10. Antineoplastics Flashcards
History of Chemotherapy
• First administration of chemo was in \_\_\_\_ with the use of nitrogen mustard gases ○ Noticed a lowered WBC count, and significant toxicities • \_\_\_\_ were developed in 1950 • 1960's: more natural forms of medications ○ \_\_\_\_ from yew tree ○ Camptothecans from \_\_\_\_ • 1970's: anthracyclines - backbone of therapy • 1990's: supportive care ○ Combined with \_\_\_\_ in order to stabilize patients
1942 antifolates taxanes apples antibiotics
Gompertzian Tumor Growth
Most sensitive to chemotherapy: high ____, small ____
• Tumor cells grow at an \_\_\_\_ rate ○ Once you develop a tumor burden - cannot sustain cancer cell with living function ○ There's a point when you only have 1-10 cells > cannot physically see them • Prime area of \_\_\_\_ - when recognize tumor on scans, and still actively growing ○ Grow more rapidly - more sensitive to the chemotherapeutic • Going to give multiple medications at multiple times ○ One medication on day 1, and then another on 2,3 etc. ○ More than just giving one \_\_\_\_ • More \_\_\_\_ of chemotherapies - the more you're able to break down those cancer cells
growth fraction tumor burden treating drug cycles
The Cell Kill Hypothesis
Each chemo cycle kills ____% of malignant cells
1000100101
Most tumors need several cycles of treatment
Tumor burden will never reach ____
Assumes once < ____, immune system eliminates micrometastases
Assumptions
Lack of metastatic disease (i.e. stage doesn’t matter)
All cells (and all tumors) have ____ sensitivity to chemotherapy and equal % of dividing cells
— Non-dividing cells less ____ to chemotherapy
All drugs (single agent vs. combinations) kill the same ____ percentage
Role of chemotherapy resistance?
* In most cases, \_\_\_\_ disease is incurable * Some cells do develop resistance to chemotherapy - selectively choosing cells
90 zero 105 equal sensitive fixed
metastatic
G1
•____ of DNA replication
S • \_\_\_\_ synthesis • Interfere with \_\_\_\_ (G, C, T, A) • Interfere with \_\_\_\_ unwinding DNA
G2
• ____ production, proteins
for mitosis
M
• ____ & mitotic spindles
proteins/pathways DNA bases enzymes RNA tubulin
Cell Cycle Specificity
CCNS agents
Cells do not have to be in the ____ to be killed, although they are most effective in ____ phase
Dose response curve: Cell kill is ____ to dose (not schedule)
CCS agents
Only effective against cells going into the ____
Repeated ____ or infusions for best effect
Once all cells in cycle are effected, ____ has occurred
• CCNS agent - if you give the medication to a patient, it doesn't matter what phase that cell is in, it will still be able to kill off some of those cells ○ May be more effective in S phase, because it's more highly metabolic ○ The higher dose you give, is the dose we're going to administer [???] • CCS agent - only effective if the cancer cell is in the phase that the medication is effective for ○ These work better the longer you're able to expose the tumor cells to the agent § Repeated dosing (day 1, 2, 3) § Continuous infusions (more effective than large/bolus dose) • Agent tells you how a cancer may work ○ Agents that are specific to S phase, impact on DNA replication - \_\_\_\_ ○ Agents may impact enzyme that's needed for DNA replication
cell cycle
S
proportional
cell cycle
dosing
max. killing
antimetabolites
Drug targets
• CCNS agents ○ \_\_\_\_ (all phases) • CCS agents ○ \_\_\_\_ (???) § A little bit more specific ○ Antimetabolites (\_\_\_\_) ○ Vinca alkaloids (\_\_\_\_) § Impact on \_\_\_\_ ○ Taxanes (late \_\_\_\_)
AA topoisomerase S M microtubules M
Chemotherapy regimens
Single agent
Combination
Multimodal approaches
