized DNA polymerase expressed in immature, pre-B, pre-T lymphoid cells, and acute lymphoblastic leukemia/lymphoma cells
What CD marker do B cells show w/ lymphomas?
CD5
