Chemotherapeutic Flashcards
What are characteristics of cancer cells?
- Persistent proliferation
- unresponsive to feedback mechanisms that regulate cells
- Invasive growth/formation of mets
- malignant cells free of constraints that inhibit invasive growth–> cells of solid tumor can penetrate adjacent tissues and spread of cancer
- immortality
- cancer cells undergo endless division
- due to telomerase
What are the 6 hallmarks of cancer cells?
- Sustaining proliferative signaling
- evading growth supressors
- activation invasion and metastasis
- enabling replicative immortality
- inducing angiogenesis
- resisting cell death
How do cancers differ?
Based on phenotye, aggressiveness, responsiveness to drugs
What 3 ways are cancers treated?
surgery
radiation
pharmacologic agents
How does chemotherapy kill cancers (what order?)
1st order kinetic matter, generally kill 50% proportion
What is palliative chemo curve representative of?
Treatment of a terminal Ca that does not have a cure.
More for symptom management
WHat is adjuvant chemo?
Used after surgery to minimize tumor regrowth
What needs to happen in order to reach a cure of cancer
Entirely free of disaes, and has same life expectancy as a cancer free individual
What is a complete resposne from chemo?
Complete disappearance of all cancer without evidence of new disease for at least 1 month
What is a partial response from chemo?
50% decrease in tumor size or other objective markers
What is stable disease?
A patient whose tumor size neither grows nor shrinkgs by more than 25%
What is tumor progression?
25% increase in tumor size or devleopment of new lesions while on tx
Order of cell cycle events?
G0–> G1–> S–> G2–> Mitosis–> G0
What is mitosis?
cell division
time span 1/2-1 hour (need high concentration of drugs)
What is G0?
Resting
cells not committed to cell divison
(all neurons in resting)
What is G1?
Postmitotic
enzymes necessary for DNA synthesis are made
What is S phase?
Synthesis
10-20hours
cell doubles its DNA
What is G2?
Premitotic phase
2-10 hours
Specialized proteins and RNA synthesis
What are 7 calsses of chemotherapy/antineoplastic drugs?
- Alkylating agents
- antimetabolites
- antitumor antibiotics
- topoisomerase inhibitors
- tubulin binding drugs
- signal transduciton modifiers
- immunotherapy**< new approach
Why are chemotherapy drugs combined?
Combination therapy preferred in order to:
- delay drug resistance
- decrease toxicity
- improve cancer cell death
What is a broad summary of toxicity from chemo drugs?
-
Bone marrow suppressio (leukopenia, thrombocytopenia, anemia
- iatrogenic infection
- may need extra preop lab testing
- GI tract damage
-
N/V
- electolyte distubance, hypovolemia
- Aloplecia
-
mucosal ulceration
- avoid using oral airways, LMA, esophageal stethoscope
-
Reproductive
- infertility, teratogenic (1st semester, risk highest)
-
Urinary stones (uric acid crystals)
- Formed from breakdown DNA following cell death
- Extravasation: local injury
-
End organ damage and hepatic enzyme induction
- consider altered respones to anesthetics
- Promotion of secondary cancers
What are the most common chemo drugs to cause extravasation?
- Anthracyclines
- Vinca alkaloids
- Taxanes
Symptoms of extravasation?
- Pain
- burning
- swelling
- redness
- lack of blood return
- may require skin grafting/surgery
What are some examples of aklylating agents?
- Nitrogen mustards
- Cyclophosphamide
- Nitrosureas
- Carmustine
- Platinum compounds
- Cisplatin
- Carboplatin
What is the MOA of akylating agents
- Reactive alkyl groups form covalent bonds with nucleotide bases in DNA/RNA
- Makes DNA be stuck in super coil
- if it cannot uncoil, can’t replicate
- disrupts DNA synthesis and cell division–> miscoding and strand breaks
Common toxicities in alkylating agents?
-
Bone marrow suppression- greatest concern
- neutropenia, hemolytic anemia, thrombocytopenia
- mucositis
- skeletal muscle weakness
- sz
-
pneumonitis and pulm fibrosis
- carmustine pulm toxicity similar to bleomycin 20-30% with mortality 24-90%
- Pericarditis and pericardial effusion
- inappropriate ADH secretion (Water toxicity)
- uric acid induced nephropathy
-
impaired pseudocholinesterase activity (2-3 weeks)
- caution succ, mivacurium, esmolol, remi
What are the platinum compounds and toxicities?