• Multimodal approach ○ Using a different method aside from \_\_\_\_ to treat patients § Chemo may be used as an \_\_\_\_ therapy (it compliments something else, such as receiving surgery first) § Chemo may be combined with radiation □ Agents have \_\_\_\_ with radiation itself
chemotherapy
adjuvant
synergy
Principles of Combination Therapy
- Drugs with single agent activity
- Drugs with synergy
- Minimize overlapping ____
- Maximize ____ of agents with respect to tumor cells and drug kinetics• Single agent activity
○ Not many times using agents that have same ____ of action
§ Using a CCNS and a CCS at the same time
○ Differing mechanism of action increase the ____ of agents
• Some agents do have more synergy with other agents than others
• Minimize toxicity
○ If hallmark of agent is cardiotoxicity; won’t give it with another agent that is cardiotoxic
• Maximize dose/schedule
○ Give CCNS agent as a ____ dose, and give the CCS as a ____ infusion
toxicity
dose/schedule
mechanism
synergy
bolus
continuous
Chemotherapy administration
Goal: deliver sufficient concentration of chemotherapy to tumor site and produce a clinical response/cure without excessive/undesired toxicity to normal tissue
Scheduled in most effective and tolerated manner
____: repetition of regimen
Ex: every 21 to 28 days, weekly dosing
____ allow normal tissues to recover without impacting treatment efficacy
• Cycle - same exact \_\_\_\_ repeated in a regimen ○ Giving a patient to recover its WBC from the chemo
cycles
rest periods
doses
Chemotherapy Treatment
____ therapy
In conjunction with surgery, radiation, or both
Goal to eradicate micrometastatic disease
Neoadjuvant therapy
Before another ____ (ex: surgery)
“____ or “downstage” the tumor to improve removal/resection and improve treatment success
Salvage therapy
Next line ____ when most effective treatments
no longer work
Palliative therapy
____ disease, treatment of symptoms
• Neoadjuvant ○ Used for \_\_\_\_ cancer ○ Give chemo, shrink the tumor, and make it more amenable to surgery and make it less cosmetically affecting • Salvage ○ Given therapy before, and progression in their disease • Palliative ○ Won't cure patients of disease ○ Will help with symptoms that are related directly to the cancer that they have
adjuvant modality shrink treatment incurable
Chemotherapy
Terminology for hematologic malignancies
____, consolidation, maintenance
Is chemotherapy alone curative?
Possibly:
– ____, testicular cancer, some lymphomas
Usually not, combined ____ therapy needed:
– Late stage ____, colorectal, ____, bladder, ____, head + neck
Management of most cancers is a ____ approach
• Induction ○ given in the \_\_\_\_ stage ○ given for a new patient • Consolidation ○ \_\_\_\_ therapies in their patients • Maintenance ○ towards the end, given the chemo at \_\_\_\_ doses to assure cure • Impact on curing disease is based on the \_\_\_\_ of disease, and the \_\_\_\_ of disease they have • Require surgeons, nursing, pharmacists, etc.
induction acute leukemia modality breast sarcomas GYN multidisciplinary first subsequent lower type amount
Alkylating Agents \_\_\_\_ \_\_\_\_ \_\_\_\_ \_\_\_\_ agents
nitrogen mustards
triazines
nitrosureas
platinum
Nitrogen Mustards
____ intermediates that attack ____ sites
Most common: ____
Bifunctional alkylating agents; form ____ & ____ strand DNA adducts
Not ____ specific, most active in ____ phase
• Alkylating agents ○ CCNS activity - \_\_\_\_ DNA damage, regardless of what cycle the cell is in § The more \_\_\_\_ dividing cell - the more sensitive it will be
electrophilic nucleophilic N7 of guanine inter intra cell cycle G1 or S direct faster
Common Mustard Alkylators
Mechlorethamine – ____, intralesional administration
— Caution: ____!
