Chemotherapy Flashcards
Average tumor doubling time?
~50 days
What is log kill in tumor kinetics?
Log kill:
- Only a fraction of cell killed with each treatment, not a consistent number
- Only when log kill is very large (>99%) and treatment is repetitive can single agent chemotherapy can be curative
- Prolongation of survival or cure can only be achieved when the cell population is reduced to between 10 –1000 cells (not clinically detectable)
What is Gompertzian growth?
- Gompertzian model of growth describes the complex pattern of tumor growth.
- The curve has an early, almost exponential growth rate followed by slower growth rate which reaches a plateau as tumors grow larger in size
How many cells in a clinically detectable tumor?
109 cells
Describe the different phases of the cell cycle and its checkpoints
Cell cycle phases
- G0: Resting state; quiescent
- G1: continue in cell cycle or differentiate; can be quite variable; DNA repair, RNA and protein synthesis occur
- M: mitosis; chromosome division
- S: new DNA is synthesized
- G2: RNA and protein synthesis; 1N cell with twice the DNA –relatively short
Cell cycle checkpoints
- Cell growth checkpoint
- DNA synthesis checkpoint
- Mitosis checkpoint
What are general principles of effective combination chemotherapy?
- Drugs must be active alone
- Different mechanisms of action
- Different spectra of toxicity
- Tumor cell resistance
- Dose scheduling
What is the Goldie-Coldman hypothesis?
Goldie-Coldman hypothesis
- Mutation toward resistance occurs spontaneously at a rate of one mutation per million cell divisions or higher
- Thus, the likelihood of spontaneous mutation increases as the mass increases; drug exposure further increases mutations
What are phase I and phase II of drug metabolism?
Phase I:
- Drug undergoes catabolic reactions –e.g., hydrolysis, reduction, oxidation, condensation
- Some of the resulting substances (metabolites) can be pharmacologically active in themselves
Phase II:
- Drug undergoes a conjugation reaction that forms a covalent linkage with an endogenous substance such as glucuronicacid, glutathione, amino acids, etc.
- Resulting substances from Phase II reactions for the most part are pharmacologically inactive
Give examples of resistance to therapy
Altered DNA repair
- Resistance to alkylating or platinum drugs
- Sensitivity to PARP inhibitors
Defective transport
- Drug cannot enter cell or is actively excreted
Altered hormone receptor concentration
- E.g., decreased PR
Gene amplification
- MTX resistance through increased dihydrofolatereductase
Impaired activation
- 5-FU low uridine kinase; MTX low polyglutamation
Multidrug resistance
- Increased drug efflux through MDR gene product
- Involved in resistance to taxanes, vincaalkaloids
What is the MOA of cisplatin?
DNA binding-produces cross-links and DNA adducts
How do you administer cisplatin?
- 0.9% saline; don’t use aluminum
- Maintain high urine output (can use mannitol); pre-and post-hydrate
What are the side effects of cisplatin?
- Anaphylacticreactions
- Nausea/vomiting
- Nephrotoxicity
- Ototoxicity
- Neurotoxicity
- hypomagnesemia
Why do you give paclitaxel before cisplatin or carboplatin?
Higher risk of neutropenia if platinum is given first.
What is the MOA of carboplatin?
DNA cross-links with slower resolution
What are the side effects of carboplatin?
- Thrombocytopenia
- Nephrotoxicity is limited –but can have loss of K and Mg
- Neurotoxicity uncommon
- Risk of leukemia (occurs at about 4 years)
How do you calculate dosing for carboplatin?
Calvert formula
- AUC for dosing
- Target dose = AUC (GFR + 25)
Modified Cockcroft-Gault
- GFR is difficult to assess so creatinine clearance is usually substituted
- GFR = [(140 –age)(wt)(0.85)]/(72)(Cr)
- Must dose reduce in renal failure
What are side effect profile differences between cisplatin and carboplatin?
cisplatin > carboplatin:
- nausea/vomiting, renal dysfunction
- peripheral neuropathy, ototoxicity, vesicant
carboplatin > cisplatin:
- myelosuppression, delayed hypersensitivity
What is the risk of developing leukemia after platinum agents?
- Relative risk after platinum-based combination chemotherapy about 4.0
- Dose-response relation
- Secondary leukemia develops after average of 4 years
How are cisplatin and carboplatin excreted?
Urinary excretion
What is the MOA of paclitaxel?
Stabilizes microtubules by preventing depolymerization (different from vincaalkaloids)
What is special about taxane administration?
- Steroid premedication (decreases hypersensitivity from 30% to 2%)
- Dissolved in cremophor (must invert bag several times because if not, then cremophor will sink to the bottom and patient will get a “bolus” of cremophor)
How is taxane excreted?
hepatic and biliary excretion?
Side effect profile of paclitaxel?
- Myelosuppression
- Alopecia
- Neurotoxicity
- hypersensitivity
What class of drug is doxorubicin?
Anthracycline
What is the MOA of doxorubicin?