Cisplatin, carboplatin
-
Nephrotoxicity- cumulative and dose limiting; potassium and mag wasting and decreased GFR
- dose limiting toxicity for cisplatin
- hydration/supplemental electolytes
- may be on furosemide/mannitol to prevent
- hypomagnesium common
- can also impact NM function
-
Peripheral neuropathy
- dose limited toxicity fo oxaliplatin
- presents as tingling around mouth, fingers, toes
- avoid cold contact
What are examples of antimetabolites?
- Folate analogues
- Methotrexate
- Pyrimidine analogues
- Fluorouracil (5FU)
- Purine analogues
- Mercaptopurine
What is MOA of antimetabolites?
- Strucutral analogues of natural metabolites (nucleic acid synthesis inhibitors)
- inhibit replication/repair of DNA by:
- Direct inhibition of enzymes needed for repair
- Incorporation of antimetabolite, directly into DNA
- inhibit replication/repair of DNA by:
What is methotrexate’s target of action?
- Folate must be taken up by cell and reduced to FH2–> FH4 by dihydrofolate reductase in order to produce nucleosides
- Methotrexate has higher affinity for dihydrofolate reductase than does FH2, thereby preventing its reduciton to FH4
Toxicities of methotrexate?
- Pulmonary fibrosis (8%) and /or noncardiogenic pulmonary edema
- neutropenia and thrombocytopenia
- mucositis and GI ulceration
- GI perf possible
- Renal toxicity (10%)
- alkalinize urine and hydrate
- Hepatic toxicity
- often reversible
What is MOA of fluorouracil? Class of drug?
- Class= pyrimidine analog (antimetabolite)
- MOA- inhibits thymidylate synthetase–> inhibits nucleotide production–> inhibits DNA synthesis
Toxicity associated with fluorouracil?
-
Incrased risk of MI for 1 week after admin
- Low threshold for EKG, echo, beta blocker, art line
- Myelosuppression (leukopenia, thrombocytopenia, and anemia)
- alopecia
-
neuro defects
- ataxia (cerebellum)
-
GI toxicity (d/c if stomatitis/mucositis/diarrhea)
- Pt at risk for GI ulceration and perf
-
Hand and foot syndrome
- sx- tingling, redness, burning, flaking, swelling and blistering of palms/soles
What are examples of topoisomerase inhibitors?
- Anthracyclines (Doxorubucin, daunorubicin)
- Non-anthracyclines (Bleomycin)
What is MOA of topoisomerase inhibitors?
- Inhibition of topoisomerase I and II and intercalation of DNA–> double strand DNA breaks and inhibition of DNA& RNA synthesis (replication)
- topoisomerase II relaxes DNA supercoil and breaks strand for replication
- topoisomerase II also critical to the DAN strande being put back togheter
- Generation of hydroxyl free radicals
- oxidative damage
What are some relatively minor s/e of anthracyclines?
- Bone marrow suppression (anemia, thrombocytopenia, low WBC 70% pt)
- Red/orange color of urine/swear
What is connection b/w cardiotoxicity and doxorubicin?
- May be sensitive to cardiac depressive s/e of anesthetics even in normal resting echo
- free radical produciton causes myocardial damage
- Acute (10%): tachycardia and arrhythmias
- transiet and rare
- ekg and acute EF reduciton
- usually lasts 1-2 mon
- transiet and rare
- Chornic (2% but with 60% fatality)SEVERE cmp/CHF
- related to cumulative dose
- protective therapies
What are some protective therapies for doxorubicin?
- Dexrazoxane
- prevents free radical formation
- ACE inhibitors
When would etomidate vs propofol be perferred in regards to cardiac dysfunction?
- If vasculature issue only, can still use propofol because myocardium hasn’t been affected
- once myocardium affected, then etomidate is preferred
- can mix etomidate/propofol or give propofol very slowly and mitigate some effects
- If RSI and can’t go slow, then etomidate preferred
What is MOA of bleomycin? Class?
Class= water soluble glycopeptides
- MOA- Topoisomerase inhibition and binds DNA and chelates iron leading to formation of free radicals that cause single and double strand DNA breaks
Main toxicity for bleomycin?
PUlmonary toxicity 4% (1% life threatening)
- Lungs take up high concentration of drug and lack hydrolase enzyme to inactivate bleomycin
- increased risk with:
- increased cumulative dosing
- age
- chest radiation
- pulmonary co morbidities
- oxygen exposure
- other chemo drugs
- genetics
- D/C agent at 1 st sign of dry cough, dyspnea, tachypnea and infiltrates on CXR
- may progress–> pulm fibrosis–> severe fibrosis–> death
- decreased diffusion capacity
- KEEP FIO2 CONCENTRAITON AT OR BELOW 30% DURING ANESTHESIA IF POSSIBLE
What can bleomycin cause r/t hypersensitivity?