____ - IV, PO
Ifosfamide – IV
____ – IV, PO
— Oral: ____ absorption, uncommonly used
• Oral delivery - won't be able to tolerate the dose • Some agents can be a vesicant - if given IV, you want it to go directly into the vein ○ Sometimes, the needle may go outside the vein and into other tissue space § If a vesicant administered into tissue space it develops symptoms □ Skin \_\_\_\_, plastics involved, surgeries □ Want to limit \_\_\_\_ of a vesicant
IV vesicant cyclophosphamide melphan unpredictable
Cyclophosphamide Bioactivation
• Some agents are prodrugs - they're not in their most active form ○ \_\_\_\_ (and ifosamide) § Requires activation by liver enzymes to be developed into a more active metabolite § Has a metabolite that is not active, but causes \_\_\_\_ □ \_\_\_\_ - not the active part of the metabolite ® In patients who are receiving of cyclo/ifosamide, it binds to mucosa of bladder and causes irritation; ultimately developing \_\_\_\_ (inflammation of bladder that bleeds) • Hemorrhagic cystitis ○ \_\_\_\_ - prevents binding of acrolein to the bladder ○ Given in \_\_\_\_ things (1:1) depending on the chemotherapy ○ Won't impair \_\_\_\_ of cyclo/ifosamide
cyclophosphamide toxicity acrolein hemorrhagic cystitis MESNA dose-specifc activity
Ifosfamide Bioactivation via CYP3A4 & CYP2B6
____ metabolite
- Effect similar to chloral hydrate
- Sedation, confusion, cerebellar symptoms, psychosis
- ____
- Tx: ____, thiamine until resolved
- Prophylactic thiamine?
Hemorrhagic Cystitis:
• Ifosfamide makes ____ as much acrolein as cyclophosphamide so MESNA is absolutely required
• Neurotoxicity seen more with ifosfamide ○ \_\_\_\_ - altered mental status ○ More likely to develop in HC • Best way to treat - stop the \_\_\_\_ ○ Improves within 24-72 hours • Some consideration of giving other medications ○ Methylene blue, thiamine ○ Not much data available • Used mostly in an \_\_\_\_ setting
neurotoxic reversible methylene blue 4x encepholopathy drug intake inpatient
Mustard Alkylator Side Effects
Dose limiting = ____
Moderate-highly emetogenic, alopecia
Secondary malignancies
____ (esp. Mechlorethamine)
____ (Ifosfamide)
Ifosfamide: nephrotoxicity, ____ wasting (K, Mg, phos)
____ (Ifosfamide, high dose cyclophosphamide)
____ (esp. Melphalan) – use ice chips (oral cryotherapy)
• Naturally dividing cells may also be affected ○ Myelosuppression - decrease in WBC, RBC, and platelets § WBC go down in number faster (shorter half-life) • Relatively non-specific \_\_\_\_ damage ○ Can result in other malignancies § Secondary malignancies § Develop at a lower rate, and patients are monitored to make sure they're not expressing signs for these malignancies □ Bladder cancer, or acute myeloid leukemia (cyclophosphamide)
myelosuppression sterility encephalopathy electrolyte hemorrhagic cystitis mucositis
DNA
Hemorrhagic cystitis
Aggressive oral + IV ____ to minimize bladder mucosal contact
– Advise patient to void frequently
– Take oral ____ in the AM and drink frequently
Mesna prophylaxis
Does not interfere with ____ . Does not prevent any other ____
Dose: 60%-100% of ifosfamide dose
Short infusion ifosfamide, 60% regimen: 20% IV bolus 15 min prior to
ifosfamide, 20% at 4 hours, 20% at 8 hours
Continuous infusion ifosfamide, 60% regimen: 20% IV bolus 15 min prior to ifosfamide, then mesna as a separate continuous infusion to end 12-24 hr after ifosfamide completion
100% regimen, continuous infusion ifosfamide: mixed with ifosfamide
Daily ____ recommended for patients receiving ifosfamide
Mesna is not 100% ____
hydration cyclophosphamide efficacy toxicity urinalysis effective
Non-Mustard Alkylators: Triazines
Dacarbazine
____ only – poor GI absorption
Poor ____ penetration
Highly ____
Temozolamide
100% ____ = PO capsules, also IV
Crosses the ____ barrier
PCP prophylaxis needed if in combo with XRT
Response ____ proportional to activity of MGMT
*Dose limiting toxicity: ____
• High doses of these agents may cause cystitis, and \_\_\_\_ will help prevent • These may also be \_\_\_\_ ○ Improves \_\_\_\_ of these agents - absorb more in the GI tract when its in prodrug form
