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
Methotrexate Drug interactions \_\_\_\_, sulfonamides, tetracyclines, ciprofloxacin \_\_\_\_, salicylates \_\_\_\_ inhibitors
Acute side effects – due to ____, not Cmax
____*
Mucositis*
____
Hepatotoxicity
____
* Adverse effects minimized by ____ administration in high-dose MTX protocols
Chronic side effects: ____, pneumonitis, hepatic fibrosis
• Have to clear out these medications because the symptoms are so severe • [NOTES] • Get highest dose into patient, and clear it as quickly as possible • Mucositis - sores within the mouth ○ Develop micro perforations, and transmit bacteria into blood from the gut and develop sepsis § Does not play with myelosuppression
penicillins NSAIDs proton pump AUC myelosuppression nephrotoxicity neurotoxicity leucovorin
cirrhosis
Safe Administration of High Dose MTX
- Check renal function
a. HD-MTX contraindicated if CrCl < ____ ml/min - Interacting medications?
a. Discontinue at least ____ hr prior to MTX dose - ____ spacing fluid? (physical exam, imaging)
a. Pleural effusions, ascites? Drain prior to MTX - Urine alkalinization & IV hydration
a. Na-bicarbonate or Na-acetate; goal urine pH > ____ - [MTX] monitoring – by specific protocol
- ____ administration• MTX likes to go into third space fluids and slowly leach out
○ Ascites - fluid in abdomen
○ Not given to patients with ascites and pleural effusions
• Want urine to be basic
50 48 third 7 leucovorin
Leucovorin bypasses DHFR inhibition
• Leucovorin is reduced \_\_\_\_ ○ Bypass the mechanism of action of MTX and rescue healthy cells from the activity of MTX ○ Timing is important - if bypassing MTX, you want to administer MTX and wait a few \_\_\_\_, and then you start leucovorin ○ [NOTES]
folate
hours
Methotrexate Toxicity Management
Leucovorin dosing based on time-sensitive MTX levels:
* Dosing is based on how the patient is \_\_\_\_ * Not \_\_\_\_ to patients, ultimately released through the urine as well
clearing
toxic
Methotrexate Toxicity Management
____ (glucarpidase; Voraxaze®)
Recombinant enzyme that rapidly hydrolyzes MTX into two inactive ____
— Decreases [MTX] by ≥____% within 15 minutes and sustained for up to 8 days, independent of ____
Indication: toxic plasma [MTX] (>____ μM) in patients with delayed clearance due to renal impairment
NOT indicated when MTX clearance is within expected range or with normal renal function or mild renal impairment
• If not clearing MTX effectively
carboxypeptidase metabolites 97 renal functino 1
Pemetrexed
Adverse effects
____, mucositis, rash, diarrhea
Grade ____ myelosuppression + GI toxicity predicted by pre-treatment assessment of ____, folate, and ____ levels
• Seen more often in lung cancer patients • Have to give these patients \_\_\_\_ supplementation ○ Folic acid, and B12 shots in order to prevent myelosuppression
myelosuppression 3/4 homocysteine B12 vitamin B
Pemetrexed
Pretreatments
____ 400-1000mcg/d PO 7 days prior to 1st pemetrexed dose, then daily until 21 days after last dose
____ 1000mcg IM 7 days prior to 1st pemetrexed dose then q3 cycles thereafter
____ 4mg PO BID x 3 days beginning the day prior to pemetrexed doses minimizes cutaneous reactions
Avoid in patients with ____ (CrCl < 45 ml/min)
Drug interactions: ____ delay clearance
Avoid NSAIDs 2-5 days pre and 2 days post pemetrexed
Clearance not affected by ____ spacing fluid
folic acid
vitamin B12
