Exam 2 Lecture 1 Flashcards
What is one of the most feared side effects induced by chemo
CNIV (Chemotherapy induced nausea and vomiting)
Complications that could result from CNIV
inability to deliver the intended full dose of chemotherapy.
could lead to dehydration, fatigue, depression, electrolyte abnormalities
What are some potential causes of nausea/vomiting in cancer patients
Therapy related- chemo, post surgical, radiation therapy
Gastrointestinal- constipation, gastroparesis, bowel obstruction
Neurologic- Severe chronic pain, anticipatory N/V,
Metabolic- hypercalcemia, hyperglycemia, hyponatremia
drugs- opioids, anesthetics
psychophysiologic- anxiety
what are the types of Nausea/vomiting? describe them
Anticipatory- learned response conditioned by severity and duration. can be provoked by sight, smell or sound
Acute- emetic response within 24 hrs of receiving chemotherapy
Delayed- related to chemotherapy occuring >24 hrs (probably due to substance P binding to neurokinin 1)
breakthrough- N/V occuring even if on scheduled anti-emetics prior to chemo
Refractory- N/V that persists despite appropriate anti-emetics
Why does nausea/vomiting happen during chemotherapy?
cytotoxic chemotherapy induces damage to the epithelial cells lining the GI tract.
Enterochromaffin cells lining the GI tract contain large stores of serotonin
These are released in massive quantities after exposure to chemo
Where in the brain is vomiting induced
The chemoreceptor trigger zone (CTZ) stimulates the vomiting center (Located in nucleus tractus solitarii in medulla)
What are the neurotransmitters implicated in CINV
Serotonin, Substance P (NK-1), dopamine, histamine, acetylcholine
Describe Serotonin and substance P role in CINV
serotonin- Plays a pivotal role in CINV in acute phase. Receptors are abundant in GI tract, area postrema and nucleus tractus solitari. There is an increased level of serotonin during exposure to chemotherapy. This is evidenced by the increase in serotonin metabolite 5-HIAA in urine after exposure to cisplatin.
Substance P- mammalian tachykinin found in neurons, including vagal afferent fibers innervating the brain-stem nucleus tractus solarii and area postrema. The biologic action of this neurokinin is mediated via NK-1
Describe the roles Dopamine, Histamine and acetylcholine play in CINV
Dopamine- D2 receptors are abundant in the area postrema of the medulla appears to mediate CINV. Primary sire of action is CTZ
Histamine- Histamine receptors are present in the nucleus tractus solitarii, efficacy of histamine antagonists is moderate. Useful when emesis is associated with motion
Acetylcholine- Muscarinic receptors are present near the CTZ, may have mild activity for motion associated n/v
What is the compound with the highest emetogenic chemotherapy potential
Cisplatin
How would level 1 and 2 agents contribute to emetogenicity of the regimen? What about adding level 3 and 4 agents?
Level 1 and 2 agents do not contribute to the emetogenicity of the regimen.
Adding level 3 or 4 agents increase emetogenicity by 1 level per agent
What are some risk factors for CINV
-Women>men
-Younger patients>old
-Prior h/o of motion sickness
-previous CINV tend to do worse
-anxiety/high pretreatment anticipation of nausea
- chronic alcoholism tends to be protective
Can we substitute different 5-HT3 antagonists for each other?
What are the 4 types of drugs used for prophylaxis of emesis
Yes.
NK-1 antagonist
Steroid
5-HT3 antagonist
Atypical antipsychotic
What are NK-1 antagonists drugs used for emetogenic prophylaxis
Aprepitant oral
Aprepitant Injectavle
Fosaprepitant
Rolapitant
Netupitant/palonsetron
Fosnetupretant/palnosetron
What are steroids used in steroids
Dexamethasone
What are the 5-HT3 antagonists used for prophylaxis in emesis
Dolasetron
Granisetron
Ondansetron
Palonsetron
WHat are atypical antispychotics used for prophylaxis in emesis
Olanzapine
What are the two classes of antiemetics that are always used regardless of what regimen we choose?