1) Intercalation of DNA
- inhibits DNA and RNA synthesis; not cell cycle specific but acts maximally during S-phase
- inhibits DNA topoisomerase II
2) Free radical formation by reaction with iron and copper
Special considerations with administration of doxorubicin?
- Strong vesicant
- Should be short IV push/bolus
What is the maximum cumulative dose of doxorubicin?
cumulative dose should not exceed 550 mg/m2
How is doxorubicin metabolised?
Extensively metabolized in the liver and 40% excreted in bile/feces
What are side effects of doxorubicin?
- Local skin and deep tissue damage if extravasated–may need surgical debridement
- Cardiac effects:
- Rare myocarditis
- Cardiomyopathy – dose related; resembles CHF.
- Risk factors include dose >550 mg/m2, chest radiation, age >70, prior cardiac disease.
- Can occur years after drug stopped.
- Dose dependent
- <500 (<1%)
- 501 –600 (11%)
- >600 (30%).
- Dexrazoxane (chelates iron) may protect against cardiac effects
- Radiation recall
- Palmar-plantar erythrodysesthesia(PPE)
- Dyspigmentation
- Flare reaction
What agent can help mitigate cardiotoxicity side effects of doxorubicin?
Dexrazoxane (chelates iron) may protect against cardiac effects
What is the dose limiting toxicity of anthracycline?
Bone marrow suppression
What are side effect differences between doxorubicin and pegylated liposomal doxorubicin?
Doxorubicin > PLD:
- Cardiac
- nausea, vomiting
- Myelosuppression
- Radiation recall
- vesicant
PLD > doxorubicin:
- Hand-foot syndrome
- Mucositis
- Infusion reactions
What is radiation recall?
Radiation recall is a severe skin reaction that occurs when certain chemotherapy drugs are administered during or soon after radiation treatment.
What drug class is ifosfamide?
alkylating agent
What is the MOA of ifosfamide?
Alkylating agent
- requires activation by hydroxylation by microsomal enzyme systems
- occurs more slowly than cyclophosphamide
- produces more chloracetaldehyde
- NOT cell cycle specific
What are administration considerations for ifosfamide?
- IV by short infusion or continuous infusion over several days
- Need adequate hydration pre-and post-infusion (72 hours after)
- Hydration and Mesna (binds to the acrolein metabolite) must be utilized to prevent renal toxicity and hemorrhagic cystitis
- Dose reductions for prior RT, chemo, impaired renal function or albumin <3.5
What is the metabolism of ifosfamide?
- metabolized by liver
- Acrolein is an alkylating metabolite found in urine (use Mesna and hydration to reduce nephrotoxicity and hemorrhagic cystitis)
- Nephrotoxic drugs (e.g., cisplatin) may increase renal damage
What are the side effects of ifosfamide?
- Urinary tract toxicity is dose limiting, especially hemorrhagic cystitis; increased by bolus regimens
- Can get Fanconi syndrome (defect in proximal tubule transport involving amino acids, glucose, phosphate, Na, K, HCO3, and proteins)
- Prior cisplatin treatment can increase nephrotoxicity
- Nausea/vomiting
- Lethargy/confusion/coma –due to chloracetaldehyde; usually reversible; can be compounded by low albumin.
- Give methylene blue (electron accepting; may reduce further chloracetaldehyde formation) 50 mg dose IV q 4 hrs
- Alopecia
- Transient LFT elevations
Does limiting toxicity of ifosfamide?
Urinary tract toxicity is dose limiting, especially hemorrhagic cystitis
What drug class is gemcitabine?
nucleoside analogue
What is the MOA of gemcitabine
Inhibits ribonucleotide reductase and depletes the deoxynucleotide pools necessary for DNA synthesis
- Prodrug (hydrophilic)– Enters the cell as gemcitabine then undergoes multiple phosphorylations by deoxycytidine kinase intracellularly to the active DiPh and TriPh forms of drug.
*Gemcitabine TriPh - This is incorporated into DNA a false base pair. When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to “masked chain termination” because gemcitabine is a “faulty” base, but due to its neighboring native nucleoside it eludes the cell’s normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cell’s DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.
*Gemcitabine DiPh inhibits the enzyme ribonucleotide reductase, which is needed to create new DNA nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which also increases uptake of gemcitabine.
Special considerations for administration of gemcitabine?
30 minute infusion; can have flu like symptoms with longer (>60 min) infusions
Metabolism of gemcitabine?
Rapid clearance; may increase platinum AUC
Toxicities of gemcitabine?
- Flu like symptoms (infusion time dependent)
- Myelosuppression and hepatic toxicity
- Fever (up to 37% of patients)
- Can cause capillary leak syndrome
What is the drug class of actinomycin D?
Antitumor antibiotic
What is the MOA of dactinomycin?
- Intercalates into DNA around a pyrimidine/purine pair (usually GC); inhibits RNA synthesis and bound drug dissociates very slowly
- Maximal cell killing in G1, but is cell cycle non-specific
- Resistance: overexpression of p-glycoprotein
Special administration concerns for dactinomycin?