dexamethasone
renal failure
NSAIDs
third
Fludarabine: ____ Antagonist
Mechanism of action
Inhibition of ____ (major MOA)
Inhibition of ____ (minor MOA)
Integration into ____ (minor MOA)
____ only in U.S., oral formulation in Europe
Renal elimination: contraindicated if CrCl < ____ ml/min
Side effects:
____, ____, ____ infections (PCP, HSV)
purine
DNA polymerase
ribonucleotide reductase
RNA
IV 30 myelosuppression neurotoxicity opportunisitic
Cytarabine (ara-C): ____ Antagonist
False base: integration into DNA -> \_\_\_\_ inhibition and \_\_\_\_ termination Bioactivation Ara-C -> \_\_\_\_ by deoxycytidine kinase (dCK) -> ara-C-DP -> \_\_\_\_ (active form) \_\_\_\_: rate limiting step to bioactivation Resistance via upregulation of \_\_\_\_
pyrimidine DNA polymerase chain ara-C monophosphate ara-C-TP dCK cytidine deaminase
Cytarabine
Administration: IV, IT, subcutaneous
Side effects at ____ dosing (< 100mg/m2/dose): ____, rash
High dose (HiDAC; > 1g/m2/dose):
– Dose limiting: ____
• ____ prior to each dose
• Risk factors: elderly age, renal failure
– ____: ____ eye drops q6h until 48 hr after last dose of ara-C
– ____ syndrome
standard
myelosuppresion
cerebellar syndrome neurochecks conjunctivitis dexamethasone hand-foot
5-Fluorouracil: Pyrimidine Antagonist
MOA: depends on rate of infusion
Continuous (CIVI): inhibition of ____
—____ deficiency -> inhibition of DNA synthesis
– ____ enhances stability of the FdUMP-TS complex
Bolus: false base integration into ____
Administration: IV, topical Clearance: \_\_\_\_ (DPD) -- Pharmacogenomics: DPD deficiency --- 2% homozygous, 5% heterozygous for point mutations in the general population increased \_\_\_\_ and \_\_\_\_ toxicity
thymidylate synthase
thymidine
leucovorin
RNA
dihydropyrimidine dehydrogenase
hematologic
GI
• Prodrug of 5FU - given orally, and then activated into 5FU
○ ____
• Toxicities: similar to CIVI 5FU - more GI toxicities
Capecitabine
5-Fluorouracil
Bolus + continuous infusion combined: ____
Leucovorin 400mg/m2 day 1, 5-FU bolus 400mg/m2 day 1, followed by
2.4g/m2 CIVI (46h)
Side effects
Dose limiting: ____ (with bolus)
Dose limiting: ____ toxicity, ____ (with continuous infusion)
____, rash, hand-foot syndrome
____ (bolus) - caution in ischemic heart disease
Drug interactions
____ – results in marked elevation in INR, presumably due to CYP ____ inhibition
Overdose antidote: ____
10g PO q6 hours x 20 doses ASAP
FOLFOX myelosuppression GI mucositis coronary vasospasm/angina
warfarin
CYP 2C9
uridine triacetate
Capecitabine (oral prodrug of 5FU)
____ dosing
Usually BID dosing, 2 weeks on, 1 week off (21 day cycles)
Renal elimination - dose reduce if CrCl < ____ ml/min Contraindicated if CrCl < ____ ml/min
Drug interactions
____ – results in marked elevation in INR, presumably
due to CYP 2C9 inhibition
Side effects Dose limiting: \_\_\_\_ Hand-foot syndrome (can be \_\_\_\_ a few months) Mucositis, N/V/D Asymptomatic \_\_\_\_ elevation \_\_\_\_ (angina, arrhythmia)
confusing
50
30
warfarin myelosuppression delayed bilirubin cardiotoxicity
Gemcitabine: pyrimidine antagonist
Bioactivation similar to ____
Gem-TP inserted into DNA, inhibits ____ (major)
Gem-DP inhibits ____ (minor)
Side effects: Dose limiting: \_\_\_\_ (esp. platelets) \_\_\_\_-like syndrome, rash, transient increase in LFTs, drug fever Rare but severe: \_\_\_\_ syndrome \_\_\_\_ toxicity
cytarabine
DNA polymerase
ribonucleotide reductase