5HT3 antagonists
Steroid
Describe regimen A for prophylaxis of highly emetogenic susbatnces
NK-1 antagonists
Steroid
5-HT3 antagonist
Atypical antipsychotic
Describe regimen B for prophylaxis of HIGHLY emetogenic substance
Atypical antipsychotic
5-HT3 antagonist
Steroid
Describe regimen C for prophylaxis of highly emetogenic substance
NK-1 antagonist
Steroid
5 HT3 antagonist
Describe regimen A of moderately emetogenic substances
Steroid
5 HT3 antagonist
Describe regimen B of moderately emetogenic substances
Olanzapine
Palonsetron
Dexamethasone
Describe regimen C of moderately emetogenic substances
NK-1 antagonist
steroid
5 HT3 antagonist
Describe drugs used in low emetogenic regimens
Dexamethasone
Metoclopramide
Prochlorperazine
5HT3 antagonist
What are drugs used in breakthrough N/V
-DOpamine receptor antagonists (haloperidol, metoclopramide)
-Phenothiazines (prochlorperazine, promethazine)
-Antipsychotic (olanzapine)
-BZD (lorazepam)
-Cannabinoids (dronabinol, nabilone)
-Serotonin antagonists (dolansetron, granisetron, ondansetron)
-steroids (dexamethasone)
-anticholinergic (scopolamine)
Drugs used in delayed N/V
Dexamethasone
NK-1 antagonist
Olanzapine
What are preventive, behavioral etc actions we can take to prevent anticipatory N/V
Preventive- antiemetic tx
behavioral- hypnosis, yoga, desensitization
lorazepam
acupuncture
Emesis prevention strategy for oral chemotherapy
high emetogenic risk- 5HT3 antagonist (start before chemo and continue daily)
Low emetogenic risk- Metoclopramide, prochlorperazine, 5-HT3 antagonist (start before chemo and continue daily)
Prevention strategy for radiation induced emesis
Start pretreatment for each day of radiation therapy (granisetron PO +/-dexamethasone
Ondansetron PO +/- dexamethasone)
Antiemetics should be given ________ before strat of amino acid infusion
30 minutes
What are antiemetic drugs to be given for radiopharmaceuticals like lutetium dotatate? Which ones to avoid?
5-HT3 antagonists or NK-1 antagonists
Not steroids due to downregulation of somatostatin receptor
What are serotonin 5HT3 antagonist drugs and toxicities associated with them
Ondansetron
Granisetron
Dolasetron
Palonosetron
toxicities
Headache, EKG changes, constipation
What are corticosteroid drugs and what are the toxicities associated with them
Dexamethasone- (short term use)- anxiety, euphoria, insomnia, hyperglycemia, increased appetite
Name substance P antagonist drugs and their common toxicities
Aprepitant, fosaprepitant, rolapitant, netupitant,
common toxicities- hiccups, can have drug interactions
Name dopamine antagonist drugs and their common toxicities
chlorpromazine, haloperidol, metoclopramide
common toxicities include- Extra pyrimidal side effects, diarrhea, sedation
Name an agent and common toxicities for these class of antiemetics
atypical antipsychotics, phenothiazines, cannabinoids, BZDs, anticholinergics
-Atypical- olanzapine, dystonic rxn, sedation
-phenothiazine- prochloperazine, chloperazine- sedation, akathesia, dystonia (IV promethazine= tissue damage)
-cannabinoids- dronabinol (drowsiness, dizziness, euphoria, mood changes, hallucination, increased appetite)
BZDs- lorazepam- (sedation, hypotension, urinary incontinence, hallucination
ANticholinergic- scopolamine patch, (anticholinergic side effects) (cant see, cant pee, cant spit, cant shit)
EPS is a risk with which antiemetic drugs
Metoclopramide, phenothiazine
What does it mean when we say emetogenicity is additive
Two agents that are each moderately emetogenic make a highly emetogenic regimen
Is emetogenic potential the same everyday?
No, we have different potential on different days of treatment. (for multiple day chemotherapy, potential is high on day 1, moderate day 2 and 3)
When are antiemetics most effective?
When given as prophylaxis
When to begin antiemetics for patient undergoing chemotherapy? What are other important principles for before/after chemo?
Administer 5 to 30 minutes prior to chemotherapy
administer around the clock until chemotherapy is complete and provide PRN agents for breakthrough N/V
provide PRN medication for them to take home
What is mucositis? Compare continous IV vs short infusion)
Inflammation of mucosal (mucous membranes lining mouth and along the GI tract)
May range from mild inflammation to bleeding ulcers
occur more in Continous infusions
Risk factors for mucositis?
pre-existing oral lesions
poor dental hygiene, ill-fitting denture
prevention of mucositis
Diet recommendations
- avoid rough food (toast, chips), spice, salt and acidic fruit
avoid smoking and alcohol
eat soft and liquid, non acidic foods
What are general mouth care strategies
pre treatment dental screening,
soft bristle tooth brushes
saliva substitute
baking soda rinse
-
pain management for mucositis
-topical anesthetics (magic mouthwash)
-oral cryotherapy (ice chips, causes vasoconstriction)
-Sucralfate (forms protective barrier, increases prostaglandin E2)
-Oral and parenteral opioid analgesics
What is the most common dose limiting toxicity of chemotherapy
Range of WBC for neutropenia
Bone marrow suppression
Neutropenia- <0.5*10^3
What is the normal range of WBC? What is the decreased range? What is decreased range called? RIsk with lower range?