- IV push followed by flush
- It is a vesicant–pain, swelling, poorly healing necrotic ulcers
Toxicity profile of dactinomycin?
- Myelotoxicity–can be dose limiting, 7 –10 days after dosing
- Can have GI effects –mucositis
- Alopecia
- Radiation recall
- Potentiates pulmonary RT
What drug class is methotrexate?
Antimetabolite
What is the MOA of methotrexate?
- Dihydrofolate reductase inhibitor
- results in block of thymidylate synthetase and purine synthesis and thus DNA/RNA/protein synthesis blockage.
- Resistance via increases in dihydrofolatereductase can occur
- Cell cycle specific (S phase)
Special administration of methotrexate?
- IM/PO/IV/intra-arterial/intrathecal
- Reduce dose by 50% for renal insufficiency
- Do not give if creatinine clearance <40 or Cr >2
- High doses require leucovorinrescue
Metabolism concerns of MTX?
- 50 –60% protein bound
- Can accumulate in effusions and slowly released back into system
- Interactions: other protein bound drugs may displace and increase toxicity (e.g., salicylates, sulfa); alcohol can increase hepatotoxicity; aspirin can decrease renal tubule secretion of MTX
Toxicity profile of MTX?
- BM suppression
- Hemoglobin nadir around 13d
- Leukocytes at 4-7 days
- Platelets 5-12 days
- Nausea/vomiting
- stomatitis
- hepatotoxicity
- alopecia
- dermatologic toxicities
What drug class is bleomycin?
Glycopeptide antibiotic
What is the MOA of bleomycin?
- Chelates metal ions (primarly complexes with ferrous iron) and acts as an oxidase –> O2 free radicals –> DNA strand breaks
- It is schedule and cell cycle dependent (G2)
What are special administration issues with bleomycin?
- Infusion
- Can be given in doses as high as 30 mg/week; often used as mg/m2/day over 4 days
- Not a vesicant
- MAXIMUM dose = 400 mg total
What is the maximum dose of bleomycin?
400 mg total
What is the metabolism of bleomycin?
- 70% is renally excreted
- may need to adjust for renal compromise
Toxicities of bleomycin?
- Pulmonary fibrosis –up to 10%
- increased by age, chest RT, hypoxia, renal insufficiency and cumulative doses > 400 mg
- Myelosuppressionis uncommon
- Mucositis, cutaneous reactions
- Fever, chills
- alopecia
- Discontinue for DLCO <30% of baseline value
What drug class is etoposide?
podophyllotoxin derivative
What is the MOA of etoposide?
- Maximal effects in G2 phase, some in late S
- Produces protein-linked DNA strand breaks by inhibiting DNA topoisomerase II
Administration considerations for etoposide?
- IV over at least 30 minutes
- Oral administration available
- In BEP (100 mg/m2 days 1-5 on q 4 week schedule)
Metabolism for etoposide?
- Half life is 7 hrs
- Liver metabolism
- Renal excretion accounts for 30%; biliary secretion 2-16%
- Protein binding for 95% of drug
- Increased bilirubin or decreased albumin will have higher drug levels
What are the toxicities for etoposide?
- Bone marrow suppression –leukopenia, thrombocytopenia
- Nausea/vomiting
- Alopecia
- Severe hypotension –if IV dose given too quickly
- Leukemia (~1%); dose dependent; can be as high as 5% with dose >2000 mg/m2
What drug class is topotecan?
Topoisomerase I inhibitor
What is the MOA of Topotecan?
- Topoisomerase I inhibitor
- active lactone form intercalates between DNA bases in the topo-I cleavage complex
- potent HIF1-alpha inhibitor
Metabolism of topotecan?
- ~30% excreted in urine; terminal half-life 2-3 hrs
- Renal clearance is an important determinant of topotecan elimination
Toxicity of Topotecan?
- Hematologic (primarily neutropenia) –nadir around 11 d
- GI (mild to moderate N/V); diarrhea
- Alopecia
What are the differences between 3-hour vs 24-hour paclitaxel infusions?
- 24-hour infusion was given to avoid hypersensitivity
- 3-hour infusion of Taxol is safe when given with premedication and is associated with less myelosuppression.
- No difference in response rates
[Eisenhauer EA et al. (1994) JCO 12(12): 2654-2666]
What are the differences between paclitaxel and docetaxel in terms of safety and efficacy?
What about albumin-bound nab-palitaxel?
Docetaxel 60-75 mg/m2
- Less neurotoxicity
- Greater myelotoxicity
- Equivalent PFS and OS
[Vasey PA et al. (2004) J Natl Cancer Inst; 96:1682-1691]
Albumin-bound (nab) Paclitaxel (Abraxane)
- Has not been directly compared
When patients receive carboplatin and paclitaxel, which drug is given first and why?
paclitaxel is given first because it is associatd with less myelosuppressive activity.
-Why? The theory is there is less clearance of paclitaxel if platinum is given first.