myelosuppression
flu
hemolytic-uremic
pulmonary
Antimicrotubule agents
____
____
taxanes
vinca alkaloids
Antimicrotubule Agents
• MT subunits bind ____ of chromosomes and bring to the equatorial plane during metaphase
• ____ movement of the MT-kinetochore complex occurs
• Inhibition of movement activates the spindle checkpoint which
leads to ____
• \_\_\_\_ phase specific chemo agents
kinetochores
pole-ward
apoptosis
M
Microtubules: a dynamic system
• Develop MT in \_\_\_\_ M phase, and \_\_\_\_ M phase you have to break them down ○ Two classes of agents that impact MT assembly § Vinca alkyloids - \_\_\_\_ M phase □ Prevent ability to assemble MT (from \_\_\_\_) § Taxanes - \_\_\_\_ M phase □ \_\_\_\_ MT so they can't break down
early late early tubulin late stabilize
Paclitaxel
From Taxus ____ (Pacific Yew Tree)
____, intraperitoneal administration
Extremely ____, requires ____ (polyoxyethylated castor oil) for dissolution
\_\_\_\_ reactions – premeds required! \_\_\_\_ 20mg 12 hrs and 6 hrs pre-dose OR 30 min pre-infusion (most common) \_\_\_\_ 25-50mg 30 min pre-infusion \_\_\_\_ (ex: famotidine) 20mg 30 min pre-infusion
• MT have important role in signaling of nerves ○ Hallmark toxicity of these MT-affecting agents - \_\_\_\_ • Taxane agent - stabilizes MT • Premeds include a good number of steroids
brevifolia
IV
hydrophobic
cremophor EL
hypersensitivity
dexamethasone
diphenhydramine
H2 blocker
neurotoxicity
Paclitaxel Dosing and Administration
Paclitaxel dosing controversy
Weekly (80mg/m2) vs. q 3 weeks (175mg/m2)?
Greater efficacy w/____ vs. q 3 wk but more ____ and more patient inconvenience
IV over 3 hr vs. 24 hr?
24 hr infusion increases ____ and ____ but decreases
____ and ____ vs. 3 hr infusion
When administered on the same day as cisplatin, give the ____ FIRST
Cisplatin impairs paclitaxel clearance 25% = worsened ____
• Sequence in giving these agents is important • Going to give taxel agent first that includes a regimen giving a platinum and taxane agent ○ If give platinum first - develop more myelosuppression
weekly
neuropathy
neutropenia
mucositis
hypersensitivty
neuropathy
paclitaxel
myelosuppression
Docetaxel
• Semisynthetic agent derived from Taxus ____ (European Yew Tree)
Hydrophobic, requires ____ for dissolution
Premedications required to prevent ____ syndrome
and ____ reactions
____ 8 mg po BID x 3 days (1 day before, day of chemo, day after chemo)
* \_\_\_\_ phase - stabilizes MT * Administered with steroids, because of capillary leak (edema)
baccata polysorbate 80 capillary leak hypersensitivity dexamethasone late M
Taxanes
Side effects
Peripheral neuropathy (dose limiting for ____, > docetaxel)
Myelosuppression (dose limiting for ____, > paclitaxel)
Hypersensitivity reactions (____ > docetaxel)
Full body ____ loss
Nail changes
Fluid retention (____)
Epiphora (docetaxel)
Myalgia, arthralgia (____> docetaxel)
Up to 60% w/paclitaxel, onset 2-3 days post infusion
Clearance
Hepatic elimination via CYP3A4
Resistance mechanism: both are ____ substrates
* Myelosuppression depends on dose and infusion rates * Alopecia - hair loss * Have to watch out for drug interactions because broken down by CYP3A4
paclitaxel docetaxel paclitaxel hair docetaxel paclitaxel
P-glycoprotein
Vinca Alkaloids - VinCRIStine
MOA: inhibit ____ polymerization (assembly)
Isolated from Catharanthus roseus (Madagascar
periwinkle)
Dosing: usually 1.4mg/m2 (capped at 2mg)