Normal- 4.8-10.8 x10^3
decreased WBC (neutropenia- <0.5*10^3), leukopenia, granulocytopenia
Risk of life threatening infections
What is the normal range of Megakaryocyte (? What is the decreased range? What is decreased range called? RIsk with lower range?
-Megakaryocyte=platelet
-normal range- 140-440 x 10^3
-Decreased platelets are is called thrombocytopenia (<100x10^3)
-Causes risk of bleeding
Normal range of RBC?
Decreased RBC name?
Risk?
4-6-6.2x10^12
decreased RBC=anemia
risk of hypoxia and fatigue
Most common dose limiting toxicity of chemotherapy
Bone marrow suppression
What is the nadir
The lowest value the blood counts fall to during a cycle of chemotherapy (usually measured by ANC or neutrophil count)
When do nadirs occur?
Generally occurs 10-14 days after chemotherapy administration and counts recover after 3-4 weeks.
Only exceptions are mitomycin C and nitrosoureas which nadir around 4-6 weeks
What are the typical blood counts required to administer Chemotherapy in a patient
WBC>3x10^3 OR
absolute neutrophil count (ANC) of 1.5*10^3 AND platelet count >or= 100x10^3
severe neutropenia is defined as
ANC < 0.5 x 10^3
neutropenic patients are at an increased risk of developing serious infections.
define febrile neutropenia
ANC<0.5*10^3 and a single oral temperature >101 F or >100.4 for at least an hour.
What are high risk patients defined as for neutropenia
-pre existing neutropenia due to disease
- extensive prior chemo
- previous irradiation to pelvis or other areas containing a lot of bone marrow
difference between primary and secondary prophylaxis for neutropenia
Primary prophylaxis- If the patient is to receive a chemotherapy regimen that is expected to cause >20% incidence of febrile neutropenia
secondary prophylaxis - The patient experienced a neutropenic event from a previous cycle of chemo and we want to prevent it from occurring again (use CSF preventively with next cycle of chemotherapy)
What are other uses for CSF
- support patients through dose dense chemotherapy
-can be used alone, after chemo or in combination with plerixafor to mobilize peripheral blood progenitor cells - after a stem cell transplant to reduce duration of severe neutropenia
What are the different CSF agents
- Filgrastim (Neupogen) G-CSF
-Pegfilgrastim (neulasta) - sargramostim (leukine) GM-CSF
MOA of filgrastim, pegfilgratim and sargramostim.
Filgrastim- regulates production, maturation and function of neutrophil cell line. Has dose dependent elevation in neutrophil count. Has a RAPID DROP in WBC and neutrophil count following discontinuation (50% decrease within 24 hrs)
Pegfilgrastim- differs from filgrastim by a pegylated molecule attached to it. Just like filgrastim, ot stimulates production, maturation and function of neutrophil precursors. Non linear PK and clearance increases with increasing neutrophil count
sargramostim- effects on phagocytic accessory cells which mediates its action on neutrophil lineage. Drops in WBC count and neutrophil count following discontinuation. (50% decrease within 24 hrs)
Which agent is the first biosimilar CSF to be approved in the US
Filgrastim-SNZD
Patient should remain on whichever agent it is started on and not switch
between manufactured product
filgrastim and pegfilgrastin dose and when to start
Filgrastim- 5 mcg/kg/day
Start 3-4 days after completion of chemotherapy and continue until post nadir
Pegfilgrastim- 6 mg SQ x 1 dose
start atleast 24 hours after chemotherapy and can be given 3-4 days after chemotherapy (atleast 14 days should pass between dose and next cycle of chemo) (do not do same day therap)
Filgrastim vial sizes and adverse effects
Filgrastim vials come in 300 and 480 mcg vials.
adverse effects- flu like symptoms, bone and joint pain, DVT
What percent of patients receiving CSF have bone or muscoskeletal pain? why do they have bone or muscoskeletal pain?
rare adverse events of CSF
20-30% have muscoskeletal or bone pain.
These pains can be attributed to rapid proliferation of bone marrow myeloid cells
Enlargement of spleen with long term use
Thrombocytopenia definition? When does increased risk of bleeding occur.
Usually defined as a platelet count of <100x10^3
increased risk of bleeding occurs at <20x10^3 and may require a tranfusion (ASCO guidelines recommends a threshold of transfusion at 100x10^3)
What are the general causes of anemia
-decreased RBC production (cancer therapy, tumor infiltration into bone marrow)
-decreased Erythropoietin production (renal dysfunction)
-decreased body stores of vitamin B12, iron or folic acid
-blood loss
When should patients undergo a work up for chemo induced anemia
Patients with hemoglobin <11 g/dl or >2g/dl decrease from baseline
What to do if patient is symptomatic for chemo induced anemia
Transfuse as indicated
Consider use of ESA (erythropoietic stimulating agent)
perform iron studies
black box warning for ESA
ESA increases risk for death, MI, stroke, VTE
When are ESAs not recommended?