- Lymphoma pt; fever, chills, confusion, hypotension and wheezing
- test dose recommended for lymphoma pts before standard doses
Is myelosuppression seen with bleomycin?
No!
What are examples of vinca alkyloids?
- (vincristine, vinblastine, binorelbine)
What is MOA of vinca akyloids??
aka tubulin-binding drugs
- binds to tubulin (microtubule dimers) to block microtubules assembly (preventing polymerization (aka forming) of dimers)–> cell division arrested during metaphase –> apoptosis
Side effects of vincristine?
(Class of vincristine?)
Vincristine= vinka alkaloid (tubulin binding drugs)
- Very little bone marrow suppression: good in combo therapy
- hyponatremia (inappropriate ADH secretion)
- Peripheral neuropathy via damage to neurotubules in almost 100% of aptients (reported to get wrose wiht sx/anesthesia)
What are some concerns with peripheral neuorpathy with vincristine?
- sensory loss,
- weakenss,
- autonomic dysfunction
- (constipation, ST, dry mouth, urinary retention, reflex lsos, cranial nerve– laryngeala and extraocular dysfunction)
- usually resolves after treamtent
- uncertain w/ regional
- reduce local doses
- use US guidance
- no vasoconstrictors added
What is main side effect with vinblastine?
bone marrow suppression
What are examples of taxanes?
- Taxanes
- Paclitaxel
- Docetaxel
What is MOA of taxanes??
(Taxanes= tubulin-binding drugs)
- stabilizes microtubule bundles and prevents disassembly (prevents depolymerization)–> inhibitng cell division and producing apoptosis
- (kind of opposite from vincristine)
What are some toxicities associated with taxanes?
- Peripheral neuropathy (esp hand and feet)
- muscle and joint pain
- hypersentiivity reactions 25-30% of pt
- Cardiaac
- bradycardia, heart block, MI
- Myelosuppression
- neutropenia develops in almost all pt
- 1% sepsis related deaths (11% if liver dx)
What are signal transduciton modulators?
Antiestrogens (tamoxifen)
antiandrogens (flutamide)
Monoclonal antibodies
aromatase inhibitors
MOA of antiestogens/antiandrogens?
- Disrupt aberrant growth factor: receptor interactions in cancerous cells preventing intracellular signaling that leads to cellular proliferation and survivial OR target mutated receptors that give a signal to proliferate even without any growth factors bound
How do anti-hormone drugs work?
- Work if the cancer cells expresses the particular receptor (and in proportion to the level of receptor expression)
- Tamoxifen- act as estrogen antagonist in certain cells (Breast and ovarian) and an estrogen agonist in other cells (uterus, liver, bone)
- s/e related to agonist activity : DVT, endometrial ca, menopausal symptoms, increased bone density (beneficial) and improves serum cholesterol panel (beneficial)
-
Antiadnrogens (prostate)- gynecomastia, hot flasehs, muscle weakness and osteoporsis
- Flutamide- methemoglobinemia
- Tamoxifen- act as estrogen antagonist in certain cells (Breast and ovarian) and an estrogen agonist in other cells (uterus, liver, bone)
What is hte MOA of monoclonal ab?
- Antibodies target specific proteins expresssed on immune cells, or that promote pro-survivial signaling in Ca cells
What is Gleevac?
Gleevac (Imantinib) is a tyrosine kinase inhibitor/antibody that can treat cancer when tyrosin kinase is mutated to be always on (BCR-Abl in chornic myelogenous leukemia)
- amazing drug that seems to cure problem
- can cause flu like symptoms
- used in autoimmune as well
What are aromatase inhibitors MOA?
- Aromatase is an enzyme complex that converts androgens to estrone peripherally
- Helpful to decrease estrone levels in some post-menopausal women with breast Ca
What is bevacizumab?
- Anti-angiogenic
- Trade name: avastin
- Monoclonal antibody that blocks angiogenesis
- Inhibits vascular endothelial growth factor-A
- without vascularization, tumors cannot survive
What is the basis for how immunotherapy works in cancer? Major s/e?
- Dendritic cells loaded with tumor lysate, the use of vaccines targeting tumor-sepcific epitopes, the generation of chimeric antigen receptor T cells and checkpoint inhibitors
- autoimmune reaction major concern with these approches
- flu like sympetomes
-
Biologically directed therapy
- engineered viruses (oncolytic viral therapy)
General counseling guidliens for chemotherapy?
- These drugs are often mutagenic, carcinogenic and tertogenic: protect wourself if you are caring for someone still eliminating chemo!
- avoid contact with skin, eyes and mucous membrane
- follow hospital protocols