– Cap is ____, thought to limit neuropathy
– Administer q7 days at most to limit neuropathy
Administration: ____ only
____ administration is rapidly FATAL!
* Early M phase - prevent creation of MT * Not given intrathecally via lumbar puncture, because 100% fatal
microtubule
arbitrary
IV
intrathecal
Vincristine Side Effects
Hepatic clearance via CYP3A4
Very sensitive to hepatic function and drug interactions
AVOID ____, voriconazole
Side effects Dose limiting: \_\_\_\_ “Enteric neuropathy” -- Consider prophylactic \_\_\_\_ regimen Rare: SIADH, hepatotoxicity Not \_\_\_\_ – good addition for \_\_\_\_ regimens
• Peripheral neuropathy is so profound that it doesn't just happen in fingers/toes - also happens in the bowels ○ \_\_\_\_ is common ○ In order to keep things moving in the bowels
posaconazole peripheral neuropathy bowel myelosuppressive combination
Vinblastine and Vinorelbine
Vinblastine \_\_\_\_ (dose limiting) Neuropathy less common No dose cap, still limited at q7 days max \_\_\_\_ + fatal if given \_\_\_\_
Vinorelbine Semi-synthetic derivative of \_\_\_\_ Greater lipophilicity allows for high \_\_\_\_ concentrations \_\_\_\_ (dose limiting) Neuropathy less common, constipation
• A part of the vinka alkyloid class
myelosuppression
vesicant
IT
vinblastine
pulmonary
myelosuppression
Topoisomerase Inhibitors
Topoisomerase I: ____ derivatives
Topoisomerase II: ____, ____, ____
camptothecan
anthracyclines
anthracenedione
epipodophyllotoxins
Irinotecan (CPT-11)
Synthetic ____ derivative
— Camptotheca acuminata
MOA: inhibition of ____
— ____-strand DNA breaks
Bioactivation and deactivation
De-____ by carboxylesterases (serum, hepatic)
SN-38 ____ by uridine glucoronyl transferase (UGT)
• It is a \_\_\_\_ • Side effect: GI toxicity, diarrhea ○ "\_\_\_\_" • Topoisomerase I inhibitor ○ Used to unwind DNA ○ Cause enough conformational strain that causes a break in DNA ○ I - causes a single strand break; II - causes \_\_\_\_ strand breakage
campthothecin
topoisomerase I
single
esterification
glucuronidation
prodrug
I ran to the can
double
Irinotecan
Side effects
Acute (< 24h) ____ due to cholinergic stimulation
– Often within 1 hr of infusion completion
– ____ agonist + ____ inhibitor
– Treatment/prophylaxis: IV atropine 0.25-1mg
Delayed diarrhea (> 24h): GI mucosal damage
– Treatment: ____ drugs (ex: ____)
____, ____ (dose limiting)
Pharmacogenomics
UGT1A1*28 – impaired ____ of SN-38
• Enzyme that helps metabolizes the toxic metabolite of IT - UGT1A1 Have a specific type - they have a higher risk of developing this toxicity
diarrhea cholinergic acetylcholinesterase oral antidiarrheal loperamide
alopecia
myelosuppression
glucuronidation
Etoposide (VP-16): Epipodophyllotoxin
Semisynthetic ____ derivative
– Extract from roots of Podophyllum peltatum (mandrake plant)
MOA: ____ inhibitor
- - Cell cycle specific: ____ phases
- - ____-strand breaks -> apoptosis
Cell-cycle specific (S + G2 phases)
Oral and IV formulations
GI absorption saturable > 200mg /dose
PO is 50% bioavailable
IV precipitates if concentration > ____mg/mL