When are ESAs recommended?
Not recommended when
- patients receiving myelosuppressive chemo with curative intent
-cancer patients not receiving chemo
-patients receiving non-myelosuppressive chemo
consider using
- cancer and CKD
-Patients undergoing palliative chemo
-patients without identifiable causes
Benefits and risk of ESA in cancer induced anemia
Benefit- 1. transfusion avoidance
2. gradual improvement in anemia symptoms
Risk- 1. increased thromboembolic event
2. possible decreased survival
3. time to tumor progression shortened
Benefits and risk of blood transfusion in cancer induced anemia
Benefits- 1. rapid increase of hemoglobin and hematocrit
2. rapid improvement in anemia related symptom fatigue
risk- 1. transfusion rxn
2. Transfusion related circulatory verload
3. virus transmission (HIV, Hepatitis
4. bacterial contamination
5. iron overload
6. increased thromboembolic event
7. possible decreased survival
What is epoetin alfa? What does it do? Where is it produced? What is it regulated by?
-It is a glycoprotein that stimulates RBC production
-it stimulates division and differentiation of committed erythroid progenitors in the bone marrow.
- Produced in kidney
- endogenous production regulated by level of tissue oxidation
recommendations for epoetin alfa in chemotherapy associated anemia
Dose should be adjusted to maintain the lowest hgb level
If hgb increases more than 1 g/dl in a 2 week period, the dose should be decreased by 25% for epoetin alfa and 40% for darbapoietin.
MOA of darbapoietin? Indication?
Stimulates erythropoiesis by binding to epoetin receptor like erythropoietin
indicated in anemia in patients with non-myeloid malignancies where anemia is caused by chemo
All oncology patients who are prescribed ESAtherapy should have what baseline taken?
Iron
If no other causes for anemia is identified what should we do
Oral iron supplementation
How is iron absorption affected by food
Iron absorption will be reduced, by about one half if food is eaten 2 hrs before or 1 hr after ingestion
Myalgias and arthralgias are caused by what chemo agents? How to treat myalgias and arthralgias
Paclitaxel, docetaxel, anastrazole, letrozole, exemestane
Treatment- NSAIDs, maybe opioids
Which chemo agents cause hemorrhagic cystitis? how to treat hemorrhagic cystitis
high dose cyclophosphamide, ifosfamide
Treatment- Hydration, mesna (both prevention)
Which chemo agents cause heart failure? How to treat this?
anthracyclines, high dose cyclophosphamide, trastuzumab (other HER2 therapies)
treatment- monitor cumulative dose, assess for risk factors, Dexrazoxane
Which chemo drugs cause peripheral neuropathy? treatment?
taxanes, vinca alkaloids, platinums
treatment- change infusion rate for paclitaxel
adjunctive pain meds like gabapentin and amitriptyline
Pulmonary toxicity is caused by what chemo drugs? treatment?
caused by bleomycin
treatment- corticosteroids
Mechanism of cardiac toxicity in chemo drugs? why is myocardium more susceptible?
formation of iron-dependent oxygen free radicals due to stable anthracycline-iron complexes, which cause catalysis of electron transfer.
Myocardium is more susceptible due to lower levels of detoxifying oxygen free radicals compared with other tissue.
What are the different type I chemotherapy related cardiac toxicity
Acute
chronic
late-onset
Difference between acute, chronic and late onset (when it occurs? How common and dangerous? cumulative? symptoms?)
acute- occurs immediately after a single dose or course of therapy with an anthracycline. Uncommon and transient. May involve abnormal ECG findings like QT prolongation and arrythmias. Congestive HF and pericarditis. Not related to cumulative dose.
Chronic- onset usually within a year of receiving anthracycline therapy. common and life threatening. Rapid onset and progression. Related to cumulative dosing. Symptoms include tachycardia, tachypnea, exercise intolerance, pulmonary and venous congestion.
Late onset- develops several years (even decades) after therapy. Manifests as ventricular dysfunction, CHF, conduction disturbances and arrythmias. Occurs more in childhood/adolescence cancer survivor who received anthracycllines.
What drug causes type II chemo related cardiac dysfunction?
Is it dose related?
is it associated with cardiac damage?
MOA?
reversible?
incidence?
What causes increase in cardiac toxicity?
- not dose related
- Not associated with cardiac damage
- mechanism involves eGFR pathway which blunts effects of stress signaling pathway that are required to maintain cardiac function
-reversible - Incidence is ~ 3% in non-anthracycline treated
patients and increases to 5% in those who have
received previous anthracyclines
-If trastuzumab is given concurrently with
anthracycline, the incidence can increase up to
27% cardiac toxicity