IV
CNS
emetogenic
bioavailability
blood-brain
inversely
myelosuppression
mesna
prodrugs
bioavailability
Carmustine (BCNU)
• ____ alkylator
• Highly ____ , hallmark is ability to cross the blood-
brain barrier
• *Dose limiting: ____, delayed ____ – cycles spaced 6 weeks
• ____ administration; also as Gliadel wafer®
• Flushing during infusion due to ____ vehicle
• ____ toxicity
• Prolonged myelosuppression regarding this agent • Because lipophilic - used additional agents and make it more \_\_\_\_ in order to administer IV ○ Cannot precipitate ○ Use alcohol to improve the solubility • Usually given \_\_\_\_, and administered in the evening (so experience lower number of symptoms) • Long term toxicity ○ Pulmonary toxicity
nitrosurea lipophillic myelosuppression nadir IV EtOH pulmonary
diluent
inpatient
Platinum Derivatives
How discovered: ____ growth disrupted when a current was delivered through growth media via a platinum electrode – the birth of cisplatin
• Cisplatin was being released from platinum ○ Derivatives: \_\_\_\_ and \_\_\_\_ ○ Considered \_\_\_\_, and are alkylating agents (direct \_\_\_\_ damage)
bacterial oxaliplatin carboplatin CCNS DNA
Cisplatin Mechanism of Action
Cisplatin bioactivation through ____ (H2O addition)
- Similar bioactivation w/carboplatin
Intra-strand ____ formation + adduct formation between ____ residues on adjacent DNA strands
aquation
crosslink
guanine
Cisplatin Nephrotoxicity
*dose limiting toxicity* Max \_\_\_\_mg/m2 per dose or per cycle Mg/K/Ca/Phos wasting, ↑ \_\_\_\_ Pre + post \_\_\_\_ w/NaCl + Mg + KCl Historical: loop diuretics, mannitol --- No overwhelming evidence that the use of mannitol or furosemide significantly reduces the risk of nephrotoxicity over hydration alone. \_\_\_\_ with normal saline is currently the most important measure for preventing cisplatin-induced nephrotoxicity.
• Dose limiting toxicity ○ Nephrotoxicity, renal failure § Prevention - \_\_\_\_ doses, and not confusing with another \_\_\_\_; and hydration in order to flush the kidneys ○ Electrolyte wasting (low K+, low Mg+ blood levels) § Patients may require \_\_\_\_ either orally or IV
dose 100 creatinine hydration hydration
limiting
platinum
supplementation
Cisplatin: Side Effects
Highly \_\_\_\_ (acute + delayed) \_\_\_\_: tinnitus, high-frequency loss --- \_\_\_\_ or bilateral Motor and sensory neuropathy --- \_\_\_\_ dose related, uncommon Minimal \_\_\_\_ \_\_\_\_ is rare, desensitization protocols exist
• Emetogenic - develop \_\_\_\_ • Cisplatin is gold standard to study antimemtics ○ Must receive \_\_\_\_ medications beforehand • Ototoxicity - hearing loss
emetogenic ototoxicity unilateral cumulative myelosuppression anaphylaxis
nausea/vomitting
anti-nausea
Carboplatin
Cisplatin derivative w/ ____ non-heme toxicities
— Substitution of less reactive ____ group
Side effects
*Dose limiting: ____(____) Less emetogenic than ____
Very rare: nephrotoxicity, neurotoxicity
____
— Increased incidence with increased exposure (> 6 ____)
— Desensitization protocols exist
Often substituted for cisplatin due to improved tolerability
Likely therapeutically equivalent except in ____ and ____ cancer
• Less toxicity on the kidneys, and a little bit less nausea/vom compared to oxiplatin • Myelosuppression - decreases in platelet counts (TC) • Dosed on AuC - takes into account exposure and rates of TC that we see ○ [NOTES]
decreased
leaving
myelosuppression thrombocytopenia cisplatin anaphylaxis cycles testicular non small cell lung
Carboplatin: Dosing by Calvert Equation
GFR and platelet nadir closely related due to renal elimination of carboplatin
Dose (mg) = AUC x (GFR + 25)
AUC = area under the concentration vs. time curve
— Usual target ____; ____ if debilitated patient
____ target AUC of subsequent cycles if excessive myelosuppression and palliative intent
GFR = glomerular filtration rate (calculated ____ clearance by Cockcroft-Gault equation used)
GFR MUST BE CAPPED AT ____ml/min!