• Usually given IV ○ May develop \_\_\_\_
podophyllin
topoisomerase II
S and G2
double
0.4
hypersensitivity
Etoposide Side effects of etoposide \_\_\_\_ Hypotension (due to EtOH diluent, infuse over 30-60 min) \_\_\_\_ taste during infusion Alopecia Secondary \_\_\_\_
Mechanism of resistance: ____ substrate
myelosuppression
metallic
leukemias
P-glycoprotein
Antitumor Antibiotics Isolated from soil \_\_\_\_ species Topoisomerase II inhibitors -- \_\_\_\_ -- \_\_\_\_ (mitoxantrone) Bleomycin
streptomyces
anthracyclines
anthracenedione
Anthracyclines Intercalating topoisomerase inhibitors - Topoisomerase \_\_\_\_ inhibition (major) - \_\_\_\_ intercalation (minor) - \_\_\_\_ formation (minor) All are \_\_\_\_ substrates
• CCNS agents because they have many mechanisms of activity ○ T inhibit - CCS ○ DNA intercalation - CCNS ○ Free radical formations - CCNS
II
DNA
free radical
P-glycoprotein
Anthracyclines: Adverse Effects
____
Cardiotoxicity
– ____ related to chronic/cumulative dose
– LVEF > 50% prior to administration recommended
____
N/V – moderate single agent emetogenicity
Alopecia – role of scalp hypothermia?
____ urine
Erythematous streaking at site of infusion (“Adriamycin flare”)
Radiation recall (can be delayed, concurrent XRT not necessary)
Secondary ____
Hepatic elimination: dose reduce based on ____
• Red agents • \_\_\_\_ is common - long term cardiomyopathy ○ Heart failure who are taking anthracyclines ○ There is a \_\_\_\_ dose that you're able to receive of anthracyclines § If you go beyond life time dose - risk of HF increases dramatically ○ Don't administer in patients with HF
myelosuppression cardiomyopathy mucositis red leukemias bilirubin cardiotoxicity lifetime
Mitoxantrone: Anthracenedione
Synthetic ____ analog
No ____ moiety, tricyclic (vs. tetracyclic) gives a ____ color
MOA
Topoisomerase ____ inhibition (major)
____ intercalation, much lower potential for ____ formation
____ only, irritant but not a vesicant
Side effects: similar to doxorubicin Dose limiting: \_\_\_\_ Less cardiotoxicity; preferred agent for pre-existing \_\_\_\_ Less mucositis, less alopecia \_\_\_\_ urine discoloration
• Similar to anthracyclines ○ The only difference - mitoxanthrone is blue
anthracene
sugar
blue
II
DNA
free radical
IV
myelosuppression
cardiomyopathies
blue-green
Bleomycin
Bleomycin-Fe complex reduces O2 to reactive oxygen species – DNA ____ strand breaks (major)
____ intercalation (minor)
Cell cycle specific: ____ phase
Doses expressed in units of drug ____
IV, IM, subcutaneous, intralesional, pleural administration (____ agent)
* Anti-tumor antibiotics * Hallmark: \_\_\_\_ toxicity - fibrosis that is \_\_\_\_
single DNA G2 and M activity scleorising pulmonary irreversible
Bleomycin
Side effects
Tissues lacking bleomycin ____
– Skin ____, keratosis, desquamation, ulceration
– ____ changes
– ____ (dose related)
—- PFTs at baseline and prior to each cycle
—- Risk factors: ____ age, pre-existing lung disease, > ____ units total lifetime dose
—- Often ____
____, flu-like symptoms
Minimal benefit of test doses
Not ____!