* [NOTES] * \_\_\_\_ is directly used to calculate your dose of carboplatin
5-6 4 reduce creatinine 125
renal function
Oxaliplatin
____ resistant cisplatin analog
____ complex (vs. divalent w/cis and carbo)
Bulkier, more ____ adducts – more effective at inhibiting ____ synthesis and more difficult to repair
Enhanced spectrum of ____ vs. other platinum agents
Effective in cisplatin/carboplatin ____ cell lines
Side effects
*Dose limiting: ____
Not heavily myelosuppressive, nephrotoxic, or
ototoxic
Rare: anaphylaxis; desensitization protocols exist
• Dose limiting side effect - neurotoxicity ○ Exacerbated by \_\_\_\_ ○ Patients may still be walking around with \_\_\_\_ - if touch something cold it may worsen the pain § More pronounced in \_\_\_\_
non-cross tetravalent hydrophobic DNA activity resistant
neurotoxicity
cold
gloves
hands/feet
Oxaliplatin Induced Neuropathy
2 distinct types of neurotoxicity:
Acute: sensitivity to ____ temperature
– Laryngopharyngeal spasms
– Upper + lower extremity ____
– Minutes to hours after the infusion
– Counseling: Avoid cold for ____ days post infusion. Use oven mitts when entering the freezer.
Delayed, progressive, ____ neuropathy
— Cumulative doses > ____mg/m2
• Peripheral neuropathy - changes in sensation, in fingers and toes ○ May be decreased \_\_\_\_ (asthesia), or increased \_\_\_\_ (dysasthesia)
cold paresthesias 4 peripheral 850 sensation pain
Antimetabolites: S-Phase Specific
Resemble \_\_\_\_ occurring nuclear structural components (“metabolites”) Examples \_\_\_\_ Purine analogs \_\_\_\_ analogs
• Impair DNA replication ○ Disguise as purines or pyramidines ○ May also affect cancer cells ability to \_\_\_\_ the purines/pyr
naturally
antifolates
pyrimidine
develop
Methotrexate (MTX)
Primary mechanism of action: ____ inhibitor
Uptake and activation
____ receptors on cell membrane undergo receptor mediated
endocytosis
____ of MTX by folylpolyglutamyl synthetase (FPGS) increases polarity = increased cellular ____
• Antifolate medication ○ Inhibits dihydrofolate reductase § Bactrum is similar ○ Higher doses for \_\_\_\_-penetration
dihydrofolate reductase
folate
retention
CNS
Methotrexate
Administered IV, IT, IM, or PO
PO absorption saturable/erratic when > ____mg/m2
Dosing
Low dose: < ____mg/m2 (usually weekly)
Intermediate dose: 100-500mg/m2 (often requires leucovorin)
High dose (HD): > ____mg/m2/dose (always requires ____)
• IT - intrathecal ○ \_\_\_\_ puncture and administered into intrathecal space the (CSF) • Most toxicities seen in high dose administration
25 100 500 leucovorin lumbar