aminohydrolase hyperpigmentation nail pulmonary older 400 reversible hypersensitivity myelosuppressive
Secondary Malignancies
Most common: ____ and ____ syndrome – poor prognosis
Etoposide + anthracyclines: ____ years
Alkylating agents (cyclophosphamide): ____ years
Radiation –secondary ____ tumors and ____
Most commonly noted after chemotherapy for ____ and ____
– For most, benefit for primary malignancy outweighs the risk of secondary malignancy
• Worse prognosis of leukemia than those who develop it de novo • Radiation - non-specific DNA damage • Breast cancer - AC - anthracycline and cyclophosphamide ○ Anthra - life-time dose
acute myeloid leukemia
myelodysplastic
1-5 7-10 solid leukemias breast cancer lymphoma
Gastrointestinal toxicity: mucositis
Upper GI: painful ulcerations in ____
Lower GI: ____, abdominal pain
Complications
____, FN
____, dehydration
Severe: loss of ____, requires intubation
oral mucosa diarrhea infection malnutrition airway
Gastrointestinal Toxicity: Mucositis
Causes of mucositis
Head/neck ____
Doxorubicin, fluorouracil, methotrexate, cytarabine
____ transplant conditioning chemotherapy (busulfan, melphalan)
mTOR inhibitors: ____, temsirolimus
Prevention
Most effective: good ____, baking soda or salt water rinses
High risk patients with poor dentition should see dentist prior to chemo
____ (recombinant keratinocyte growth factor)
— ____ stem cell transplant conditioning, use limited by cost
Treatment
____anesthetics/mucosal agents: viscous lidocaine 2%, “magic mouthwash” (2%
lidocaine, maalox, diphenhydramine), supersaturated calcium phosphate (Caphasol®)
Systemic analgesia – as needed IV ____ or patient controlled analgesia (PCA) pump
Rule out possible ____ or herpes simplex virus infections
IV ____, assess need for parenteral nutrition if long term/severe
* Topical or oral pain medications are the only things that help with mucositis * Conditioning treatment for stem-cell transplant - very high \_\_\_\_ * Main way to prevent mucositis - practice good oral hygiene
radiation
bone marrow
everolimus
oral hygiene
palifermin
autologous
topical
opiates
candida
hydration
dosing
Gastrointestinal Toxicity: Constipation
Multifactorial in cancer patients
Medications: ____, chemotherapy, ondansetron
— Vincristine, azacitidine – consider ____ bowel regimen
Decreased PO intake, decreased ____ activity
Intestinal obstruction, bowel surgery, hypercalcemia of malignancy
Symptoms of severe constipation:
Abdominal ____, nausea/vomiting, urinary incontinence
Treatment Stimulant laxatives – \_\_\_\_, bisacodyl Osmotic laxatives – \_\_\_\_ 17g PO BID, lactulose 20g PO TID, sorbitol 30mL PO TID Prokinetic agent – \_\_\_\_ 5-10mg AC + HS Opioid related – \_\_\_\_
• Constipation ○ Can develop bowel blockage and rupture • Methylnaltrexone - \_\_\_\_ administration
opiates
prophylactic
physical
pain/distention sennosides polyethylene glycol metoclopramide methylnaltrexone
subcutaneous
Gastrointestinal Toxicity: Diarrhea
Chemotherapy-related: secretory diarrhea
____, fluorouracil, ____, cytarabine, stem cell transplant
conditioning (especially ____)
Antibiotics, metoclopramide
Other etiologies in cancer patients
Secretory GI tract tumors
Infection: neutropenic ____, clostridium difficile
____ induced colitis
Treatment
Opioid receptor ____ anti-diarrheal medications
– ____ 4mg PO x 1, then 2mg q4h after each loose stool (max 16mg/day)
– Diphenoxylate/____ 1-2 tabs q6h
– Tincture of ____ 10-15 drops in water q3-4 hours
Octreotide 100 mcg subcutaneous q8h (max 500mcg q8h)
IV ____ and electrolyte repletion (K, Mg)
Consider ____ rest and parenteral nutrition in severe cases
• Metoclopramide - further nausea inducing
irontecan
methotrexate
melphalan
colitis
radiation
agonist
loperamide
atropine
opium
hydration
bowel
Dermatologic Toxicity: Alopecia
____
Usually limited to the head (except ____)
10-14 days following chemotherapy, apparent 2-3 months after chemo started
Diffuse hair loss or clumping
Moderate to severe: ____, ifosfamide, etoposide, taxanes,
vinblastine, irinotecan, methotrexate
Mild to no alopecia: fludarabine, azacitidine, cytarabine, cetuximab, bevacizumab, ____, gemcitabine, dacarbazine, ____, oxaliplatin
Many drugs cause change in hair ____ or consistency
Eye lash growth: ____, other EGFR inhibitors
Prevention: ____ caps (scalp hypothermia) – not recommended for ____, lymphoma, others at risk of head/neck/CNS metastasis
• Higher dosing of AA, anthracyclines, and taxanes are more common agents that cause alopecia
reversible taxanes doxorubicin cisplatin fluorouracil pigmentation cetuximab cooling leukemia
Dermatologic Toxicity: Hand-Foot Syndrome (HFS)
Causative agents: ____, doxorubicin (____ > conventional), cytarabine, fluorouracil (____> bolus)
• Pain and desquamation on palms of hands and on soles of feet
capecitabine
liposomal
CIVI
Dermatologic Toxicity: Hand-Foot Syndrome (HFS)
TKI-related hand-foot skin reaction (HFSR) :
Sorafenib, sunitinib: similar to hand-foot syndrome from cytotoxics, more localized to ____ skin lesions (calluses) in areas of trauma, ____ (palms, soles of feet)
Prevention of TKI related HFSR
____ removal
20% ____ cream in sorafenib/sunitinib treated patients
Avoid ____ water, vigorous ____, ____ fitting shoes
Treatment of HFS and HFSR
20% ____ cream, clobetasol cream 0.05%
Grade 3+: hold ____
Pain control
• Exercising and lifting can exacerbate the symptoms
hyperketatotic
friction
callus urea hot exercise tight
urea
chemotherapy
Anthracycline Dose Conversions
Note that DOXOrubicin and DAUNOrubicin are NOT ____!
• Lifetime dose of anthracyclines ○ Carries from \_\_\_\_ to \_\_\_\_
LOOK AT THIS TABLE!
1:1
agent
agent
Mechanisms of drug resistance
____
Tumor sanctuary site (from chemotherapy, from immune system) due to physiologic barriers or poor perfusion
Pharmacologic: acquired or inherited
Decreased activation of pro-drugs
– Ex: cytarabine, ____, fludarabine
Decreased drug uptake (downregulation of transport systems)
– Ex: ____
Target alteration (decreased binding affinity)
– Ex: ____ inhibitors, methotrexate, taxanes
Upregulation of DNA repair enzymes
– Ex: ____, platinum agents, fluorouracil, etoposide
• Not all chemo agents will be effective ○ Tumor is in areas where you don't get good penetration § \_\_\_\_ and CNS • Cancer drugs can impair activation of prodrugs into active form
gemcitabine methotrexate topoisomerase alkylators testes
Mechanisms of drug resistance
Increased drug inactivation/metabolism
– Ex: ____, fludarabine
Target up regulation
– Ex: ____, fluorouracil
Upregulation of antioxidant synthesis (ex: glutathione)
– Ex: ____
Drug efflux pumps (ex: P-glycoprotein)
– Natural compounds: ____, taxanes, vincas, etoposide
Insensitivity to/loss of pro-apoptotic signals (ex: p53 mutation)
– Ex: ____
• Drug efflux pumps ○ Natural enzymes that we see on the cell ○ Cancer cells can upregulate these pumps, like P-glycoprotein ○ Work as pumps that directly pump chemotherapy agents outside of the cell § May be getting correct \_\_\_\_ movement, but then it pumps it right back out § May not be getting the cxn you may need within the cell in order to get effective cell kill
cytarabine methotrexate anthracyclines anthracyclines fludarabine intracellular
Chemotherapy Resistance: Efflux Pumps
P-glycoprotein (Pgp)
- ____ gene
- Efflux pump for natural products with ____ structures
- Inhibited by: verapamil, ____• Can develop resistance by ____ the amount of efflux pumps that are present on the cell membrane
MDR-1
unrelated
cyclosporine
